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系統識別號 U0026-1807201113321600
論文名稱(中文) 利用自組裝胜肽奈米纖維進行梗塞後心血管再生
論文名稱(英文) Tissue Engineering Approaches to Post-infarction Cardiovascular Regeneration Using Self-assembling Peptide Nanofibers
校院名稱 成功大學
系所名稱(中) 醫學工程研究所碩博士班
系所名稱(英) Institute of Biomedical Engineering
學年度 99
學期 2
出版年 100
研究生(中文) 林意棟
研究生(英文) Yi-Dong Lin
學號 P8896110
學位類別 博士
語文別 英文
論文頁數 111頁
口試委員 口試委員-王水深
口試委員-蔡偉博
口試委員-張志涵
共同指導教授-葉明龍
指導教授-謝清河
中文關鍵字 生醫材料  心肌組織工程  骨髓幹細胞  血管內皮生長因子  心肌梗塞 
英文關鍵字 biomaterials  cardiac tissue engineering  bone marrow stem cell  vascular endothelial growth factor  myocardial infarction 
學科別分類
中文摘要 缺血性心血管疾病之罹病率與所造成的死亡率在全球各國皆居高不下,在已開發國家當中尤甚。心肌梗塞即是最具威脅的缺血性心血管疾病之一,其常見於冠狀動脈因阻塞而造成下游的心肌缺血,進而在短時間內引發心肌細胞大量死亡,並進入病態的心室重塑,最後走向不可逆的心衰竭。當心肌梗塞發生之後,傳統的方式並無法有效改善與治療。因此,心血管組織工程與再生醫學是一門極待發展的新興技術。幹細胞移植即是一具有潛力的治療方式,然而,細胞移植的存留率與存活率不佳是一尚待克服的難關;另外一項有潛力的治療方式是打入生長因子誘導血管再生,然而,局部控制釋放不佳是此一方式的最大瓶頸。
在此,我們提出可以利用一自組裝胜肽奈米纖維(NFs)來克服上述瓶頸。本研究主要包含兩部份的研究,在第一個部份以迷你豬作為大動物實驗模型,我們假設自組裝胜肽奈米纖維(NFs)的材料充填可增加梗塞後的心壁厚度,同時提高自體骨髓單核細胞(MNCs)移植後的存留率,進而改善梗塞後有害的心肌重塑與功能異常。我們的結果顯示,胜肽奈米纖維注射即可改善梗塞後的心舒張功能,並減緩惡性心室重塑的效果;而注射自體骨髓細胞則以改善收縮功能為主。唯有將胜肽奈米纖維混合骨髓細胞作治療時,才能同時改善心臟收縮與舒張功能,提供較高的移植細胞存留率,進而達到較佳的血管新生與心肌保護之效果。
而在第二部份,我們以大鼠作為動物實驗模型,我們假設胜肽奈米纖維可以作血管內皮生長因子(VEGF)的局部與長效釋放,進而改善梗塞後血管新生。我們的結果證實胜肽奈米纖維混合內皮生長因子可顯著改善梗塞後的血管新生、動脈新生、與心收縮功能。重要的是,此部份的研究證實胜肽奈米纖維不只可以當作血管內皮生長因子控制釋放的載體,還可以建立心肌內合適組織再生的微環境,進而誘發內生性的動脈新生與潛在的心肌再生。
我們的結果顯示胜肽奈米纖維可以有效增強細胞與生長因子療法的功效。重要的是,在第一部份的研究中,我們以大動物實驗模型證實了本方法於臨床上使用的可行性與安全性;而在第二部份的研究中,我們藉由小動物實驗模型,進一步探討奈米纖維有利心肌組織工程的內在機制,並證實胜肽奈米纖維所建立的微環境可幫助新血管再生。我們相信本研究所提供兩種新穎治療技術與策略,不但能夠對基礎的組織工程研究提供珍貴的經驗與洞見,亦能在不遠的未來轉譯並應用於臨床上,嘉惠眾多受苦於心臟疾病的病患。
英文摘要 Ischemic cardiovascular disease (ICD) such as myocardial infarction (MI) is the leading cause of morbidity and mortality throughout the world. MI is often attribute to sudden occlusion of cornary arteries, which subsequently results in irreversible myocardium damage and heart failure. The current treatments, including drug prescription and surgical intervention, can only partially ameliorate the symptoms. Cardiac tissue engineering is thus an imperative need for vascular or myocardial regeneration. Accumulating studies have suggested that numerous adult progenitor / stem cells can contribute to de novo cardiovascular regeneration. Besides, angiogenesis can also be promoted by delivery of growth factors to induce vascular cell proliferation, differentiation, survival and migration. Nevertheless, the present clinical trials appear to be un-satisfactory and controversial. The major hurdle for cell therapy is low survival and retention rate of transplanted cells, while the problems associated with the growth factor administration is local-controlled and sustained delivery within the microenvironments.
Here, we provide a novel self-assembling peptide nanofibers (NFs) based therapy to overcome these difficulties. The nanofibrous hydrogel can not only function as scaffold to prolong cell retention but also control local delivery of proteins, and thereby enhancing angiogenic effects of delivered cells and proteins. Therefore, this thesis is divided into two parts. In the first part, we hypothesize that intramyocardial injection of NFs thickens the infarcted myocardium and increases transplanted autologous bone marrow mononuclear cell (MNC) retention to attenuate cardiac dysfunction. Our data revealed NF injection significantly improved diastolic function and reduced ventricular remodeling 28 days after treatment. Injection of MNCs alone ameliorated systolic function only, whereas injection of MNCs with NFs significantly improved both systolic and diastolic functions, increased transplanted cell retention, and promoted capillary density in the peri-infarct area.
