骨修复药物控释微球支架的多级构建及干细胞介导分化研究
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摘要
可控的器官再生与功能重建是人类有史以来长期的梦想,组织工程的发展为这一梦想的最终实现提供了新的途径。组织工程支架是组织工程研究的重要构成部分,本文致力于骨修复药物控释支架的构建及其细胞生物学特性的研究。
由感染、肿瘤、外伤等造成的骨组织缺损是临床上的普遍问题,自体或异体骨移植是最常见的骨修复手段。然而,有限的来源和免疫排斥反应限制自体及异体骨移植应用。有鉴于此,通过构建能够快速介导细胞生长,诱导细胞特异性分化、维持细胞分化表型以及形成特定形态功能的组织的骨修复支架作为早期植入的支撑方法便成为现代骨组织修复重要手段,也即为本文的主旨所在。
本文构建具有多级成分和纳米(纳米颗粒)—微米(微球)—宏观(支架)多级结构的支架作为植入载体,承载干细胞的移植,并同时原位控释相关药物,以期得到最佳的修复效果。本研究将广泛应用于控释领域的聚乳酸-羟基乙酸(PLGA)微球通过低温焙烧的方法形成形貌可控的三维立体支架。与常见的骨修复支架相比,该支架有以下优点:优良的力学性能;可控的降解性能;优良的药物负载和控释性能等。本文对药物控释的PLGA微球支架及其对干细胞的介导分化作用进行深入研究和探讨。
(1)药物控释骨修复支架的多级构建
由于PLGA表面缺少有利于细胞黏附的基团,为提高支架的药物负载性能、生物相容性及细胞生物学特性,需要对PLGA微球支架进行必要的改性并构建细胞特异性识别位点。本论文分别通过复合生物分子和复合纳米材料两种技术对PLGA支架进行多级构建,并考察了它们的理化性能、药物控释和细胞生物学性能。(1)构建复合生物分子的多级成分支架:将卵磷脂天然生物分子引入到支架中,发现卵磷脂含量为5%的支架表现出优良的细胞生物学性能,如较高的碱性磷酸酶活性、I型胶原表达等。但是随着卵磷脂在支架中的含量提高,该性能则显著降低; (2)构建具有纳米(纳米颗粒)—微米(微球)—宏观(支架)多级结构支架:将三种纳米材料(介孔硅/羟基磷灰石(MSH)、羟基磷灰石(HA)和二氧化钛)分别引入到PLGA微球支架。结果显示改性后支架的力学性能、蛋白黏附性能和细胞生物学性能都有明显改善。比较研究发现,复合纳米材料的微球支架特别是复合MSH和HA的支架具有低的细胞毒性、优良的力学性能及优良的生物学性能,本研究选择这两种支架材料作为药物控释载体。
(2)骨修复药物控释微球支架对干细胞的特异性介导
通过体外实验研究微球及微球支架的药物缓释功能及对干细胞的介导分化作用。结果发现PLGA/MSH以及PLGA/HA支架对阿伦膦酸钠以及地塞米松都有良好的控释性能,控释周期长达一个月以上。控释的阿伦膦酸盐能够抑制破骨细胞的前体细胞-巨噬细胞的增殖和活性,同时能够提高成骨细胞的活性和促进成骨细胞相关成骨基因的表达和蛋白分泌,这一性能对骨缺损再生修复具有重要作用。更有意义的是负载了阿伦膦酸钠和地塞米松的PLGA微球还成功的诱导了滑膜干细胞的成骨转化,这方面的研究鲜有报道。使易于成软骨且具有高增殖速率的滑膜干细胞向成骨方向分化,可以解决骨髓间质干细胞增殖速度慢及随着细胞代数提高细胞分化能力降低的问题。体内实验发现,埋植于裸鼠皮下的阿伦膦酸钠与地塞米松控释微球支架与干细胞的复合体在4周时,异位生成骨组织。此外,在建立的兔骨缺损模型中,将负载阿伦膦酸钠与地塞米松的PLGA/HA微球支架植入兔体内8周后发现其骨修复效果明显好于未负载任何药物的PLGA/HA微球支架。
负载阿伦膦酸钠的PLGA微球支架为具有刺激细胞生物应答的功能化组织工程支架的构建提供了崭新的途径。这种方法是控释技术与组织工程相互结合的新的探索,并通过领域交叉赋予了组织工程支架新的功能。
Controlled organ regenerational and fuction construction is always a dram for human being . The development of tissue engineering offer a path for this dream. The aim of this thesis is developing a functional controlled release tissue engineering scaffold for bone repair.
