WO2022033260A1 - 适用于骨缺损及脊柱融合移植的植入材料、植入物及其制备方法 - Google Patents
适用于骨缺损及脊柱融合移植的植入材料、植入物及其制备方法 Download PDFInfo
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- WO2022033260A1 WO2022033260A1 PCT/CN2021/105956 CN2021105956W WO2022033260A1 WO 2022033260 A1 WO2022033260 A1 WO 2022033260A1 CN 2021105956 W CN2021105956 W CN 2021105956W WO 2022033260 A1 WO2022033260 A1 WO 2022033260A1
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- WIPO (PCT)
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- filling material
- implant
- bone defect
- spinal fusion
- mrna
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
- A61F2002/30667—Features concerning an interaction with the environment or a particular use of the prosthesis
- A61F2002/30677—Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2/3094—Designing or manufacturing processes
- A61F2002/30971—Laminates, i.e. layered products
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
- A61F2310/00005—The prosthesis being constructed from a particular material
- A61F2310/00011—Metals or alloys
- A61F2310/00023—Titanium or titanium-based alloys, e.g. Ti-Ni alloys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/258—Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Definitions
- the invention relates to the technical field of implants used in bone defect transplantation and spinal fusion surgery.
- the surgical implant materials used for bone defect transplantation and spinal fusion surgery usually use a hollow metal structure frame (titanium metal cage scaffold) to fill with autologous bone fragments or other allogeneic bone-forming materials, or directly use autologous or allogeneic bone blocks supplemented with Osteogenic material grafting fills the middle part of the defect with autologous bone fragments or other allogeneic osteogenic materials scattered during the operation.
- a hollow metal structure frame titanium metal cage scaffold
- the purpose of the present invention is to provide an implant suitable for bone defect and spinal fusion transplantation, which can adapt to the microenvironment of different regions of the injury site and adjust the repair process in an orderly manner.
- An implant material suitable for bone defect and spinal fusion transplantation characterized in that the implant material is used to fill the inner cavity of the titanium cage bracket or the bone defect site, which consists of an upper layer, a lower layer and a layer located between the upper layer and the lower layer.
- the middle layer is composed of an annular wrapping area located on the periphery and a central area located inside the annular wrapping area.
- the central area is filled with a first filling material, and the first filling material is a gel material containing pro-osteogenic effect.
- the annular encapsulation area is filled with a second filling material, and the second filling material is a gel material with the effect of regulating epigenetics; the upper and lower layers are filled with a third filling material, and the third filling material is a material that can regulate immune inflammation. and stress-responsive gel materials.
- the first filler material is composed of self-healing hydrogel-encapsulated bioglass loaded with chemotactic and osteogenic mRNA and miRNA.
- the chemotactic and osteopromoting mRNAs and miRNAs are MCP1 or IL8, or a mixture of both.
- the second filler material is coated with self-healing hydrogels loaded with mRNAs/proteins related to inflammation regulation and osteogenesis angiogenesis-related mRNAs and loaded with proteins.
- Active glass and nucleic acids loaded with epigenetic regulation related to osteogenesis signals. and protein molecules composed of nanoliposomes.
- the molecules loaded with mRNA/protein related to inflammation regulation and mRNA and protein related to osteogenesis and angiogenesis are selected from one or more of RUNX2, OSX, BMP2/7, TGFB1, FGF2 and VEGF;
- the bone signaling-related epigenetically regulated nucleic acid and protein molecules are selected from RNA-liposome complexes of one or more of miR424, miR146, and miR200a.
- the third filling material is composed of a self-healing hydrogel-wrapped bioglass loaded with mRNA/protein molecules related to hypoxic stress and inflammation regulation.
- mRNA/protein molecules associated with hypoxic stress and inflammatory regulation selected from one or a mixture of HIF-1 or timp1.
- the self-healing hydrogel contains 10%-15% by mass of gelatin methacrylate, 2%-8% by mass of oxidized dextran, 2.5%-10% by mass of gelatin, and 2.5%-10% by mass of gelatin. 0.1-0.5% photoinitiator Irgacure 2959.
- the second object of the present invention is to provide an implant suitable for bone defect and spinal fusion transplantation, which includes a titanium cage bracket and the implant material as described above filled in the cavity of the titanium cage.
- the third object of the present invention is to provide the above-mentioned preparation method of the implant material suitable for bone defect and spinal fusion transplantation.
- the present invention adopts the following technical solutions: a method for preparing an implant material suitable for bone defect and spinal fusion transplantation as described in any of the above, comprising the following steps:
- the invention designs a multi-layered area structure that can respond to the damage microenvironment and the bone repair process according to the mechanical characteristics of the bone defect site, and divides it into three different areas according to the area characteristics of the damage repair.
