无线光刺激与神经传感系统

光遗传神经调控正在向闭环技术发展,针对实验动物可自由活动的需求,研发具有大范围光刺激、神经信号同步记录、无线程控等功能的无线光刺激与神经传感系统。该系统包括光刺激—电记录神经接口、刺激传感模块、无线收发模块以及上位机软件。可无线实时调节光刺激频率、幅度和占空比等参数,并同步采集神经信号。给予小鼠刺激运动皮层30Hz光刺激,小鼠运动明显增强,同时记录到刺激诱发的脑电信号。系统为光遗传技术提供多功能神经调控平台,有助于神经环路和神经疾病的长时程研究。     

基于PCA和改进K均值算法的动作电位分类

微电极阵列记录的神经元信号往往是电极临近区域数个神经元的动作电位信号以及大量背景噪声的混叠,研究神经系统的信息处理机制以及神经编码、解码机理需了解相关每个神经元的动作电位,因此需从记录信号中分离出每个神经元的动作电位.基于此,提出基于主元分析(PCA)和改进K均值相结合的动作电位分类方法.该方法采用PCA提取动作电位特...     

局部场电位和微分特性影响下神经元网络发放锋电位的检测

在利用多电极阵列(multielectrode arrays,MEA)记录离体培养海马神经元网络的电生理研究中,发现电极附近神经元群体同步放电形成了局部场电位(local field potential,LFP),同时细胞外记录信号为跨膜电压信号的微分,这些因素使检测网络发放的锋电位遇到困难。为正确检测锋电位(spike),在综合比较多种检测方法的基础上,提出一种改进的峰值检测法,以0.6ms为判决阈值,有效解决了原峰值检测法因滑动窗分界导致的重复检测。通过该方法检测发育成熟的网络发放的锋电位,虚警率和漏报率分别为:5%±1%和2%±1%,效果优于传统的阈值检测法。上述结果表明,改进的方法适合于神经元网络电活动的研究。     

基于柔性印刷工艺的表面肌电电极阵列装置的设计

设计了一种基于柔性印刷工艺的表面肌电电极阵列装置。该电极阵列由12个直径1.2mm的镀金圆电极分成两列组成,内部电极间距为3mm。电极载体材料(聚酰亚胺,厚50μm)具有较高的机械柔性,表面镀金(厚度2μm)的电极具有较低的阻抗,特制的聚酯双面胶带用于可重复使用的电极阵列装置的固定。在单指力量输出任务时记录指浅屈肌的多通道表面肌电(surface Electromyogram,sEMG)信号的实验中得到了稳定的基线和较好的sEMG信号。初步的实验结果表明,设计的这种低成本、体积小的高密度电极阵列装置能用于表面肌肉空间sEMG信号的检测。     

用于长期神经元放电记录的一体化可步进植入式神经电极

步进式电极是神经科学电生理记录的重要工具。传统电极支架的主要功能是电极丝支撑以及机械驱动电极丝的微推进。在慢性记录过程中，电极的位置可以推进到更深的脑组织中，从而记录更多的神经元放电活动。但传统电极支架制作和组装需要多个步骤和部件，组装过程烦琐困难、结构集成度低，且无法保证支撑板结构之间相互平行，增加了实验误差。该文提出一种可实现集成度高、结构稳定、组装容易的新型电极构架。与传统电极支架相比，新设计的电极支架具有更少的组件，且一体化的支架设计减少了不同支架之间的误差，有助于实验条件的统一。受力分析表明，该文提出的新电极具有优良的抗形变特性，且新电极比传统电极重量更小，可减轻实验小鼠头部负载压力。通过手术在小鼠大脑中植入电极，实验结果表明一体化记录电极可获得高质量的神经信号。因此，该文提出了一种新的电极设计思路，该思路有助于提高实验效率，并可应用于多种小动物在体电生理实验。     

