3D printing porous metal-ceramic assembly type composite implant as well as preparation method and application thereof

Abstract

The invention relates to a 3D printing porous metal-ceramic assembled composite implant as well as a preparation method and application thereof. The 3D printing porous metal-ceramic assembled composite implant comprises a porous metal-ceramic implant body formed by compounding a 3D printing integrated porous metal module and a 3D printing integrated porous ceramic module, the porous metal-ceramic implant body and the net-shaped metal protection body are arranged on the periphery of the porous metal-ceramic implant body in a wrapping mode, and the assembled composite implant can be accurately matched with the appearance and the combination surface of bone tissue of a defect part. The composite implant disclosed by the invention has osteogenesis environment regulation and control functionalization, and can achieve the effects of immediately recovering the movement function of defective bone tissue, improving the tissue microenvironment of a bone defect part, accelerating new bone regeneration and guiding new bone to grow towards the interior of the porous metal implant, so that rapid osseointegration of a bone / metal implant interface is realized; and the long-term treatment effect of 3D printing porous metal implant / autologous bone fusion type repair after ceramic degradation is achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of implantable medical devices, and particularly to a design, a preparation method and an application of a 3D printed porous metal-ceramic assembled composite implant with osteogenic environment regulation functionality. Background Art

[0002] The treatment of various large segmental bone defects and segmental bone defects caused by diseases (bone tumors, infections and congenital deformities) and traumas has been a long-standing problem in orthopedic clinics. Autologous bone transplantation has an ideal regeneration and repair effect. However, this treatment option has limited donor sources and problems with related complications at the bone harvesting site. Although allogeneic bone implants can solve the problem of insufficient autologous bone supply, there are also risks such as disease transmission and immune rejection. The emergence of artificial bone implants represented by titanium alloys and bioactive ceramics has provided new optional materials for the clinical treatment of various large segmental bone defects and segmental bone defects. However, traditional metal implants have problems such as poor bone integration and stress shielding due to lack of porous structure design, too high elastic modulus, low bioactivity, etc.; although bioactive ceramic implants have better bioactivity and degradability, they also have problems such as low mechanical strength and fragility, and thus cannot be used for the treatment of complex large segmental bone defects and segmental bone defects.

[0003] In recent years, with the application and development of 3D printing technology in the field of medical devices, novel 3D printed porous implants can significantly reduce the apparent elastic modulus of metal implants and provide growth space for the ingrowth and attachment of new tissues, thereby improving the bone integration effect at the bone / implant interface and preventing stress shielding problems. However, clinical studies have shown that due to the insufficient bioactivity of traditional inert metal materials (titanium and its alloys, stainless steel, cobalt-chromium alloys, etc.), 3D printed porous metal implants still need to be improved in terms of bone ingrowth depth, bone repair time, and bone integration performance. To this end, some studies have proposed methods of filling bio-ceramic powders or particles into the internal pore or cavity structures of 3D printed porous metal implants to improve the bioactivity of metal implants; however, such methods are usually only completed by doctors during the operation, with a complex process, significantly increasing the operation time, and the filled ceramic powders / particles lacking effective spatial constraints, resulting in a large amount of dropping and wandering in the patient's body, causing complications, etc.; too tight filling will block the pore structure inside the 3D printed porous metal implant, thereby reducing the vascularization ability of the implant and affecting the ingrowth of new bone. Chinese Patent No. 202220666630.2 discloses a metal prosthesis structure carrying modular ceramics, which fills porous ceramic modules one by one inside the metal frame, but in this method, the metal frame is made of solid metal, and the too large elastic modulus of the solid metal will cause stress shielding effect, leading to bone resorption and even fracture. In addition, under the complex stress and micro-strain in the body, it is difficult for the metal frame to effectively protect the ceramics, and the ceramic modules (bioactive ceramics β-TCP and HA with a porosity of 50% and a compressive strength of only 1-10 MPa) are prone to fragmentation, causing fragment wandering, resulting in physical laceration or immune response, increasing the risk of inflammation, and the metal prosthesis structure cannot adjust the appropriate ratio and structural distribution of metal and ceramics according to different surgical treatment requirements, and the repair effect is poor. Summary of the Invention

[0004] The purpose of the present invention is to provide, in view of the problems of the prior art, a 3D printed porous metal-ceramic assembled composite implant and its preparation and application method that can optimize and adjust the distribution and ratio of porous metal modules and porous ceramic modules according to the bone repair requirements of different defect sites, so that the porous metal is as much as possible within the range of the role of bioactive ceramics in promoting cell activity, maximizing the osteogenic activity of the porous metal / ceramic assembled bone repair implant material, and having good mechanical adaptability, tissue adaptability, and structural adaptability. The composite implant of the present invention has the characteristics of osteogenic environment regulation and functionalization, can immediately restore the motor function of the defect bone tissue, improve the tissue microenvironment of the bone defect site, accelerate new bone regeneration and guide new bone to grow into the 3D printed porous metal implant, realize rapid bone integration at the bone / metal implant interface, and achieve the long-term treatment effect of 3D printed porous metal implant / autologous bone fusion repair after ceramic degradation.

[0005] In order to achieve the above purpose, the specific technical solution adopted by the present invention is:

[0006] The 3D-printed porous metal-ceramic modular composite implant described in the present invention is characterized in that it includes a porous metal-ceramic implant body composed of a 3D-printed integrated porous metal module and a 3D-printed integrated porous ceramic module (also called a porous bioactive ceramic module), and a mesh metal protector wrapped around the periphery of the porous metal-ceramic implant body to form a modular composite implant, and the modular composite implant can accurately match the shape and bonding surface of the bone tissue at the defect site.

[0007] The 3D-printed porous metal module in this invention serves first as a load-bearing structure, providing mechanical support and protecting the ceramic. This structure restores the motor function of the defective bone tissue during the initial stages of osteogenesis while protecting the porous ceramic from stress damage during surgery and daily use after implantation. Second, it enables new bone to grow into the porous metal. The 3D-printed porous bioactive ceramic serves as an osteogenic environment regulator, primarily designed to improve the tissue microenvironment at the bone defect site, enhance the vascularization and bioactivity of the composite implant, accelerate new bone regeneration, and guide new bone growth into the porous metal. This achieves rapid osseointegration at the bone / metal implant interface and long-term therapeutic efficacy of 3D-printed porous metal implant / autologous bone fusion repair after ceramic degradation. Furthermore, the bioactive ceramic can directly contact the end face of bone tissue or the periosteum, maximizing its ability to regulate the osteogenesis environment and promote osteogenesis. At the end of implantation, with the complete degradation of the ceramic and remodeling of new bone, the autologous bone and porous metal implant can be integrated, achieving a "mutually supportive" bone repair effect.

