Chronologically Correlated Sweat Biosensing

在具有巨大上升潜力的非侵入性可穿戴技术中，汗液传感技术可以说是最不发达的。即便如此，兴奋正在建立，因为许多汗液电解质，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/或疾病的希望。 然而，不幸的是，许多可用于汗液的市售技术解决方案需要约10微升的样品体积，这对于连续汗液分析来说完全太大了。即使是最新的贴片或纹身在汗液传感技术的进步需要几微升的生物流体，导致缓慢的采样间隔（几十分钟甚至几小时）。如果汗液传感的最大争论之一是持续监测的潜力，那么就有一个明确而紧迫的需求，即发现强大而简单的方法，不断将最少量的汗液（纳升）带到传感器。 这绝不是一个简单的挑战，因为皮肤表面是高度可变的，并且存在许多可能混淆汗液采样的因素。如果这种技术可以被开发，则回报可能是巨大的，允许：（1）与血液的相关性具有快至约2分钟的时间分辨率;（2）对于久坐不动的用户，每天自然汗液的更多采样事件;（3）对于化学刺激的汗液，与商业产品相比，递送的化学刺激物的量减少100倍;（4）重要的是，减少来自死皮表面的混杂污染。显然，改善汗液采样是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。NSF此次提案的具体目标是首次实现以分钟级分辨率实现时间相关汗液传感的能力。 该提案的核心假设是，通过微流体的巧妙相互作用，外分泌汗管和传感器之间的流体体积可以从约1微升减少到10纳升（10- 100倍），导致新汗液到达传感器之前只有几分钟。 追求这一假设的基本原理很简单，汗液感测在患者和健康监测、体育运动、窄治疗范围药物监测等方面的应用具有巨大的上升潜力，但是不能达到其全部潜力，除非可以使用较低的出汗速率、能够实现更快的采样时间以及减轻来自皮肤表面的分析物污染。该提案还通过以下方式推进了汗液感测科学的知识：（1）创建时间模型，其预测离子、分子和蛋白质分析物从血液到汗液以及到传感器上的分配时间;（2）将最小生物流体采样和感测的前沿从微升推进到纳升制度;（3）通过实验验证所创建的模型和技术，从而引发对汗液传感科学和技术的进一步追求。

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.