复合BMSCs包芯结构骨支架材料修复兔桡骨骨缺损的实验研究
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摘要
骨科临床上造成大段骨缺损的疾病非常常见，例如：严重的创伤、骨质疏松病人的骨折、肿瘤、肌肉骨骼系统的先天性畸形等。治疗上述疾病需要切除病损的骨质，必然导致骨的大段缺损，骨缺损后的重建问题成为治疗的最大挑战。近些年，骨组织工程不断取得突破性进展，逐渐成为治疗大段骨缺损最有前景的方法。骨组织工程主要包括3个主要因素，其中骨支架材料作为种子细胞和活性因子的载体，为新生骨的生成提供支撑，成为骨组织工程最关键的一个因素。合适的结构和物理性能以及良好的生物相容性是作为理想的骨支架材料两个最重要的要求：作为临时的支撑结构，骨支架材料决定新生骨最终的生成形状，并影响复合在支架材料上的细胞间的相互作用，支架材料表面的亲水性和粗糙程度等不同，在其表面生长的细胞也会表现出不同的生物活性。
在以前的研究中，通过低温成型技术，我们已经制备出具有三维结构的PLGA/β-TCP复合支架材料，而且通过体内和体外实验均已经证实PLGA/β-TCP复合支架材料具有良好的加工和成型特性、较高的空隙率、良好的机械强度和合适的降解速度，能够满足骨组织工程理想支架材料的要求。但是，PLGA/β-TCP复合支架材料表面具有强烈的疏水性，不利于细胞的粘附、增殖和成骨分化，大大影响了其作为支架材料的修复能力。支架材料具有较好的亲水性和良好的生物相容性，不但可以确保细胞在支架材料表面的粘附、增殖和分化，而且能够促进氧气和细胞必须的营养物质顺利进入支架材料，这对于骨缺损的成功修复至关重要。因此，为了使PLGA/β-TCP复合支架材料更适合细胞的粘附、增殖和分化，改变材料的表面特性非常重要。
研究证实，多孔支架材料表面覆盖一层胶原以后，材料的吸水率会得到有效提高，而且有研究表明，骨髓基质干细胞如果在I型胶原上培养，其粘附、增殖和成骨分化能力也会得到显著提高。基于以上原因，我们制备出了内PLGA/β-TCP外I型胶原的包芯结构骨支架材料，此材料内层为PLGA/β-TCP复合支架材料，在其表面覆盖一层I型胶原。本实验主要包括以下几部分的研究：
1基于仿生学原理，模拟人体骨组织真实结构，结合低温沉积技术，构建仿生结构组织工程骨构建修复方案，开发可控的环形套管喷头，通过快速成型的方法，制造出所需的材料、结构、细胞分布高度仿生的复杂的三维结构骨支架-包芯结构骨支架材料。
2以PLGA/β-TCP复合支架材料作为对照组，通过体外和骨髓基质干细胞（BMSCs）共培养的观察实验，对包芯结构骨支架材料的物理性能和生物相容性进行评价。外观形态通过扫描电镜观测；物理性能通过如下指标测定：孔隙率、孔径、压缩强度和杨氏模量；亲水性通过吸水率评价；骨髓基质干细胞在支架材料上的粘附率通过细胞计数测定，增殖率通过MTT方法测定，成骨能力通过碱性磷酸酶活性的检测进行评价；细胞在支架材料上的生长情况通过扫描电镜观测；实验结果证实，包芯结构骨支架材料和对照组都有良好的物理性能，包芯结构骨支架材料的亲水性较对照组显著提高(p<0.01)，细胞在包芯结构骨支架材料上的粘附、增值及成骨分化能力明显优于(p<0.05)对照组。
3兔桡骨大段骨缺损修复实验：把各组支架材料和骨髓基质干细胞复合，随后植入到兔桡骨大段骨缺损模型里进行兔桡骨骨缺损修复的对比研究。通过X线、MicroCT、组织学和荧光双标等方法观察支架材料的成骨情况、降解情况和修复兔桡骨大段骨缺损的情况；实验结果证实，48周后，包芯结构骨支架材料在骨缺损部位完全降解，骨塑型完成，成功修复了兔桡骨大段骨缺损，而且支架材料的降解速度和成骨速度匹配良好，相对于PLGA/β-TCP复合支架材料，包芯结构骨支架材料表现出更好的成骨活性和修复大段骨缺损的能力。
包芯结构骨支架材料具有良好的物理性能及生物相容性，在复合BMSCs的条件下，能很好的修复兔桡骨大段骨缺损，包芯结构骨支架材料作为骨组织工程理想的支架材料，具有良好的临床应用前景。
Large bone defects, such as acute injuries, fall fractures in osteoporotic patients, or tumors and congenital malformations of the musculoskeletal system, are very common in the clinical cases of orthopedics. It is necessary to resect the affected parts of the bone, which is a major therapeutic challenge for the reconstructive surgery after resection. Recently, great progress has been made in bone tissue engineering,which is promising for treatment of bone defects and bone regeneration. Scaffold is one of the critical elements, and it is generally acknowledged that appropriate physical structure and good biocompatibility are two important characteristics that are considered ideal for bone tissue engineering. The scaffold, as a temporary template or substrate, formulates the final shape of the new bone, and the architecture of the scaffold, a key property of the scaffolds, determines its interaction with the targeted cells. Target cells behave distinctively when they grow on different scaffolds.(hydrophilicity and surface roughness, etc.).