[0008] In addition, since the range of the regulatory effect of bioactive ceramics on the tissue microenvironment is limited, the proportion and distribution of porous metal and ceramics can be adjusted according to the repair requirements of different bone defect sites. For example, porous ceramic modules can be assembled on one side of the porous metal module to form a side-assembled porous metal-ceramic composite implant body (abbreviated as the side-assembled implant body, also called the one-side implant body). It can also be that the porous ceramic module is assembled in the center of the porous metal module to form a center-type porous metal-ceramic composite implant body (abbreviated as the center-type implant body). For example, large-segment bone defects in load-bearing bones require high mechanical support. It is necessary to increase the proportion of porous metal and distribute the porous metal at the main stress points to improve support and stability, and the porous ceramics are arranged in non-main stress areas to improve the osteogenic environment of the implant. In principle, on the premise of ensuring mechanical stability, the proportion of ceramics should be increased as much as possible to increase bone repair performance and achieve rapid healing. In the repair of joints such as the spine, a combination method can be adopted in which porous ceramics are added to the non-loaded area in the center and porous metal is arranged in the peripheral loaded area. On the premise of ensuring mechanical stability, the bone repair performance of the implant can be improved as much as possible, so that the entire implant is within the optimal regulation range of ceramics, maximizing the mechanical and osteogenic activities of the 3D-printed porous metal / ceramic assembled bone repair implant material, giving full play to the best osteogenic environment regulation and osteogenic promotion effects of bioactive ceramics, and accelerating bone integration and bony healing.

[0009] Furthermore, the reticulated metal protector is at least a protective sleeve formed by buckling and assembling at least two honeycomb mesh plates.

[0010] The present invention also includes a locking plate customized according to the bone shape, and the locking plate is connected to the metal protector. Furthermore: a snap structure is provided on the reticulated metal protector, and a corresponding clamping structure capable of being assembled with the snap structure on the metal protector is provided on the locking plate. Through the snap structure on the reticulated metal protector, the close assembly of the reticulated metal protector-porous metal module-porous ceramic module and the composite implant-locking plate can be realized. The snap structure on the reticulated metal protector and the clamping structure on the locking plate can be set as required. For example, the snap structure can be composed of a clamping block and a socket for the clamping block to be inserted and clamped. The clamping structure on the locking plate can be a clamping groove for the clamping block and the socket to be inserted and positioned. Of course, the snap structure can also adopt existing snap structures.

[0011] The functions of the mesh metal protector in the present invention are as follows: 1. It serves as a connection point between the porous metal-ceramic implant body and the locking plate, and is the connection point for the assembly of various components; 2. Since the mechanical strength of the ceramic is very low, after being implanted into the body, the peripheral mesh metal protector structure can prevent the ceramic part from breaking during shear stress or impact; 3. Through the mesh metal protector, a limiting function is achieved. In the event that the ceramic part breaks, it can limit the movement of the ceramic fracture fragments and prevent them from migrating to other non-defective parts, causing immune reactions or cutting normal tissues. The mesh metal protector is a porous protective sleeve structure, and its pore size ranges from 1 to 10 mm. Preferably, it is about 5 to 8 mm.

[0012] The porous metal module and the porous ceramic module in the present invention are truss-like porous structures or porous sheet-like structures with through holes highly penetrating. The pore size range of the porous metal module and the porous ceramic module is 300 - 1000 μm, and the porosity range is 40% - 90%.

[0013] The preparation method of the 3D printed porous metal-ceramic assembled composite implant described in the present invention includes the following steps:

[0014] (1) Design the shape and modular segmentation of the composite implant according to the shape of the bone tissue in the defect site, the requirements of the joint surface, and the load-bearing requirements of the bone tissue, and obtain the volume ratio, position distribution, and shape of the required porous metal module and porous ceramic module (defect repair assembly model);

[0015] (2) Forming the porous metal module: 3D print the integral porous metal module with the required shape, and then perform cleaning, heat treatment, and surface treatment for standby;

[0016] (3) Forming the porous ceramic module: 3D print the integral porous ceramic module with the required shape, and then perform ceramic debinding and sintering for standby;

[0017] (4) 3D print the mesh metal protector, and then perform cleaning, heat treatment, and surface treatment for standby;

[0018] (5) Assemble and combine the above-mentioned porous metal module and porous ceramic module as required to form the porous metal-ceramic implant body;

[0019] (6) Wrap the mesh metal protector around the periphery of the porous metal-ceramic implant body to obtain an assembled composite implant that precisely matches the shape and joint surface of the bone tissue in the defect site.

[0020] The forming of the porous ceramic module is preferably carried out by using stereolithography 3D printing forming technology and extrusion printing technology.

[0021] The composite implant of the present invention can be customized designed and assembled according to the defect site of the patient, accurately restoring the original shape and force line of the bone tissue at the defect site, avoiding surface stress concentration caused by force line deviation or shape mismatch, increasing loosening and wear at the bone-implant interface, subsequently triggering bone resorption, osteoporosis, and even fractures, as well as unreasonable stress distribution changing the bone growth environment, resulting in bone spurs and deformities.

