CBET-EPSRC: Hybrid organic-CMOS devices for optogenetic simulation and lens-free fluorescence imaging of the brain

大脑的功能，如感知、运动控制、学习和记忆，源于分布在多个大脑区域的神经元组件的协调激活。虽然在理解单个细胞的响应特性方面已经取得了重大进展，但对电路相互作用的了解仍然很少。理解这些相互作用的根本障碍之一是很难观察到自由行为动物中大量分布的神经元群体的活动。通过将高度工程的基因编码的光敏离子通道(通常是通道视紫红质，CHR)与荧光电压或钙传感器相结合，已有可能在细胞培养以及活着和清醒的动物中利用光学技术实现对神经元网络的精确、非侵入性和高速控制和监测。传统的显微镜方法被用来建立这些光学界面，导致非常复杂的实现，这使得自由行为的动物研究变得困难。此外，传统的显微技术，即使是那些使用双光子技术或薄片成像的技术，也受到脑组织散射和吸收的限制，只能覆盖小到老鼠的大脑的表面。在这项建议中，我们将开发一种克服这些限制的光传递方法。它能够完全覆盖目标体积内的所有神经元，允许在高度分散的脑组织中进行具有细胞分辨率的功能成像，并具有人类应用的长期前景。我们的方法是基于在大脑内部分布密集的发射器和探测器像素的3-D点阵。这些像素阵列被嵌入到神经探测器上，实现为可植入的超窄小腿。通过有机LED(OLED)技术增强现有的CMOS(互补金属氧化物半导体)铸造厂，这些探头很容易生产出来。这一用于光遗传刺激和记录的混合设备平台结合了角度敏感型CMOS单光子雪崩二极管(A-SPAD)用于检测和角度发射OLED用于发光。由于其无定形的形态，用于OLED的有机材料可以直接沉积在硅片上，而不受晶格匹配的限制，从而促进了光源在CMOS工艺上的真正单片集成。

Brain functions such as perception, motor control, learning, and memory arise from the coordinated activation of neuronal assemblies distributed across multiple brain areas. While major progress has been made in understanding the response properties of individual cells, circuit interactions remain poorly understood. One of the fundamental obstacles to understanding these interactions has been the difficulty of observing the activity of large distributed populations of neurons in freely behaving animals. By combining highly engineered genetically encoded light-sensitive ion channels (typically Channelrhodopsins, ChRs) with fluorescent voltage or calcium sensors, it has become possible to achieve precise, non-invasive and high-speed control and monitoring of neuronal networks with optical techniques, both in cell culture and in live and awake animals. Conventional microscopy approaches have been employed for building these optical interfaces, resulting in very complex implementation which makes freely behaving animal studies difficult. In addition, conventional microscopy techniques, even those that use two photon techniques or light-sheet imaging, are limited by scattering and absorption in the brain tissue, allowing only superficial coverage for brains as small as that of the mouse.In this proposal, we will develop an approach for light delivery that surmounts these limitations. It enables complete coverage of all neurons within a target volume, permits functional imaging with cellular resolution in highly scattering brain tissue, and has long-term prospects for human applications. Our approach is based on distributing a dense 3-D lattice of emitter and detector pixels within the brain itself. These pixel arrays are embedded onto neural probes, realized as implantable, ultra-narrow shanks. These probes are readily producible though existing CMOS (complementary metal-oxide-semiconductor) foundries augmented by organic LED (OLED) technology. This hybrid device platform for optogenetic stimulation and recording combines angle-sensitive CMOS single-photon avalanche diodes (A-SPADs) for detection and angle-emitting OLEDs for light generation. Due to their amorphous morphology, the organic materials used in OLEDs can be deposited directly onto silicon chips, without lattice matching constraints, thus facilitating true monolithic integration of light sources on CMOS technology.