新穎介電泳細胞排列微流體平台之設計、製造與實現以體外重建大尺度仿生之人工肝臟與骨組織

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研究生：	何政達 Ho, Chen-Ta
論文名稱：	新穎介電泳細胞排列微流體平台之設計、製造與實現以體外重建大尺度仿生之人工肝臟與骨組織 Design, fabrication and implementation of a novel dielectrophoretic cell patterning microfluidic platform for in-vitro construction of large-scale biomimetic engineered liver and bone tissue
指導教授：	劉承賢 Liu, Cheng-Hsien
口試委員:
學位類別：	博士 Doctor
系所名稱：	工學院 - 動力機械工程學系 Department of Power Mechanical Engineering
論文出版年：	2009
畢業學年度：	97
語文別：	英文
論文頁數：	170
中文關鍵詞：	介電泳、細胞排列術、微流體、組織工程、肝臟晶片、骨晶片
外文關鍵詞：	Dielectrophoresis, Cell patterning, Microfluidics, Tissue engineering, Liver Labchip, Bone Labchip
相關次數：	點閱：2 下載：0
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有調節細胞外微環境的能力以促進細胞與細胞間、細胞與細胞外基質間交互作用與可溶信號的刺激對維持細胞/組織生理功能是必需的。傳統組織工程技術利用生物可降解支架控制細胞外微環境以促進被培養細胞的貼附、增生、與分化。但由於其無法精確低控制細胞在支架中的空間位置、分佈、與均勻性，因此，組織工程仍主要卓重在研發包含單一種細胞所組成的簡單組織上，如皮膚、軟骨、角膜等；至今對於由數種異質細胞所組成的複雜組織、如肝臟、腎臟與骨頭仍是一大瓶頸與挑戰。由於動物組織是由數種不同細胞型態與其獨特的架構所組成以利執行其特殊生理角色;因此有適當的操控異種細胞排列的能力去建構仿真實組織的複雜圖形以促進細胞與細胞間、細胞與細胞外基質間交互作用，不止對細胞/組織生理功能的維持亦對重建複雜人工組織是關鍵的技術。在如光微影法、微壓印法、微流體、噴墨法、雷射導引直寫、介電泳等眾多細胞排列技術中，介電泳提供在微尺度下可主動、快速、大量平行操控的細胞、微生物、微粒子的能力；是個特別適合於細胞排列應用的技術。在本研究中，我們提出一新穎介電泳細胞排列微流體平台及其設計、製造、與實現；利用這個平台我們發展了三種新穎的介電泳細胞排列電極，可以用來操控大量的細胞以體外重現仿複雜組織之圖形如肝臟、骨組織，且均能達到約85%細胞排列解析度。
以此技術平台，我們展示1. 近六千個肝與內皮細胞可被快速排列成有單一細胞解析度之放射狀交錯排列的肝/內皮細胞串珠以形成約兩豪米面積之仿肝小葉異質整合的肝組織。2. 近三千個骨母細胞與骨矩陣微粒可被快速被排列成由骨母細胞所組成的數圈同心圓圖形與由氫氧基磷灰石骨矩陣所形成的放射串珠陣列圖形兩者圖形交錯所組成的約兩豪米面積之精密仿骨元組織。3. 大於十萬個肝與內皮細胞可被快速排列成放射狀交錯肝/內皮細胞所排列的肝小葉陣列以實現兩公分等級大小的仿肝小葉之肝組織建構。這些排列後的仿組織圖形在三到五天培養下亦維持緊密的細胞間接觸、高細胞存活率、與良好的排列解析度。本研究技術的延伸可以允許建構其他更複雜的人工組織與提供仿生組織架構以利藥物篩檢與組織生理病理之研究。

