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系統識別號 U0026-2704201216071700
論文名稱(中文) 微流體技術應用於幹細胞之分離、計數、分選、培養與分化
論文名稱(英文) Microfluidic systems for separation, counting, sorting, culture and differentiation of stem cells
校院名稱 成功大學
系所名稱(中) 工程科學系碩博士班
系所名稱(英) Department of Engineering Science
學年度 100
學期 2
出版年 101
研究生(中文) 吳慧紋
研究生(英文) Huei-Wen Wu
學號 n98961292
學位類別 博士
語文別 英文
論文頁數 141頁
口試委員 指導教授-李國賓
口試委員-楊瑞珍
口試委員-謝文馨
口試委員-吳昭良
口試委員-林哲信
口試委員-吳旻憲
口試委員-黃效民
中文關鍵字 微機電系統  微流體元件  幹細胞  羊水  臍帶血  分離  記數  分選  磁珠  免疫螢光測定  細胞培養  細胞分化  細胞刺激 
英文關鍵字 MEMS  microfluidics  stem cell  MSC  HSC  amniotic fluid  cord blood  separation  isolation  counting  sorting  magnetic beads  fluorescent immunoassay  culture  differentiation  stimulation 
學科別分類
中文摘要 近日以來,微流體系統技術已經發展應用至細胞相關研究。而近期發展的微流體系統技術具有透光性、自動化操作等優點,各種細胞可以在此模擬生物體的環境中增生,並可即時地被觀察給予的刺激對細胞型態變化的影響。雖然幹細胞在大型系統中已經被廣泛地研究,但是我們對於其在生物體內環境中的行為變化像是增生以及分化現象仍舊不甚了解,因此利用微機電技術可以取代傳統上的技術進而改善其缺點。在此篇研究中,我們設計了幾個微小型的微流體晶片系統應用於幹細胞的分離、記數、分選、培養、分化以及刺激實驗中,可以提供各種方式來提供與生物體相似的培養環境,比大型系統更加能準確觀察幹細胞的生長情形。除此之外,此技術也具有體積小、分析樣本需求少、反應時間快及檢測精確度高等優點。
首先,第一個系統主要利用微雕機或者微影技術製作母模結構,再以聚二甲基矽氧烷(PDMS: poly-dimethylsiloxane)翻模建置出所需晶片。我們設計了一被動式微流體分選晶片,其中嵌有傾斜的屋簷式過濾器來將4-6 μm豐富的幹細胞篩選出來。利用緩衝液將細胞流體聚焦成一狹窄的流線後,之後進入傾斜式屋簷狀過濾器區,小顆粒慣性較小會隨著流體的路徑而通過孔徑為8 μm空隙,大顆粒則被阻擋下來而隨著往下流動的流體而帶走,來達到高分離效果。此屋簷式過濾器可以解決過濾大小細胞常見的阻塞問題。初步使用塑膠珠模擬實際狀況,結果可以得到約86 % 的分離效率。在分離羊水幹細胞實驗中可以達到良好的效率(82.8 %),而重複其步驟可以將分離效率提高至97.1 %。
同樣地,臍帶血近日也成為極為熱門的臨床研究,其中富有的造血幹細胞為近年來移植治療點之一。然而少數幹細胞存在於臍帶血中,人們無法即時計算造血幹細胞的數目,在臨床治療上人們會直接輸入大量的臍帶血治療而造成浪費。因此,第二個系統研究在於提出一種整合型微流體生醫晶片的重可快速自動化抓取造血幹細胞,並精確地計數、分選目標細胞,得以達到量化功能。其操作過程包含了混合、運輸檢體以及緩衝液、記數和分選等模組來實施。使用鍵結好抗體的磁珠來抓取造血幹細胞,並利用微流體控制模組記數細胞數目,可以自動化地完成其實驗流程。
第三個系統則是發展一個連續式的細胞培養晶片應用於羊水幹細胞上。此晶片可以自動化地培養分化羊水幹細胞。其使用微幫浦來連續地傳輸培養液,並在其中嵌入了一條微管道,讓幫浦產生的回流能直接改從微管道中傳輸到後方的廢棄物槽中,因而成功地解決汙染的問題。實驗結果驗證出使用微流體晶片培養細胞比一般的傳統方式還要來得穩定些,不僅提供了相似的培養環境,也減少了材料的耗費。
最後,我們發展了一整合性的微流體細胞刺激晶片,可以自動化地調配分化培養液中的胰島素的濃度,另一方面又可同時控制流體所產生的剪應力大小,來觀察化學和物理刺激對於間質幹細胞分化成脂肪細胞的影響。本晶片包含一化學刺激模組來自動地控制胰島素的濃度,以及一物理刺激模組使其中的PDMS薄膜變形來改變管道深度近而改變剪應力,可同時進行刺激。結果顯示脂肪生長最佳時的胰島素濃度為10 毫克/毫升。而較大的剪應力以及較快的作動頻率則會抑制脂肪細胞的生長。本研究發展出不同的微流體系統應用於幹細胞上,提供了簡單、自動化、控制容易、條件均一、低汙染之細胞操作方法,將可成為未來的幹細胞研究發展的重要工具。
英文摘要 Microfluidic techniques have been recently developed for cell-based assays. In microfluidic systems, the objective is for these microenvironments to mimic in-vivo surroundings. With advantageous characteristics such as optical transparency and the capability for automating protocols, different types of cells can be cultured, screened and monitored in real time to systematically investigate their morphology and functions under well-controlled microenvironments in response to various stimuli. Recently, the study of stem cells using microfluidic platforms has attracted considerable interest. Even though stem cells have been studied extensively using bench-top systems, an understanding of their behavior in in-vivo-like microenvironments which stimulate stem cell proliferation and differentiation is still lacking. In this paper, several stem cell studies using microfluidic systems are purposed. The various miniature systems for stem cell separation/isolation, sorting, isolation, culture, differentiation, and stimulation, are then systematically introduced. Compared with conventional cell culture protocols, the microfluidic techniques provide versatile approaches to mimic more in vivo-like extracellular conditions for more realistic cell-based assay research. There still exist several inherent advantages including low biosamples/reagents consumption, a single integrated chip with multiple functions, and ability to run the array assays simultaneously. In this study, it was presented several new microfluidic devices fabricated based on SU-8 lithography process, a computer numerical controlled (CNC) milling for molds, and polydimethylsiloxane (PDMS) replica molding processes for stem cells researches.