[0022] In the present invention, the distribution and proportion of the porous metal and porous ceramic modules can be optimized and adjusted according to the bone repair requirements of different defect sites, so that the porous metal is as much as possible within the range of the biological activity of the bioactive ceramic to promote cell activity, maximizing the osteogenic activity of the porous metal / ceramic assembled bone repair implant material. Generally, the proportion of the porous metal module is greater than 0 and less than or equal to 80%; the proportion of the porous ceramic module is at least 20%. The total ratio of the porous ceramic module and the porous metal module added together is 100%. Preferably, the proportion of the porous metal module is 10%-80%, and the proportion of the porous ceramic module is 20%-90%. Specifically, for the repair of non-weight-bearing long bones (such as the clavicle, fibula, etc.) and large segment bone defects of the femur (a large segment bone defect is defined as the length of the defective bone being more than 1.5 times the width), a side-assembled porous metal-ceramic composite implant body with a porous metal module proportion greater than 0 and less than 50% is selected (of course, it can also be a central porous metal-ceramic composite implant body, preferably side-assembled); for the repair of large segment bone defects of the femur, a side-assembled porous metal-ceramic composite implant body with a porous metal module proportion of 50% is selected, or a central porous metal-ceramic composite implant body with a porous metal module proportion of 30%-70% (preferably 50%-70%). For the repair of supra-critical bone defects of the femur, a central porous metal-ceramic composite implant body with a porous metal module proportion of 80% is selected.

[0023] Furthermore, the bioactive ceramic can directly contact the end face of the bone tissue or the outer periosteum, exerting the best osteogenic environment regulation and osteogenic promotion effects of the bioactive ceramic. At the end stage of implantation, with the complete degradation of the ceramic and the remodeling of the new bone, the integration of the autologous bone and the porous metal implant can be achieved, realizing the bone repair effect of "you have me in you and we support each other".

[0024] The present invention has the following beneficial effects compared with the prior art:

[0025] (1) The biggest feature of the present invention is that it can adjust the proportion and distribution of the porous metal module (also called the porous metal implant) and the porous ceramic module (also called the porous ceramic implant) according to the surgical treatment requirements, maximizing the mechanical and osteogenic activities of the 3D printed porous metal / ceramic assembled bone repair implant material, giving full play to the best osteogenic environment regulation and osteogenic promotion effects of the bioactive ceramic, and accelerating bone integration and osseous healing. The calcium and phosphorus ions released by the degradation of the bioactive ceramic will form a spatial concentration gradient in the in vivo tissue microenvironment under the condition of diffusion resistance, that is, near the bioactive ceramic, the concentrations of calcium and phosphorus ions will increase significantly, regulating cell behaviors such as cell proliferation, adhesion, and osteogenic differentiation; as the distance increases, the concentrations of calcium and phosphorus ions will gradually decrease, and their regulatory capabilities for the extracellular matrix microenvironment and cell behaviors such as cell proliferation, adhesion, and differentiation will also gradually weaken. Therefore, reasonably optimizing the 3D printing porous metal / ceramic assembly scheme, increasing the ceramic proportion in the non-main stress-bearing area on the basis of ensuring the mechanical strength, and making the porous metal as far as possible within the range where the bioactive ceramic promotes cell activity will maximize the osteogenic activity of the 3D printed porous metal / ceramic assembled bone repair implant material.

[0026] (2) The composite is carried out in the form of multi-piece assembly. The size and shape of the composite implant (such as the porous metal module and the porous ceramic module are 3D personalized printed according to specific circumstances and conform to the bone shape of the defect site) and the size and arc of the locking plate can be adjusted according to the bone shape and size of different defect sites; according to different surgical sites, the assembly method of the porous metal and the porous ceramic composite and the shape of the composite implant can be adjusted to achieve personalized precise repair. The locking plate and the composite implant are assembled. After bone healing, the locking plate can also be disassembled according to the needs to avoid the influence of the locking plate on subsequent healing in the body.

[0027] (3) The porous bioactive ceramic in the present invention can promote bone regeneration, achieve rapid bone integration in the initial stage of healing, and prevent nonunion or fibrous tissue ingrowth; in the middle stage of healing, it guides the growth of new bone into the porous metal, enabling the composite implant to form osseous healing with the host bone, effectively solving delayed healing and loosening and displacement of the implant connection; in the final stage of healing, with the degradation of the ceramic and the growth of new bone, the implant forms osseous healing with the host bone (it can achieve the integrated fusion of the host bone and the porous metal implant, achieving the bone repair effect of "you have me and we support each other"), and finally realizes the partial regenerative repair of segmental and large-segment weight-bearing bone defects.

[0028] (4) Both the ceramic part and the metal part are 3D printed integrated structures, and both have a certain supporting effect on the bone. They will be subjected to stress in daily activities after implantation. Under the action of micro-stress, they can promote the formation of new bone and prevent delayed healing and bone absorption problems caused by lack of force (because osteogenesis is use and disuse, if it does not have the stimulation of micro-stress, it will delay healing or bone absorption, resulting in osteogenesis or non-union in that part). The integrated porous ceramic module will not be free. Moreover, the composite implant can adjust the metal-ceramic ratio according to the force requirements of the bone defect site, which can effectively regulate the stress loaded on the ceramic, avoid too little force on the ceramic causing bone absorption, and also avoid too much force on the ceramic causing ceramic fracture and failure. The composite implant and locking steel plate of the present invention are obtained by reverse extraction of the defect model, and the force line of the defect site is reconstructed, so that the host bone and the composite implant are evenly stressed, avoiding uneven force or stress concentration.

[0029] (5) The present invention can be applied to the field of implantable medical devices.

[0030] The present invention will be further described below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a three-dimensional diagram of the first embodiment of the present invention combined with a locking steel plate.

[0032] Figure 2 for Figure 1 Schematic diagram of the top view structure.

[0033] Figure 3 for Figure 1 Schematic diagram of the structure of the mesoporous ceramic module.

[0034] Figure 4 for Figure 2 Schematic diagram of the porous metal module structure.

[0035] Figure 5 for Figure 1 A three-dimensional diagram of the assembly of the porous metal module and the porous ceramic module.

[0036] Figure 6 for Figure 1 Schematic diagram of the assembly structure.

[0037] Figure 7 FIG. 4 is a perspective view of a central implant body according to a second embodiment of the present invention.

[0038] Figure 8 for Figure 7 Top view of .

[0039] Figure 9 It is a three-dimensional diagram of the mesh metal protector of the present invention.

[0040] Figure 10 This is a perspective view of the locking plate of the present invention.

[0041] Figure 11 It is Figure 7 the assembly schematic diagram of

[0042] Figure 12 This is an isometric view of the finite element mechanical simulation of the 3D printed porous metal-ceramic assembled composite implant of the present invention.