- the gel materials and functions in each area are different. .
- the bone defect and spinal fusion grafts can respond according to the different regional characteristics of the injury microenvironment, and respond to the cell migration in the bone tissue and the formation process of the new bone tissue through the spatial structure. Intelligent and precise regulation of bone tissue by biomaterials.
- Fig. 1 is a schematic diagram of the structure of the graft of the present invention.
- Figure 2 is a schematic diagram of the structure of a filler in an implant suitable for spinal fusion.
- Titanium cage stent 10 filler 20, upper layer 21, lower layer 22, annular wrapping area 23, central area 24
- the invention designs an implant material with a multi-layer zone structure that can respond to the damage microenvironment and the bone repair process according to the mechanical characteristics of the bone defect site.
- the implant material is used to fill the inner cavity of the titanium cage or the bone defect.
- As the most basic structure it consists of an upper layer, a lower layer and an intermediate layer between the upper layer and the lower layer.
- the annular wrapping area and the central area inside the annular wrapping area are formed, the central area is filled with a first filling material, and the first filling material is a gel material containing pro-osteogenic effect; the annular wrapping area is filled with a second filling material , the second filling material is a gel material with the effect of regulating epigenetics; the upper layer and the lower layer are filled with a third filling material, and the third filling material is a gel material with the effect of regulating immune inflammation and stress response.
- the first filling material, the second filling material and the third filling material are all wrapped in a packaging bag or a closed bottle.
- the volume sizes of the first filling material, the second filling material and the third filling material are set according to different types of titanium metal cages.
- the present invention can also be made into an integral implant comprising a titanium metal cage and an implant material.
- the implant suitable for bone defect and spinal fusion transplantation includes a titanium cage 10 and a filler 20 filled in the inner cavity of the titanium cage.
- the filler 20 consists of an upper layer 21 , the lower layer 22 and the middle layer between the upper layer and the lower layer, the middle layer is composed of an annular wrapping area 23 located on the periphery and a central area 24 located inside the annular wrapping area, and the central area is filled with the first filling material.
- the region is filled with the second filling material, and the upper and lower layers are filled with the third filling material.
- the upper/lower layer area is in contact with bone tissue, mainly responding to inflammatory response and stress regulation, and the middle annular area Encapsulated region 23 regulates osteogenesis epigenetically, and central region 24 increases chemotactic signals.
- the above function adjustment can be achieved separately in different regions through the difference of different gel components and the content of the package.
- Bioglass is loaded with pro-osteogenic factors and nucleic acid or protein molecules that regulate hypoxic stress and inflammatory response; nanoliposomes are loaded with nucleic acid and protein molecules that are epigenetically regulated related to osteogenic signals, and self-healing hydrogels are compatible with
- the loaded bioglass and nanoliposomes are mixed in proportion to form gel filling materials in different layers. The details are shown in Table 1 below.
- the manufacturing steps of the present invention are as follows:
- Nano liposomes are prepared, loaded with stress-regulated nucleic acid and protein particle structures (such as IL-10, HIF-1 ⁇ and other immunosuppressive factors, hypoxic stress regulators, and microRNA or mRNA with immune regulation).
- stress-regulated nucleic acid and protein particle structures such as IL-10, HIF-1 ⁇ and other immunosuppressive factors, hypoxic stress regulators, and microRNA or mRNA with immune regulation.
- only the first filling material and the third filling material can be selected to be injected.
- the repair can be divided into the proximal area of the bone tissue on both sides and the distal area of the bone tissue in the center. Because the proximal area is in direct contact with the bone tissue, the implant material immediately participates in the injury environment.
- the hypoxic stress response and migrating cells first responded to the early events of bone repair, while the center of the implant was the distal region of the bone tissue, and the migrating cells were subjected to more intense stress, so that the osteogenesis process was relatively delayed.
- Different injection sequences can be selected according to the different temporal and spatial characteristics of different osteogenic repair microenvironments.
- a third filler material that modulates immune inflammatory and stress responses is first injected into the proximal regions of the bone tissue, i.e. upper and lower layers, followed by a first filler material that mixes chemotactic and osteogenic mRNA/protein loaded bioglass It is injected into the central area of the inner cavity of the titanium metal cage, and finally the second filling material that modulates the epigenetic effect is injected to form an annular encapsulation area outside the first filling material.
- the second filling material can be injected into the titanium metal cage first to form the outer wrapping area, then the first filling material can be injected into the titanium metal cage to form the core of the bone-forming material in the central area, and finally the third filling material The material is injected into the areas where the upper and lower layers are in contact with the bone tissue.
- the injection filling may also be performed in the order of the first filling material, the second filling material and the third filling material.
- the self-healing performance design of the double-network hydrogel scaffold is used to realize the controllable adjustment of the microenvironment of the filling area to achieve the purpose of support and bone repair.
