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研究生：	林淑萍 Lin, Shu-Ping
論文名稱：	神經元介面微電極陣列之製造與體外特性描述 Fabrication and In-Vitro Characterization of Microelectrode Array for Neuronal Interfaces
指導教授：	陳家進 Chen, Jia-Jin
學位類別：	博士 Doctor
系所名稱：	工學院 - 醫學工程研究所 Institute of Biomedical Engineering
論文出版年：	2008
畢業學年度：	96
語文別：	英文
論文頁數：	93
中文關鍵詞：	三維細胞培養基質、多點式神經元介面微電極、生物相容性、降解性材料、表面改質、阻抗量測、自我排列單分子膜
外文關鍵詞：	self-assembled monolayers, degradable biomaterials, biocompatibility, 3D cell matrix, impedance measurement, surface modification, MEA
相關次數：	點閱：96 下載：1
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本研究主要是利用體外分析量測方法探討表面改質之神經元介面多點式微電極於未來體內植入為需求之應用。藉由微機電製程的技術（MEMS techniques）製造出兩種不同以聚亞醯胺（PI）為基底之多點式神經元介面的金微電極，包括培養皿式平面微電極（Petri-dishlike planar MEA）及軟性神經植入式電極（flexible neural implant）。利用MUA的自我排列單分子膜（SAMs）進行培養皿式微電極的表面改質處理。為了增加培養皿式微電極的生物相容性，選用具有生物活性的分子—PDL固定於經MUA自我排列單分子膜修飾過的電極上。紅外線光譜儀（FTIR）的頻譜顯示其表面處理後具有特殊的共價鍵結（covalent bonding）化學官能基，其分別為醯胺I鍵結（1,613 cm-1）及醯胺II鍵結（1,548 cm-1）。以阻抗量測儀測量未經表面改質與經表面改質過後培養皿式平面微電極的阻抗變化，發現改質過後的電極阻抗從原本的352.9 ± 34.4 kΩ稍微升高至524.6 ± 55.8 kΩ（p<0.05, N=20）。此外，經由七天連續量測隨時間變化之總阻抗（由實部電阻及虛部阻抗值組成）實驗中，可以進一步推得細胞株是否健康生長接觸於電極上。藉由細胞株及活體細胞培養於修飾過後電極上，證實有非常良好的生長結果。在另一方面，軟性神經植入式電極因為具有較小的硬度，所以在植入後可以順應組織的變化以減少不必要的組織傷害。然而，軟性神經植入式電極因為有彎曲效應以致於無法穿透軟性組織。因此，PDL混合於聚乙二醇凝膠（PEG）合成之PEGDL凝膠，可以應用於批覆於軟性神經植入式電極上用以增加電極的硬度。利用紅外線光譜儀及掃瞄式電子顯微鏡（SEM）分析凝膠的化學鍵結成分、降解反應及凝膠表面的觀察。這些體外分析顯示均質地披覆凝膠於軟性神經植入式電極除了可以增加電極的硬度，而且披覆的凝膠也會隨著時間產生降解。另外，所披覆的PEGDL凝膠於體外細胞測試結果顯示具有很良好的生物相容性。掃瞄式電子顯微鏡分析顯示額外的生物活性的分子—laminin於PEGDL凝膠中可以提供神經細胞更良好的生長環境。生化測試顯示神經細胞在軟性神經植入式電極以及披覆凝膠之軟性神經植入式電極具有神經細胞固有的功能特性。所以，PEGDL凝膠披覆可以提供軟性神經植入式電極足夠的硬度及增加其生物相容性。最後，本研究亦探討結合培養皿式平面微電極與PEGDL凝膠，進一步用阻抗量測探討細胞在三維空間下的動態特性描述。在連續八天之動態阻抗量測實驗中，可推估細胞在三維結構空間下生長的情形。另外，一系列的生物相容性測試驗證此一三維細胞培養基質不但可以提供一適合細胞生長的環境。亦可以在平面電極上架構一仿生性的系統以提供未來有效電生理刺激量測之計畫及診斷檢驗。

