新型多孔磷酸钙陶瓷支架构建及其体内培育大尺寸活体骨修复体
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摘要
骨缺损是临床骨科最常见的病症之一,可由于感染、外伤、肿瘤和先天性疾病等造成,大部分骨缺损,特别是大尺寸骨缺损不能自愈而需要进行骨移植。然而各种活体骨移植都存在许多问题,如自体骨移植虽然是最理想的修复效果,但常常需要附加手术切口,可能引起诸如疼痛、出血、感染、局部麻木和破坏组织结构的完整性等缺点,而且自体骨的供给量也非常有限；异体和异种骨移植不仅存在免疫反应和感染疾病的危险,而且比自体骨的成骨能力差,所以对硬组织修复材料及新的修复方式和途径的研究探索也成为骨修复研究领域热点之一。
随着细胞生物学、分子生物学、材料科学及相关物理化学学科的发展,人们提出了组织工程概念,即应用生命科学与工程学原理及方法构建功能性的活体组织,以恢复受损组织或器官的功能。组织工程骨构建可分为体外和体内两种培育方式,但迄今为止,大量的研究结果表明,体外构建的组织工程骨在临床应用上还存在许多限制和问题,如由于体内外环境的巨大差异导致体外培养的细胞在植入体内后存活率较低、大尺寸组织工程骨的血管化问题、临床应用时限要求及活体器件的保存运输等一系列亟需解决的问题而现在尚无完善的解决方案。
本研究提出体内构建大尺寸(Φ1～1.5x3～4cm)组织工程骨,不仅要求支架材料具有良好的贯通性和孔径大小及孔级配,而且要求种子细胞和生物信号分子易于与支架进行均匀的复合,以利于新生组织及血管在支架内部形成和生长,保证大段组织工程骨的整体一致性。因此,我们创新地采用多孔生物陶瓷球形颗粒堆积的方式,构建大尺寸多孔支架。在这种构建方式中,球形颗粒堆积所产生的孔隙100%的相互连通,孔隙大小和孔隙率可以通过改变球粒的大小来控制,而且具备与生物活性物质均匀混合的能力。随后,将支架植入犬腹腔大网膜、壁层腹膜、肌肉和股骨旁4个非骨部位体,利用体内的自然生长环境构建具有生物结构和功能的活体组织。组织学分析结果显示,新型支架在未添加任何生物活性物质的前提下,在体内具有较强的异位成骨能力。除腹腔大网膜组的新生血管和新生骨相对较少外,壁层腹膜、股骨旁骨膜和肌肉的支架内毛细血管、骨样组织生长丰富,且新生血管与新生骨之间呈正相关。结果显示其它研究中关注较少的壁层腹膜因其分布量大、延展性强,材料受压程度小等特点可作为体内培育大块组织工程骨的优选种植部位。通过本研究,不仅能实现在生物材料中构建生物结构和功能,了解体内不同培育部位骨组织在新型支架中的生长情况,而且为临床提供了一类可择期应用的活体替换材料,在骨组织缺损修复应用中具有突出的意义。
In clinic, it is difficult to repair the massive bone defect. Autografts and allografts are applied to solve this problem, but autografts are limited due to donor bone supply, the second surgery and the resorption during healing while allografts have to face the risks such as the potential immune rejection and pathogen transfer. The disadvantages of autografts or allografts prompt the development of reconstructing tissues or organs by means of artificial substitutes.
Tissue engineering applies methods of materials engineering and life sciences to develop, design and reconstruct a substitute with similar morphology and function for implantation in the injured tissues to accomplish tissue repair. The process of tissue engineering is simply described:"a three-dimensional (3D) scaffold attached specific cells is cultured in vitro or in vivo for a certain period, subsequently delivered to the desired site for the purpose of tissue repair". In many experiments of reconstructing tissue engineered bone in vitro, specially in cultivating large tissue engineered bone, the currently used bone substitutes still face many unsolved problems including incomplete formation of new bone tissue, failure of neovascularization, and slow growth of the capillary network. Some researches reported the livability and quality of large tissue engineered bone would be improved with the betterment of the uniformity of biological substance and scaffold. Therefore, apart from the tailored porosity and pore structure, the scaffolds must possess the capability of improving the uniformity of biological substance such as seeded cells or growth factors inside scaffolds.
In this study, a novel scaffold with large size and controlled porous structure was designed for the aim of massive tissue engineered bone in vivo. It was composed of HA spherulites and porous HA tube coated with poly (L-lactic acid) (PLA). Taking advantage of this design, HA spherulites can easily compound with biological substance before being filled into the HA tubes. This kind of pre-compounding manner can improve the uniformity of biological substance within the scaffold to promote the formation of new tissue and neovasculariztion in large volume of engineered bone. The novel scaffolds, in subsequent experiment, were cultured in vivo in the non-repairing sites such as muscle, femur bone side, peritoneum and canine abdominal omentum to construct the real living tissue by use of the nature environment in body which can provide the abundant substances needed for the growth of tissue including cells, nourishements, enzymes and biomolecular signals. The resluts displayed, after 6 months, the rich ingrowth of capillary blood vessel and bone tissue was found in scaffolds planted in the retroperitoneal group, femoral periosteum group and muscle group. Neovascularization and new bone were less than the other three groups significantly in intra-abdominal omental group. At the same time, the results also showed that peritoneal can be used as the better target site for bone tissue engineering in vivo.