- the ingredients are: bioglass loaded with osteogenesis angiogenesis-related regulatory protein VEGF (10ng/ml) and cell chemotactic regulatory-related proteins such as MCP1 (2ng/ml).
- the ingredients are: methacrylic acid gelatin, oxidized dextran, gelatin, photoinitiator Irgacure 2959, respectively dissolved in PBS, mixed and stirred evenly, the final concentration ratio (w/v) is methacrylic acid gelatin 12%, oxidized glucose Polysaccharide 4%, gelatin 5%, photoinitiator 0.3%.
- the ingredients are: micro-nano bioactive glass loaded with mRNA of IL10 (2ng/ml) mRNA related to inflammation regulation, and RUNX2 (200 ⁇ g/ml), BMP2 (500 ⁇ g/ml) loaded with mRNA-loaded micro-nano bioactive glass related to osteogenesis and angiogenesis ml), TGFB1 (10 ⁇ g/ml), VEGF (100 ⁇ g/ml).
- the ingredients are: miR146 (200 ⁇ g/ml), which activates the osteogenic signaling pathway, forms a miRNA-liposome complex with nanoliposomes, and the outer layer is coated with 2% alginate gel.
- the ingredients are: methacrylic acid gelatin, oxidized dextran, gelatin, photoinitiator Irgacure 2959, respectively dissolved in PBS, mixed and stirred evenly, the final concentration ratio (w/v) is methacrylic acid gelatin 15%, oxidized dextran Polysaccharide 2%, gelatin 2.5%, photoinitiator 0.5%.
- step 2.4 Combine the bioglass prepared in step 2.1 with the nanoliposomes loaded with the basic structural unit of miRNA molecules prepared in step 2.2 and the self-healing hydrogel prepared in step 2.3 according to bioglass 10%, nanoliposome particles 1 % is mixed with the self-healing hydrogel to make the second filling material.
- the ingredients are: micro-nano bioactive glass loaded with hypoxic stress and inflammatory regulator HIF-1 (10 ng/ml).
- the ingredients are: methacrylic acid gelatin, oxidized dextran, gelatin, photoinitiator Irgacure 2959, respectively dissolved in PBS, mixed and stirred evenly, the final concentration ratio (w/v) is methacrylic acid gelatin 14%, oxidized glucose Polysaccharide 3%, gelatin 3.75%, photoinitiator 0.4%.
- step 3.3 The bioglass prepared in step 3.1 is uniformly mixed with the self-healing hydrogel prepared in step 3.2 in a proportion of 5% to prepare a third filling material.
- the first filler material namely the bioglass-loaded osteogenic mRNA mixed chemokine, is injected into the titanium metal cage to form the core of the osteogenic material in the central area.
- This example has the same partition form as Example 1, with different external shapes and different proportions of materials loaded in some regions. It is prepared as shown in FIG. 1 .
- the ingredients are: bioglass loaded with osteogenesis angiogenesis-related regulatory protein VEGF (10ng/ml) and cell chemotaxis regulatory-related proteins such as TIMP1 (2ng/ml).
- the ingredients are: methacrylic acid gelatin, oxidized dextran, gelatin, photoinitiator Irgacure 2959, respectively dissolved in PBS, mixed and stirred evenly, the final concentration ratio (w/v) is methacrylic acid gelatin 12%, oxidized glucose Polysaccharide 4%, gelatin 5%, photoinitiator 0.3%.
- the ingredients are: mRNA-loaded micro-nano bioactive glass for inflammation regulation-related factor IL10 (2ng/ml), and micro-nano bioactive glass OSX (200 ⁇ g/ml), BMP2 (500 ⁇ g/ml) loaded with mRNA related to osteogenesis and angiogenesis ml), VEGF (200 ⁇ g/ml).
- the ingredients are: miR424 (100 ⁇ g/ml), miR200a (200 ⁇ g/ml), which activate the osteogenic signaling pathway, and nanoliposomes to form miRNA-liposome complexes, and the outer layer is coated with 2% alginate gel.
- the ingredients are: methacrylic acid gelatin, oxidized dextran, gelatin, photoinitiator Irgacure 2959, respectively dissolved in PBS, mixed and stirred evenly, the final concentration ratio (w/v) is methacrylic acid gelatin 15%, oxidized dextran Polysaccharide 2%, gelatin 2.5%, photoinitiator 0.5%.
- bioglass prepared in step 2.1, the nanoliposomes loaded with the basic structural unit of miRNA molecules prepared in step 2.2, and the self-healing hydrogel prepared in step 2.3 were 15% bioglass and 0.1 nanolipid particles. % is mixed with the self-healing hydrogel to make the second filling material.
