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研究生：	黃順和 Huang, Shun-Ho
論文名稱：	微電極陣列平台於三維神經網路與神經疾病應用之建立與特性描述 Development and Characterization of Microelectrode Arrays Platform for Three-Dimensional Neuronal Network and Neurological Disease Applications
指導教授：	陳家進 Chen, Jia-Jin
學位類別：	博士 Doctor
系所名稱：	工學院 - 生物醫學工程學系 Department of BioMedical Engineering
論文出版年：	2014
畢業學年度：	102
語文別：	英文
論文頁數：	114
中文關鍵詞：	微電極陣列、三維細胞培養、電阻抗量測、膜外電紀錄、彈性電極、缺血缺氧中風、過磷酸化蛋白質tau 、阿茲海默疾病傳遞
外文關鍵詞：	Microelectrode arrays, 3D cell culture, Impedimetric sensing, Extracellular recording, Flexible neuroprobe, Oxygen glucose deprivation, Insulin-like growth factor 1, Hyper-phosphorylated tau, Alzheimer’s disease propagation
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神經網路電生理特性描述對於了解功能性神經網路行為扮演其重要角色。以微電極陣列為主的電阻抗量測與膜外電生理紀錄平台，藉由穩定神經細胞培養技術，可提供動態與長期觀測神經網路行為觀測。此研究目的為利用微電極陣列平台來比較體外培養與活體三維神經網路之電生理特性，並利用此平台之高度整合性，於二維體外培養神經網路下建立體外培養缺血缺氧中風與阿茲海默症等神經疾病模型應用。
為架構出三維體外神經網路，首先將大腦皮質神經細胞培養於Matrigel介質中，生長成具有不同深度之三維神經突觸分佈，且具有與二維體外細胞培養相近細胞存活率。於電阻抗量測結果中，神經網路成長與其電阻性成分具備漸增相關性。於膜外神經電生理紀錄結果中，可藉由神經活化模式與神經活化分布分析，提供三維神經網路之功能性證明。為進一步於複雜腦部組織中進行體內植入電生理訊號量測，此研究利用SU-8設計並製作出體內植入彈性探針，於體外與體內神經電生理紀錄中顯示出比傳統硬式神經植入探針更好的組織適應性。且藉由一連串機械與生物毒性測試: 體外機械性質、體外生物毒性測試、活體電生理訊號紀錄與活體免疫螢光染色結果可得到，SU-8彈性神經植入探針具有足夠的機械強度來進行手術植入，且由於其彈性機械性質可達到減少植入免疫反應，進一步得到高於七以上之高品質訊雜比神經訊號。
於神經疾病探討研究中，我們建立可以用來探討神經病理機制之體外神經疾病模型，如體外缺血性中風與近似阿茲海默症之Tau蛋白質異常沉積疾病模型。於體外缺血性中風模型建立探討中，首先藉由微循環環境產生缺血缺氧性中風，利用電阻抗量測於正常與受到生長素介質保護下之大腦皮質細胞進行電阻抗量測。於生物性測試證據中，經由50與100 ng/mL生長素介質保護之大腦皮質細胞顯示出較高的細胞存活率，且於粒線體膜電位表現中無過極化現象之產生。於電阻抗量測結果中，大腦皮質神經細胞經過缺血缺氧後，電阻抗值降低直接反應出細胞貼附性減少。但於50 and 100 ng/mL生長素介質保護之大腦皮質細胞電阻抗量測結果可發現，經過缺血缺氧實驗後，其阻抗值呈現緩慢減少到進行缺血缺氧實驗前的50%，此結果明顯表示，50 and 100 ng/mL生長素介質保護大腦皮質細胞具備較佳細胞貼附。此多時間點連續電阻抗量測結果證明，利用整合微循環系統微電極陣列平台，可於缺血缺氧中風模型下進行即時觀測，且可觀察大腦皮質細胞由生長素介質保護下之效果。
為建立體外阿茲海默症模型，此研究設計以神經突觸連結之健康與疾病大腦皮質神經元族群，應用於了解疾病傳遞之結構與功能差異。結構性資料可藉由螢光影像取得過磷酸化蛋白質tau與神經骨架變化，功能性資料則由膜外電紀錄計算其神經自發性動作電位數量比值與神經自發性大量活動數值比。於結構性結果中觀察得知，於疾病神經元族群中經由okadaic-acid誘發之過磷酸化蛋白質tau透過神經突觸連結區域，進一步對於健康神經元族群產生影響。此延遲性之神經分支退化現象可由免疫螢光影像證明其產生疾病傳遞現象。於功能性結果中觀察得知，其產生出先於結構性改變(神經分支退化)之直接反應電生理形態改變 (神經自發性動作電位數量比值降低)。利用此體外模擬疾病傳遞模型，可進一步提供挑選合適的疾病治療方法或標靶機制選擇的驗證系統。
整體來說。此研究提出之微電極陣列平台可提供活體/體外培養之三維神經網路電生理特性描述，且利用高度整合性之病態生理模型建立特殊神經疾病模擬應用。於此研究成果中得知，藉由普通生理或病理環境下之神經元培養模型可提供一個探討三維神經網路之特性描述，且呈現出其應用於神經疾病治療機制探討的重要性。

