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产生的光子计数探测器的进步，例如放射性示踪技术，包括伽马闪烁成像和正电子发射计算机断层扫描(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上，尽管空间分辨率较低，如超声、核磁共振、EPR和介电谱的光子测量，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，由完全依赖于基于强度的荧光测量的技术推动。这些方法通常只在流体自动化的背景下是定量的，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革命所需的定量复杂细胞生物学测量；对体内蛋白质的更复杂的研究仍处于初级阶段。该项目旨在开发一种专为满足光学蛋白质组学要求而设计的探测器系统；能够以高通量进行高含量分析。其目标是将多通道、高时间分辨率、光子计数系统集成到一个带有集成电子设备(每像素小99%)的小型化探测器系统中，这是下一代生物医学工具的引擎。允许进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)的成本为GB 25k/GB 50k。相比之下，传统的高通量细胞生物分析方法仅限于低含量分析。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个通道)的能力，将允许以高度灵活和经济的方式以高吞吐量进行高内容(多参数)分析(每像素成本的1%)。高水平的集成度允许轻松重新配置，因此可以在吞吐量和内容之间进行客观选择，以匹配各种特定应用，而不会损失整体性能和高动态范围包络。这项技术的应用包括(按照占领市场的可能性增加的顺序)：-1)用于医疗诊断的高容量技术。这种设备具有相对简单的真空管设计和低成本的ASIC和现场可编程门阵列电子设备的基本简单性，可以成为批量生产、负担得起、具有高护理点临床诊断特异性的设备的先驱，这种设备将拥有大量市场。2)光学层析成像。非常高的时间分辨率，再加上高吞吐量和动态范围，使该设备成为光学层析成像的合适工具，这一技术适用于新生儿和乳房成像等利基应用，在这些应用中，使用电离辐射等其他技术是不可取的。3)组织芯片的高含量细胞生物学。该设备的高通量将极大地加快组织微阵列中样品的分析速度，这是一项广泛应用的技术，应用于药物筛选和毒理学。4)无处不在的高性能荧光寿命成像工具。该设备将为荧光寿命成像提供一种具有成本效益(每像素成本的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.