- the ingredients are: micro-nano bioactive glass loaded with hypoxic stress and inflammatory regulator HIF-1 (10 ng/ml).
- the ingredients are: methacrylic acid gelatin, oxidized dextran, gelatin, photoinitiator Irgacure 2959, respectively dissolved in PBS, mixed and stirred evenly, the final concentration ratio (w/v) is methacrylic acid gelatin 14%, oxidized glucose Polysaccharide 3%, gelatin 3.75%, photoinitiator 0.4%.
- step 3.3 The bioglass prepared in step 3.1 is uniformly mixed with the self-healing hydrogel prepared in step 3.2 in a proportion of 10% to prepare a third filling material.
- the third filling material ie, the hydrogel with 10% concentration of bioglass loaded with inflammatory immunomodulatory factors, into the contact area between the upper and lower layers and the bone tissue to form a complete graft material construction.
- the first filler material namely the bioglass-loaded osteogenic mRNA mixed chemokine, is injected into the titanium metal cage to form the core of the osteogenic material in the central area.
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Abstract
一种适用于骨缺损及脊柱融合移植的植入材料、植入物及制备方法，植入材料用于填充在钛金属笼体支架（10）内腔或骨缺损部位，其由上层（21）、下层（22）及位于上层（21）与下层（22）之间的中间层构成，中间层由位于外围的环形包裹区（23）及位于环形包裹区内部的中心区（24）构成，中心区（24）由第一填充材料填充而成，第一填充材料为含有促成骨作用的凝胶材料；环形包裹区（23）由第二填充材料填充而成，第二填充材料为具有调节表观遗传作用的凝胶材料；上层（21）及下层（22）由第三填充材料填充而成，第三填充材料为具有调节免疫炎症和应激反应作用的凝胶材料。植入物能适应损伤部位不同区域的微环境和有序调节修复过程，适用于骨缺损及脊柱融合移植。
Description
本发明涉及骨缺损移植及脊柱融合手术所采用的移植物技术领域。
目前用于骨缺损移植和脊柱融合手术的外科移植材料通常采用中空金属结构外框(钛金属笼体支架)填充自体碎骨组织或其他异体成骨材料，或直接采用自体或异体骨块辅以成骨材料移植填充缺损中间部分填充手术中分散的自体碎骨组织或其他异体成骨材料。近年来由于组织工程技术的进步，多种材料被用于骨缺损和脊柱融合手术的移植，包括羟基磷灰石、活性骨水泥等其他成分。
由于骨缺损和脊柱融合修复的过程需要针对复杂的损伤微环境进行精细调节，不同的材料应答损伤微环境的程度不同，对骨组织新生的效率也有很大的不同。现有的移植材料采用的多为整体结构，无区域化特征，难以适应损伤部位不同区域的微环境和有序调节修复过程，因此在促成骨效果上仍存在局限性。尤其是移植材料的中心区域，由于远离骨组织，缺少相应的成骨微环境，材料形成的低氧环境不利于成骨细胞迁移到中心区域定植并分化形成新生骨组织和相应的骨小梁结构，对于损伤部位微环境应答和成骨修复过程缺乏智能化的精细调节过程。
