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系統識別號 U0026-0505201922275900
論文名稱(中文) 探討前驅幹細胞結合生物支架和物理治療於骨軟骨再生醫學之應用
論文名稱(英文) The Effects of Progenitor Cells Combined with Scaffolds and Physiotherapy in Osteochondral Regenerative Medicine
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 107
學期 2
出版年 108
研究生(中文) 王雪君
研究生(英文) Hsueh-Chun Wang
學號 P88011088
學位類別 博士
語文別 英文
論文頁數 103頁
口試委員 指導教授-葉明龍
召集委員-洪飛義
口試委員-蘇維仁
口試委員-王耀賢
口試委員-張乃仁
中文關鍵字 軟骨  骨軟骨修復  細胞支架  軟骨前驅幹細胞  內皮前驅幹細胞  生醫材料  再生醫學 
英文關鍵字 cartilage  osteochondral repair  scaffold  cartilage stem/progenitor cells  biomaterials  regenerative medicine  endothelial progenitor cell 
學科別分類
中文摘要 關節軟骨自我修復能力有限,因此軟骨受損便容易走向退化性關節炎。現今臨床上對於軟骨受損的治療多著重於症狀緩解,而未能有效重建透明軟骨。目前用於軟骨組織工程的細胞為軟骨細胞、間質幹細胞和組織特異性前驅細胞,其中組織特異性前驅細胞保有似幹細胞之再生潛力並保持原組織之細胞特性而不易走向非特異性分化。在此研究中探討兩種前驅幹細胞於骨軟骨再生醫學的修復潛能。內皮前驅幹細胞(EPCs)已應用於心血管疾病、骨再生及血管新生等研究;軟骨前驅幹細胞(CSPCs)為軟骨組織中之少量前驅幹細胞,目前已開始應用於軟骨修復之研究。本研究主要利用動物體內實驗及部分體外實驗去探討前驅幹細胞於骨軟骨修復之應用,分為兩大部分:Part I (EPCs與單層聚乳酸甘醇酸細胞支架(PLGA)及連續被動運動(CPM)的結合)。Part II-1 (CSPCs於體外實驗):探討CSPCs於體外培養時和退化性關節炎軟骨細胞(OACs)及髕下脂肪墊幹細胞(IFPs)之特性比較,如三重分化、再生能力、細胞標記、軟骨化能力、基因表現等;Part II-2 (CSPCs於體內之實驗):利用CSPCs結合PLGA,種植於兔子膝關節骨軟骨(股骨內側髁)缺陷,分別於四周及十二週後觀察骨軟骨修復的能力。EPCs與PLGA結合CPM於兔子體內實驗可促進早期軟骨基質-葡萄糖胺聚糖及第二型膠原蛋白(COL II)生成、長期則可降低骨生成並促進軟骨表面醣蛋白lubricin的合成,對骨軟骨缺損修復的機制則為EPCs促進軟骨下骨血管新生及CPM提供物理性刺激於軟骨表面。CSPCs於體外培養有似幹細胞特性,並且表現CSPCs特異性細胞標記、間質幹細胞標記、另外也表現出軟骨細胞基質及成骨細胞基質;而在體外培養時,CSPCs相較於OACs有較高的軟骨化基質表現,另CSPCs未有較IFPs顯著的軟骨化基因表現。CSPCs種植於PLGA於活體實驗時有良好的骨軟骨再生和整合,並發現CSPCs修復方向從軟骨層到軟骨下骨層。此研究發現兩種前驅幹細胞對骨軟骨修復皆具有潛力,若能加以結合,對於修復結構複雜的骨軟骨組織之再生醫學將會是一大幫助。
英文摘要 Articular cartilage has a limited capacity for self-repair. Injury to cartilage often progresses to development of osteoarthritis (OA). The available medical interventions can help to relieve symptoms, but fail to produce functional cartilage. Recently the cell-based therapies for cartilage repair are mainly focused on chondrocytes, mesenchymal stem cells (MSCs) or tissue specific progenitor cells. Tissue-specific progenitor cells not only possess stem cell-like proliferative potential, but also display tissue-specific phenotypes. In the present study, we investigated the osteochondral regeneration potential of two different kinds of progenitor cells. The first are endothelial progenitor cells (EPCs) have proven to have a high capacity for regeneration and vasculogenesis in different tissues. The second are cartilage stem/progenitor cells (CSPCs), which are resident, cartilage-specific, multipotent progenitor cells that have opened new avenues for cartilage repair. The objectives of the current study included Part I (in vivo study): The investigation of the effects of an EPC loaded poly lactic-co-glycolic acid (PLGA) scaffold combined with continuous passive motion (CPM) on osteochondral defect repair in rabbits. Part II-1 (in vitro study): To characterize CSPCs and compare them with osteoarthritis chondrocytes (OACs) and infrapatellar fat pad-derived stem cells (IFPs) through colony formation assay, multilineage differentiation analysis, gene expression analysis, and biochemical analysis. Part II-2 (in vivo study): To evaluate the osteochondral regeneration of the CSPC loaded PLGA scaffold during osteochondral defect repair in rabbits. We found that the combination of CPM with EPC loaded PLGA scaffolds during the regenerative process could enhance the synthesis of cartilage specific matrix, down-regulate subchondral bone formation and promote the synthesis of lubricin. The EPCs offered a microenvironment for angiogenesis; whereas, physical stimulation from CPM promoted tissue regeneration and host integration. The characteristics of CSPCs are similar to those of MSCs and they have chondrogenic and osteogenic phenotypes without chemical induction. Additionally, CSPCs displayed a significantly higher synthesis of GAGs than OACs. However, there was no significantly different in gene expression of chondrogenesis with IFPs. For in vivo study, CSPC loaded PLGA scaffolds produced a hyaline-like cartilaginous tissue, which showed good integration with host tissue and subchondral bone. More importantly, CSPCs involved the mechanism of the endochondral ossification of chondrocytes in the mineralization of the cartilage for promoting subchondral bone regeneration. Overall, this study demonstrated both CSPC and EPC progenitors had the potential to promote osteochondral regeneration. The combination of these cell-based therapies might be beneficial for the repair of complex tissues, such as osteochondral tissue.
