开发廉价快速同时诊断多种疾病的三维纸基分析器械的研究

The specific objective of this work is to develop a diagnostic system needed to address problems in infectious diseases, which will fundamentally change the cost of information needed to manage diagnosis and healthcare in resource-constrained regions. Medical diagnostics in the developing world for poverty-related conditions are often ineffective and outdated. In healthcare, when diagnostic equipment is absent, healthcare workers make their decisions based on observed symptoms. For example, up to 500 million people who live in malaria endemic regions are undiagnosed every year because they do not show symptoms. Meanwhile, they are a host for the continued spread of the infection to others. The developing world needs diagnostic devices that have the lowest practical cost, function without supporting equipment (e.g., electricity, pumps, optics, etc.), and are portable and easy to operate. Ideal diagnostic devices should measure multiple analytes simultaneously in microliter volumes of fluid, and should enable immediate diagnosis and care. Among the most successful of current systems are those that rely on movement of fluids across paper strips to distribute reagents (e.g., dipstick and lateral flow systems). These systems are useful, but limited in sensitivity, selectivity, speed, ability to run multiple assays simultaneously, capability of using small volumes of fluid, ability to process complex biological fluids, long-term stability, cost, and ease of disposal. Here we propose a new class of analytical systems made out of paper and tape that we will specifically design for applications in the developing world. We will develop three-dimensional paper-based diagnostic systems that are affordable, portable, disposable, and useful for multiplexed point-of-care diagnostics of various diseases such as HIV and malaria. Unlike traditional paper-based devices (e.g., lateral flow tests), our paper-based devices, with their ability to modify and direct flow within microfluidic channels and in three dimensions, have the capacity to split a single, low-volume sample into multiple separate portions, which can each be assayed in parallel. This allows for high-level multiplexing of independently optimized assays with discrete assay conditions and eliminates concern about cross-reactivity between assays.

本项目拟开发三维纸基分析器械，解决廉价快速同时准确诊断多种疾病的难题。在中国等发展中国家的贫困地区，由于缺少医疗设备，很多疾病的诊断只能依靠医务工作者根据病人的症状估诊，往往延误了治疗。比如，目前世界上每年约有5亿疟疾病人由于还没有明显症状未能早期诊断，导致传染了更多人。这些地区急需操作简单、廉价实用、可以随身携带、不需要电光等辅助器材的常见疾病的诊断手段。目前一种简单实用的成功诊断方法是通过液体在纸面的横向传输确诊病情（如尿液和验孕试纸），但是上述方法在检测灵敏度、选择性、速度、稳定性、待检测样品的用量等方面都有缺陷，而且不能同时诊断多种疾病。本项目计划开发的廉价、可携带、易销毁的三维纸基分析器械，可以将很少的待检测样品分成多份，通过多个通道，让样品液体横向和纵向传输，能够快速同时准确诊断疟疾和艾滋病等多种疾病。这项先进技术的实际应用和广泛推广必将为我国和世界各地亿万民众的健康作出贡献。

在中国等发展中国家的贫困地区，由于缺少医疗设备，很多疾病的诊断只能靠医务工作者依据病人的症状估诊，往往延误了治疗。比如，每年约有5亿疟疾病人由于还没有明显症状未能早期诊断，导致传染了更多的人。这些地区急需操作简单、廉价实用、可以随身携带、不需要电光器材等辅助设备的常见疾病的方便实时准确的诊断手段。目前已有的几种简单实用的成功诊断方法是通过液体在纸面的横向传输确诊病情的措施(如尿液和验孕试纸)，但是这些方法在检测灵敏度、选择性和样品用量等方面都有缺陷，而且不能同时诊断多种疾病。为此，本项目研制出了廉价、可携带、易销毁的三维纸基分析器械，用于多种疾病的同时诊断。这种新型分析器械可以将很少的样品分成多份，通过控制液体的横向和纵向多个通道的传输，快速准确检测分析不同的疾病。研究过程中，本项目通过同时检测三种不同的癌症标志物（AFP、CEA和CA199），验证了这种新型器械的确具有同时快速准确检测多种疾病的功能。我们在纸基分析器械中成功实现了荧光免疫分析方法，排除了现有显色读取方法中样品颜色对检测分析的干扰等问题，完成了一些疾病的准确分析诊断。另外，我们进一步通过在纸基材料表面修饰氧化锌纳米线阵列，极大增强了待分析的荧光信号强度，提高了检测的信噪比；还通过选择与背景荧光不同波长的荧光标记材料，成功避开了纸基材料背景荧光的干扰。我们与江苏省人民医院的医生一起成功使用三维纸基荧光免疫分析方法同时检测三种心肌疾病标志物（FABP、cTnI和myoglobin），其结果与医院医生使用大型仪器的检测结果一致，检测灵敏度提高了一个数量级，检测成本则降低了二十几倍。该项研究解决了纸基检测灵敏度低的公认技术难题，经过实际验证获得国际同行的一致认可，为研发具有我国自主知识产权的原创性快速灵敏检测器械提供了科学依据和发展途径。这项先进技术的实际应用必将为我国和世界各地亿万民众的健康作出贡献。

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