The ability to manipulate the cellular microenvironment to facilitate cell-cell interactions, cell-ECM interactions, and soluble stimuli is essential to maintain cell/tissue physiological functions. Conventional approaches for tissue engineering utilize biodegradable scaffolds to modulate extracellular microenvironment to promote adhesion, proliferation, and differentiation of cultured cells. Due to the inability to precisely control the spatial location, distribution, and uniformity of cells inside the scaffold, tissue engineering focuses primarily on relatively simple tissues comprised of homogeneous cell types such as skin, cartilage, and cornea, but to date it has been challenging to organize heterogeneous cell types to reconstruct complex tissues, such as liver, kidney and bone. Natural animal tissues contain multiple cell types organized in a unique architecture that facilitates specific physiological roles. Therefore, the appropriate organization and manipulation of multiple cell types to mimic the complex pattern of natural tissue to facilitate cell-cell interactions, cell-ECM interactions, and soluble stimuli are essential to maintain cell/tissue physiological functions and also critical to engineer complex tissue engineering for regenerative medicine applications. Comparing to different cell-patterning techniques, including photolithography, microcontact printing, microfluidic patterning, inkjet printing, and laser-guided direct writing, dielectrophoresis (DEP) offers the capability of active, rapid, and massively-parallel manipulation of large numbers of biological cells, microorganisms, and microparticles in microscale, which is a superior candidate for cell patterning application.
Here, we present the design, microfabrication, and implementation of dielectrophoretic cell patterning microfluidic platform. We develop three novel cell patterning electrodes which are capable of manipulating large numbers of cells/microparticles to in-vitro construct complex tissue-mimetic patterns of liver and bone tissue. Each of the three cell pattering techniques reaches about 85% cell patterning resolution. Using this dielectrophoretic cell patterning platform, we develop three novel cell patterning electrodes we demonstrate that 1.) About six thousands of individual hepatocytes and endothelial cells are rapidly organized into alternate radial and pearl-chain shaped cell strings to form a 2mm2 heterogeneous-integrated lobule-mimetic tissue with single cell-patterning resolution. 2.) About three thousands of individual osteoblasts and bone-matrix microparticles can be rapidly micropatterned into a precise arrangement of multiple osteoblasts-assembled concentric rings interlaced in-between the radial pearl-chain-array of hydroxyapatite-encapsulated microparticles, which form a 2 mm2 heterogeneous-integrated osteon-mimetic tissue. 3.) At least one hundred thousand of hepatocytes and endothelial cells are micropatterned into the array of multiple radial hepatic/endothelial cell strings to from the two-centimeter-scale precise lobule-mimetic liver tissue. The tissue-mimetic patterns after dielectrophoretic cell patterning also maintained intimate-cell-cell contact, high cell viability, and fine cell-patterning resolution after culturing three to five days. Extension of this research will permit the engineering of other complex tissues and investigations of tissue architecture with applications in drug screening and physiology/pathophysiology.

Table of contents

Abstract (English)    ….I
摘要    III
Acknowledgements    IV
Abbreviations    V
Table of contents    VI
List of figures    ….IX
List of tables    X

Chapter 1  Introduction
1    Background    1
2    Tissue engineering    1
3    Cell patterning approaches    3
3.1    Passive cell patterning    3
3.1.1    Photolithography    4
3.1.2    Microcontact printing    4
3.1.3    Microfluidic patterning    5
3.2    Active cell patterning    6
3.2.1    Ink-jet printing    6
3.2.2    Laser-guided direct writing    6
3.2.3    Cell patterning using dielectrophoresis    7
3.2.3.1    Cell patterning using negative dielectrophoresis......7
3.2.3.2    Cell patterning using positive dielectrophoresis…...8
3.3    Comparison of cell patterning approaches    8
4    Theory of dielectrophoresis    ….12
4.1    Introduction    12
4.2    Derivation of dielectrophoretic force on a small dielectric particle    13
4.2.1    Polarization of dielectric particle under electric field    14
4.3.2    Force on a dipole under a non-uniform electric field    15
4.2.3    Derivation of effective dipole moment method    17
4.2.3.1    Field due to a finite dipole in a dielectric medium.18
4.2.3.2    A dielectric particle in a dielectric medium under    20
4.2.3.2    uniform electric field    20
4.2.4    Force of a dielectric particle in the medium under AC field    24
4.3    Derivation of dielectrophoretic force on a cell    26
4.3.1    Clausius-Mossotti factor    27
4.4    Summary of DEP    27
4.5    Pearl-chain effect    28
5    Aim and scope of this thesis    ….29


