Particle Filtration and Accumulation by Solute-driven Transport (FAST) for bio-analysis in microfluidic devices

许多卫生干预措施的结果在很大程度上取决于能否及时发现疾病，以便及时选择最适当的治疗方法。因此，迫切需要发展保健技术，以便快速准确地检测与特定疾病和/或致病因子（如病原微生物）有关的生物标志物。微流体和芯片实验室技术为下一代快速和超灵敏的诊断和治疗应用生物分析设备的发展提供了巨大的潜力。颗粒处理操作——包括分离、过滤、浓缩、捕获和分选——在微流控诊断技术中无处不在，最终可以决定测试设备的速度、准确性和选择性。理想的颗粒处理技术将是快速（高通量），选择性（即仅针对感兴趣的颗粒），易于集成到多功能微流控装置中，最重要的是，不依赖于使用外部场。本提案旨在引入一种创新的粒子操纵技术来满足所有这些要求。本研究还将展示使用该技术开发快速和敏感的诊断测试设备的概念验证。通过收集平行多组分流动产生的与盐对比相关的化学能，在连续流动设置中，微结构表面腔内的目标颗粒的快速过滤、捕获和积累将实现。控制粒子动力学的机制将通过实验和数值技术的结合进行研究。将阐明捕获和浓缩效率与颗粒性质（特别是尺寸和表面化学）的关系。本研究的输出将是一个优化设计的微流控平台，通过该平台将开发两种体外诊断设备。一种设备将根据脂膜组成快速过滤细胞样颗粒（如脂质体），这是细胞健康状态的重要指标。该试验将为药物诱导细胞死亡的早期检测和药物药代动力学的快速筛选提供新的机会。另一种设备将能够快速、超灵敏地检测病理状况的生物标志物，包括动脉粥样硬化、胰腺炎和某些形式的癌症。合成的生物相容性颗粒将在样品溶液中孵育，其中与疾病生物标志物的特定相互作用将导致i)颗粒的荧光信号发射和ii)颗粒表面化学的变化。后一种效应旨在使化学能（以盐对比的形式储存）转化为粒子运动。因此，生物标志物激活的荧光颗粒将被快速捕获并积聚在设备的目标区域内，而非荧光颗粒将不受盐存在的影响。这将为诊断分析提供大量的信号放大，从而快速准确地检测分析样品中的生物标志物浓度。总之，这项研究将为开发一系列新的低成本便携式生物分析设备奠定基础，这些设备基于溶质驱动运输（FAST）的颗粒过滤和积累，可用于诊断和治疗。这些创新和高度敏感的诊断工具将使临床医生能够进行快速和准确的诊断，从而做出及时和知情的临床治疗决定，这更有可能导致成功的健康结果。

The outcomes of many health interventions critically depend on the ability to identify the disease in a timely manner so the most appropriate therapy can be chosen promptly. Consequently, there is an immediate and growing need to develop healthcare technologies for rapid and accurate detection of bio-markers, associated with specific diseases, and/or disease causative agents, such as pathogenic microorganisms. Microfluidics and lab-on-a-chip technology offer a huge potential for the development of next generation fast and ultra-sensitive bio-analytical devices for diagnostic and therapeutic applications.Particle handling operations - including separation, filtration, concentration, trapping and sorting - are ubiquitous in microfluidic diagnostic technologies and can ultimately dictate the speed, accuracy and selectivity of testing devices. An ideal particle handling technique would be fast (high-throughput), selective (i.e. targeting only the particles of interest), easy to integrate into a multifunctional microfluidic device and, most importantly, not reliant on the use of external fields. This proposal aims to introduce an innovative particle manipulation technique to address all these requirements. This research will also demonstrate the proof-of-concept for using this technique to develop fast and sensitive diagnostic testing devices.Rapid filtration, trapping and accumulation of target particles within the cavities of micro-structured surfaces will be achieved in continuous flow settings by harvesting the chemical energy associated with salt contrast generated by parallel multi-component flows. The mechanisms governing the particle dynamics will be investigated through a combination of experimental and numerical techniques. The dependence of trapping and concentration efficiency on particle properties (especially size and surface chemistry) will be elucidated. The output of this study will be an optimally-designed microfluidic platform, through which two in-vitro diagnostic devices will be developed. One device will enable the rapid filtration of cell-like particles (e.g. liposomes) based on their lipid membrane composition which is an important indicator of a cell's state of health. This assay will offer new opportunities for early detection of drug induced cell death and rapid drug pharmacokinetics screening. Another device will enable the fast and ultrasensitive detection of a biomarker indicative of pathological conditions, including atherosclerosis, pancreatitis and some forms of cancers. Synthetic bio-compatible particles will be incubated in a sample solution where the specific interaction with the disease biomarkers will cause i) the fluorescent signal emission from the particle and ii) a change in particle surface chemistry. The latter effect is intended to enable the conversion of the chemical energy - stored in the form of salt contrast - into particle motion. As a result, the biomarker-activated fluorescent particles will be rapidly trapped and accumulated within target regions of the device whereas the non-fluorescent particles will remain unaffected by the presence of the salt. This will enable a massive signal amplification for the diagnostic assay and, consequently, a fast and accurate detection of biomarker concentration in the analysed sample.In summary, this research will lay the foundation for the development of a new family of low-cost, portable bio-analytical devices based on particle filtration and accumulation by solute-driven transport (FAST) for diagnostic and therapeutic applications. These innovative and highly-sensitive diagnostic tools will enable clinicians to perform rapid and accurate diagnosis and, hence, make timely and informed clinical treatment decisions which are more likely to lead to successful health outcomes.