Electrophysiological characterization of neuronal networks plays important roles on understanding functional network behaviors. Microelectrode arrays (MEAs)-based platform with impedimetric sensing and extracellular recording could not only monitoring the onset dynamic neuronal network behavior but also with highly feasibility working as long-term observation tool thorough stable cell culture environment. The aims of this study are utilizing MEAs-based platform for comparing fundamental electrophysiological properties of in vitro/ in vivo 3D neuronal network. It also proven with the capacities works as in vitro 2D neurological disease models for ischemic stroke and Alzheimer’s disease (AD) model for pathological mimicking condition.
For constructing 3D neuronal network, cortical neuronal cells were cultured on Matrigel which could grow in a 3D distribution with neurite extension in different depths and exhibit comparable cell survival rate to 2D neuronal culture. The impedimetric measurement was applied to monitor the neuronal growth which was correlated to gradual increase of resistive component of impedance. The neuronal firing pattern exhibited typical spike waveform. The spike raster plot also proved the functional activity of 3D neuronal network. For In-vivo recording, a flexible neuroprobe using SU-8 was designed and fabricated as implant device for complex brain tissue. In vitro and in vivo electrical sensing showed that the improved tissue compatibility compared to that of the traditional rigid neuroprobe. The validation of neuroprobe was achieved by in vitro mechanical and cytotoxicity tests as well as in vivo neural recording and immunohistological staining. Our studies showed that SU-8 neuroprobe possessed enough stress for pentrated into brain tissue and remained flexibility to comply micro-movement of soft tissue with minor immune responses. The proposed SU-8 neuroprobe can achieve in vivo electrophysiological recordings at a signal-noise-ratio of greater than 7.
The in vitro neurological disease models provide an opportunity for getting insight into the pathological mechanism of diseased neuronal networks including ischemic stroke model and AD-like tauopathy model in this study. For the in vitro ischemic stroke model, we utilized impedimetric sensing technique for monitoring the time-course impedimetric changes in normal and insulin-like growth factor 1 (IGF-1)-protected cortical neurons under the ischemic insult of oxygen glucose deprivation (OGD) created in a micro-perfusion environment. From biological evidences, the cortical neurons treated with 50 and 100 ng/mL IGF-1 showed higher survival rates and no occurrence of the hyperpolarization of MMP during the re-oxygenation period. The impedimetric sensing results demonstrated that the measured impedance of cortical neurons decreased due to cell detachment under the insult of OGD. The measured impedance of IGF-1-protected cortical neurons slowly decreased to about 50% of the original value compared to saline control which indicates improved cell adhesion under OGD conditions. The time-course impedimetric sensing results showed that the proposed MEAs-based platform incorporated with a microperfusion environment can be used for the real-time monitoring of cortical neurons under in vitro OGD and the IGF-1 protective effect against OGD-induced ischemic neuronal death.
For AD disease model, we designed the disease propagation through a simple in vitro cortical neuronal network which were used for investigating the structural and functional differences between diseased and healthy neuronal populations at an axon-connected manner. The structural data via hyper-phosphorylated tau (hp-tau) and cytoskeleton alternation were captured from fluorescence imaging. Also, the functional data via spike number ratio and burst number per minute ratio were calculated from extracellular recording. From the structural data, we observed a disease propagation from diseased neuron population (hp-tau induced by okadaic-acid (OA) treatment), spreading through an axon-connected region then affecting the healthy neuron. The delayed response of neuritic degeneration from diseased neuron population propagated to the healthy neuron population was also observed through the neuronal cytoskeleton alternation from immunocytochemistry staining. From the functionality of AD cell models, we observed immediate electrophysiological pattern changes (spike number decreased) prior to the structural alternation occurring (neuritic degeneration). With advance in this simulated disease propagation model, the candidate treatment method or possible target mechanism could be validated.
In summary, this proposed MEAs-based platform provides electrophysiological characterization functionalities for in vitro/in vivo 3D neuronal network and also with integrated pathological environmental setup opens the way for specific neurological application. Our designed physiological/ pathological neuronal culture model not only could help the investigation of fundamental electrophysiological properties of 3D neuronal network but also reveal the potential treatment mechanism through neurological disease simulation environment.