In the previous study, we had fabricated3-dimensional porous poly(lactic-co-glycolic acid)(PLGA)/β-tricalciumphosphate (β-TCP)(PLGA/β-TCP) scaffold via low-temperature deposition manufacturing (LDM). In vitro and in vivo experiments had proved that the scaffold had favourable mechanical strength, high pority ratio, adjustable biodegradation rate, and facility of process and molding, which satisfied the essential requirements of the scaffold for the bone tissue engineering. However, the hydrophobic surface of PLGA/β-TCP is not adequate for cell adhesion, proliferation and osteoblastic differentiation, which limited the repairing ability of the scaffold. Satisfactory hydrophilicity and favourable biocompatibility of the scaffold could guarantee the cells to adhere, proliferate and differentiate, and it also could promote infiltration of oxygen and nutritive material of the body fluid inside the scaffold, which is vital to the successful repair of bone defects. Therefore, it is important to modify the surface of the scaffold to achieve satisfied surface characteristics for cell adhesion, proliferation and differentiation.
Research proved that water-absorption ratio of the porous scaffold could be improved remarkably by covering the surface of the scaffold with collagen. Some studies reported that the adhesion, proliferation and the differentiation to osteoblast directionally of the bone marrow stromal cells (BMSCs) could be improved when the cells cultured on the Type Ⅰ collagen. For these reasons, we have fabricated the core-sheath structure composite scaffold composed of PLGA/β-TCP skeleton wrapped with Type Ⅰ collagen on the surface.
This research can be subdivided into the following3parts:
1. Preparation of the core-sheath structure composite scaffold. The core-sheath structure composite scaffold was a3-dimensional structural bone bracket stuff fabricated by a kind of controllable tachy-forming annulus drivepipe sprayer via LDM. Its materials and structure of the scaffold are fairly biomimetic, and the production of the scaffold is based on the bionic principle through simulating human bone actual architecture.
2. Examining the physical properties and the biocompatibility of the core-sheath structure composite scaffold in comparison with PLGA/β-TCP skeleton in vitro. Physical properties were evaluated by means of analyzing the pority ratio, aperture, compressive strength and Young's modulus. The morphology of the scaffolds and the BMSCs on the surfaces of the scaffolds were investigated by Scanning electron microscope (SEM). The hydrophilicity was assessed by means of water absorption, and the proliferation of the cells were assessed by3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay (MTT). The function of the differentiated BMSCs was monitored by measuring alkaline phosphates activity (ALP) of the cells. The results indicated that physical properties of the novel scaffold were as good as those of the control group, hydrophilicity was observably better (p<0.01) than that of control group, and abilities of proliferation and osteogenic differentiation of BMSCs on novel scaffold were significantly greater (p<0.05) than those of control group.
3. Study on treatment of bone defect of rabbit radius of the core-sheath structure composite scaffold in comparison with PLGA/β-TCP skeleton. BMSCs were seeded into each group of the composite scaffold in order to repair1.5cm segmental defect of the rabbit radius. The scaffolds'degradation rate and the new bone formation were evaluated by radiograph, Micro CT and histology. The results suggested that the core-sheath structure composite scaffold was degradated completely in bone defect position and bone remodeling was completed at the same time, and repaired the bone defect successfully in48weeks after postoperation, in addition, the new bone formation rate and the scaffolds'degradation rate was matching. The osteogenic capacity and the ability of repairing the bone defect of the novel scaffold were significantly greater than those of control group.