海马神经细胞网络传感器及其记录5-HT对网络活动的作用

海马神经网络活动在调节记忆和学习等行为中具有重要作用,而五羟色胺是调节此类行为的重要神经递质。目前,某些研究手段揭示了5-HT对海马神经元活动的作用,但是这些手段并没有直观展示海马神经元网络的电生理活动。因此,为了研究5-HT在体外海马神经元网络活动中的作用,本实验建立了微电极阵列（Microelectrode Array,MEA）的检测平台。利用60通道MEA芯片,可以实时无损地记录5-HT作用前后的多位点信号,实验结果证明5-HT对海马神经元的动作电位有抑制作用,但是对低频振荡没有明显变化。该实验表明,这种海马神经元网络传感器可以对神经元进行无损、长时间的记录。上述研究结果表明,这种新的细胞网络传感器有望成为神经元网络活动研究中的一种重要手段。     

基于Parylene的柔性神经微电极的研制和表征

衬底集成的微电极是植入式微系统中的重要部件,起着对神经进行电刺激并记录神经信号的关键作用。采用微细加工技术在新型柔性基底——聚对二甲苯(Parylene)上制作微电极阵列。阐述了Parylene基微电极阵列的加工工艺,并利用光学显微镜和电化学表征技术对微电极的表面形貌和电学性能进行了研究。结果表明:在工作频率范围内(104~105Hz),柔性神经微电极的阻抗值低(400~1000Ω),相位延迟小(-20°),适于用作视网膜修复。     

下丘脑背内侧核对焦虑的调控机制研究

下丘脑背内侧核(Dorsomedial Hypothalamic Nucleus，DMH)是自主神经系统的重要组成部分，同时与调控焦虑情绪的边缘系统存在广泛联系。然而，DMH 调控焦虑等负性情绪的细胞机制目前尚不明确。该文应用光遗传技术特异性调控小鼠的谷氨酸能神经元和 γ-氨基丁酸能神经元发现，兴奋 DMH 的谷氨酸能和 γ-氨基丁酸能神经元均能显著诱发焦虑样行为和心率上升，抑制两种神经元均能抑制焦虑样行为并降低心率。该研究证实了 DMH 特定类型的神经细胞对焦虑的双向调控作用，并有望为神经精神疾病的临床干预提供新的调控靶点。     

SpikeTools:用于神经元网络锋电位分类的软件

使用多电极阵列可无损的记录神经元网络的电活动，但是单个电极往往会同时记录到多个神经元的活动，因而需要将所记录的信号进行分类。本文通过幅度、形状、主成分等分类方法与聚类方法实现了对锋电位的分类，并在MATLAB平台下编写了相应的可视化软件spike Tools对模拟数据的分类结果表明：均有90％以上的锋电位得以正确归类。对实验数据的分类结果表明：阈值分类方法能对幅值有明显区别的锋电位进行合理分类，形状分类方法能对幅值接近的锋电位进行分类，而主成分分类方法区分波形的整体差异，能分离前两种方法难以区别的类；聚类方法可实现自动分类。开发的spike Tools软件能对各种锋电位群数据进行分类处理，为锋电位信号的分析提供了有力的工具。     

基于细胞电生理检测的在体及离体微电极设计仿真

生物传感器的微型和集成化为细胞电生理研究提供了强有力的手段.当前国内电极阵列设计的量化分析工具尚为欠缺.着重采用有限元工具分析电极形状对输出影响,对相同设计参数下圆形与矩形电极的电场分布进行比较;采用Monte-Carlo模型判断细胞与电极耦合的有效性,结果显示表面处理时,大分子生物素宜最后贴附处理以增大有效贴附率;采用SPICE工具对细胞并行电生理检测串扰性进行分析.结果说明细胞与电极的耦合性比阵列间距和数目对串扰影响更大.从而为有源电极的集成设计、细胞-电极耦合有效性和电生理测试提供量化分析工具.     

Ultra high aspect ratio penetrating metal microelectrodes for biomedical applications

Studying the functioning of the brain through the use of penetrating microelectrodes has revolutionized our understanding of the brain and has the potential to treat physical conditions such as the aftermath of a stroke, disease or other neural problems. Cochlear implant electrodes have transformed the lives of people who were suffering from cochlear auditory disorders. However, limitations of manufacturing procedures restrict the choice of work materials to mostly silicon based materials, and biocompatibility issues have constrained the extensive use of these devices. Metal microelectrodes can absolve this limitation and enable extensive study of the neural centers. In this paper we report the fabrication of tungsten penetrating microelectrodes using electrochemical machining. Ultra high aspect ratio penetrating metal microelectrodes with diameters 10 μm and below, with surface roughness (Ra) values in the range of 300–500 nm, have been fabricated by electrochemical machining process. Details regarding the fabrication process and a mathematical model developed for the electrochemical machining process are discussed in this paper.     

