Bionic bone scaffold customized body and preparation method and application thereof

Abstract

The invention relates to a bionic bone scaffold customized body and a preparation method and application thereof, and belongs to the technical field of biomedical materials. The invention provides a preparation method of a bionic bone scaffold customized body, which comprises the following steps: scanning and recording a cranio-maxillofacial hard tissue defect form, and constructing a digital scaffold model through an algorithm model and / or artificial design based on the recorded data; performing three-dimensional reconstruction on the obtained digital scaffold model to generate bionic bone scaffold customized volume data meeting the personalized requirements of cranio-maxillofacial tissue defects; and converting the obtained customized body data of the bionic bone scaffold into a customized body of the bionic bone scaffold by utilizing a 3D printing technology. Modeling is conducted through real bone defect data, a bionic bone scaffold customized body of the bone defect part is prepared through the 3D printing technology, the outer contour is attached to the bone defect side form, the ideal bone form is reconstructed, the inner contour is a fine substructure of the defect part, and the bionic bone scaffold has a bionic pore structure and biomechanical performance; the method can be used for reconstructing personalized cranio-maxillofacial tissues.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biomedical materials, in particular to a kind of bionic bone scaffold customization body and its preparation method and application. BACKGROUND

[0002] The craniofacial bone is an important multifunctional organ, and its contour shape has strong individualized characteristics, and it also bears complex physiological functions, including coordinating the mastication, swallowing, language and social functions of the craniofacial system. The craniofacial bone defects caused by long-term edentulous, severe periodontitis and maxillofacial tumor can seriously affect the appearance, pronunciation and mastication functions of the patient, thereby reducing the quality of life of the patient and endangering the mental health. Individualized reconstruction of craniofacial defects has become a research frontier of international and domestic concern. According to a research report, the market size of bone regeneration reconstruction materials in China will grow at a compound annual growth rate of 14%, and will exceed 5.302 billion US dollars by 2030. However, the bone regeneration reconstruction materials in China are mainly products of the Swiss company Geistlich, which accounts for about 70% of the market share in China, while domestic products only account for 15% of the market share. Therefore, the craniofacial tissue bone defect regeneration reconstruction material has great social and economic benefits.

[0003] Bone biological scaffold is a key material for treating bone defect regeneration, and its fine porous structure and bioactive components provide a good osteogenesis space and osteogenesis contour for bone regeneration. At present, the gold standard of bone biological scaffold is autologous bone, which has a natural porous structure and autologous biological components, making it have good bone conduction, bone induction and osteogenesis. However, autologous bone transplantation has problems such as opening a second operation area, expanding surgical damage, limited bone supply, bone resorption, and limited osteogenesis contour. Therefore, allogeneic bone is used for bone regeneration treatment in clinical application, which has good bone conduction, does not need to open a second operation area, and provides good structural support. However, allogeneic bone has disadvantages such as disease transmission, immune rejection, and limited osteogenesis contour, and its clinical application is still limited. Therefore, whether a bionic bone scaffold customization body with reproducible natural bone structure can be customized based on real jawbone data is a major clinical scientific problem faced by individualized reconstruction of craniofacial tissue defects.

[0004] The natural bone has the highest content of inorganic components of hydroxyapatite (HA), and the artificial synthetic bone biological scaffold is mostly based on HA biological ceramics. According to the characteristics of natural bone, a biomimetic bone scaffold with precise porous structure is prepared. Common preparation methods include gas foaming, phase separation method and freeze casting, etc. to precisely control the porosity and pore size of the scaffold to reach the level of natural bone parameters. However, these methods cannot reproduce the fine substructure of real bone such as cortical bone and trabecular bone, which is not the ideal choice for preparing biomimetic bone scaffolds. In recent years, with the development of manufacturing technology, digital light processing (DLP) 3D printing technology has occupied a dominant position in the 3D printing of biomedical ceramics due to its obvious advantages in spatial resolution, pattern fidelity and manufacturing speed. The DLP 3D printing technology is introduced into the study of bone scaffolds to prepare precise porous structures combined with the required osteogenic profile to manufacture bone scaffolds with the required shape and porosity. However, in order to save costs and simplify the process, 3D printing technology often uses artificial design templates with similar bone scaffold porosity to natural bone parameters, rather than real jaw bone data, which still cannot reach the level of autologous bone gold standard. SUMMARY

[0005] The purpose of the present application is to overcome the shortcomings of the prior art and provide a biomimetic bone scaffold customization body close to the structure of natural bone and a preparation method and application thereof.