Our research has demonstrated that the core-sheath structure composite scaffold possesses preferable physical properties and biocompatibility, and can repair the bone defect successfully supplemented with bone marrow stromal cells, which suggests that the novel scaffold may act as an ideal implant into bone defect, and has high value in bone tissue engineering.
在以前的研究中，通过低温成型技术，我们已经制备出具有三维结构的PLGA/β-TCP复合支架材料，而且通过体内和体外实验均已经证实PLGA/β-TCP复合支架材料具有良好的加工和成型特性、较高的空隙率、良好的机械强度和合适的降解速度，能够满足骨组织工程理想支架材料的要求。但是，PLGA/β-TCP复合支架材料表面具有强烈的疏水性，不利于细胞的粘附、增殖和成骨分化，大大影响了其作为支架材料的修复能力。支架材料具有较好的亲水性和良好的生物相容性，不但可以确保细胞在支架材料表面的粘附、增殖和分化，而且能够促进氧气和细胞必须的营养物质顺利进入支架材料，这对于骨缺损的成功修复至关重要。因此，为了使PLGA/β-TCP复合支架材料更适合细胞的粘附、增殖和分化，改变材料的表面特性非常重要。
研究证实，多孔支架材料表面覆盖一层胶原以后，材料的吸水率会得到有效提高，而且有研究表明，骨髓基质干细胞如果在I型胶原上培养，其粘附、增殖和成骨分化能力也会得到显著提高。基于以上原因，我们制备出了内PLGA/β-TCP外I型胶原的包芯结构骨支架材料，此材料内层为PLGA/β-TCP复合支架材料，在其表面覆盖一层I型胶原。本实验主要包括以下几部分的研究：
1基于仿生学原理，模拟人体骨组织真实结构，结合低温沉积技术，构建仿生结构组织工程骨构建修复方案，开发可控的环形套管喷头，通过快速成型的方法，制造出所需的材料、结构、细胞分布高度仿生的复杂的三维结构骨支架-包芯结构骨支架材料。
2以PLGA/β-TCP复合支架材料作为对照组，通过体外和骨髓基质干细胞（BMSCs）共培养的观察实验，对包芯结构骨支架材料的物理性能和生物相容性进行评价。外观形态通过扫描电镜观测；物理性能通过如下指标测定：孔隙率、孔径、压缩强度和杨氏模量；亲水性通过吸水率评价；骨髓基质干细胞在支架材料上的粘附率通过细胞计数测定，增殖率通过MTT方法测定，成骨能力通过碱性磷酸酶活性的检测进行评价；细胞在支架材料上的生长情况通过扫描电镜观测；实验结果证实，包芯结构骨支架材料和对照组都有良好的物理性能，包芯结构骨支架材料的亲水性较对照组显著提高(p<0.01)，细胞在包芯结构骨支架材料上的粘附、增值及成骨分化能力明显优于(p<0.05)对照组。
3兔桡骨大段骨缺损修复实验：把各组支架材料和骨髓基质干细胞复合，随后植入到兔桡骨大段骨缺损模型里进行兔桡骨骨缺损修复的对比研究。通过X线、MicroCT、组织学和荧光双标等方法观察支架材料的成骨情况、降解情况和修复兔桡骨大段骨缺损的情况；实验结果证实，48周后，包芯结构骨支架材料在骨缺损部位完全降解，骨塑型完成，成功修复了兔桡骨大段骨缺损，而且支架材料的降解速度和成骨速度匹配良好，相对于PLGA/β-TCP复合支架材料，包芯结构骨支架材料表现出更好的成骨活性和修复大段骨缺损的能力。
包芯结构骨支架材料具有良好的物理性能及生物相容性，在复合BMSCs的条件下，能很好的修复兔桡骨大段骨缺损，包芯结构骨支架材料作为骨组织工程理想的支架材料，具有良好的临床应用前景。
Large bone defects, such as acute injuries, fall fractures in osteoporotic patients, or tumors and congenital malformations of the musculoskeletal system, are very common in the clinical cases of orthopedics. It is necessary to resect the affected parts of the bone, which is a major therapeutic challenge for the reconstructive surgery after resection. Recently, great progress has been made in bone tissue engineering,which is promising for treatment of bone defects and bone regeneration. Scaffold is one of the critical elements, and it is generally acknowledged that appropriate physical structure and good biocompatibility are two important characteristics that are considered ideal for bone tissue engineering. The scaffold, as a temporary template or substrate, formulates the final shape of the new bone, and the architecture of the scaffold, a key property of the scaffolds, determines its interaction with the targeted cells. Target cells behave distinctively when they grow on different scaffolds.(hydrophilicity and surface roughness, etc.).