[0043] Figure 13 This is a front view of the finite element mechanical simulation of the 3D printed porous metal-ceramic assembled composite implant of the present invention.

[0044] Figure 14 It is the gradient change of the ion concentration of calcium and phosphorus ions released by the biodegradation of bioactive ceramics with distance in the GelMA hydrogel tissue-mimicking microenvironment.

[0045] Figure 15a It is the influence of the gradient change of calcium and phosphorus ion concentration on cell proliferation behavior.

[0046] Figure 15b It is the influence of the gradient change of calcium and phosphorus ion concentration on cell adhesion and differentiation behavior.

[0047] Figure 15c It is the influence of the gradient change of calcium and phosphorus ion concentration on cell osteogenic differentiation behavior.

[0048] Figure 16 This is the surgical implantation diagram of the 3D printed porous metal-ceramic assembled composite implant of the present invention.

[0049] Figure 17a This is the MASSON staining section diagram of the 3D printed porous metal-ceramic assembled composite implant with different assembly methods (central type and side combination type) of porous metal and porous ceramic of the present invention.

[0050] Figure 17b This is the enlarged MASSON staining section diagram at the inner part of the ceramic, the metal-ceramic interface and the metal of the 3D printed porous metal-ceramic assembled composite implant of the present invention.

[0051] Figure 18 It is the bone repair effect of the 3D printed porous ceramic implant and the 3D printed porous metal implant.

[0052] Figure 19 This is the bone repair effect of the 3D printed porous metal-ceramic assembled composite implant with different ratios of metal and ceramic of the present invention.

[0053] Figure 20Stereogram of the combination of the third embodiment of the present invention and the locking plate.

[0054] Figure 21 Stereogram of the combination of the fourth embodiment of the present invention and the locking plate.

[0055] Figure 22 Stereogram of the combination of Comparative Example 1 and the locking plate (porous metal module accounts for 100%, porous ceramic module accounts for 0%).

[0056] Figure 23 Stereogram of the combination of Comparative Example 2 and the locking plate (porous metal module accounts for 0%, porous ceramic module accounts for 100%).

[0057] Figure 24 Stereogram of the combination of the fifth embodiment of the present invention and the locking plate (porous metal module accounts for 50%, porous ceramic module accounts for 50%). Detailed implementation mode

[0058] The 3D printed porous metal-ceramic assembled composite implant of the present invention includes a porous metal-ceramic composite implant body formed by assembling and combining a 3D printed integral porous metal module 11 and a 3D printed integral porous ceramic module 12, and a mesh metal protector 13 wrapped around the outer periphery of the porous metal-ceramic composite implant body to form an assembled composite implant (hereinafter referred to as the implant) that can accurately match the shape and bonding surface of the bone tissue at the defect site. An integrated locking plate 14 can also be designed on the implant, or other locking plates with non-integrated designs can be used; the locking plate can be a detachable structure or a non-detachable structure; the locking plate can be personalized according to the bone shape, and the size and curvature of the implant and the plate can be adjusted according to the shape and size of the bone defect at different parts; the shape of the implant can be adjusted according to different surgical sites to achieve personalized and accurate repair. The 3D printed porous metal module and the 3D printed porous ceramic module in the present invention are combined in an assembled manner, which can achieve rapid bone integration and guide bone to grow into the metal interior, shorten the bone healing time, and promote the growth depth of the host bone. Solve the problems of slow bone integration speed, easy occurrence of nonunion and fibrous tissue wrapping in the treatment of segmental and large-segment load-bearing bone defects.

[0059] In addition, since the regulatory effect of bioactive ceramics on the tissue microenvironment is limited, the ratio and distribution of metal and ceramics can be adjusted according to the repair requirements of different bone defect sites. For example, a porous ceramic module can be assembled on one side of a porous metal module to form a side-assembled porous metal-ceramic composite implant body. It can also be that a porous ceramic module is assembled in the center of a porous metal module to form a center-assembled porous metal-ceramic composite implant body. Specifically, on the premise of meeting the mechanical support requirements, it is preferred to maximize the proportion of the ceramic module. This design can make full use of the excellent biocompatibility and bone integration performance of bioactive ceramics, while providing the necessary mechanical support through the porous metal module and the mesh metal protector to ensure the load-bearing capacity and stability of the structure. By optimizing the distribution ratio of metal and ceramics, the best balance between mechanical properties and biointegration performance can be achieved, thereby improving the overall functionality and use effect of the implant. Generally, the proportion of the porous metal module is greater than 0 and less than or equal to 80%; the proportion of the porous ceramic module is at least 20%. For the repair of non-large femoral segment bone defects, a side-assembled porous metal-ceramic composite implant body with a porous metal module ratio of 30%-50% can be selected; for the repair of large femoral segment bone defects, a side-assembled porous metal-ceramic composite implant body with a porous metal module ratio of 50% or a center-assembled porous metal-ceramic composite implant body with a porous metal module ratio of 50%-70% can be selected.

[0060] In the present invention, in principle, the metal part is mainly responsible for bearing weight; the porous ceramic part is used to regulate the osteogenic environment of the defect site, improve the bioactivity of inert metal, and the calcium and phosphate ions released by the degradation of the ceramic can up-regulate the expression of osteogenesis-related genes such as ALP, OCN, OPN, and Runx2 by activating signal pathways such as Wnt / β-catenin, thereby guiding rapid bone growth and achieving bone integration. The specific proportion range of the porous metal-ceramic is adjusted according to the force condition of the implantation site and the size of the defect, and the goal is to increase the ceramic proportion while meeting the force requirement. For example, for non-weight-bearing long bones such as the fibula, clavicle, and radius, if the defect site does not reach a large segment bone defect and mainly relies on the locking plate and the reticular metal protector to prevent fractures caused by impact and shear stress and can basically meet the mechanical requirements for repair, the ceramic proportion can be increased to nearly 100%, such as 90%-95%; if it reaches the length of a large segment bone defect, the metal proportion needs to be increased to improve its supporting effect, such as a 30% porous metal module - 70% porous ceramic module (hereinafter referred to as 30% metal - 70% ceramic). Preferably, while meeting the daily activity requirements, the ceramic proportion is increased as much as possible to accelerate the bone repair process. In the repair of weight-bearing long bones such as the tibia and humerus, due to higher mechanical requirements, the proportion of the porous metal module will be increased to avoid complications such as fractures caused by implant fractures, such as a 50% porous metal module - 50% porous ceramic module (hereinafter referred to as 50% metal - 50% ceramic). Another example is the largest weight-bearing bone such as the femur. According to the repair requirements of large segment bone defects in animal experiments, the proportion of the porous metal module will be increased to 50% or 70%. Another example is a more extreme bone defect case, such as a supercritical bone defect caused by the resection of a large area of bone tumor. The proportion of the porous metal module may be increased to 80%, and the implant is designed in the way of a central porous ceramic module and a peripheral porous metal module, that is, a central porous metal-ceramic implant body, to ensure the mechanical requirements and increase the porous ceramic module as much as possible to promote repair.