Chapter 2  Development of engineered lobule-mimetic liver tissue
1    Abstract    31
2    Design, principle and simulation    32
2.1    Liver structure    32
2.2    Manipulation machanism: field induced dielectrophoresis    32
2.3    Design of liver cell patterning microfluidic chip    34
2.4    Operation principle of lobule-mimetic liver cell patterning    36
2.5    Numerical simulation    36
3    Materials and methods    40
3.1    Microfabrication processes    40
3.2    Cell culture and medium    42
3.3    Cell preparation for DEP manipulation    42
3.4    Surface modification of the cell-patterning chamber for cell adhesion    42
    enhancement    42
3.5    Experiemental setup for cell patterning experiments    43
3.6    Cell adhesion, grouth and viability assessment in the cell-patterning    43
    chamber    43
4    Results and discussion    44
4.1    The parameter setup for DEP operation    44
4.2    On-chip in-parallel cell-patterning demonstration    45
4.3    In-situ cell-viability assessment for DEP cell patterning    48
4.4    Enhancement of cell adhesion via poly-D-lysine coating and medium    49
    replacement    49
4.5    Heterogeneous integration of HepG2 cells and HUVECs for liver cell    50
    patterning    50
5    Conclusions    53


Chapter 3  Development of engineered osteon-mimetic bone tissue
1    Abstract    54
2    Design, principle and simulation    55
2.1    Bone structure    55
2.2    Design concept of dielectrophoresis………..    58
2.3    Biochip design for osteon-mimetic bone cell patterning    60
2.4    Operation principle of osteon-mimetic bone cell patterning    61
2.5    Numerical simulation of field-enhanced dielectrophoresis    62
3    Materials and methods    65
3.1    Microfabrication processes    65
3.2    Cell culture of human fatel osteoblasts (hFOB)    67
3.3    Preparation of FITC-hydroxyapatite-PLGA microparticles    67
3.4    Cell preparation for DEP manipulation    67
3.5    Surface modification for enhancing the cell-to-substrate adhesion    68
    and establishing extracellular bone matrix    68
3.6    Experimental apparatus for osteon-mimetic bone cell patterning    68
3.7    Liquid regulation processes inside the microfluidic chamber    69
3.8    Cell viability assay    69
3.9    Confocal microscopy setup and 3D image analysis    70
4    Results and discussions    71
4.1    DEP characterization    71
4.2    In-parallel manipulation and on-chip culturing of bone cell pattenring    72
4.3    Cell viability assesment in sugar buffer and AC field treatment    75
4.4    Characterization of pearl-chain effect via 3D image reconstruction    79
4.5    Cell adhesion enhancement via extracellular matrix (ECM) coating    83
    and medium regulation    83
4.6    Heterogeneous integration of osteoblasts and hydroxyapatite    85
    microparticles via the enhanced DEP cell patterning    85
5    Conclusions    90

Chapter 4  Development of centimeter-scale construction of lobule-mimetic liver tissue
1    Abstract    92
2    Design, principle and simulation    94
2.1    Design of large-area liver cell patterning microfluidic chip    94
2.2    Operation principle of lobule-mimetic liver cell patternin    98
3    Materials and methods    100
3.1    Microfabrication processes    100
3.2    Cell culture    103
3.3    Cell preparation for DEP manipulation    103
3.4    Surface modification of Type I collagen    104
3.5    Experimental apparatus for liver cell patterning    104
3.6    Liquid regulation processes inside the microfluidic chamber    105
3.7    Cell viability assay    106
4    Results and discussions    106
4.1    DEP characterization    106
4.2    Massively-parallel manipulation and on-chip culturing of liver cell.    118
    patterning.    110
4.3    In-situ cel viability assessment for DEP cell pattenring.    112
4.4    Centimeter scale construction and heterogeneous integration of    114
    HepG2 cells and HUVECs via the enhanced DEP cell patterning.    114
5    Conclusions    119


Chapter 5  General discussion
1    Target and trend    122
2    The available force in the microscale    124
3    Selection of positive or negative DEP as cell manipulation force    129
4    Comparison between simulation and experimental results    130
5    Effect of electric field treatment on DEP manipulated cell    136
5.1    Heat production form joule heating    136
6    Effect of medium on DEP manipulated cell    142
6.1    Effect of medum conductivity on DEP force    142
6.2    Effect of medum conductivity on cell viability    144
7    Uniformity of cell patterning    146
8    General rules and key parameters    149
9    Towards the 3D cell patterning    151


Chapter 6  Conclusions and future perspectives
1    Conclusion    154
2    Future perspectives    158

References        161
List of publications and patents    …. 168

                                

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