[0006] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows: In a first aspect, the present application provides a preparation method of a biomimetic bone scaffold customization body, comprising the following steps: S1, scanning and recording the morphology of craniofacial hard tissue defects, and constructing a digital scaffold model based on the data of the recorded morphology of craniofacial hard tissue defects through an algorithm model and / or artificial design; S2, three-dimensional reconstruction of the digital scaffold model obtained in step S1 to generate biomimetic bone scaffold customization body data meeting the individual needs of craniofacial tissue defects; S3, converting the biomimetic bone scaffold customization body data obtained in step S2 into an entity by using DLP 3D printing technology, wherein the entity is the biomimetic bone scaffold customization body.

[0007] The application utilizes real bone defect data for modeling, prepares a bionic bone scaffold customized body for the bone defect site through DLP 3D printing technology, the outer contour is fitted with the shape of the bone defect side and reconstructs the ideal shape of the bone, and the inner contour is the fine substructure (bone cortex, bone trabecula and other structures) of the defect site, has a bionic pore structure and certain biomechanical properties, is used for reconstructing personalized craniofacial tissues, and restores personalized appearance and function. Meanwhile, the bionic bone scaffold customized body can also promote the new bone formation of the bone defect site, and further promotes the repair of the bone defect.

[0008] As a preferred embodiment of the preparation method of the application, in step S1, the algorithm model is mainly based on a digital scaffold model generation algorithm developed by artificial intelligence deep learning.

[0009] As a preferred embodiment of the preparation method of the application, in step S1, the artificial design is mainly to generate a digital scaffold model by using a digital auxiliary design software by artificial.

[0010] As a preferred embodiment of the preparation method of the application, in step S1, the digital auxiliary design software includes but is not limited to at least one of GeomagicWrap, Mimics, Simplant and 3Shape.

[0011] As a preferred embodiment of the preparation method of the application, in step S1, the digital scaffold model meets at least one of the following conditions (1) to (3): (1) The outer contour in the digital scaffold model is fitted with the shape of the bone defect side, and the gap is not more than 0.5mm; (2) The bone shape on the side away from the bone defect in the digital scaffold model is restored, and the surface overlap degree with the bone or ideal implant implantation bone shape of the same name part without defect is ≥90%; (3) The inner contour in the digital scaffold model has a volume difference of ≤50% with the bone of the same name part without defect.

[0012] As a preferred embodiment of the preparation method of the application, in step S3, the DLP 3D printing technology mainly includes the following operations: (a) converting the bionic bone scaffold customized body data obtained in step S2 into data recognizable by a 3D printer; (b) using a 3D printer based on DLP technology to print a bionic bone scaffold customized body green body using a bioceramic slurry as raw material; (c) washing, drying and sintering the bionic bone scaffold customized body green body obtained in step (b) to obtain a bionic bone scaffold customized body.

[0013] As a preferred embodiment of the preparation method of the present application, in step (a), the biomimetic bone scaffold customized body data obtained in step S2 is segmented using Autodesk Netfabb or Flash DLPrint software and exported as data recognizable by a 3D printer.

[0014] As a preferred embodiment of the preparation method of the present application, in step (a), the segmentation parameters using Autodesk Netfabb or Flash DLPrint software are 0.001-0.5 mm per layer thickness.

[0015] As a preferred embodiment of the preparation method of the present application, the segmentation parameters are 0.03-0.05 mm per layer thickness.

[0016] As a preferred embodiment of the preparation method of the present application, in step (b), the bioceramic slurry comprises a bioceramic system and a photocuring system.