[0061] In the animal experiment on New Zealand white rabbits of this application, a large segmental bone defect model of the right femur with a defect length 1.61 times the width was selected. The side - combined porous metal - ceramic composite implant body with 50% porous metal module and 50% porous ceramic module has a better repair effect, with the most osteogenesis amount and bone ingrowth depth, and the bone ingrowth depth can reach 4 unit structures (i.e., 4 mm). Secondly, it is the central - type porous metal - ceramic composite implant body with 50% porous metal module and 50% porous ceramic module. Because the porous ceramic module is in the middle and in contact with the femoral cortical bone, the bone ingrowth depth is insufficient in the initial stage of treatment. However, new bone formation occurs inside both the porous metal module and the porous ceramic module. It can be seen that the central - type porous metal - ceramic composite implant body has better mechanical properties compared with the side - combined porous metal - ceramic composite implant body and is suitable for repairs with higher mechanical requirements, such as super - critical bone defects of the femur. For the side - combined composite implant body of 70% porous metal module - 30% porous ceramic module (hereinafter referred to as 70% metal - 30% ceramic), the bone ingrowth depth inside the porous metal adjacent to β - TCP and the femur can reach 4 unit structures (i.e., 4 mm). However, as the distance increases (exceeding 4 mm), the osteogenesis amount inside the porous metal decreases significantly, indicating that as the distance increases, the regulatory effect of β - TCP on the tissue micro - environment decreases significantly. Therefore, the osteogenesis amount inside the porous metal far from the femur and β - TCP decreases significantly. For the side - combined composite implant body of 30% porous metal module - 70% porous ceramic module, a large amount of new bone formation can be observed inside the porous ceramic and it gradually migrates and grows into the porous metal. However, the ceramic sometimes has micro - fractures, which has a certain risk. Therefore, a reticular metal protector is needed to play an auxiliary mechanical support and protection role. For the composite implant body of 100% porous ceramic module, malunion occurs because it cannot provide mechanical support. The composite implant body of 100% porous metal module has no osseous union with the bone, is prone to implant loosening and pain, and may even cause fractures in severe cases. In the experiment, because the selected rabbit model has relatively thin cortical bone and the rabbits mainly move by jumping, the force they receive is greater in terms of impact and pressure compared to walking and they are more prone to fractures. Therefore, the embodiment of 50% metal - 50% ceramic was mainly selected in the experiment for comparison with other embodiments. Through experimental comparison, for the repair of non - large segmental bone defects of the femur, a side - combined composite implant body with 30% - 50% porous metal module can be selected. For large segmental bone defects of the femur, a side - combined composite implant body with 50% porous metal module or a central - type composite implant body with 50% - 70% porous metal module can be selected. For super - critical bone defects of the femur, a central - type composite implant body with more than 70% porous metal module can be selected. To ensure the osteogenesis amount and bone integration performance, the ceramic proportion should be at least about 20%. The ceramic part should be set near 4 unit structures of the metal to regulate its osteogenic environment and guide bone growth inward.Therefore, the maximum proportion of the porous metal module is 80%.

[0062] The 3D printed porous metal module and the 3D printed porous ceramic module in the present invention preferably adopt a truss-like porous structure or a highly penetrating patch-like porous structure, which can support the adhesion and growth of cells and provide space for the ingrowth of new bone and the extension of the vascular network.

[0063] The present invention will be further described below through specific embodiments.

[0064] First Embodiment: This embodiment provides a design of a 3D printed porous metal-ceramic assembled composite implant for the repair of segmental and large-segment weight-bearing bone defects.

[0065] Taking the side-fitting 3D printed porous metal-ceramic assembled composite implant as an example, as Figure 1 、 Figure 2 and Figure 3 shown, the proportion of the porous metal module is 50%, and the proportion of the porous ceramic module is 50%. The composite implant includes four parts, namely, a 3D printed one-piece porous metal module 11, a 3D printed one-piece porous ceramic module 12, a 3D printed honeycomb-shaped mesh metal protector 13, and a 3D printed locking plate 14. There are locking screw channels 15 on the locking plate 14, and a snap structure 16 on the mesh metal protector, which plays a role in connecting and assembling each part.

[0066] It should be noted that after the porous metal module and the porous ceramic module are assembled, they are accurately fitted to the shape of the defect site, which helps to restore the original force line of the defect site, avoid deformity after healing, or internal stress concentration and change of the stress environment in the bone due to force line deviation after repair, resulting in loosening, pain, deformity or fracture. The metal part can be medical titanium and titanium alloys, 316L stainless steel, tantalum metal, etc. In the present invention, Ti6Al4V alloy is taken as an example. The metal part is preferably formed by powder bed additive manufacturing technology. In the present invention, the SLM method 3D printing forming technology is taken as an example. The ceramic part can be calcium phosphate-based bioactive ceramics, bioglass, magnesium whitlockite, etc. In the present invention, β-tricalcium phosphate (β-TCP) is taken as an example.

[0067] Second Embodiment: As Figure 20 shown, for the side-fitting 3D printed porous metal-ceramic assembled composite implant body, the proportion of the porous metal module is 30%, and the proportion of the porous ceramic module is 70%. The rest is the same as above.

[0068] Third Embodiment: Figure 21 shown, for the side-fitting 3D printed porous metal-ceramic assembled composite implant body, the proportion of the porous metal module is 70%, and the proportion of the porous ceramic module is 30%. The rest is the same as above.