A polymer-based spiky microelectrode array for electrocorticography

The advanced technology of microelectromechanical systems (MEMS) makes possible precise and reproducible construction of various microelectrode arrays (MEAs) with patterns of high spatial density. Polymer-based MEMS devices are gaining increasing attention in the field of electrophysiology, since they can be used to form flexible, yet reliable electrical interfaces with the central and the peripheral nervous system. In this paper we present a novel MEA, designed for obtaining neural signals, with a polyimide (PI)—platinum (Pt)—SU-8 layer structure. Electrodes with special, arrow-like shapes were formed in a single row, enabling slight penetration into the tissue. The applied process flow allowed reproducible batch fabrication of the devices with high yield. In vitro characterization of the electrode arrays was performed with electrochemical impedance spectroscopy in lactated Ringer’s solution. Functional tests were carried out by performing acute recordings on rat neocortex. The devices have proven to be convenient tools for acute in vivo electrocorticography.     

Evaluation of microparticle materials for enhancing the performance of fluorescence lifetime based optrodes

Fiber optic based sensors have many advantages over electrochemical sensors, and as a result have broad application for sensing in agriculture, basic biology, the environment, and medicine. An important component of a fiber optic sensor is the sensing element, usually a solid-state matrix containing the analyte specific fluorescent dye, immobilized on an optical fiber. The fluorescence output of the dye can be calibrated to analyte concentration based on intensity or lifetime. The membrane matrix immobilizes and entraps the fluorescent dye molecules by providing the mechanical support at the optrode tip. The present study used micro- and nanoparticles of TiO₂ and microparticles of different materials (BaSO₄, Cr, CuO, diamond, Au, PbO and ZnS) to investigate the phenomena underlying the role of accessory materials for optrode performance enhancement. We found that 2 μm particles amplified fluorescence intensity better than 10–150 nm particles. Materials with high refractive indexes performed better, provided that they have low absorbance across the visible region. Microparticles with either high refractive indices or high reflectance will amplify the fluorescence output, but microparticles with both properties enhance optrode performance at lower dye concentrations. The results of these experiments have allowed us to engineer membrane microparticle content to optimize a platinum-tetra-fluoro-phenyl-porphyrin (PtTFPP) O₂ optrode.     

2,3-二巯基乙二酸自组装膜的电化学行为及应用研究

利用石英晶体微天平、电化学法、交流阻抗以及拉曼光谱法研究了2,3-二巯基乙二酸(DMSA)自组装膜的电化学性质及其在电极表面的组装过程.发现DMSA分子借助两个巯基自组装到了金电极表面.相对于在裸金电极表面,多巴胺和尿酸在此修饰电极表面的氧化峰电流均有明显的增加,且氧化峰电位大大降低,说明此自组装膜对于多巴胺和尿酸的氧化能够起到明显的电催化作用.     

Capacitive flexible pressure sensor: microfabrication process and experimental characterization

Kapton-based flexible pressure sensor arrays are fabricated using a new technology of film transfer. The sensors are dedicated to the non-invasive measurement of pressure/force in robotic, sport and medical applications. The sensors are of a capacitive type, and composed of two millimetric copper electrodes, separated by a polydimethylsiloxane (PDMS) deformable dielectric layer. On the flexible arrays, a very small curvature radius is possible without any damage to the sensors. The realized sensors are characterized in terms of fabrication quality. The inhomogeneity of the load free capacitances obtained in the same array is ±7 %. The fabrication process, which requires 14 fabrication steps, is accurate and reproducible: a 100 % transfer yield was obtained for the fabrication of 5 wafers gathering 4 sensor arrays each (215 elementary sensors). In the preliminary electro-mechanical characterization, a sensor (with a PDMS dielectric layer of 660 μm thickness and a free load capacitance of 480 fF) undergoes a capacitance change of 17 % under a 300 kPa normal stress.     