The current replacement procedures for bone defect therapy mainly depended on autologous tissue which is the golden standard. Unfortunately, the origination of autologous bone is often limited in supply, and the allogenous bone takes an increased risk of disease transmission. Tissue engineering strategy, which utilizes an alternative approach to assist tissue repair via forming a microenvironment that effectively promotes cellular growth and proliferation in a synthetic or natural scaffold to produce extracellular matrix and regenerate tissue, can overcome the limitations that were induced by autologous and allogenous tissuetransplantation for bone repair.
Microsphere sintering technique was used in this thesis for fabricating the scaffolds with muti-component and muti-structure (nano scale-micro scale-macro scale). PLGA based microspherical sintering scaffolds were developed in this studies. These scaffolds possess regulated biodegradation, drug controlled release, as well as good mechanical property.
(1) Muti-level construction of cntrolled release tissue engineering scaffolds
Firstly, as a synthetic polymer, PLGA lacks functional groups, and the improvement of biocompatibility is also demanded. Many approaches have been carried out to enhance the bio-functionality of PLGA, and blending PLGA with biomolecules or nano bioceramic particles provides a simple and effective pathway for this purpose. In this work, two methods were applied to modify PLGA scaffold: modification with natural biomolecules and blending with nano particles. (1) Modification with natural biomolecules: lecithin was introduing into PLGA scaffold, and the results indicated that the scaffold with 5% lecithin showed better cell biological properties such as higher alkaline phosphatase (ALP) activity, higher calcium secretion and stronger type I colllagen gene expression. Howerver, the rising lecithin content in the scaffolds produced a lower cell biological properties, which may be due to the higher hydrophilicity of scaffold surfaces. (2) Modification with nano particles: Mesoporous silica-HA (MSH), nano TiO2, and HA were introducing into PLGA scaffolds respectively. The results demonstrated that after modifiaction by nano particles, the scaffolds showed improved mechanical propertes, trapping protein and cell biliogical properties. Additionally, PLGA-MSH scaffolds also exhibited beneficial drug delivery property. After a comprison among PLGA-MSH, PLGA-HA and PLGA-TiO2 scaffolds, PLGA-MSH and PLGA-HA scaffolds showed better properties than PLGA-TiO2, therefore our following studies will focus on these scaffolds.
(2) controlled release tissue engineering scaffolds for cell differentiation
In this work, dexamethasone (Dex), ascorbic acid (AA) andβ-glycerophosphate (GP) , the key components of ostoegenic media, were loaded into PLGA micropspherical scaffolds, and the osteogenesis in situ of mesenchymal stem cells (MSCs) on the scaffolds were evaluated. Ther results indicated that, after 14 days and 28 days of culture, MSCs on the drug laden scaffold exhibited strong osteoblastic properties. In-vitro osteogenesis was induced in the mesenchymal stem cells from the highly chondrogenic synovium mesenchymal stem cells (SMSCs) and the bone marrow (BMSCs), and also the effect on macrophages and osteoblasts by controlled release of a nitrogenous bisphosphonate additive - alendronate (AL) from PLGA/MSH and PLGA/HA scaffolds were assessed. AL is a nitrogenous bisphosphonate (BP) consisting of stable analogues of natural pyrophosphate compounds that inhibit bone resorption by osteoclasts. The resulted demonstrated that AL can inhibite the activity of macroiphages and also promote tha activity of osteoblast. In addition, AL and Dex laden PLGA/MSH microspheres was successfully induced in-vitro osteogenesis in SMSCs. AL and Dex laden PLGA/HA also exhibited the similar effect on BMSCs osteogenic commitment in vitro and in vivo. BMSCs laden PLGA/HA-AL-SMS and PLGA/HA-Com-SMS were also implanted into the back subcutis of mice and bone defects surgically created on rabbit femurs. The histology and immunohistochemistry results indicated that the scaffolds promoted MSCs osteogenic commitment and also the new bone formation in vivo. In addtion, these in situ AL delivery systems could effectively inhibit the growth of macrophage while enhance the proliferation and commitment of osteoblasts.