In the second part, we hypothesize that intramyocardial injection of NFs along with vascular endothelial growth factor (VEGF) allows controlled local delivery with prolonged effect of VEGF and therapeutic angiogenesis. Our results demostrated intramyocardial injection of VEGF along with nanofibrous hydrogel has significantly improved post-infarction angiogenesis, arteriogenesis and thus cardiac performance. Importantly, this approach not only allowed controlled local delivery with prolonged effect of VEGF without systemic harmful effects, but also created a favorable microenvironment in vivo for recruitment and vascular integration of mural cells. Strikingly, the engineered vascularized microenvironment further attracted a population of cardiomyocyte-like small myocytes stained positive for cardiac troponin I, indicating the potential induction of cardiac regeneration.
Our results demonstrate that NF injection enhances the effcacy of cell and protein therapy. Importantly, we validate the feasibility and safety of this approach in the large animal study as a pre-clinical trial in the first part of thesis. Besides, we investigate the underlysing mechanism of beneficial NF injection using rodent model in the second part of thesis. We believe the unprecedented study holds not only valuable inspiration for basic biomedical research but also potency for translational application in the foreseeable future.
論文目次 Abstract I
摘要 III
誌謝 V
Index of Contents VII
Index of Figures XII
Index of Tables 1
Chapter1 Introduction 2
1.1 Cardiovascular disease is a leading cause of death 2
1.2 Current treatment to heart disease is inadequate 2
1.2.1 Medicine 2
1.2.2 Percutaneous coronary intervention 3
1.2.3 Surgery 3
1.3 Cardiac tissue engineering is a promising approach 4
1.3.1 Cell therapy 5
1.3.2 Growth factor therapy 8
1.3.3 Gene therapy 10
1.4 Challenges of cardiac regeneration 11
1.5 Novel delivery system leads revolutionary pharmaceutical treatment 12
1.6 Self-assembling peptide nanofibers 12
1.7 Overall approach 14
Chapter2 Intramyocardial NF injection improves post-MI ventricular remodeling and efficacy of MNC therapy in pigs 15
2.1 Background 15
2.2 Materials and methods 16
2.2.1 Experimental animals 16
2.2.2 Autologous bone marrow mononuclear cell isolation and DiI labeling 17
2.2.3 Myocardial infarction and treatment 18
2.2.4 Echocardiography 21
2.2.5 Hemodynamics 21
2.2.6 Ratio of necrotic tissue area, length, and thickness measurements 22
2.2.7 Collagen content measurement 22
2.2.8 Immunohistochemistry and fluorescence microscopy 22
2.2.9 Determination of NFs degradation after injection. 23
2.2.10 Blood chemistry 23
2.2.11 Quantitative evaluation of leukocytes 24
2.2.12 Statistical analysis 24
2.3 Results 24
2.3.1 Injection of NFs alone increases interventricular septum thickness, and prevents ventricular remodeling after infarction 24
2.3.2 Injection of NFs along with autologous MNCs improves both systolic and diastolic functions after infarction 32
2.3.3 Injection of NFs along with autologous MNCs decreases necrotic tissue and collagen content in the remote area after infarction 33
2.3.4 Injection of peptide nanofibers along with bone marrow mononuclear cells increases transplanted cell retention and differentiation as well as angiogenesis after infarction 33
2.3.5 Injection of NFs Reduce C-Reactive Protein Levels after Infarction 47
2.4 Discussion 49
2.4.1 Local repair by biomaterial injection preserves cardiac geometry and function 49
2.4.2 Cell retention determines cardiac functional improvement by cell therapy 50
2.4.3 MNC/NF injection has complementary effects for clinical application 50
2.4.4 Mechanisms of MNC Therapy remain to be determined 51
2.5 Summary and future direction 55
Chapter3 Nanofibrous Scaffold with VEGF Creates Intramyocardial Microenvironments for Arteriogenesis and Cardiac Benefits after Infarction 56
3.1 Background 56
3.2 Materials and methods 57
3.2.1 VEGF functional assay 57
3.2.2 NFs/VEGF binding capacity and in vitro releasing kinetics 58
3.2.3 Animals and experimental myocardial infarction 58
3.2.4 Preparation of treatments and in vivo releasing kinetics 58
3.2.5 Therapeutic study and echocardiography 59
3.2.6 Tissue processing and infarct size estimation 59
3.2.7 Fluorescence microscopy and analysis 60
3.2.8 Vascular permeability study 60
3.2.9 Bone marrow cell injection study 61
3.2.10 Cardiomyocyte-specific fate-mapping study 61
3.2.11 Statistical Analysis 62
3.3 Results 62
3.3.1 Intramyocardial NF/VEGF injection achieves sustained VEGF delivery and improves cardiac performance at 28 days after MI 62
3.3.2 NF/VEGF injection promotes both angiogenesis and arteriogenesis at 28 days after MI 70
3.3.3 Local delivery of VEGF along with NFs does not cause systemic harmful effects 75
3.3.4 NF injection recruits α-SMA+ cells and NF/VEGF injection achieves arteriogenesis 78
3.3.5 NF/VEGF injection recruits cardiomyocyte-like cTnI+ small myocytes after MI 84
3.4 Discussion 87
3.4.1 High dosage of VEGF achieves effective angiogenesis but not arteriogenesis and cardiac benefits 87
3.4.2 NFs/VEGF injection creates biomimic microenvironments to enhance therapeutic effects 88
3.4.3 NF/VEGF injection creates a vascular niche for cardiac regeneration 90
3.5 Summary and future direction 91
Chapter4 Conclusion 92
References 93
Curriculum Vitae 110
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