A custom microchip amplifier for patch clamp electrophysiological recording

描述(申请人提供)：自20世纪70年代末问世以来，膜片钳电生理学一直是神经科学和药物研究的中心工具。全细胞膜片钳技术利用玻璃微吸管和灵敏的模拟电子技术来监测单个神经元或其他细胞的离子通道电流和细胞内电压。几十年来，这 这项技术是由训练有素的科学家在显微镜下使用微操作器煞费苦心地引导电极与单个细胞接触(或称“膜片钳”)进行的。一旦接触到，大型昂贵的放大器模块就被用来监控或操纵微小的蜂窝电信号。在过去的十年里，自动化的进步导致了廉价的机器人系统的开发，这些系统能够在几分钟内自动膜片钳住体内的许多神经元，成功率与熟练的研究人员持平或超过。作为这项创新的结果，膜片钳技术正在适应更广泛的实验方案和目标物种，研究人员现在正在同时从多个细胞进行记录。然而，传统的机架安装式放大器电子系统的尺寸和成本是继续发展大规模高度自动化的细胞内记录系统的一个重要瓶颈。能够进行电流钳位和电压钳位测量的单通道放大器通常是安装在机架上的大盒子，重达几公斤，每个通道的成本超过10,000美元。至少有八家公司生产这种仪器，就尺寸、质量和成本而言，这是现代膜片钳记录系统的主要组成部分。转向多渠道自动化系统只会加剧这个问题。Intan Technologies计划将膜片钳记录所需的所有敏感电子设备集成到一个小型、低功耗、廉价的硅微芯片(“PatchChip”)上，该芯片将取代传统的膜片钳放大器。先进微电子技术的使用将使体积庞大、价格昂贵的放大系统缩小到一张邮票大小。集成放大器可以安装在大型自动记录系统中的每个微吸管附近，从而减少噪音拾取和尺寸。贴片芯片将具有进行电压钳和电流钳测量的能力，并将具有足够的灵敏度来解析皮安级突触电流和毫伏级细胞内电压。新颖的电路架构消除了对片内精密电阻的需求，并允许标准的膜片钳位功能，如串联电阻补偿和快速瞬时电容补偿。该芯片将设计一个易于使用的USB接口电路板；这个带有开源软件的评估系统将允许仪器制造商将这一新技术整合到先进的膜片钳系统中。

DESCRIPTION (provided by applicant): Patch clamp electrophysiology has been a central tool of neuroscience and pharmaceutical research since its advent in the late 1970s. Whole-cell patch clamping utilizes glass micropipettes and sensitive analog electronics to monitor the ion-channel currents and intracellular voltages of individual neurons or other cells. For decades, this has been performed by highly trained scientists using micromanipulators under a microscope to painstakingly guide an electrode to contact (or "patch clamp") a single cell. Once in contact, large, expensive amplifier modules are used to monitor or manipulate the small cellular electrical signals. In the last ten years, advances in automation have led to the development of inexpensive robotic systems capable of automatically patch clamping many neurons in vivo in minutes, with success rates matching or exceeding those of skilled investigators. As a result of this innovation, patch clamp techniques are being adapted to a wider variety of experimental protocols and target species, and researchers are now recording from multiple cells simultaneously. However, the size and expense of the traditional rack-mounted amplifier electronics systems present a significant bottleneck in the continued development of large-scale highly automated intracellular recording systems. Single-channel amplifiers capable of current-clamp and voltage- clamp measurements are typically large rack-mounted boxes weighing several kilograms and costing more than $10,000 per channel. At least eight companies produce such instruments, which represent the dominant component of modern patch clamp recording systems in terms of size, mass, and cost. The move to multi- channel automated systems will only exacerbate this problem. Intan Technologies proposes to integrate all the sensitive electronics needed for patch clamp recording onto a small, low-power, inexpensive silicon microchip ("PatchChip") that will replace traditional patch clamp amplifiers. The use of advanced microelectronics will reduce the bulky and expensive amplifier systems down to the size of a postage stamp. Integrated amplifiers could be mounted in close proximity to each micropipette in a large-scale automated recording system, reducing noise pickup and size. The PatchChip will have the capability to conduct both voltage-clamp and current-clamp measurements, and will have sufficient sensitivity to resolve picoampere-level synaptic currents and millivolt-level intracellular voltages. A novel circuit architecture eliminates the need for of-chip precision resistors and allows for standard patch clamp functions like series resistance compensation and fast transient capacitance compensation. An easy-to-use USB interface circuit board will be designed for the chip; this evaluation system with open-source software will allow instrumentation manufacturers to incorporate this new technology into advanced patch clamp systems.