First, a passive separation chip with louver-like structures in the microchannel is proposed as a filter to separate mesenchymal stem cells (MSCs) from amniotic fluid. Buffer solution is used to squeeze the sample flow by using the syringe pumps to form a narrow stream so that the sample flows close to the louver-like structures to obtain a higher separating efficiency. The device can alleviate the clogging problem and avoid the use of the external force such that cells will not be damaged during the separation process. Preliminary results show that the developed microfluidic device can perform a good separation of 86% (beads). It also shows that that the developed microfluidic device can perform a good separation of 82.8 % for MSCs. Furthermore, the separation process can be repeated to improve the separation efficiency to 97.1 %.
Another magnetic-bead technology integrated with the microfluidic system was purposed to develop a platform capable of isolating, counting, and sorting the hematopoietic stem cells. Since there is only an extremely small amount of stem cells existing in the umbilical cord blood, it is crucial to isolate and count the cell sample. In this research, the processes including mixing, transporting, counting and sorting can be completed automatically using the microfluidic control module. The target stem cells will be first captured by the antibody coated onto the magnetic beads, and then be successfully counted and sorted by a detection system.
In addition, a continuous microfluidic device capable of automating culturing and differentiating the MSCs was proposed. Microfluidic-based pneumatic trumpet-like micropump activated by two electromagnetic valves (EMVs) with three air chambers plus an elusive side-channel was used to suck the culture medium so that the medium in the culture area can be continuously supplied. Moreover, the waste can be moved through the elusive side-channel without contamination. The results represented that MSCs can be cultured and differentiated into different kinds of phenotypes stably for a long time. The stem cell culture chip not only can provide stable and well-defined microenvironments, but also features in low consumption of research resource.
Finally, an integrated microfluidic system capable of fine-tuning the insulin concentration automatically and applying different levels of shear stresses simultaneously was developed to investigate the effects of chemical and mechanical stresses on adipogenic differentiation of MSCs. It is comprised of a dilution device which can automatically fine-tune the concentrations of insulin for chemical stimulation on stem cells and three different levels of shear stresses produced by deflecting the PDMS membranes used to induce stem cells at the same time. The experimental results showed that an optimum insulin concentration of 10 μg/ml for differentiation of adipocytes can be determined. Moreover, the adipogenic differentiation can be suppressed by applying stronger shear stress and higher pulsation frequency of mechanical stimulation.