随着细胞生物学、分子生物学、材料科学及相关物理化学学科的发展,人们提出了组织工程概念,即应用生命科学与工程学原理及方法构建功能性的活体组织,以恢复受损组织或器官的功能。组织工程骨构建可分为体外和体内两种培育方式,但迄今为止,大量的研究结果表明,体外构建的组织工程骨在临床应用上还存在许多限制和问题,如由于体内外环境的巨大差异导致体外培养的细胞在植入体内后存活率较低、大尺寸组织工程骨的血管化问题、临床应用时限要求及活体器件的保存运输等一系列亟需解决的问题而现在尚无完善的解决方案。
本研究提出体内构建大尺寸(Φ1～1.5x3～4cm)组织工程骨,不仅要求支架材料具有良好的贯通性和孔径大小及孔级配,而且要求种子细胞和生物信号分子易于与支架进行均匀的复合,以利于新生组织及血管在支架内部形成和生长,保证大段组织工程骨的整体一致性。因此,我们创新地采用多孔生物陶瓷球形颗粒堆积的方式,构建大尺寸多孔支架。在这种构建方式中,球形颗粒堆积所产生的孔隙100%的相互连通,孔隙大小和孔隙率可以通过改变球粒的大小来控制,而且具备与生物活性物质均匀混合的能力。随后,将支架植入犬腹腔大网膜、壁层腹膜、肌肉和股骨旁4个非骨部位体,利用体内的自然生长环境构建具有生物结构和功能的活体组织。组织学分析结果显示,新型支架在未添加任何生物活性物质的前提下,在体内具有较强的异位成骨能力。除腹腔大网膜组的新生血管和新生骨相对较少外,壁层腹膜、股骨旁骨膜和肌肉的支架内毛细血管、骨样组织生长丰富,且新生血管与新生骨之间呈正相关。结果显示其它研究中关注较少的壁层腹膜因其分布量大、延展性强,材料受压程度小等特点可作为体内培育大块组织工程骨的优选种植部位。通过本研究,不仅能实现在生物材料中构建生物结构和功能,了解体内不同培育部位骨组织在新型支架中的生长情况,而且为临床提供了一类可择期应用的活体替换材料,在骨组织缺损修复应用中具有突出的意义。
In clinic, it is difficult to repair the massive bone defect. Autografts and allografts are applied to solve this problem, but autografts are limited due to donor bone supply, the second surgery and the resorption during healing while allografts have to face the risks such as the potential immune rejection and pathogen transfer. The disadvantages of autografts or allografts prompt the development of reconstructing tissues or organs by means of artificial substitutes.
Tissue engineering applies methods of materials engineering and life sciences to develop, design and reconstruct a substitute with similar morphology and function for implantation in the injured tissues to accomplish tissue repair. The process of tissue engineering is simply described:"a three-dimensional (3D) scaffold attached specific cells is cultured in vitro or in vivo for a certain period, subsequently delivered to the desired site for the purpose of tissue repair". In many experiments of reconstructing tissue engineered bone in vitro, specially in cultivating large tissue engineered bone, the currently used bone substitutes still face many unsolved problems including incomplete formation of new bone tissue, failure of neovascularization, and slow growth of the capillary network. Some researches reported the livability and quality of large tissue engineered bone would be improved with the betterment of the uniformity of biological substance and scaffold. Therefore, apart from the tailored porosity and pore structure, the scaffolds must possess the capability of improving the uniformity of biological substance such as seeded cells or growth factors inside scaffolds.
In this study, a novel scaffold with large size and controlled porous structure was designed for the aim of massive tissue engineered bone in vivo. It was composed of HA spherulites and porous HA tube coated with poly (L-lactic acid) (PLA). Taking advantage of this design, HA spherulites can easily compound with biological substance before being filled into the HA tubes. This kind of pre-compounding manner can improve the uniformity of biological substance within the scaffold to promote the formation of new tissue and neovasculariztion in large volume of engineered bone. The novel scaffolds, in subsequent experiment, were cultured in vivo in the non-repairing sites such as muscle, femur bone side, peritoneum and canine abdominal omentum to construct the real living tissue by use of the nature environment in body which can provide the abundant substances needed for the growth of tissue including cells, nourishements, enzymes and biomolecular signals. The resluts displayed, after 6 months, the rich ingrowth of capillary blood vessel and bone tissue was found in scaffolds planted in the retroperitoneal group, femoral periosteum group and muscle group. Neovascularization and new bone were less than the other three groups significantly in intra-abdominal omental group. At the same time, the results also showed that peritoneal can be used as the better target site for bone tissue engineering in vivo.
引文
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