[0069] Comparative Example 1:Figure 22 As shown, it is an implant body with a 100% proportion of porous metal modules and a 0% proportion of porous ceramic modules. The rest is the same as above.

[0070] Comparative Example 2: Figure 23 As shown, it is an implant body with a 0% proportion of porous metal modules and a 100% proportion of porous ceramic modules. The rest is the same as above.

[0071] Fourth Embodiment: Figure 24 As shown, it is a central 3D printed porous metal-ceramic assembled composite implant body. A modular implant with a 50% proportion of porous metal modules, a 50% proportion of porous ceramic modules, the porous ceramic modules in the center, and the porous metal modules around. The rest is the same as above.

[0072] Figure 18 In the figure are Masson staining diagrams 12 weeks after implantation of a composite implant body with 100% porous ceramic modules and an implant body with 100% porous metal modules respectively in the repair of large segmental bone defects of the femur. It can be seen from the figure that in the comparative example using the composite implant body with 100% porous ceramic modules, although there is more new bone formation, the locking plate and the mesh metal protector alone cannot provide the required mechanical support, resulting in the fracture of the porous ceramic modules and triggering malunion, that is, the autologous bone in the proximal femur is concave, causing malunion. In the comparative example using the implant body with 100% porous metal modules, there is only a small amount of bone ingrowth at the contact between the porous metal modules and the autologous bone inside, and there is no bone ingrowth deep inside the porous metal. The composite implant and the bone do not form bone union, and it is easy to cause fractures under stress. Therefore, both have disadvantages in the treatment of large segmental weight-bearing bone defects. And Figure 17a In the side-assembled and central porous metal-ceramic assembled composite implant embodiments, the composite implant basically ensures mechanical stability and promotes the bone repair process.

[0073] In the present invention, if the length of a large segment of bone defect is reached, the proportion of the porous metal module needs to be increased to enhance its supporting effect. For example, a side-combined or center-combined porous metal-ceramic assembled composite implant comprising 30% porous metal module - 70% porous ceramic module can be adopted. In the repair of long load-bearing bones such as the tibia and humerus, a side-combined or center-combined porous metal-ceramic assembled composite implant comprising 50% porous metal module - 50% porous ceramic module can be used. For another example, in the case of the largest load-bearing bone such as the femur, according to animal experiments, the metal proportion for the repair of a large segment of bone defect may be increased to 50% - 70%, that is, a side-combined or center-combined porous metal-ceramic assembled composite implant comprising 50% porous metal module - 50% porous ceramic module is used, or a center-combined porous metal-ceramic assembly composite comprising 70% porous metal module - 30% porous ceramic module is used. For yet another example, in the case of more extreme bone defect cases, such as the supercritical femoral defect caused by the resection of a large area of bone tumor, the proportion of the porous metal module can be increased to 80%, and an implant body is designed in the way of having a porous ceramic module structure in the middle and porous metal modules on the periphery, that is, a center-type implant body, to ensure the mechanical requirements and increase the ceramic as much as possible to promote repair. When the proportion of the porous metal module reaches 80% and the porous ceramic module reaches 20%, the distal end of the porous metal module in the center-type implant body is exactly within about 4 unit structures away from the porous ceramic module, that is, within the range of the optimal osteogenic environment regulation of the ceramic. If the proportion of the porous metal module exceeds 80% and the porous ceramic module is less than 20%, it is difficult for the calcium and phosphate ions released by the degradation of the ceramic to migrate to this area inside the porous metal module far from the ceramic part, and its osteogenic environment cannot be effectively regulated, resulting in the weakening of the expression of osteogenesis-related genes (such as OCN, OPN, ALP, etc.) in the local microenvironment, which will lead to insufficient osteogenic performance inside it, and then it is difficult for bone to grow into the inside of the porous metal module far from the ceramic part; in addition, the decrease in the calcium and phosphate ion concentration will also lead to the increase in the expression of osteoclast-related genes such as TRAP, triggering abnormal healing and bone resorption, resulting in the risk of forming a cavity or being wrapped by fibrous tissue inside the metal far from the ceramic action area, causing aseptic inflammatory reaction; in addition, there is not enough bone growth in this area, and in the late stage of healing, it will lead to abnormal stress states in the cavity part of the implant, that is, uneven stress causes stress concentration or bone resorption, increasing the risk of implant loosening, and even may lead to bone spurs and malunion.

[0074] The method for constructing the above 3D printed porous metal-ceramic assembled composite implant comprises the following steps:

[0075] (1): According to the Micro-CT scan data of the defect model, feature parameter extraction and three-dimensional reconstruction are carried out, and the shape of the composite implant is personalized and accurately designed through three-dimensional mapping software. According to the osteogenesis-load-bearing requirements of the defect site, modular segmentation is carried out, and the proportion, distribution and shape adjustment of the porous metal module and the porous ceramic module are set.

[0076] (2): 3D printed integrated porous metal module with a designed porosity of 70% and a pore size of 700 μm. The porous metal module of the side-assembled porous metal-ceramic assembled composite implant is as shown in Figure 4 and the porous metal module of the central porous metal-ceramic assembled composite implant is as shown in Figure 7 as shown therein.

[0077] (3): 3D printed integrated porous ceramic module with a designed porosity of 65% and a pore size of 800 μm. The ceramic part can be calcium phosphate-based bioactive ceramics, bioglass, whitlockite, etc. In this invention, β-tricalcium phosphate is taken as an example. The 3D printing of the porous ceramic module preferably uses stereolithography 3D printing technology and extrusion printing technology. In this invention, the DLP method 3D printing technology is taken as an example. The porous ceramic module of the side-assembled porous metal-ceramic assembled composite implant is as shown in Figure 3 and the porous ceramic module of the central porous metal-ceramic assembled composite implant is as shown in Figure 7 as shown therein. After printing, it is dried in an oven and then degreased and sintered.

[0078] (4): 3D printed reticular (such as honeycomb-shaped) metal protection part with a pore size of 5 mm, designed as shown in Figure 9 and shown therein. The reticular protector is formed by buckling two semi-circular honeycomb mesh plates, and its snap structure includes four snap blocks and snap sleeves, which play a role in connection and assembly.