Contents
致謝	IV
中文摘要	V
Abstract	VII
Contents	X
List of Tables	...XIIII
List of Figures	...XIIII

Chapter 1 Introduction
1.1 Introduction to planar microelectrode arrays	1
1.2 Impedance measurement of the neuron-electrode interface	2
1.3 Extracellular stimulation and recording of in vitro neuronal networks	3
1.4 Three-dimensional cell culture	4
1.5 Three-dimensional microelectrode arrays	6
1.6 Impedance measurement for in vitro 3D cellular environment	7
1.7 Extracellular recording of in vitro 3D neuronal networks	8
1.8 Novel flexible microelectrode arrays	9
1.9 Toward disease model application: in vitro ischemic stroke model	10
1.10 Impedimetric monitoring for in vitro ischemic stroke conditions	11
1.11 Toward disease model application: in vitro Alzheimer’s disease model	12
1.12 Hyper-phosphorylated microtubule-associate protein tau in Alzheimer’s disease	12
1.13 Compartmentalized microfluidic neuronal culture	13
1.14 The aims of this study	14

Chapter 2 Material and Methods
2.1 Fabrication and characterization of 3D tip-based MEAs	17
2.1.1 Fabrication process of 3D tip-based MEAs	17
2.1.2 In vitro 3D cortical neuronal culture	18
2.1.3 Florescence imaging of in vitro 3D cortical culture	19
2.1.4 Electrophysiological characterization of in vitro 3D neuronal networks	19

2.2 Fabrication and characterization of SU-8 Flexible Neuroprobe	20
2.2.1 Design and fabrication of SU-8 neuroprobe	20
2.2.2 Evaluation of mechanical properties of SU-8 neuroprobe	22
2.2.3 In vitro viability test and extracellular recording using neuroprobe	24
2.2.4 In vivo electrophysiological recording and immunobiological assays	24

2.3 Impedimetric monitoring of IGF-1 protection of in vitro cortical neurons under
   ischemic conditions	27
2.3.1 Fabrication of microelectrode arrays	27
2.3.2 Cell culture and oxygen-glucose deprivation model	28
2.3.3 Impedance sensing under normal and OGD conditions	30
2.3.4 Measurement of cell viability and mitochondrial membrane potential	32
2.3.5 Statistical analysis	33

2.4 Disease Propagation of Okadaic Acid-Induced Tauopathy Model via
 Compartmentalized MEAs Device	33
2.4.1 Design and integration of compartmentalized microfluidic device with 
MEAs	33
2.4.2 Preparation and plating procedure for cortical neuronal culture	36
2.4.3 Induction of tau-hyperphosphorylation via okadaic acid treatment	37
2.4.4 Extracellular recording of cortical neuronal population inside
 compartmentalized MEAs	38
2.4.5 Immunocytochemistry staining	39
2.4.6 Statistical analysis	40

Chapter 3 Results 
3.1 Fabrication and characterization of 3D tip-based MEAs	41
3.1.1 Fabrication of 3D tip MEAs	41
3.1.2 Morphological observations and cell viability of 2D versus 3D cell culture	41
3.1.3 Impedimetric sensing of in vitro 3D neuronal network formation	43
3.1.4 Extracellular recording of in vitro 3D neuronal activities	45
3.2 Fabrication and characterization of SU-8 Flexible Neuroprobe	46
3.2.1 Fabrication and electrical characterization of SU-8 neuroprobe	46
3.2.2 Mechanical characterization of SU-8 neuroprobe	48
3.2.3 In vitro cytotoxicity testing assay and extracellular physiological recording	50
3.2.4 In vivo immune response and electrophysiological recording	52
3.3 Impedimetric monitoring of IGF-1 protection of in vitro cortical neurons under
      ischemic conditions	54
3.3.1 Time-course resistive component of impedance monitoring of cell growth
 on the electrode	54
3.3.2 Cell viability assessment	56
3.3.3 MMP assay	57
3.3.4 Time-course resistive component impedance monitoring of OGD-induced
cell detachment	59
3.4 Disease Propagation of Okadaic Acid-Induced Tauopathy Model via 
Compartmentalized MEAs Device	60
3.4.1 Compartmentalized microfluidic device integrated with MEAs	60
3.4.2 Cytoskeleton alternation under OA-induced disease propagation	61
3.4.3 Propagation of tau hyper-phosphorylation between diseased and healthy
 Neuronal populations	64
3.4.4 Spike number ratio of spontaneous activities during disease propagation	67
3.4.5 Bursts per minute ratio of spontaneous activities during disease propagation	68