In the previous study, we had fabricated3-dimensional porous poly(lactic-co-glycolic acid)(PLGA)/β-tricalciumphosphate (β-TCP)(PLGA/β-TCP) scaffold via low-temperature deposition manufacturing (LDM). In vitro and in vivo experiments had proved that the scaffold had favourable mechanical strength, high pority ratio, adjustable biodegradation rate, and facility of process and molding, which satisfied the essential requirements of the scaffold for the bone tissue engineering. However, the hydrophobic surface of PLGA/β-TCP is not adequate for cell adhesion, proliferation and osteoblastic differentiation, which limited the repairing ability of the scaffold. Satisfactory hydrophilicity and favourable biocompatibility of the scaffold could guarantee the cells to adhere, proliferate and differentiate, and it also could promote infiltration of oxygen and nutritive material of the body fluid inside the scaffold, which is vital to the successful repair of bone defects. Therefore, it is important to modify the surface of the scaffold to achieve satisfied surface characteristics for cell adhesion, proliferation and differentiation.
Research proved that water-absorption ratio of the porous scaffold could be improved remarkably by covering the surface of the scaffold with collagen. Some studies reported that the adhesion, proliferation and the differentiation to osteoblast directionally of the bone marrow stromal cells (BMSCs) could be improved when the cells cultured on the Type Ⅰ collagen. For these reasons, we have fabricated the core-sheath structure composite scaffold composed of PLGA/β-TCP skeleton wrapped with Type Ⅰ collagen on the surface.
This research can be subdivided into the following3parts:
1. Preparation of the core-sheath structure composite scaffold. The core-sheath structure composite scaffold was a3-dimensional structural bone bracket stuff fabricated by a kind of controllable tachy-forming annulus drivepipe sprayer via LDM. Its materials and structure of the scaffold are fairly biomimetic, and the production of the scaffold is based on the bionic principle through simulating human bone actual architecture.
2. Examining the physical properties and the biocompatibility of the core-sheath structure composite scaffold in comparison with PLGA/β-TCP skeleton in vitro. Physical properties were evaluated by means of analyzing the pority ratio, aperture, compressive strength and Young's modulus. The morphology of the scaffolds and the BMSCs on the surfaces of the scaffolds were investigated by Scanning electron microscope (SEM). The hydrophilicity was assessed by means of water absorption, and the proliferation of the cells were assessed by3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay (MTT). The function of the differentiated BMSCs was monitored by measuring alkaline phosphates activity (ALP) of the cells. The results indicated that physical properties of the novel scaffold were as good as those of the control group, hydrophilicity was observably better (p<0.01) than that of control group, and abilities of proliferation and osteogenic differentiation of BMSCs on novel scaffold were significantly greater (p<0.05) than those of control group.
3. Study on treatment of bone defect of rabbit radius of the core-sheath structure composite scaffold in comparison with PLGA/β-TCP skeleton. BMSCs were seeded into each group of the composite scaffold in order to repair1.5cm segmental defect of the rabbit radius. The scaffolds'degradation rate and the new bone formation were evaluated by radiograph, Micro CT and histology. The results suggested that the core-sheath structure composite scaffold was degradated completely in bone defect position and bone remodeling was completed at the same time, and repaired the bone defect successfully in48weeks after postoperation, in addition, the new bone formation rate and the scaffolds'degradation rate was matching. The osteogenic capacity and the ability of repairing the bone defect of the novel scaffold were significantly greater than those of control group.
Our research has demonstrated that the core-sheath structure composite scaffold possesses preferable physical properties and biocompatibility, and can repair the bone defect successfully supplemented with bone marrow stromal cells, which suggests that the novel scaffold may act as an ideal implant into bone defect, and has high value in bone tissue engineering.
引文
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