有鉴于此，有必要研发新的外科移植材料，能解决以上问题。
发明内容
本发明的目的在于提供一种能适应损伤部位不同区域的微环境和有序调节修复过程的适用于骨缺损及脊柱融合移植的植入物。
为了实现上述目的，本发明采用了以下技术方案：
一种适用于骨缺损及脊柱融合移植的植入材料，其特征在于所述植入材料用于填充在钛金属笼体支架内腔或骨缺损部位，其由上层、下层及位于上层与下层之间的中间层构成，中间层由位于外围的环形包裹区及位于环形包裹区内部的中心区构成，中心区由第一填充材料填充而成，第一填充材料为含有促成骨作用的凝胶材料；环形包裹区由第二填充材料填充而成，第二填充材料为具有调节表观遗传作用的凝胶材料；上层及下层由第三填充材料填充而成，第三填充材料为具有调节免疫炎症和应激反应作用的凝胶材料。
进一步地，第一填充材料由自修复水凝胶包裹负载有趋化作用和促成骨mRNA和miRNA的生物玻璃构成。
优选地，有趋化作用和促成骨mRNA和miRNA的为MCP1或IL8，或两者的混合。
进一步地，第二填充材料由自修复水凝胶包裹负载有炎症调节相关mRNA/蛋白以及成骨成血管相关的mRNA和负载蛋白活性玻璃和负载有与成骨信号相关的表观遗传调节的核酸和蛋白分子的纳米类脂体构成。
优选地，负载有炎症调节相关mRNA/蛋白以及成骨成血管相关的mRNA和蛋白分子选自RUNX2、OSX、BMP2/7、TGFB1、FGF2、VEGF之中的一种或多种的混合；与成骨信号相关的表观遗传调节的核酸和蛋白分子选自miR424、miR146、miR200a之中的一种或多种的RNA-类脂体复合体。
进一步地，第三填充材料由自修复水凝胶包裹负载有与低氧应激以及炎症调节相关的mRNA/蛋白分子的生物玻璃构成。
优选地，有与低氧应激以及炎症调节相关的mRNA/蛋白分子选自HIF-1或timp1之中的一种或它们的混合。
优选地，自修复水凝胶含量有质量份为10％-15％的甲基丙烯酸明胶、质量份为2％-8％的氧化葡聚糖、质量份为2.5％-10％的明胶、质量份为0.1-0.5％的光引发剂Irgacure 2959。
本发明的第二目的在于提供一种适用于骨缺损及脊柱融合移植的植入物，其包括钛金属笼体支架及填充于钛金属笼体内腔的如上任一所述的植入材料。
本发明的第三目的在于提供上述适用于骨缺损及脊柱融合移植的植入材料的制备方法。
为了实现这一目的，本发明采用了以下技术方案：一种如上任一所述的适用于骨缺损及脊柱融合移植的植入材料的制备方法，其括以下步骤：
(1)制备生物玻璃；
(2)制备纳米类脂体；
(3)制备自修复水凝胶；
(4)将自修复水凝胶与生物玻璃或将自修复水凝胶与生物玻璃及纳米类脂体颗粒混合，从而分别制得第一填充材料、第二填充材料和第三填充材料。
本发明根据骨缺损部位的机构特征设计能够响应损伤微环境和骨修复过程的多层区结构，按照损伤修复的区域特征分为三个不同的区域，每个区域中的凝胶材料、功能不同。利用不同区域材料的不同成分差异，使骨缺损和脊柱融合移植物能根据损伤微环境的不同区域特征分别产生响应，并通过空间结构来应对骨组织中细胞迁移和新生骨组织的形成过程，实现了生物材料对骨组织的智能化和精准化的调节。
图1是本发明的移植物结构示意图。
图2是适用于脊柱融合的植入物中填充物的结构示意图。
钛金属笼体支架10，填充物20，上层21，下层22，环形包裹区23，中心区24
本发明根据骨缺损部位的机构特征设计能够响应损伤微环境和骨修复过程的多层区结构的植入材料。所述植入材料用于填充在钛金属笼体支架内腔或骨缺损部位，作为最基本的结构，其由上层、下层及位于上层与下层之间的中间层构成，中间层由位于外围的环形包裹区及位于环形包裹区内部的中心区构成，中心区由第一填充材料填充而成，第一填充材料为含有促成骨作用的凝胶材料；环形包裹区由第二填充材料填充而成，第二填充材料为具有调节表观遗传作用的凝胶材料；上层及下层由第三填充材料填充而成，第三填充材料为具有调节免疫炎症和应激反应作用的凝胶材料。
考虑到实际应用的方便，第一填充材料、第二填充材料及第三填充材料均包裹于封装袋内或封闭瓶内。第一填充材料、第二填充材料及第三填充材料的体积大小根据不同型号的钛金属笼来设置。
考虑到使用的便捷性，本发明还可以制作成一种包含了钛金属笼与植入材料的整体性植入物。如图1所示的适用于骨缺损及脊柱融合移植的植入物，其包括钛金属笼体支架10及填充于钛金属笼体支架内腔的填充物20，所述填充物20由上层21、下层22及位于上层与下层之间的中间层构成，中间层由位于外围的环形包裹区23及位于环形包裹区内部的中心区24构成，中心区由第一填充材料填充而成，环形包裹区由第二填充材料填充而成，上层及下层由第三填充材料填充而成。