Design and fabrication of microlens arrays as beam relay for free-space optical interconnection

In this paper we report the design and fabrication of a beam relay for free space optical interconnection using microlens arrays. Multiple microlens arrays with same focal lengths were designed and fabricated in an out-of-plane layout. This design can be easily integrated with silicon-based optical interconnection devices. The beam relay was fabricated using direct lithography of SU-8 photoresist, and then replicated using UV curable polymer molded with a PDMS intermediate mold. The optical performance was tested and the experimental results show that the optical performances are mainly limited by the aberration of microlenses. Further study needs to be conducted to improve the surface quality of the lenses to reduce the aberrations.     

High-throughput battery materials testing based on test cell arrays and dispense/jet printed electrodes

A cost effective and reliable technology for the fabrication of electrochemical test-cell arrays for battery materials research, based on batch-fabricated glass micro packages was developed and tested. Jet dispensing was investigated for the first time as a process for fabricating battery electrode arrays and separators and compared to micro dispense printing. The process shows the reproducibility over the whole range of investigated materials and battery cell structures that is required for battery materials research. Such setup gives rise to a significantly improved reliability and reproducibility of electrochemical experiments. Cost-effective fabrication of our test chips by batch processing allows for their single-use in electrochemical experiments, thereby preventing contamination issues due to repeated use as in conventional laboratory test cells. In addition, the integration of micro pseudo reference electrodes is demonstrated. Thus, the test cell array together with the developed electrode/electrolyte deposition technology provide a highly efficient tool for speedy combinatorial and high throughput testing of battery materials on a system level (full cell tests). Experimental results are shown for the microfabrication of lithium-ion test cells with help of several electrode and binder materials. The influence of jetting parameters on electrode lateral dimensions and thickness, reproducibility of the electrode mass as well as the use of integrated micro-reference electrodes for impedance spectroscopy and cyclic voltammetry measurements in micro cells are presented in detail.

     

Wafer‐scale monolithic hybrid integration of Si‐based IC and III–V epi‐layers—A mass manufacturable approach for active matrix micro‐LED micro‐displays

Hybridization of silicon integrated circuits (ICs) with compound semiconductor device arrays are crucial for making functional hybrid chips, which are found to have enormous applications in many areas. Although widely used in manufacturing hybrid chips, the flip‐chip technology suffers from several limitations that are difficult to overcome, especially when the demand is raised to make functional hybrid chips with higher device array density without sacrificing the chip footprint. To address those issues, Beida Jade Bird Display Limited has developed its unique wafer‐level monolithic hybrid integration technology and demonstrated its advantages in making large‐scale hybrid integration of functional device arrays on Si IC wafers. Active matrix micro‐light‐emitting diode micro‐displays with a resolution of 5000+ pixel per inch were successfully fabricated using Beida Jade Bird Display Limited's monolithic hybrid integration technology. The general fabrication method is described, and the result is presented in this paper. The fabricated monochromatic micro‐light‐emitting diode micro‐displays exhibit improved device performance than do other micro‐display technologies and have great potentials in applications such as portable projectors and near‐to‐eye projection for augmented reality. More importantly, the wafer‐scale monolithic hybrid integration technology offers a clear path for low‐cost mass production of hybrid optoelectronic IC chips.     

Membrane microcantilever arrays fabrication with PZT thin films for nanorange movement

Lead zirconate titanate (PZT) piezoelectric thin films have been prepared by sol-gel method to fabricate microcantilever arrays for nano-actuation with potential applications in the hard disk drives. In order to solve the silicon over-etching problem, which leads to a low production yield in the microcantilever fabrication process, a new fabrication process using DRIE etching of silicon from the front side of the silicon wafer has been developed. Silicon free membrane microcantilevers with PZT thin films of 1 μm in thickness have been successfully fabricated with almost 100% yield by this new process. Annealing temperature and time are critical to the preparation of the sol-gel PZT thin film. The fabrication process of microcantilever arrays in planar structure will be presented. Key issues on the fabrication of the cantilever are the compatible etching process of PZT thin film and the compensation of thin film stress in all layers to obtain a flat multi-layer structure.