[0017] As a preferred embodiment of the preparation method of the present application, in step (b), the bioceramic system in the bioceramic slurry comprises at least one of hydroxyapatite, zirconium oxide, and barium titanate.

[0018] As a preferred embodiment of the preparation method of the present application, in step (b), the photocuring system in the bioceramic slurry comprises a photocuring polymer resin, an initiator, and a dispersant.

[0019] As a preferred embodiment of the preparation method of the present application, in step (b), the photocuring polymer resin in the photocuring system comprises at least one of, but is not limited to, polyethylene glycol diacrylate, hexamethylene diacrylate, trimethylolpropane triacrylate, tripropylene glycol diacrylate, methacrylated gelatin, acrylated epoxy soybean oil, polyurethane acrylate, and epoxy acrylate.

[0020] As a preferred embodiment of the preparation method of the present application, in step (b), the initiator in the photocuring system comprises at least one of, but is not limited to, phenyl bis(2,4,6-trimethylbenzoyl) phosphine oxide, 1-hydroxycyclohexyl phenyl ketone, 2-benzyl-2-dimethylamino-1-(morpholinophenyl) butanone-1, and bis(2,6-difluoro-3-pyrrolylphenyl) titanium dioxide.

[0021] As a preferred embodiment of the preparation method of the present application, in step (b), the dispersant in the photocuring system comprises at least one of acrylic block copolymer, BYK 2155, BYK-111, and SN-5027.

[0022] As a preferred embodiment of the preparation method of the present application, in step (b), the bioceramic slurry further comprises at least one of a toughening biomaterial and a colorant.

[0023] As a preferred embodiment of the preparation method of the present application, in step (b), the toughening biomaterial comprises, but is not limited to, at least one of carbon fiber, bioactive glass, tricalcium phosphate, zirconium oxide, titanium oxide, calcium carbonate silicon dioxide, zinc oxide, aluminum oxide, and barium titanate.

[0024] As a preferred embodiment of the preparation method of the present application, in step (b), the bioceramic slurry is mainly prepared by mixing the bioceramic system and the photocuring system, and mechanically grinding and dispersing to obtain the bioceramic slurry.

[0025] As a preferred embodiment of the preparation method of the present application, in step (b), the bioceramic slurry is mainly prepared by mixing the bioceramic system, the photocuring system, the colorant, and the toughening biomaterial, and mechanically grinding and dispersing to obtain the bioceramic slurry.

[0026] As a preferred embodiment of the preparation method of the present application, in step (b), the power density of the 3D printer is 0.1-50 mW / cm 2 , and the exposure time is 10-45 s.

[0027] As a preferred embodiment of the preparation method of the present application, in step (b), the power density of the 3D printer is 1-3 mW / cm 2 , and the exposure time is 10-30 s.

[0028] As a preferred embodiment of the preparation method of the present application, in step (b), the power density of the 3D printer is 2 mW / cm 2 , and the exposure time is 20 s.

[0029] As a preferred embodiment of the preparation method of the present application, in step (c), the sintering parameter conditions are as follows: the maximum temperature is 800-2000 ℃, and the holding time is 10-300 min.

[0030] As a preferred embodiment of the preparation method of the present application, in step (c), the sintering parameter conditions are as follows: the maximum temperature is 1150-1200 ℃, and the holding time is 60-180 min.

[0031] As a preferred embodiment of the preparation method of the present application, the preparation method of the biomimetic bone scaffold customized body further comprises the following steps: S4, soaking the biomimetic bone scaffold customization body obtained in step S3 into a hydrogel prepolymer solution, vacuum treatment, and draining after taking out, to obtain a biologically modified biomimetic bone scaffold customization body.

[0032] As a preferred embodiment of the preparation method of the application, in step S4, the hydrogel prepolymer solution contains a gelatin-based hydrogel.

[0033] As a preferred embodiment of the preparation method of the application, the gelatin-based hydrogel includes but is not limited to at least one of a gelatin hydrogel cross-linked by ninipin, a gelatin hydrogel cross-linked by glutaraldehyde, a methacrylated gelatin hydrogel, and a chitosan-gelatin composite hydrogel.