除了促成骨的基本功能外，上/下层、环形包裹区及中心区还存在其他功能上的差别，主要差别为：上/下层区与骨组织接触，主要应答炎症反应和应激调节，中间环形包裹区23通过表观遗传调节成骨，中心区24增加趋化信号。在不同的区域通过不同的凝胶成份及所包裹的内容物的差异，可以分别实现以上功能调节。
生物玻璃负载促成骨作用因子以及低氧应激和炎症反应调节作用的核酸或蛋白分子；纳米类脂体负载与成骨信号相关的表观遗传调节的核酸和蛋白分子，自修复水凝胶与结合有负载的生物玻璃和纳米类脂体按照比例混合形成不同层区的凝胶填充材料。具体如下表1。
表1
本发明的制作步骤如下：
1、制备生物玻璃,负载有促成骨作用的核酸或蛋白颗粒结构(如BMP-2等促成骨蛋白以及调节骨形成作用的microRNA或mRNA)。
2、制备纳米类脂体，负载有应激调节的核酸和蛋白颗粒结构(如IL-10、HIF-1α等免疫抑制因子和低氧应激调节因子以及具有免疫调节作用的microRNA或mRNA)。
3、制备自修复水凝胶，按表1中的比例准备好各配料，其中明胶和氧化葡聚糖先通过可逆的席夫碱反应形成可自动修复所受损伤的水凝胶，然后甲基丙烯酸明胶通过紫外光固化形成提升水凝胶机械强度的第二网络结构，最终制备形成具有较高机械强度的双网络 自修复水凝胶。
4、按照表1中的比例将自修复水凝胶与负载有核酸和蛋白颗粒的生物玻璃及纳米类脂体颗粒混合，从而分别制得第一填充材料、第二填充材料和第三填充材料。
5、通过注射方式将第一填充材料、第二填充材料及第三填充材料分别填充到对应的骨缺损区域；或待第一填充材料、第二填充材料和第三填充材料的自修复水凝胶冷冻干燥后将干燥后的填充体整体填充至脊柱融合的金属钛笼内或骨缺损部位，接触组织后吸水膨胀，紫外照射成型。
依据具体情况，对于某些情况下的骨缺损区域的修复，可以选择只注射第一填充材料和第三填充材料。
根据骨修复区域的微环境差异，可将修复区分为双侧的骨组织近端区域和中央的骨组织远端区域，近端区域由于直接与骨组织接触，植入材料第一时间参与损伤环境的低氧应激反应以及迁移细胞首先响应骨修复早期事件，而植入物的中央为骨组织远端区域，迁移细胞经受更为强烈应激，使成骨过程相对滞后。根据不同的成骨修复微环境的不同时间和空间特征，可以选择不同的注射顺序。例如，首先将调节免疫炎症和应激反应的第三填充材料注射至骨组织近端区域，即上层和下层，再将混合负载趋化作用和促成骨mRNA/蛋白的生物玻璃的第一填充材料注射到钛金属笼体内腔的中心区，最后调节表观遗传作用的第二填充材料注射在第一填充材料外形成环形包裹区。针对钛金属笼体，可以先将第二填充材料注射进入钛金属笼体形成外层包裹区，再将第一填充材料注射进入钛金属笼体形成中心区成骨材料核心，最后将第三填充材料注射至上层和下层与骨组织接触区域。在适用的情况下也可以是按照第一填充材料、第二填充材料和第三填充材料的顺序来进行注射填充。
利用双网络水凝胶支架的自修复性能设计，实现填充区域微环境可控调节以达到支撑与骨修复的目的。
实施例一
制备如图2所示的适用于脊柱融合植入的植入物中的填充物。
一、制备第一填充材料。
1.1通过核酸分子磷酸基团化学反应方法构建促成骨的生物玻璃负载蛋白分子。
配料为：成骨成血管相关调控蛋白VEGF(10ng/ml)以及细胞趋化调节相关蛋白如MCP1(2ng/ml)等装载的生物玻璃。
1.2制备gelMA的双网络自修复水凝胶体系。
配料为：甲基丙烯酸明胶、氧化葡聚糖、明胶、光引发剂Irgacure 2959，分别溶于PBS后混合搅拌均匀，是最终浓度配比(w/v)为甲基丙烯酸明胶12％、氧化葡聚糖4％、明胶5％、光引发剂0.3％。
1.3将步骤1.1制得的生物玻璃以10％浓度与步骤1.2制得的自修复水凝胶混合交联从而制得第一填充材料。
二、制备第二填充材料。
2.1通过核酸分子磷酸基团化学反应等方法构建促成骨的生物玻璃负载mRNA/蛋白分子。
配料为：炎症调节相关因子IL10(2ng/ml)mRNA装载的微纳米生物活性玻璃，并负载与成骨成血管相关的mRNA负载的微纳米生物活性玻璃RUNX2(200μg/ml)、BMP2(500μg/ml)，TGFB1(10μg/ml),VEGF(100μg/ml)。