[0079] (5): After the porous metal module and the porous ceramic module are assembled as required, a composite implant body is formed; the assembly of the side-assembled composite implant body is as shown in Figure 5 and the assembly of the central composite implant body is as shown in Figure 7 as shown therein. Then, after the assembled composite implant body is installed into the opened reticular metal protector, the snap blocks and snap sleeves on the sides of the two semi-circular honeycomb mesh plates are aligned and inserted to complete the assembly of the composite implant, thereby obtaining a 3D printed porous metal-ceramic assembled composite implant that precisely matches the shape and bonding surface of the bone tissue at the defect site.

[0080] Before assembly, a locking plate can also be 3D printed, designed as shown in Figure 10As shown, it is designed with a radian of 6-8°, which conforms to the mechanical axis of the composite host bone. The locking plate is designed with 6 locking screw channels for fixation after implantation. The locking screw channels (screw ports) adopt M2-0.5 threads. Then, the assembled composite implant is installed on the locking plate through the reticular metal protector. After installation, it is sterilized at high temperature and high pressure. After sterilization, physiological saline is added, and it is centrifuged with a low-speed centrifuge to remove the air bubbles in the micropores of the implant, and then the implantation surgery can be carried out. It is preferably that the distance from the end face of the defective bone tissue or the outer periosteum after implantation does not exceed 10 mm, and more preferably within 4 mm. It is further preferred that the bioactive ceramic can directly contact the end face of the bone tissue or the outer periosteum after implantation.

[0081] The porous metal module and the reticular (honeycomb) metal protector. After these metal parts are printed, they are cleaned with alkane and ethanol to remove the residual powder and surface stains during printing. After the cleaning of the metal parts is completed, they are dried in a drying oven and heat-treated in a vacuum or inert atmosphere to eliminate the residual stress. After the heat treatment of the metal parts, surface treatment is carried out; for the rough surface, the sandblasting treatment method is used, and the sandblasting pressure is 0.2-0.6 MPa to form a rough metal surface (suitable for the repair of non-articular defects) to promote cell adhesion and growth; for the smooth surface, the plasma polishing technology is used to form a smooth metal surface (suitable for the repair of articular defects) to reduce the friction between implants or between the implant and the autologous bone.

[0082] Figure 12 As shown, the orthographic view of the finite element simulation of the implant after loading compressive and torsional stresses. The implant is uniformly stressed and there is no stress concentration.

[0083] Figure 13 As shown, the front view of the finite element simulation of the implant after loading compressive and torsional stresses. The implant is uniformly stressed and there is no stress concentration.

[0084] As Figure 14 As shown, the gradient change of the ion concentration of calcium and phosphorus ions released by the degradation of the bioactive ceramic with distance in the GelMA hydrogel tissue-like microenvironment. The bioactive ceramic degrades and releases calcium and phosphorus ions. In the in vivo tissue microenvironment with a diffusion resistance state, a spatial concentration gradient will be formed, that is, near the bioactive ceramic, the concentrations of calcium and phosphorus ions will increase significantly, and as the distance increases, the concentrations of calcium and phosphorus ions will gradually decrease. The gradual decrease of its ion concentration indicates that the regulatory effect of the bioactive ceramic on the tissue microenvironment is limited, and it also suggests that the distribution and proportion of metal and ceramic have an important impact on the repair effect of the implant.

[0085] As Figure 15aAs shown, the effects of the changes in calcium and phosphate ion concentration gradients on cell proliferation behavior. Near the bioactive ceramic, the concentrations of calcium and phosphate ions will increase significantly, regulating cell proliferation behavior; while with the increase in distance, the concentrations of calcium and phosphate ions will gradually decrease, and their regulatory ability on the extracellular matrix microenvironment and cell proliferation behavior will also gradually weaken.

[0086] As Figure 15b shown, the effects of the changes in calcium and phosphate ion concentration gradients on cell adhesion behavior. Near the bioactive ceramic, cell adhesion behavior is regulated, and the cell spreading area increases significantly; while with the increase in distance, the cell spreading area decreases significantly.

[0087] As Figure 15c shown, the effects of the changes in calcium and phosphate ion concentration gradients on cell osteogenic differentiation behavior. Near the bioactive ceramic, the concentrations of calcium and phosphate ions will increase significantly, activating the Wnt / β-catenin signaling pathway and regulating cell behaviors such as osteogenic differentiation, and the expression of osteogenesis-related genes is significantly up-regulated; while with the increase in distance, the concentrations of calcium and phosphate ions will gradually decrease, and their regulatory ability on the extracellular matrix microenvironment and cell differentiation and other behaviors will also gradually weaken. This result also suggests that by reasonably optimizing the distribution and proportion of 3D printed porous metal and ceramic modules, it is beneficial to maximize the osteogenic performance of 3D printed porous metal / ceramic modular bone repair implants.

[0088] As Figure 16 shown, after the implant is implanted into the femur of New Zealand white rabbits, the implant can individually and precisely repair the shape of the defect site and restore the original bone force line.

[0089] As Figure 17a shown, Masson staining images of hard tissue sections of implants with different distributions of porous metal and porous ceramics 12 weeks after implantation in vivo. Under the influence of ceramics, there is also a large amount of newly formed bone tissue inside the porous metal module in the central and lateral combined modular composite implants, and the phenomenon of newly formed bone migrating and growing from inside the ceramic to inside the metal can be seen.

[0090] As Figure 17b shown, Masson staining images of hard tissue sections 12 weeks after the implant is implanted in vivo, with a large amount of newly formed bone generated inside the ceramic. The calcium and phosphate ions released by the degradation of the ceramic diffuse into the metal, improving the microenvironment inside the metal, and then the phenomenon of newly formed bone migrating and growing into the metal can be seen.

[0091] As Figure 18As shown, it is the Masson staining diagram of hard tissue sections after 3D-printed porous ceramic implants and 3D-printed porous metal implants are implanted in the body for 12 weeks. In the repair of segmental and large-segment bone defects in load-bearing joints, even with the support of an internal fixation plate, the 3D-printed porous ceramic implants still cannot provide good mechanical support. The ceramic part breaks, resulting in dislocation and deformation of both the proximal and distal ends of the femur, leading to malunion. In the repair of segmental and large-segment bone defects in load-bearing joints, due to the extreme osteogenic environment, the 3D-printed porous ceramic implants have insufficient bone integration and bone ingrowth depth. There is only a bone ingrowth depth of 2-3 unit structures near the autologous bone end, and no new bone formation is seen in the rest of the implant. The bone marrow cavity at the distal end of the femur has been closed, and it can be initially judged clinically as nonunion. Since the implant and the autologous bone do not have bony union, long-term implantation will lead to implant loosening and even fracture.