[0034] As a preferred embodiment of the preparation method of the application, in step S4, the hydrogel prepolymer solution further contains an active factor.

[0035] As a preferred embodiment of the preparation method of the application, the active factor can be loaded by the hydrogel, and the active factor includes but is not limited to at least one of stem cell vesicles and cytokines.

[0036] As a preferred embodiment of the preparation method of the application, the cytokine includes but is not limited to at least one of IL-4, IGF-2, CXCL12, IGF-1, and ANGPTL4.

[0037] In a second aspect, the application provides a biomimetic bone scaffold customization body, which is mainly prepared by the above preparation method.

[0038] In a third aspect, the application provides an application of the above biomimetic bone scaffold customization body in preparing a regenerative material for reconstructing craniofacial bone and / or composite tissue defects.

[0039] Compared with the prior art, the application has the following beneficial effects: (1) The biomimetic bone scaffold customization body design system of individual jawbone imaging data, combined with the adaptive adjustment of the bioceramic 3D printing technology, realizes the full-link connection from design to manufacturing of the bone regeneration scaffold customization body similar to the individual autologous bone. The biomimetic bone scaffold customization body not only restores the ideal regeneration contour, but also has a pore structure close to the individual bone and a biomechanical support, providing a regeneration scaffold closer to the gold standard of bone transplantation, i.e., autologous bone, for craniofacial tissue defects, solving the problems of increased operation time, increased treatment cost, and mismatch between bone grafting material and defect morphology caused by intraoperative cutting of bone grafting material, meeting the regeneration needs of craniofacial personalized defects, and significantly improving the tissue regeneration potential compared with the prior art (such as a 3D printed scaffold with an artificial design structure).

[0040] (2) The application utilizes the bioceramic 3D printing technology based on digital light processing technology, and realizes the precise printing of the customized body of the biomimetic bone by adjusting the power density, exposure time and sintering procedure, so as to realize the fine substructure replication of the real bone, provide a feasible manufacturing model for the high-precision personalized bone biological scaffold manufacturing, meet the demand of the high individual characteristics of the craniofacial bone, and have a wide application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 The preparation process of the biomimetic bone scaffold customized body of the application; Figure 2 The comparison diagram of the design file of the application comparative example 2 and the CT scan reconstruction model of the real object; Figure 3 The comparison diagram of the design file of the application comparative example 3 and the photo of the real object; Figure 4 The comparison diagram of the data of different biomimetic bone scaffold customized bodies in the application effect example 1 and the real object, wherein A is the biomimetic bone scaffold customized body obtained in example 1, B is the biomimetic bone scaffold customized body obtained in example 2, and C is the biomimetic bone scaffold customized body obtained in example 3; Figure 5 The comparison result of the biomimetic bone scaffold customized body of example 5 in the application effect example 1 and the bone defect position; Figure 6 The scanning electron microscope diagram of different biomimetic bone scaffold customized bodies in the application effect example 1; Figure 7 The HE staining of the section of the bone defect part when the different biomimetic bone scaffold customized bodies in the application effect example 2 are applied in the rat bone defect model, wherein NB refers to the new bone deposition part; Figure 8 The new bone volume statistical result of the bone defect part when the different biomimetic bone scaffold customized bodies in the application effect example 2 are applied in the rat bone defect model, wherein the "*" indicates that there is a significant difference between the two groups (P<0.05), the "**" indicates that there is a significant difference between the two groups (P<0.01), and the "***" indicates that there is a significant difference between the two groups (P<0.001); Figure 9 The fitting analysis diagram of the data of the biomimetic bone scaffold customized body of example 1 in the application effect example 2 and the CT scan reconstruction model of the real object after being applied in the rat bone defect part. DETAILED DESCRIPTION

[0042] In order to better illustrate the purpose, technical scheme and advantages of the application, the application will be further described below in combination with specific examples.

[0043] Other materials, reagents, etc. used in the examples, comparative examples and effect examples can be obtained from commercial channels unless otherwise specified.