2.2制备负载miRNA分子的基本结构单元的纳米类脂体，其外层包裹具有缓释效果的海藻酸盐水凝胶。
配料为：激活成骨信号通路的miR146(200μg/ml)与纳米类脂体形成miRNA-类脂体复合体，外层包裹2％海藻酸盐凝胶。
2.3制备gelMA的双网络自修复水凝胶体系。
配料为：甲基丙烯酸明胶、氧化葡聚糖、明胶、光引发剂Irgacure 2959，分别溶于PBS后混合搅拌均匀，是最终浓度配比(w/v)为甲基丙烯酸明胶15％、氧化葡聚糖2％、明胶2.5％、光引发剂0.5％。
2.4将步骤2.1制得的生物玻璃与步骤2.2制得的负载miRNA分子的基本结构单元的纳米类脂体及步骤2.3制得的自修复水凝胶按照生物玻璃10％，纳米类脂体颗粒1％的比例与自修复水凝胶混合，从而制得第二填充材料。
三、制备第三填充材料
3.1通过核酸分子磷酸基团化学反应方法构建促成骨的生物玻璃负载蛋白分子。
配料为：与低氧应激以及炎症调节因子HIF-1(10ng/ml)装载的微纳米生物活性玻璃。
3.2制备gelMA的双网络自修复水凝胶体系。
配料为：甲基丙烯酸明胶、氧化葡聚糖、明胶、光引发剂Irgacure 2959，分别溶于PBS后混合搅拌均匀，是最终浓度配比(w/v)为甲基丙烯酸明胶14％、氧化葡聚糖3％、明胶3.75％、光引发剂0.4％。
3.3将步骤3.1制得的生物玻璃按照5％比例与步骤3.2制得的自修复水凝胶均匀混合从而制得第三填充材料。
四、将第三填充材料，即5％浓度生物玻璃负载炎症免疫调节因子的水凝胶注射进入钛金属笼体上、下层与骨组织接触区域，形成完整的移植材料构建。
五、将第一填充材料，即生物玻璃负载促成骨mRNA混合趋化因子经双网络自修复水凝胶包裹形成的凝胶混合物注射进入钛金属笼体形成中心区成骨材料核心。
六、将第二填充材料，即生物玻璃负载促成骨mRNA结合表观遗传调控因子通过双网络自修复水凝胶形成的凝胶混合物注射进入钛金属笼体形成外层包裹区。
实施例二
制备适用于腰椎融合植入的填充物,其形状可采用图1所示的填充物形状。
本例与实施例一分区形式相同，外部形状不同，部分区域材料负载的成分比例不同，按照图1所示制备。
一、制备第一填充材料。
1.1通过核酸分子磷酸基团化学反应方法构建促成骨的生物玻璃负载蛋白分子。
配料为：成骨成血管相关调控蛋白VEGF(10ng/ml)以及细胞趋化调节相关蛋白如TIMP1(2ng/ml)等装载的生物玻璃。
1.2制备gelMA的双网络自修复水凝胶体系。
配料为：甲基丙烯酸明胶、氧化葡聚糖、明胶、光引发剂Irgacure 2959，分别溶于PBS后混合搅拌均匀，是最终浓度配比(w/v)为甲基丙烯酸明胶12％、氧化葡聚糖4％、明胶5％、光引发剂0.3％。
1.3将步骤1.1制得的生物玻璃以15％浓度与步骤1.2制得的自修复水凝胶混合交联从而制得第一填充材料。
二、制备第二填充材料。
2.1通过核酸分子磷酸基团化学反应等方法构建促成骨的生物玻璃负载mRNA/蛋白分子。
配料为：炎症调节相关因子IL10(2ng/ml)mRNA装载的微纳米生物活性玻璃，并负载与成骨成血管相关的mRNA负载的微纳米生物活性玻璃OSX(200μg/ml)、BMP2(500μg/ml)，VEGF(200μg/ml)。
2.2制备负载miRNA分子的基本结构单元的纳米类脂体，其外层包裹具有缓释效果的海藻酸盐水凝胶。
配料为：激活成骨信号通路的miR424(100μg/ml)、miR200a(200μg/ml)与纳米类脂体形成miRNA-类脂体复合体，外层包裹2％海藻酸盐凝胶。
2.3制备gelMA的双网络自修复水凝胶体系。
配料为：甲基丙烯酸明胶、氧化葡聚糖、明胶、光引发剂Irgacure 2959，分别溶于PBS后混合搅拌均匀，是最终浓度配比(w/v)为甲基丙烯酸明胶15％、氧化葡聚糖2％、明胶2.5％、光引发剂0.5％。
2.4将步骤2.1制得的生物玻璃与步骤2.2制得的负载miRNA分子的基本结构单元的纳米类脂体及步骤2.3制得的自修复水凝胶按照生物玻璃15％，纳米类脂体颗粒0.1％的比例与自修复水凝胶混合，从而制得第二填充材料。
三、制备第三填充材料
3.1通过核酸分子磷酸基团化学反应方法构建促成骨的生物玻璃负载蛋白分子。
配料为：与低氧应激以及炎症调节因子HIF-1(10ng/ml)装载的微纳米生物活性玻璃。
3.2制备gelMA的双网络自修复水凝胶体系。