論文目次 中文摘要 I
ABSTRACT III
誌謝 VI
CHAPTER 1: INTRODUCTION 1
1.1 ANATOMY AND COMPOSITION OF ARTICULAR CARTILAGE 1
1.2 OSTEOCHONDRITIS DEFECT AND OSTEOARTHRITIS (OA) 4
1.3 CURRENT TREATMENTS OF CARTILAGE REPAIR 5
1.4 CELLS SELECTION IN OSTEOCHONDRAL TISSUE ENGINEERING 9
1.4.1 Endothelial Progenitor Cells 11
1.4.2 Cartilage Stem/Progenitor Cells 12
1.5 SCAFFOLD SELECTIONS 14
1.5.1 Poly(lactide-co-glycolide) (PLGA) 16
1.6. ENVIRONMENT STIMULI 18
1.6.1 Continuous Passive Motion Treatment (in situ) 18
1.7 PURPOSES 19
1.7.1 Part I : Endothelial Progenitor Cells (EPCs) in vivo study 19
1.7.2 Part II-1 : Cartilage Stem/Progenitor Cells (CSPCs) in vitro study 19
1.7.3 Part II-2 : Cartilage Stem/Progenitor Cells (CSPCs) in vivo study 19
CHAPTER 2: MATERIALS AND METHODS 20
2.1 PART I: EPC-LOADED PLGA SCAFFOLD COMBINED WITH CPM IN OSTEOCHONDRAL REGENERATION IN RABBITS 20
2.1.1 Isolation and Culture of EPCs 20
2.1.2 Tracking the Implanted EPCs 21
2.1.3 Fabrication of Porous PLGA and EPC/PLGA Scaffolds 22
2.1.4 Animal Procedures 23
2.1.5 Macroscopic Assessment 26
2.1.6 Micro-CT Evaluations 27
2.1.7 Staining, Histology, Scores, and Immunostaining 28
2.1.8 Evaluation of Immunohistochemistry 29
2.1.9 Statistical Analysis 30
2.2 PART II-1: CHARACTERIZE CSPCS AND COMPARE THEM WITH OACS AND IFPS 31
2.2.1 Cell Isolation 31
2.2.2 Colony Formation Analysis 33
2.2.3 Multilineage Differentiation and Quantification 34
2.2.4 mRNA Extraction and Quantitative Reverse Transcription Polymerase Chain Reaction Analysis 35
2.3 PART II-2: CSPC-LOADED PLGA SCAFFOLD IN OSTEOCHONDRAL REGENERATION IN RABBITS 36
2.3.1 Fabrication of Porous PLGA and CSPCs/PLGA Scaffolds 36
2.3.2 Tracking the Implanted CSPCs 37
2.3.3 Animal Procedures 38
2.3.4 Macroscopic Evaluations 39
2.3.5 Micro-CT Evaluations 40
2.3.6 Histological and Immunohistochemical Processing 41
CHAPTER 3: RESULTS 43
3.1 PART I: EPC-LOADED PLGA SCAFFOLD COMBINED WITH CPM IN OSTEOCHONDRAL REGENERATION IN RABBITS 43
3.1.1 Characteristics of the 3D PLGA Scaffolds 43
3.1.2 To Trace the Location of EPCs by an In Vivo Imaging System (IVIS) and Spectrum CT Analyses In vivo 45
3.1.3 Macroscopic Observations and Quantitative Scores 47
3.1.4 Micro-CT Analysis 50
3.1.5 Histology 54
3.2 PART II-1: CHARACTERIZE CSPCS AND COMPARE THEM WITH OACS AND IFPS 60
3.2.1 Assessment of CSPCs Attachment and Spreading 60
3.2.2 Colony Formation Analysis 62
3.2.3 Multilineage Differentiation and Quantification 63
3.2.4 The Expression of Chondrogenic Differentiation 64
3.2.5 Biochemical Analysis 65
3.2.6 The Morphology of CSPCs on PLGA Scaffolds 67
3.3 PART II-2: CSPC-LOADED PLGA SCAFFOLD IN OSTEOCHONDRAL REGENERATION IN RABBITS 68
3.3.1 To Trace the Location of CSPCs by an In Vivo Imaging System (IVIS) and Spectrum CT Analyses In Vivo 68
3.3.2 Macroscopic Observations and Quantitative Scores 71
3.3.3 Micro-CT Analysis 74
3.3.4 Histology 78
CHAPTER 4: DISCUSSION 82
4.1 PART I: EPC-LOADED PLGA SCAFFOLD COMBINED WITH CPM IN OSTEOCHONDRAL REGENERATION IN RABBITS 82
4.2 PART II-1: CHARACTERIZE CSPCS AND COMPARE THEM WITH OACS AND IFPS 88
4.3 PART II-2: CSPC-LOADED PLGA SCAFFOLD IN OSTEOCHONDRAL REGENERATION IN RABBITS 90
CHAPTER 5: CONCLUSION 92
REFERENCES 94
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