Chapter 4 Discussion
4.1 Fabrication and characterization of 3D tip-based MEAs	71
4.2 Fabrication and characterization of SU-8 Flexible Neuroprobe	73
4.3 Impedimetric monitoring of IGF-1 protection of in vitro cortical neurons under
      ischemic conditions	76
4.4 Disease Propagation of Okadaic Acid-Induced Tauopathy Model via 
Compartmentalized MEAs Device	80

Chapter 5 Conclusion	88

References	91



List of Tables
Table 1 Summary of numerical data of spike number ratio and bursts per minute ratio under high and low concentration (600 nM and 60 nM, respectively) of OA treatment at all selected experiment time period  	70

List of Figures
Figure.1 (a) Fabrication process of 3D tip MEAs. (b) Scanning electron microscopic imaging of tip structure. (c) Assembled 3D tip MEAs with external PCB for interfacing extracellular recording hardware.	18
Figure 2 Schematic representation of the fabrication processes for SU-8 neuroprobe in oblique and cross section views. (a) E-beam evaporation of Al sacrificial layer on a glass substrate, (b) spin-coating and definition of SU-8 neuroprobe pattern, (c) E-beam evaporation of Ti/Au electrode layer, (d) spin-coating and definition of electrode trace and pad by photoresist (PR), (e) etching of unwanted metal using wet etching solution, (f) removal of photoresist via acetone wash, (g) spin-coating and definition of opening via SU-8 patterning, (h) release of complete SU-8 neuroprobe via etching of Al sacrificial layer, and (i) layout of SU-8 neuroprobe with two groups of microelectrode for two different depths of brain regions, i.e. cortex and striatum....	22
Figure 3 Mechanical analytical model of SU-8 neuroprobe during insertion process	23
Figure 4 Schematic diagrams of the fabrication of MEAs. (a) A 15-µm-thick photosensitive PI film was utilized as the substrate for the deposition of metals. (b) A gold layer (2000 Ǻ) was then deposited after a titanium layer (200 Ǻ) as the adhesion layer above the PI. Mask 1 was used to create the trace of electrodes by wet etching. (c) A gold electrode and pad trace pattern was formed by etched away unwanted metal then followed by removed the photoresist. (d) 20-µm-thick spin-coated PI film was used to encapsulate the electrodes. Mask 2 was then applied to expose microelectrodes and contact pads. (e) MEAs were then baked at 100 °C for 1 hr. The fabricated MEAs has total 60 microelectrodes and each active electrode site has diameter of 50 μm in circle.	28
Figure 5 Schematic diagram of microperfusion OGD system with electrophysiological measurement functionality. Whole measurement system could be easily equipped into inverted microscope for real-time observation of cell behavior.	30
Figure 6 Photos  of (a) integrated devices consisting of compartmentalized microfluidic device and microelectrode array; (b) microscopic view of three culture region with twenty microelectrode arrangement; (c) fluorescence imaging of separated neuronal population connected with axons (green: MAP II, red: Smi 312, blue: DAPI).  ..	36
Figure 7 Phase-contrast microscopic imaging for observing of morphological difference between 2D and 3D neuronal culture: (a) 2D neuronal network in petri-dish surface, (b) 2D neuronal culture in 3D tip MEAs surface, (c) Matrigel-based 3D neuronal culture inside petri-dish culture, (d) Matrigel –based 3D neuronal culture inside 3D tip MEAs culture..	42
Figure 8 Cell viability of 2D and 3D neuronal culture during 21 DIVs culture period. The observation time point was selected as following: after 4 hours cell seeding as 0 DIVs, 7 DIVS, 14 DIVs and 21 DIVs, (n=10, *p<0.05). The cell viability was calculated as the number of live cells divided by the sum of live and dead cells 	43
Figure 9 Impedimetric measurement results during 2D and 3D neuronal network formation during 21 DIVs culture period.....	44
Figure 10 Typical extracellular recorded spike from in vitro 3D neuronal network after 17 DIVs culture period	45
Figure 11 Spike raster train from in vitro 3D neuronal network after 17 DIVs culture period.	46
Figure 12 SEM images of SU-8 neuroprobe of  (a) whole probe structure and  (b) one group of microelectrodes with four microelectrodes for electrophysiological recording (circular shape) and one reserved for future integration of electrochemical sensing (rectangular shape). Higher magnification of (c) single recording microelectrode and (d) wire bonding to external PCB for recordings...	47