由感染、肿瘤、外伤等造成的骨组织缺损是临床上的普遍问题,自体或异体骨移植是最常见的骨修复手段。然而,有限的来源和免疫排斥反应限制自体及异体骨移植应用。有鉴于此,通过构建能够快速介导细胞生长,诱导细胞特异性分化、维持细胞分化表型以及形成特定形态功能的组织的骨修复支架作为早期植入的支撑方法便成为现代骨组织修复重要手段,也即为本文的主旨所在。
本文构建具有多级成分和纳米(纳米颗粒)—微米(微球)—宏观(支架)多级结构的支架作为植入载体,承载干细胞的移植,并同时原位控释相关药物,以期得到最佳的修复效果。本研究将广泛应用于控释领域的聚乳酸-羟基乙酸(PLGA)微球通过低温焙烧的方法形成形貌可控的三维立体支架。与常见的骨修复支架相比,该支架有以下优点:优良的力学性能;可控的降解性能;优良的药物负载和控释性能等。本文对药物控释的PLGA微球支架及其对干细胞的介导分化作用进行深入研究和探讨。
(1)药物控释骨修复支架的多级构建
由于PLGA表面缺少有利于细胞黏附的基团,为提高支架的药物负载性能、生物相容性及细胞生物学特性,需要对PLGA微球支架进行必要的改性并构建细胞特异性识别位点。本论文分别通过复合生物分子和复合纳米材料两种技术对PLGA支架进行多级构建,并考察了它们的理化性能、药物控释和细胞生物学性能。(1)构建复合生物分子的多级成分支架:将卵磷脂天然生物分子引入到支架中,发现卵磷脂含量为5%的支架表现出优良的细胞生物学性能,如较高的碱性磷酸酶活性、I型胶原表达等。但是随着卵磷脂在支架中的含量提高,该性能则显著降低; (2)构建具有纳米(纳米颗粒)—微米(微球)—宏观(支架)多级结构支架:将三种纳米材料(介孔硅/羟基磷灰石(MSH)、羟基磷灰石(HA)和二氧化钛)分别引入到PLGA微球支架。结果显示改性后支架的力学性能、蛋白黏附性能和细胞生物学性能都有明显改善。比较研究发现,复合纳米材料的微球支架特别是复合MSH和HA的支架具有低的细胞毒性、优良的力学性能及优良的生物学性能,本研究选择这两种支架材料作为药物控释载体。
(2)骨修复药物控释微球支架对干细胞的特异性介导
通过体外实验研究微球及微球支架的药物缓释功能及对干细胞的介导分化作用。结果发现PLGA/MSH以及PLGA/HA支架对阿伦膦酸钠以及地塞米松都有良好的控释性能,控释周期长达一个月以上。控释的阿伦膦酸盐能够抑制破骨细胞的前体细胞-巨噬细胞的增殖和活性,同时能够提高成骨细胞的活性和促进成骨细胞相关成骨基因的表达和蛋白分泌,这一性能对骨缺损再生修复具有重要作用。更有意义的是负载了阿伦膦酸钠和地塞米松的PLGA微球还成功的诱导了滑膜干细胞的成骨转化,这方面的研究鲜有报道。使易于成软骨且具有高增殖速率的滑膜干细胞向成骨方向分化,可以解决骨髓间质干细胞增殖速度慢及随着细胞代数提高细胞分化能力降低的问题。体内实验发现,埋植于裸鼠皮下的阿伦膦酸钠与地塞米松控释微球支架与干细胞的复合体在4周时,异位生成骨组织。此外,在建立的兔骨缺损模型中,将负载阿伦膦酸钠与地塞米松的PLGA/HA微球支架植入兔体内8周后发现其骨修复效果明显好于未负载任何药物的PLGA/HA微球支架。
负载阿伦膦酸钠的PLGA微球支架为具有刺激细胞生物应答的功能化组织工程支架的构建提供了崭新的途径。这种方法是控释技术与组织工程相互结合的新的探索,并通过领域交叉赋予了组织工程支架新的功能。
Controlled organ regenerational and fuction construction is always a dram for human being . The development of tissue engineering offer a path for this dream. The aim of this thesis is developing a functional controlled release tissue engineering scaffold for bone repair.