In summary, we have demonstrated several microfluidic based platforms of separation/isolation, counting, sorting, culture, differentiation and stimulation for the stem cell which may provide a promising development in the this new medical field.
論文目次 Contents
Abstract I
摘要 IV
誌謝 VI
Contents VII
List of table XI
List of figure XII
Nomenclature XVII
Abbreviations XVIII
Chapter 1 Introduction 1
1.1 Microfluidics 1
1.2 Stem cells 3
1.2.1 Embryonic stem cells (ESCs) 3
1.2.2 Adult stem cells 4
1.2.3 Stem cell types and applications in microfluidics 7
1.3 Motivation and objectives 7
1.4 Scope and structure of the dissertation 8
Chapter 2 Theory 13
2.1 Fundamental of pneumatically-driven membrane-based actuators 13
2.2 The mechanism of the hormone 14
Chapter 3 Materials and Methods 16
3.1 Fabrication of microfluidic chips 16
3.1.1 Fabrication of masters using photolithography 16
3.1.2 Fabrication of masters using computer numerical control (CNC) milling 17
3.1.3 PDMS replication process 18
3.1.4 Chip packaging 18
3.2 Performances of microfluidic devices 18
3.2.1 Evaluation of the pumping rates 18
3.2.2 Experimental setups for fluidic control 19
3.2.3 Observation of the high-speed motions 19
3.3 Staining assay 20
3.3.1 Oil Red O staining 20
3.3.2 Alkaline phosphatase staining 20
Chapter 4 Development of the separation systems for stem cells 22
4.1 Introduction 22
4.2 Development of louver-array structures for separation of amniotic fluid mesenchymal stem cells 28
4.2.1 Design and Fabrication 28
4.2.1.1 Design 28
4.2.1.2 Fabrication 30
4.2.2 Experimental 30
4.2.2.1 Setup 30
4.2.2.2 MSCs immunofluorescence staining assay 31
4.2.2.3 Evaluation of the passive microfilter with louver-like structures 31
4.2.3 Results and discussions 32
4.2.3.1 Bead separation 32
4.2.3.2 Amniotic stem cell separation 35
4.2.4 Summary 36
4.3 Development of a integrated microfluidic system for isolation, counting and sorting of hematopoietic stem cells 37
4.3.1 Experimental 37
4.3.1.1 Procedure 37
4.3.1.2 Chip design 38
4.3.1.3 Fabrication process 40
4.3.1.4 Sample preparation 40
4.3.2 Result and discussion 41
4.3.2.1 Characterization of the microfluidic system 41
4.3.2.2 Cell isolation 43
4.3.2.2.1 Isolation of simulated cell samples 43
4.3.2.2.2 HSCs isolation 44
4.3.2.3 Cell detection 45
4.3.3 Summary 47
Chapter 5 Development of a continuous culture and differentiation platform for mesenchymal stem cells 62
5.1 Introduction 62
5.2 Design and fabrication 65
5.2.1 Design 65
5.2.2 Fabrication 66
5.3 Experimental 67
5.3.1 Setup 67
5.3.2 MSCs culture assay 68
5.3.3 MSCs differentiation assay 69
5.4 Result and discussion 71
5.4.1 Characterization of the microfluidic system 71
5.4.2 Culture and differentiation of AFMSCs 72
5.4.3 Immunofluorescence staining for AFMSCs 74
5.5 Summary 74
Chapter 6 Chapter 6 Development of a mechanical and chemical stimulation platform for mesenchymal stem cells 84
6.1 Introduction 84
6.2 Design and fabrication 88
6.2.1 Chip design 88
6.2.2 Fabrication 90
6.3 Experimental 90
6.3.1 Setup 90
6.3.2 MSCs culture and differentiation assay 91
6.3.2.1 MSCs culture assay 91
6.3.2.2 MSCs differentiation assay 92
6.3.2.3 Measurement of the differentiated adipocyte expression 92
6.4 Result and discussion 93
6.4.1 Characterization of the microfluidic system 93
6.4.1.1 Characterization of micropumps 93
6.4.1.2 Performance of the dilution device 94
6.4.2 Chemical stimulation of MSCs 95
6.4.3 Mechanical stimulation of MSCs 98
6.5 Summary 102
Chapter 7 Conclusions and Future Work 112
7.1 Discussion and Conclusions 112
7.2 Future Work 114
Reference 116
Curriculum Vitae 139
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