[0044] Example 1 This example provides a kind of bionic bone scaffold customization body and its preparation method, the flow of the preparation method is as shown in Figure 1 Specifically includes the following steps: A1, rats are anesthetized and disinfected, a long about 2cm incision is made along the rat supraorbital interfrontal midline to bone surface, the mucous membrane flap is separated and turned over, a full-thickness bone defect with a diameter of 5mm is prepared on both sides of the midline, the integrity of the dura mater is ensured, the bone piece is carefully taken out, and the skull wound hole shape is trimmed to construct a rat skull bone defect model; A2, the rat skull bone defect model obtained in step A1 is CT scanned to record the skull bone defect morphology, and a digital scaffold model is artificially constructed based on the data recorded by using digital auxiliary design software Geomagic; The digital scaffold model meets the following conditions: the middle and outer contours on the side close to the bone defect conform to the defect morphology, the gap is ≤0.5mm; the side away from the bone defect restores the appropriate bone morphology, and the surface overlap of the same named part of the bone without defect is >90%; the inner contour is based on the bone trabecular structure of the jaw bone data, which meets the bionic pore structure and biomechanical support required for the regeneration scaffold, and the volume difference with the same named part of the bone without defect is <50%; A3, the digital scaffold model obtained in step A1 is three-dimensionally reconstructed to generate a bionic bone scaffold customization body design file data meeting the individual needs of the skull bone defect; A4, a bioceramic system and a photocuring system are mixed, mechanically ground and dispersed to obtain a bioceramic slurry; The bioceramic system is hydroxyapatite, and the photocuring system is a photocuring polymer resin, an initiator, a dispersant and a colorant hiding agent, wherein the photocuring polymer resin uses polyethylene glycol diacrylate, the initiator uses phenyl bis (2, 4, 6-trimethyl benzoyl) phosphine oxide (819), and the dispersant uses BYK-2155; A5, the bionic bone scaffold customization body data obtained in A3 is segmented by using AutodeskNetfabb software, and is set to have a layer thickness of 0.03mm, to obtain data recognizable by a 3D printer; A6, the bioceramic slurry obtained in step A4 is used as raw material, and a 3D printer based on DLP technology is used for printing to obtain a bionic scaffold customization green body; The setting parameters of the 3D printer are as follows: power density 1mW / cm 2 , exposure time 10s; A7, the obtained biomimetic bone scaffold custom body (hydroxyapatite content is 100%) is obtained by sintering after the biomimetic scaffold custom body obtained in step A6 is washed and dried; The sintering parameter conditions are as follows: the highest sintering temperature is 1150℃, and the holding time is 60min.

[0045] Example 2 The embodiment provides a biomimetic bone scaffold custom body and a preparation method thereof, and the preparation method is similar to that in Example 1, and the difference is as follows: In step A2, the inner contour in the digital scaffold model is based on the cortical bone trabecular structure of the jaw bone data; In step A4, the bioceramic system is mixed with the photocuring system, mechanically ground and dispersed to obtain a bioceramic slurry; the bioceramic system is zirconium oxide and hydroxyapatite, and the mass ratio of the zirconium oxide and the hydroxyapatite is zirconium oxide:hydroxyapatite = 15:85; In step A5, the thickness of each layer is 0.05mm; In step A6, the setting parameters of the 3D printer are as follows: the power density is 2mW / cm 2 , the exposure time is 10s; In step A7, the sintering parameter conditions are as follows: the highest sintering temperature is 1200℃, and the holding time is 60min.

[0046] Example 3 The embodiment provides a biomimetic bone scaffold custom body and a preparation method thereof, and the preparation method is similar to that in Example 1, and the difference is as follows: In step A2, the inner contour in the digital scaffold model is based on the cortical bone trabecular structure of the jaw bone data; In step A4, the bioceramic system is mixed with the photocuring system, mechanically ground and dispersed to obtain a bioceramic slurry; the bioceramic system is zirconium oxide and hydroxyapatite, and the mass ratio of the zirconium oxide and the hydroxyapatite is zirconium oxide:hydroxyapatite = 15:85; In step A5, the thickness of each layer is 0.05mm; In step A6, the setting parameters of the 3D printer are as follows: the power density is 2mW / cm 2 , the exposure time is 10s; In step A7, the sintering parameter conditions are as follows: the highest sintering temperature is 1200℃, and the holding time is 60min.