Figure 13 Mechanical evaluation of SU-8 neuroprobe during insertion process and images acquired during (a) buckling test and (b) bending test...	49
Figure 14 Insertion and retraction behavior of flexible SU-8 neuroprobe during three different samples. The insertion resistance force exhibited different patterns for 0.6% agar brain phantom (solid line), brain with dura and pia (dotted line), and brain with pia only (dashed line). The insertion of neuroprobe was operated at fixed speed of 100 µm/s to around 6 mm in depth. Before retraction at 80 sec, the resistance force dropped to about zero after insertion....	49
Figure 15 Cytoxicity test of SU-8 neuroprobe. Cortical neurons cultured in culture dish for (a) 7 DIVs and (c) 14 DIVs. Cortical neurons cultured on SU-8 neuroprobe for (b) 7 DIVs and (d) 14 DIVs. (e) Quantification of cell viability for culture and neuroprobe (N=10 for each group)....	51
Figure 16 Extracellular spontaneous action potential of cortical neurons cultured on SU-8 neuroprobe was recorded from 17-DIV cortical neurons, (a).  Magnified view of signals recorded from SU-8 neuroprobe can be distinguished from background noise, (b)....	52
Figure 17 Immunohistological staining of tissue reaction around implantation site. Anti-MAPII/GFAP staining around implanted neuroprobe in (a) cortex region and (b) striatum 14 days after implantation (anti-MAPII stained red for neuron marker; anti-GFAP stained green for astrocyte marker)....	53
Figure 18 (a) Electrophysiological recording of neural signals after SU-8 neuroprobe implantation. Two action potential signals extracted from those marked with arrows in (a)with (b) minimum and (c) maximum SNR....	54
Figure 19 Time-course monitoring results of impedance of cells on the electrode over 7 DIVs (n=4). The curve of cortical neuron represents neurons cultured for 7 DIVs. The cells were deliberately damaged on day 8 via adjustment of osmolarity....	55
Figure 20 Cell viabilities of control and IGF-1-protected (50 ng/mL and 100 ng/mL) group of rat cortical neurons before OGD, after 30-min of OGD, and after 24 hr of re-oxygenation (re-oxy), (n=4, *p < 0.05). The cell viability was calculated as the number of live cells divided by the sum of live and dead cells....	57
Figure 21 Normalized JC-1 fluorescence change of normal and IGF-1-protected (50 ng/mL and 100 ng/mL) cortical neurons during 30-min of OGD and 2 hr of re-oxygenation. JC-1 fluorescence was normalized and valinomycin was used to force the MMP to be at the level of depolarization....	58
Figure 22 Impedimetric monitoring results of normal and IGF-1-protected rat cortical neurons during 30-min of OGD and controls without OGD insult....	60
Figure 23 Pictures of (a) microscopic view of three culture region with twenty microelectrode arrangement, (b) fluorescence imaging of separated neuronal population connected with axon (green: MAP II, red: Smi 312, blue: DAPI)....	61
Figure 24 The diseased and healthy neuronal population under OA and without treatment. The cytoskeleton alternation visualized as green color by MAP II immunocytochemistry staining for  (a) high concentration OA treatment (600 nM), (b) low concentration OA treatment (60 nM).,,....	63
Figure 25 Disease propagation process during high concentration OA treatment (600 nM). Hp-tau was visualized as green color by pS262 immunocytochemistry staining.....	66
Figure 26 Disease propagation process during low concentration OA treatment (60 nM). Hp-tau was visualized as green color by pS262 immunocytochemistry staining....	66
Figure 27 Spike number ratio acquired by extracellular recording during two concentration of OA treatment (600 nM, 60 nM) which represented the functional pattern changed during disease propagation, (N = 5, * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.005), The spike number ratio was calculated as the value of each recovery period (75min + 0h, 6h, 24h and 48h) divided by the value of before 75min OA as control value.....	68
Figure 28 Bursts per minute ratio acquired by extracellular recording during two concentration of OA treatment (600 nM, 60 nM) which represented the functional pattern changed during disease propagation, (N = 5, * p < 0.05, ** p < 0.01, *** p < 0.005, **** p < 0.001), The bursts per minute ratio was calculated as the value of each recovery period (75min + 0h, 6h, 24h and 48h) divided by the value of before 75min OA as control value....	70
 

                                    

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