A Scaled-up High Content Photon-Counting Detector for Life Science Applications

长期以来，医学成像一直受益于粒子和空间物理学所产生的光子计数探测器的进步，例如辐射示踪技术，包括伽马闪烁成像和PET。在过去的几十年里，光子科学的其他进展已经转移到医学成像的应用中，尽管空间分辨率较低，如超声、核磁共振、EPR和介电光谱的光子测量，以及拉曼和荧光。过去15年的基因组学革命，以备受瞩目的人类基因组计划为例，是由完全依赖于基于强度的荧光测量的技术推动的。这些方法通常只在流体自动化环境中定量，这种方法不适用于生物医学研究的下一个主要圣杯——蛋白质组学革命所需的定量复杂细胞生物学测量；对体内蛋白质的复杂得多的研究仍处于起步阶段。本项目旨在开发一种专门设计的检测系统，以满足光学蛋白质组学的要求；能够在高通量下进行高含量分析。目标是将多通道、高时间分辨率、光子计数系统集成到一个集成电子器件的小型探测器系统中（每像素缩小99%），这是下一代生物医学工具的引擎。允许执行高含量分析的现有时间分辨方法与高通量方法不兼容：每次测量需要几分钟，每个空间分辨元素（像素）花费25k / 50k英镑。相比之下，传统的高通量细胞生物学测定仅限于低含量分析。然而，该设备具有高时间分辨率（20 ns）和多通道并行分析（多达384通道）的能力，将允许以高度灵活和经济的方式（每像素成本<1%）以高吞吐量进行高内容（多参数）分析。高度集成允许易于重新配置，因此可以在吞吐量和内容之间做出客观选择，以匹配各种特定应用，而不会损失整体性能，并且在高动态范围内。该技术的应用包括（按市场捕获可能性增加的顺序）：- 1)用于即时诊断的大批量技术。该设备具有相对简单的真空管设计和低成本的ASIC和FPGA电子器件的潜在简单性，可能是大规模生产的先驱，价格合理，具有高特异性的护理点临床诊断设备，这将占据大量市场。2)光学断层成像。非常高的时间分辨率，加上高通量和动态范围，使该设备成为光学断层扫描的合适工具，一种适合小众应用的技术，如新生儿和乳房成像，在其他技术，如使用电离辐射等，是不可取的。3)组织微阵列的高含量细胞生物学。该设备的高通量将大大加快组织微阵列样品的分析，这是一种广泛应用于药物筛选和毒理学等应用的技术。4)无处不在，高性能，荧光寿命成像工具。该设备将为荧光寿命成像提供具有成本效益（每像素成本<1%）的高科技工具，提供比现有系统更高的性能，并且所有生命科学实验室都负担得起。

Medical imaging has long benefited from advances in photon counting detectors arising from particle and space physics e.g. radiometric tracer techniques, including gamma scintigraphy, and PET. Other advances in photon science over the last few decades have migrated to applications in medical imaging, albeit with lower spatial resolution, such as photonic measurement of ultrasound, NMR, EPR and dielectric spectroscopies, as well as Raman and fluorescence. The genomics revolution of the past 15 years, exemplified by the high profile Human Genome Project, has been fuelled by technologies wholly reliant on intensity based fluorescence measurements. These methods are generally only quantitative in a fluidic automation context, a method that is not applicable to the quantitative complex cell biology measurements required for the next major holy grail of biomedical research, the proteomic revolution; the much more complicated study of proteins in vivo which is still in its infancy. This project aims to develop a detector system specifically designed to address the requirements of optical proteomics; to be capable of high content analysis at high throughput. The goal is to integrate a multi-channel, high time resolution, photon counting system into a single miniaturized detector system with integrated electronics (>99% smaller per pixel), an engine for the next generation of biomedical tools. Existing time resolved methods which allow high content assays to be performed are not compatible with high throughput methods: each measurement takes minutes and costs £25k / £50k per spatially resolved element (pixel). In comparison, conventional high throughput cell biological assays are limited to low content analysis. However this device, with its capability for high time resolution (20 ns), and multi-channel parallel analysis (up to 384 channels), will allow high content (multi-parametric) analysis to be undertaken at high throughput in a highly flexible and economic way (<1% of the cost per pixel). The high level of integration allows easy reconfigurability, so an objective choice can be made in the trade-off between throughput and content to match a variety of specific applications, without loss of overall performance and within a high dynamic range envelope. Applications of this technology include (in order of increasing likelihood of market capture) :- 1) High volume technology for point-of-care diagnostics. This device, with the underlying simplicity of a relatively simple vacuum tube design and low cost ASIC and FPGA electronics, could be the precursor to a mass produced, affordable device with high specificity for point of care clinical diagnostics, which would command a high volume market. 2) Optical Tomography. Very high time resolution, coupled with high throughput and dynamic range make this device a suitable tool for optical tomography, a technique suitable for niche applications such as neo-natal and breast imaging where other techniques, such as using ionizing radiation etc., are undesirable. 3) High content cell biology for tissue microarrays. The high throughput of this device will greatly speed up analysis of samples in tissue microarrays, a widely used technique with applications such as drug screening and toxicology. 4) Ubiquitous, high performance, fluorescence lifetime imaging tool. This device will provide a cost effective (<1% of the cost per pixel) high technology tool for fluorescence lifetime imaging, providing enhanced performance over existing systems, and affordable by all life science laboratories.