[0047] Example 4 The embodiment provides a biomimetic bone scaffold custom body and a preparation method thereof, and the preparation method is similar to that in Example 3, and the difference is as follows: In step A2, the inner contour in the digitalized scaffold model is based on the trabecular structure of the jawbone data; The surface of the biomimetic bone scaffold customization body obtained in step A7 is coated with a hydrogel coating, and the specific operation is as follows: A8, a 5wt% gelatin hydrogel prepolymer solution is prepared, and the biomimetic bone scaffold customization body obtained in step A7 is immersed in the 5wt% gelatin hydrogel prepolymer solution, vacuum treatment for 1min, and the biomimetic bone scaffold customization body is taken out and crosslinked in a room temperature environment to obtain a biomimetic bone scaffold customization body coated with a hydrogel coating. The 5wt% gelatin hydrogel prepolymer solution contains 5wt% gelatin, 8mM genipin and 0.1wt% extracellular vesicles derived from bone marrow mesenchymal stem cells.

[0048] Example 5 This example provides a biomimetic bone scaffold customization body and a preparation method thereof, and the preparation method is similar to that of Example 1, and the difference is as follows: In step A1, the construction of the rat skull bone defect model is replaced by real human bone defect data; In step A2, the inner contour in the digitalized scaffold model conforms to the biomimetic pore structure and biomechanical support required for the regenerated scaffold; The remaining steps and parameter conditions are unchanged.

[0049] Example 6 This example provides a biomimetic bone scaffold customization body and a preparation method thereof, and the preparation method is similar to that of Example 1, and the difference is as follows: In step A6, the setting parameters of the 3D printer are as follows: power density 3mW / cm 2 , exposure time 45s; In step A7, the sintering parameter conditions are as follows: the highest sintering temperature is 800℃, and the holding time is 180min.

[0050] Comparative Example 1 This comparative example provides a biomimetic bone scaffold customization body and a preparation method thereof, and the preparation method is similar to that of Example 1, and the difference is as follows: In step A2, the inner contour in the digitalized scaffold model is based on the outer contour structure of the jawbone data, without biomimetic pore structure, and the structure of the inner contour and the outer contour is the same, and the remaining steps and parameters are unchanged.

[0051] Comparative Example 2 This comparative example provides a biomimetic bone scaffold customization body and a preparation method thereof, and the preparation method is similar to that of Example 1, and the difference is as follows: In step A1, the rat skull bone defect model was replaced by the beagle box defect model. Specifically, after the P3 to M2 teeth of the beagle mandible were removed and healed for 2 months, a 9×8×4mm defect was prepared in the extraction area. In step A2, the inner contour of the digital scaffold model conforms to the biomimetic pore structure and biomechanical support required for the regenerative scaffold; In step A5, each layer is 0.05 mm thick; In step A6, the 3D printer settings are as follows: power density 1 mW / cm³. 2 Exposure time: 100 seconds; The remaining steps and parameters remain unchanged.

[0052] The biomimetic bone scaffold custom-made body prepared above was subjected to CT scanning, and the results are as follows: Figure 2 As shown, if the exposure time is not appropriate, the prepared custom body cannot reproduce the level of detail in the design file. Although the general structure is the same, the pore size and pore structure are quite different from the design file. Therefore, specific parameter settings are required to convert the design data into an ideal physical object.

[0053] Comparative Example 3 This comparative example provides a customized biomimetic bone scaffold and its preparation method. The preparation method is similar to that of Example 1, with the following differences: In step A1, the construction of a rat skull bone defect model is replaced by the construction of a rabbit skull bone defect model. Specifically, the operation is as follows: At the midline of the skull, an incision is made from the nasal bone to the occipital bone to the periosteum. The periosteum is then dissected, revealing that the coronal and sagittal sutures divide the skull into four regions. Circular full-thickness bone defects with a diameter of 8 mm are prepared in each region. In step A2, the inner contour of the digital scaffold model conforms to the biomimetic pore structure and biomechanical support required for the regenerative scaffold; In step A6, the 3D printer settings are as follows: power density 1 mW / cm³. 2 Exposure time: 100 seconds; In step A7, the sintering parameters are as follows: maximum sintering temperature 700℃; The remaining steps and parameters remain unchanged.