配料为：甲基丙烯酸明胶、氧化葡聚糖、明胶、光引发剂Irgacure 2959，分别溶于PBS后混合搅拌均匀，是最终浓度配比(w/v)为甲基丙烯酸明胶14％、氧化葡聚糖3％、明胶3.75％、光引发剂0.4％。
3.3将步骤3.1制得的生物玻璃按照10％比例与步骤3.2制得的自修复水凝胶均匀混合从而制得第三填充材料。
四、将第三填充材料，即10％浓度生物玻璃负载炎症免疫调节因子的水凝胶注射进入上、下层与骨组织接触区域，形成完整的移植材料构建。
五、将第一填充材料，即生物玻璃负载促成骨mRNA混合趋化因子经双网络自修复水凝胶包裹形成的凝胶混合物注射进入钛金属笼体形成中心区成骨材料核心。
六、将第二填充材料，即生物玻璃负载促成骨mRNA结合表观遗传调控因子通过双网络自修复水凝胶形成的凝胶混合物注射进入钛金属笼体形成外层包裹区。
以上实施方式仅用于说明本发明，而并非对本发明的限制，有关技术领域的普通技术人员，在不脱离本发明的精神和范围的情况下，还可以做出各种变化和变型，因此所有等同的技术方案也属于本发明的范畴，本发明的专利保护范围应由权利要求限定。
Claims (10)
- 一种适用于骨缺损及脊柱融合移植的植入材料，其特征在于所述植入材料用于填充在钛金属笼体支架内腔或骨缺损部位，其由上层、下层及位于上层与下层之间的中间层构成，中间层由位于外围的环形包裹区及位于环形包裹区内部的中心区构成，中心区由第一填充材料填充而成，第一填充材料为含有促成骨作用的凝胶材料；环形包裹区由第二填充材料填充而成，第二填充材料为具有调节表观遗传作用的凝胶材料；上层及下层由第三填充材料填充而成，第三填充材料为具有调节免疫炎症和应激反应作用的凝胶材料。
- 根据权利要求1所述的适用于骨缺损及脊柱融合移植的植入材料，其特征在于：第一填充材料由自修复水凝胶包裹负载有趋化作用和促成骨mRNA和miRNA的生物玻璃构成。
- 根据权利要求2所述的适用于骨缺损及脊柱融合移植的植入物，其特征在于：有趋化作用和促成骨mRNA和miRNA的为MCP1或IL8，或两者的混合。
- 根据权利要求1所述的适用于骨缺损及脊柱融合移植的植入材料，其特征在于：第二填充材料由自修复水凝胶包裹负载有炎症调节相关mRNA/蛋白以及成骨成血管相关的mRNA和负载蛋白的活性玻璃和负载有与成骨信号相关的表观遗传调节的核酸和蛋白分子的纳米类脂体构成。
- 根据权利要求4所述的适用于骨缺损及脊柱融合移植的植入材料，其特征在于：负载有炎症调节相关mRNA/蛋白以及成骨成血管相关的mRNA和蛋白分子选自RUNX2、OSX、BMP2/7、TGFB1、FGF2、VEGF之中的一种或多种的混合；与成骨信号相关的表观遗传调节的核酸和蛋白分子选自miR424、miR146、miR200a之中的一种或多种的RNA-类脂体复合体。
- 根据权利要求1所述的适用于骨缺损及脊柱融合移植的植入材料，其特征在于：第三填充材料由自修复水凝胶包裹负载有与低氧应激以及炎症调节相关的mRNA/蛋白分子的生物玻璃构成。
- 根据权利要求6所述的适用于骨缺损及脊柱融合移植的植入材料，其特征在于：有与低氧应激以及炎症调节相关的mRNA/蛋白分子选自HIF-1或TIMP1或其他相关调节因子之中的一种或它们的混合。
- 根据权利要求1所述的适用于骨缺损及脊柱融合移植的植入材料，其特征在于：自修复水凝胶含量有质量份为10％-15％的甲基丙烯酸明胶、质量份为2％-8％的氧化葡聚糖、质量份为2.5％-10％的明胶、质量份为0.1-0.5％的光引发剂Irgacure 2959。
- 一种适用于骨缺损及脊柱融合移植的植入物，其特征在于：包括钛金属笼体支架及填充于钛金属笼体内腔的如权利要求1～8任一所述的植入材料。
- 一种如权利要求1～8任一所述的适用于骨缺损及脊柱融合移植的植入材料的制备方法，其特征在于包括以下步骤：(1)制备生物玻璃；(2)制备纳米类脂体；(3)制备自修复水凝胶；(4)将自修复水凝胶与生物玻璃或将自修复水凝胶与生物玻璃及纳米类脂体颗粒混合，从而分别制得第一填充材料、第二填充材料和第三填充材料。
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| CN212756629U (zh) * | 2020-08-13 | 2021-03-23 | 中山大学附属第一医院 | 适用于骨缺损及脊柱融合移植的植入物 |
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