Chronologically Correlated Sweat Biosensing

在具有巨大发展潜力的非侵入式可穿戴技术中，汗液传感技术可以说是最不发达的。尽管如此，随着汗液中电解质、代谢物、氨基酸、蛋白质和其他生物标志物显示出监测精神和身体状态和/或疾病的前景，人们的兴奋之情正在增强。然而，不幸的是，许多可用于汗液的商业技术解决方案需要~10微升的样品体积，这对于连续汗液分析来说完全太大了。即使是最新的汗液传感贴片或纹身技术也需要几微升的生物流体，这导致采样间隔较慢（10分钟甚至数小时）。如果对汗液传感的最大争论之一是持续监测的潜力，那么显然迫切需要发现强大而简单的方法来持续地将最微量的汗液（纳升）输送到传感器中。这绝不是一个简单的挑战，因为皮肤表面是高度可变的，并且呈现出许多可能混淆汗液采样的因素。如果这项技术能够开发出来，其回报将是巨大的，它可以实现：(1)与血液的相关性，最快可达2分钟的时间分辨率；(2)对于久坐不动的用户，每天的自然汗液采样事件较多；(3)对于化学刺激的汗液，与商业产品相比，化学刺激量减少了100倍；(4)重要的是，减少来自死皮表面的混杂污染。显然，改进汗液取样是一个值得研究人员关注的核心挑战。此外，通过将研究与高中和本科生的研究和教学相结合，这样的研究课题也是培养和激励下一代科学家和工程师的理想选择。这项NSF提案的具体目标是首次实现以分钟级分辨率实现按时间顺序相关的汗液传感的能力。该提案的核心假设是，通过微流体的巧妙相互作用，汗腺导管和传感器之间的流体体积可以从1微升减少到10纳升（10-100倍），从而在新的汗液到达传感器之前仅几分钟。追求这一假设的基本原理很简单，汗液传感在病人和健康监测、体育运动、窄治疗范围药物监测等方面具有巨大的应用潜力，但除非能够使用更低的出汗率，更快的采样时间，并减轻皮肤表面的分析物污染，否则无法充分发挥其潜力。该提案还通过以下方式推进了汗液传感科学的发展：(1)建立了时间模型，该模型预测了离子、分子和蛋白质分析物从血液中进入汗液并进入传感器的时间；(2)将最小生物流体采样和传感技术的前沿从微升推进到纳升；(3)通过实验验证所创建的模型和技术，从而点燃对汗液传感科学技术的进一步追求。

Among non-invasive wearable technologies with a large upside potential, sweat sensing technology is arguably the most underdeveloped. Even so, excitement is building, as many sweat electrolytes, metabolites, amino acids, proteins, and other biomarkers are showing promise for monitoring both mental and physical status and/or disease. However, unfortunately many of the commercially available technology solutions that could be used for sweat require ~10's of microliters sample volumes, which are entirely too large for continuous sweat analysis. Even the latest patch or tattoo advances in sweat sensing technology require several microliters of biofluid, resulting in slow sampling intervals (10's of minutes or even hours). If one of the biggest arguments for sweat sensing is the potential for continuous monitoring, then there is a clear and pressing need to discover powerful yet simple methods to continuously bring the tiniest amounts of sweat (nanoliters) to sensors. This is by no means a simple challenge, as the skin surface is highly variable and presents numerous factors that can confound sweat sampling. If such technology could be developed the payoff could be huge, allowing: (1) correlations with blood with as fast as ~2 min. time resolution; (2) for sedentary users, more sampling events per day of natural sweat; (3) for chemically stimulated sweat, a 100X reduction in the amount of chemical stimulant delivered compared to commercial products; (4) importantly, reducing confounding contamination coming from the dead skin surface. Clearly, improved sweat sampling is a central-challenge worthy of attention by researchers. Furthermore, such a research topic is also ideal for cultivating and inspiring the next generation of scientists and engineers through integration of research with both high-school and undergraduate student research and teaching.The specific objective of this NSF proposal is to create for the first time, the ability to achieve chronologically correlated sweat sensing with minute-level resolution. The proposal's central hypothesis is that through a clever interplay of microfluidics, the fluidic volume between eccrine sweat ducts and sensors can be reduced from ~1's of microliters down to 10's of nanoliters (10-100X), resulting in only minutes before new sweat reaches the sensors. The rationale for pursuing this hypothesis is simple, sweat sensing has enormous upside potential for applications in patient and wellness monitoring, athletics, narrow therapeutic-range pharmaceutical monitoring, etc., but cannot reach its full potential unless lower sweat rates can be used, faster sampling times enabled, and analyte contamination from the skin surface mitigated. The proposal also advances knowledge in sweat sensing science by: (1) creating temporal models which predict the time for partitioning of ionic, molecular, and protein analytes from blood, into sweat, and onto the sensors;(2) advancing the frontiers of minimum biofluid sampling and sensing from the microliter to the nanoliter regime;(3 experimentally validating both the created models and technology, and therefore igniting further pursuit of sweat sensing science and technology.