[0054] like Figure 3 As shown, the bionic bone scaffold custom-made body prepared in Comparative Example 3 has low strength, and some structures fall off or are damaged after printing, failing to maintain the structure corresponding to the design file and failing to achieve the expected results. This demonstrates that only within specific 3D printing and sintering parameter ranges can the design file be well reproduced to prepare a bionic bone scaffold custom-made body with ideal strength, complete structure, fitting of damaged areas, and fine substructure.

[0055] Effect Example 1 The biomimetic bone scaffold customization bodies of Examples 1-6 were tested to be blank controls for the rat skull implanted with the scaffold, and the specific scheme is as follows: 1. The data (design file) of the biomimetic bone scaffold customization body obtained in Example 1-3 step A3 was compared with the actual biomimetic bone scaffold customization body corresponding thereto, as shown in Figure 4 , Example 1 has a trabecular-like biomimetic structure, Example 2 has a cortical bone-trabecular-like biomimetic structure, and Example 3 has a cortical bone-like biomimetic structure, and the outer contours of all of them fit the rat skull defect area and meet the ideal regeneration form.

[0056] 2. The data of the biomimetic bone scaffold customization body obtained in Example 5 A3 was compared with the bone defect form, as shown in Figure 5 , the designed biomimetic bone scaffold customization body has high fit degree with the bone defect form, and the inner contour of the biomimetic bone scaffold customization body has a cortical bone-trabecular-like biomimetic structure from the three views of the data, which meets the individualized demand and has good mechanical properties.

[0057] 3. The biomimetic bone scaffold customization bodies obtained in Example 1 and Example 6 (surface and cross section) were observed by scanning electron microscopy, as shown in Figure 6 , the hydroxyapatite crystals on the surfaces of the biomimetic bone scaffold customization bodies obtained in Example 1 and Example 6 can be seen, micropores are formed on the surfaces, and different sintering parameter conditions will cause certain changes in the structure of the micropores.

[0058] 4. The comparative example 1 and comparative example 2 printed after adjusting the printing parameters and sintering parameters cannot realize the manufacture of the fine structure inside the design file, and the outer contour of comparative example 2 is damaged.

[0059] The above results show that the biomimetic bone scaffold customization body of the present application better reproduces the details of the design file, has high coincidence degree with the corresponding bone defect part and good mechanical properties, and can realize individualized customization of the biomimetic bone scaffold customization body adapted to the bone defect site.

[0060] Effect Example 2 The biomimetic bone scaffold customization bodies obtained in Examples 1 and 4 were implanted into the rat skull defect, with the rat skull defect model as a blank control and comparative example 1 of a regular bone scaffold without a biomimetic inner contour as a control group (the bone scaffold does not have fine substructures such as cortical bone and trabecula), and the skull was sampled and sectioned after 4 weeks, and the results were observed and quantified by HE staining, as shown in Figures 7-8 .

[0061] As shown in Figures 5-6As shown, the bionic bone scaffold custom body obtained in Example 1 and Example 4 maintained stable trabecular structure in vivo in rats, contacted with the bone section of the defect edge, and new bone deposition was visible (P < 0.05) Figure 6 The NB label in the middle) was deposited, the defect center maintained a good bone regeneration profile, and new bone deposition was also visible inside the scaffold, and the new bone volume was significantly improved compared with the blank group and the control group, indicating that the bionic bone scaffold custom body of the application can better maintain the stability of the defect site and promote bone regeneration at the defect site.