The current replacement procedures for bone defect therapy mainly depended on autologous tissue which is the golden standard. Unfortunately, the origination of autologous bone is often limited in supply, and the allogenous bone takes an increased risk of disease transmission. Tissue engineering strategy, which utilizes an alternative approach to assist tissue repair via forming a microenvironment that effectively promotes cellular growth and proliferation in a synthetic or natural scaffold to produce extracellular matrix and regenerate tissue, can overcome the limitations that were induced by autologous and allogenous tissuetransplantation for bone repair.
Microsphere sintering technique was used in this thesis for fabricating the scaffolds with muti-component and muti-structure (nano scale-micro scale-macro scale). PLGA based microspherical sintering scaffolds were developed in this studies. These scaffolds possess regulated biodegradation, drug controlled release, as well as good mechanical property.
(1) Muti-level construction of cntrolled release tissue engineering scaffolds
Firstly, as a synthetic polymer, PLGA lacks functional groups, and the improvement of biocompatibility is also demanded. Many approaches have been carried out to enhance the bio-functionality of PLGA, and blending PLGA with biomolecules or nano bioceramic particles provides a simple and effective pathway for this purpose. In this work, two methods were applied to modify PLGA scaffold: modification with natural biomolecules and blending with nano particles. (1) Modification with natural biomolecules: lecithin was introduing into PLGA scaffold, and the results indicated that the scaffold with 5% lecithin showed better cell biological properties such as higher alkaline phosphatase (ALP) activity, higher calcium secretion and stronger type I colllagen gene expression. Howerver, the rising lecithin content in the scaffolds produced a lower cell biological properties, which may be due to the higher hydrophilicity of scaffold surfaces. (2) Modification with nano particles: Mesoporous silica-HA (MSH), nano TiO2, and HA were introducing into PLGA scaffolds respectively. The results demonstrated that after modifiaction by nano particles, the scaffolds showed improved mechanical propertes, trapping protein and cell biliogical properties. Additionally, PLGA-MSH scaffolds also exhibited beneficial drug delivery property. After a comprison among PLGA-MSH, PLGA-HA and PLGA-TiO2 scaffolds, PLGA-MSH and PLGA-HA scaffolds showed better properties than PLGA-TiO2, therefore our following studies will focus on these scaffolds.
(2) controlled release tissue engineering scaffolds for cell differentiation
In this work, dexamethasone (Dex), ascorbic acid (AA) andβ-glycerophosphate (GP) , the key components of ostoegenic media, were loaded into PLGA micropspherical scaffolds, and the osteogenesis in situ of mesenchymal stem cells (MSCs) on the scaffolds were evaluated. Ther results indicated that, after 14 days and 28 days of culture, MSCs on the drug laden scaffold exhibited strong osteoblastic properties. In-vitro osteogenesis was induced in the mesenchymal stem cells from the highly chondrogenic synovium mesenchymal stem cells (SMSCs) and the bone marrow (BMSCs), and also the effect on macrophages and osteoblasts by controlled release of a nitrogenous bisphosphonate additive - alendronate (AL) from PLGA/MSH and PLGA/HA scaffolds were assessed. AL is a nitrogenous bisphosphonate (BP) consisting of stable analogues of natural pyrophosphate compounds that inhibit bone resorption by osteoclasts. The resulted demonstrated that AL can inhibite the activity of macroiphages and also promote tha activity of osteoblast. In addition, AL and Dex laden PLGA/MSH microspheres was successfully induced in-vitro osteogenesis in SMSCs. AL and Dex laden PLGA/HA also exhibited the similar effect on BMSCs osteogenic commitment in vitro and in vivo. BMSCs laden PLGA/HA-AL-SMS and PLGA/HA-Com-SMS were also implanted into the back subcutis of mice and bone defects surgically created on rabbit femurs. The histology and immunohistochemistry results indicated that the scaffolds promoted MSCs osteogenic commitment and also the new bone formation in vivo. In addtion, these in situ AL delivery systems could effectively inhibit the growth of macrophage while enhance the proliferation and commitment of osteoblasts.
引文
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