[0092] As Figure 19 shown, it is the methylene blue-basic fuchsin staining diagram of hard tissue sections of modular bone repair implants with different ratios of porous metal and porous ceramic. In the metal (30%)-ceramic (70%) modular composite implant, the porous metal part is within the optimal osteogenic regulation range of the ceramic, and new bone formation is seen inside, showing good bone integration effect, new bone mass and bone ingrowth depth. The metal (70%)-ceramic (30%) modular composite implant shows good bone integration effect near the ceramic side (within about 4 unit structures), while little new bone formation is seen basically far from the ceramic (more than 4 unit structures). This conclusion also suggests that the calcium and phosphorus-containing ions released by the biodegradation of bioactive ceramics will also form differences in ion concentration and spatial distribution in the osteogenic environment at the defect site in the body, and the spatial distribution of ions will also have an important impact on the bone repair performance of the modular composite implant. Therefore, when designing metal / ceramic modular implants, the modular form should be fully considered. On the premise of ensuring the mechanical stability of the implant, optimizing and increasing the proportion of bioactive ceramics in the modular implant can give full play to its regulatory role in the osteogenic environment, effectively regulate the osteogenic environment of the defect area by the composite implant, and improve the overall bone repair performance of the implant.

[0093] As described above, the present invention can be preferably realized. The above embodiments are only the preferred embodiments of the present invention and are not used to limit the implementation scope of the present invention; that is, all equal changes and modifications made according to the content of the present invention are covered by the scope required to be protected by the claims of the present invention.

Claims

1. A 3D printed porous metal-ceramic assembled composite implant, characterized in that : A modular composite implant that can precisely match the shape and bonding surface of the bone tissue at the defect site, formed by a 3D-printed integrated porous metal module (11) and a 3D-printed integrated porous ceramic module (12) assembled and combined together, and a mesh metal protector (13) wrapped around the periphery of the porous metal-ceramic composite implant body.

2. The 3D printed porous metal-ceramic assembled composite implant according to claim 1, wherein: The porous ceramic module (12) is assembled on one side of the porous metal module (11) to form a side-assembled porous metal-ceramic composite implant body, or the porous ceramic module (12) is assembled in the center of the porous metal module (11) to form a center-assembled porous metal-ceramic composite implant body.

3. The 3D printed porous metal-ceramic assembled composite implant according to claim 1, characterized in that: It also includes a locking plate (14) customized according to the bone shape, and the locking plate (14) is connected to the mesh metal protector (13).

4. The 3D printed porous metal-ceramic assembled composite implant according to claim 3, characterized in that: The mesh metal protector (13) is provided with a snap structure (16), and the locking plate (14) is correspondingly provided with a clamping structure that can be assembled with the snap structure (16) on the mesh metal protector (13). Through the snap structure (16) on the mesh metal protector (13), a tight assembly of the mesh metal protector - porous metal module - porous ceramic module and the composite implant - locking plate can be achieved.

5. The 3D printed porous metal-ceramic assembled composite implant according to claim 1, characterized in that: In the porous metal-ceramic composite implant body, the proportion of the porous metal module (11) is: greater than 0 and less than or equal to 80%; the proportion of the porous ceramic module (12) is at least 20%, and the sum of the porous ceramic module and the porous metal module is 100%.

6. The 3D printed porous metal-ceramic assembled composite implant according to claim 5, characterized in that: For the repair of non-weight-bearing long bone and non-femoral large segment bone defects, a side-assembled porous metal-ceramic composite implant body with a porous metal module (11) accounting for more than 0 and less than 50% is selected; for the repair of femoral large segment bone defects, a side-assembled porous metal-ceramic composite implant body with a porous metal module (11) accounting for 50% or a center-assembled porous metal-ceramic composite implant body with a porous metal module (11) accounting for 30% - 70% is selected.

7. A preparation method of the 3D-printed porous metal-ceramic modular composite implant as described in claims 1 - 6, comprising the following steps: (1) Design the shape and modular segmentation of the composite implant according to the requirements of the shape and bonding surface of the bone tissue at the defect site and the load-bearing requirements of the bone tissue, and obtain the volume ratio, position distribution, and shape of the required porous metal module (11) and porous ceramic module (12); (2) Forming the porous metal module: 3D-printing the integrated porous metal module (11) with the required shape, and then cleaning, heat-treating, and surface-treating it for standby; (3) Forming the porous ceramic module: 3D-printing the integrated porous ceramic module (12) with the required shape, and then performing ceramic debinding and sintering treatment for standby; (4) 3D-printing the mesh metal protector (13), and then cleaning, heat-treating, and surface-treating it for standby; (5) Assembling and combining the above-mentioned porous metal module (11) and porous ceramic module (12) to form a porous metal-ceramic composite implant body; (6) Wrap the processed reticulated metal protector (13) around the outer periphery of the porous metal-ceramic composite implant body to obtain a 3D printed porous metal-ceramic assembled composite implant that can precisely match the shape and bonding surface of the bone tissue at the defect site.

8. The preparation method of the 3D printed porous metal-ceramic assembled composite implant according to claim 7, wherein: After the porous metal module (11) and the reticulated metal protector (13) are printed, they are cleaned with alkane and ethanol to remove the residual powder and surface stains during printing. After drying in a drying oven, they are heat-treated in a vacuum or inert atmosphere to eliminate residual stress.

9. The preparation method of the 3D printed porous metal-ceramic assembled composite implant according to claim 7, characterized in that: A locking plate (14) that is personalized according to the bone shape is connected to the assembled composite implant, and the locking plate (14) is connected to the reticulated metal protector (13).

10. Application of a 3D printed porous metal-ceramic assembled composite implant according to any one of claims 1-9, characterized in that: It is applied to the field of implantable medical devices.

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