[0062] The bionic bone scaffold custom body in vivo in the rats in Example 1 was removed and subjected to CT scanning, and the data obtained by scanning was compared with the data of the bionic bone scaffold custom body obtained in Example 1, as shown in Figure 9 As shown, the morphology and structure of the bionic bone scaffold custom body obtained in Example 1 differed from the data of the bionic bone scaffold custom body by <0.1 mm, and the root mean square (RMS) was 0.190 ± 0.007 mm (x ± SD), which was likely to be caused by new bone production when the bionic bone scaffold custom body was in vivo in rats, indicating that the bionic bone scaffold custom body in Example 1 could maintain the basic structure of the scaffold design based on the real jawbone in vivo.

[0063] In summary, the bionic bone scaffold custom body of the application can effectively maintain the structure and profile of the bone scaffold, guide tissue regeneration, and achieve personalized morphological reconstruction of craniofacial tissues.

[0064] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the application and not to limit the protection scope of the application. Although the application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the application can be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the application.

Claims

1. A method for preparing a biomimetic bone scaffold, characterized in that, Includes the following steps: S1. Scan and record the morphology of craniofacial hard tissue defects. Based on the recorded data of craniofacial hard tissue defect morphology, construct a digital scaffold model through algorithm model and / or manual design. S2. Reconstruct the digital scaffold model obtained in step S1 in three dimensions to generate bionic bone scaffold customized body data that meets the personalized needs of craniofacial tissue defects. S3. Using DLP 3D printing technology, the data of the customized bionic bone scaffold obtained in step S2 is converted into a physical object, which is the customized bionic bone scaffold.

2. The preparation method according to claim 1, characterized in that, In step S1, the digital scaffold model meets at least one of the following conditions (1) to (3): (1) The outer contour of the digital scaffold model is close to the bone defect side and fits the defect shape, with a gap of no more than 0.5 mm; (2) The digital scaffold model restores a suitable bone morphology on the side away from the bone defect, and the surface overlap of the bone morphology with the bone of the same name without defect or the ideal implant bone morphology is ≥90%. (3) The volume difference between the inner contour of the digital scaffold model and the bone of the same location without defects is ≤50%.

3. The preparation method according to claim 1, characterized in that, In step S3, the DLP 3D printing technology mainly includes the following operations: (a) Convert the bionic bone scaffold customized body data obtained in step S2 into data that can be recognized by a 3D printer; (b) Using bioceramic slurry as raw material, a biomimetic bone scaffold customized body blank was obtained by printing using a 3D printer based on DLP technology; (c) The biomimetic bone scaffold custom body obtained in step (b) is washed, dried and then sintered to obtain the biomimetic bone scaffold custom body.

4. The preparation method according to claim 3, characterized in that, In step (a), the bionic bone scaffold customized body data obtained in step S2 is segmented using AutodeskNetfabb or FlashDLPrint software and exported as data recognizable by a 3D printer.

5. The preparation method according to claim 3, characterized in that, In step (b), the bioceramic slurry includes a bioceramic system and a photocuring system.

6. The preparation method according to claim 3, characterized in that, Includes at least one of the following (Ⅰ) to (Ⅱ): (I) In step (b), the bioceramic system in the bioceramic slurry includes at least one of hydroxyapatite, zirconium oxide and barium titanate; (II) In step (b), the photocuring system in the bioceramic slurry includes a photocurable polymer resin, an initiator, and a dispersant.

7. The preparation method according to claim 3, characterized in that, Includes at least one of the following (III) to (IV): (III) In step (b), the power density of the 3D printer is 0.1-50 mW / cm². 2 (IV) In step (c), the sintering parameters are as follows: the maximum temperature is 800-2000℃ and the holding time is 10-300min.

8. The preparation method according to claim 1, characterized in that, The method for preparing the biomimetic bone scaffold also includes the following steps: S4. The biomimetic bone scaffold customized body obtained in step S3 is immersed in a hydrogel prepolymer solution, vacuum treated, removed and drained to obtain a biomodified biomimetic bone scaffold customized body.

9. A custom-made biomimetic bone scaffold, characterized in that, It is mainly prepared by the preparation method described in any one of claims 1-8.

10. The application of the biomimetic bone scaffold custom body as described in claim 9 in the preparation of regenerative materials for reconstructing craniofacial bones and / or composite tissue defects.

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