This study aims to investigate surface-modified microelectrodes on the microelectrode arrays (MEAs) for neuronal interfaces with in vitro cell culture. Two kinds of polyimide (PI) MEA, including Petri-dishlike planar MEA and flexible neural implant (NI), were fabricated by using micro-electro-mechanical systems (MEMS) techniques. Self-assembled monolayers (SAMs) of 11-mercaptoundecanoic acid (MUA) were utilized to modify the microelectrode surface of the planar MEA. To increase biocompatibility, the poly-D-lysine (PDL) was immobilized on the SAMs' modified microelectrodes. Spectra of the Fourier transform infrared reflection (FTIR) revealed that covalent amide bonding, amide I (at 1,613 cm-1) and amide II (at 1,548 cm-1), existed in PDL-MUA-SAMs modified surfaces. The impedance measurement of PDL-MUA-SAMs modified MEA only increased slightly to an average of 524.6 ± 55.8 kΩ from 352.9 ± 34.4 kΩ of bare gold microelectrode (p<0.05, N=20). In order to infer the growth of cell lines on the electrode contact of modified MEA, the time-course changes of total impedance resulting from cell sealing resistance and gap reactance were recorded for 7 days. The experiment of cell-line and primary-cell culture on the modified MEAs displayed a good adhesion rate.
On the other hand, flexible NIs with reduced stiffness are desirable for future implantation applications. Implantable NIs require the flexibility to conform to tissue movement, but they can easily affected by bending effect on mechanical properties and subsequently render them incapable of penetrating soft tissues. Poly(ethylene glycol) hydrogel supplemented with PDL (PEGDL) as a coat for flexible NIs was synthesized to enhance the stiffness of material surface. The PEGDL-coated and uncoated NIs were compared the mechanical properties by tensiometry. FTIR microscopy and scanning electron microscopy (SEM) were employed to characterize the chemical bonding, degradation, and surface topography of the PEGDL coat. These analyses indicated that a homogeneous coating increased the stiffness of NIs and the coating can be degraded over time in in-vitro tests. The ability of our coated implants to support the growth and differentiation of NIH3T3 fibroblasts and cortical neurons in vitro was examined as a measure of biocompatibility and found to be excellent. Furthermore, Western blot analysis of cell lysates from neurons treated with glutamate indicated proper neuronal function on our engineered material. Our observations indicate that PEGDL coating exhibits an increase in stiffness and improvement in biocompatibility.
Finally, the combination of PEGDL on surface-modified planar MEA was constructed to characterize the cell growth on 3D matrix MEA by using impedance measurement. The time-course changes of total impedance, cell sealing resistance, and gap reactance were recorded for 8 days for inferring the growth of cells in the 3D culture hydrogel system on the MEA. In addition, serial biocompatibility assays demonstrated that 3D matrix can not only provide a good environment for cell growth but also construct a biomimetic system on our planar MEA for effective electrophysiological stimulation/sensing schemes or diagnostic examinations in the future.

Qualified certification of oral defense ..................I
Chinese abstract .......................................III
Abstract..................................................V
Acknowledgements in Chinese............................ VII
Contents ..............................................VIII
List of Tables.........................................XIII
List of Figures........................................ XIV

Chapter 1 Introduction................................... 1
1 Introduction of MEA.................................. 1
2 Cogitation of MEA.....................................3
3 Surface modification – self-assembled monolayers ....3
4 Biocompatibility .................................... 5
5 Impedance measurement................................ 6
6 Considerations of flexible interface................. 7
7 Aims of this study ................................. 10

Chapter 2 Materials and Methods......................... 12
1 Fabrication of MEA ................................. 12
2 Characterization of surface-modified planar MEA..... 14
2.1 Surface modification for planar MEA .............. 14
2.2 FTIR analysis .................................... 15
2.3 Surface topography for planar MEA................. 16
3 Impedance evaluation of surface-modified planar MEA..16
4 Assessments of biocompatibility of planar MEA ...... 18
4.1 Preparation of cell lines and primary cultures.... 18
4.2 Cell adhesion rate and growth assays ............. 19
5 PEGDL synthesis and flexible NI electrode coating... 20
6 Characterization of hydrogels ...................... 22
6.1 Mechanical test................................... 22
6.2 FTIR analysis .................................... 22
6.3 Evaluation of degradation......................... 22
7 Biocompatibility of hydrogel........................ 23
8 Western blot for neuronal function.................. 25
9 Application of hydrogel on planar MEA .............. 26
10 Characterization of 3D matrix on planar MEA ....... 27
10.1 Quantification of degradation of 3D matrix....... 27
10.2 FTIR analysis for degraded 3D matrix............. 28
10.3 Swelling test and degraded area evaluation of 3D matrix.................................................. 28
11 Cell growing on 3D matrix MEA ..................... 28
11.1 Cell culture..................................... 28
11.2 Cell viability assay............................. 29
11.3 Fluorescent observation.......................... 29
11.4 Impedance measurement for 3D matrix MEA.......... 30

Chapter 3 Results....................................... 32
1 Appearance of MEA .................................. 32
2 Quantification of chemical bonding on surface-modified Petri-dishlike MEA. .................................... 33
3 Quantifying the surface-modified Petri-dishlike MEA..36
4 Impedance evaluation for cell lines cultured on modified Petri-dishlike MEA. ........................... 38
5 Biocompatibility studies for Petri-dishlike MEA..... 41
6 Synthesis and characterization of hydrogel.......... 44
6.1 Synthesis of hydrogel ............................ 44
6.2 Mechanical property............................... 45
6.3 Characterization of chemical bonding on PEGDL-coated NI ..................................................... 47
6.4 Qualitative and quantitative analysis of degradation of hydrogel ............................................ 49
7 Assessments of biocompatibility for physical coating NI ..................................................... 51
8 Biochemical assay for neuronal function ............ 56
9 Characterization of a 3D cell culture hydrogel in in-vitro planar MEA........................................ 57
9.1 Evaluation of degradation of 3D matrix ........... 57
9.2 Characterization of chemical bonding of degraded 3D matrix ................................................. 58
9.3 Swelling test and degraded-area evaluation of 3D matrix ................................................. 59
10 Cell viability and fluorescent image on 3D matrix MEA .................................................... 61
11 Impedance evaluation for 3D matrix on MEA ......... 65

Chapter 4 Discussion ................................... 71

Chapter 5 Conclusions................................... 79

References.............................................. 81

Appendix................................................ 91
                                    

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校內：2009-01-28公開
校外：2009-01-28公開

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