EAGER: Sweat, Sense, and Signal (S3) ? Demonstration of fM to pM Electrical Sensing of BioMarkers in Sweat

与血液、尿液、呼吸和唾液相比，汗液在医学诊断中的作用在很大程度上被忽视了。 研究表明，许多用于健康监测或诊断的水溶性生物标志物可以在汗液中发现，其浓度与血液中的浓度相当。因此，医学科学可能处于非侵入性生理传感基本方法的变革性转变的边缘。 具有特别影响的是可穿戴生物标志物传感器，其提供浓度的快速读出。 然而，这将需要新的电感测技术，因为目前的汗液生物标志物生物传感仅能够进行无机离子传感（水合作用、婴儿囊性纤维化）。 朝着汗液中的分子生物传感发展将需要在1-10 pM范围内感测生物标志物浓度。 生物流体中的电感测的初步研究表明，感测到pM水平是可能的。 然而，在实际的复杂汗液样品基质中的感测和亚pM感测都没有被证明。 证明汗液中生物标志物的亚pM电传感将为可穿戴汗液生物传感产品的可行性提供突破性证据。智力价值EAGER提案的总体目标是证明在真实的汗液中至少3种重要医学诊断生物标志物的亚pM电阻抗谱检测。 选择阻抗谱是因为它对于固定在感测电极表面上的各种生物识别元件是高度可调谐的，并且它提供多方面的检测，包括电阻、电容、电荷转移和电压响应形状变化，因为生物标记物被生物识别元件捕获。 所提出的生物标志物的重点将是那些存在于汗液中的至少1-10 pM浓度范围：（1）促炎和抗炎细胞因子;和（2）神经递质。 导致亚pM灵敏度的具体目标包括：（1）交叉指型电极与生物标记/生物识别元件响应的频率匹配;（2）发现生物识别元件的最佳和高度均匀的表面取向以获得最大阻抗响应;（3）深入研究电荷转移、形状变化、离子屏蔽以及作为诸如波形形状的更精细刺激的函数的其他因素，电势大小、电解质溶液pH和离子强度。 这些目标的成功将激发人们对汗液生物传感的兴趣，并使人们能够追求广泛的商业产品。 更广泛的影响：预计拟议工作的成功将通过推进个性化医疗和预防保健来降低总的医疗保健成本。 广泛的社会影响包括运动员和消防员的热应激管理，提高飞行员和卡车司机的警觉性，士兵PTSD预防以及高级治疗诊断学的健康基线。 传播计划包括组织一次自我维持的年度国际研讨会，讨论汗液中的生物标志物。 EAGER将加强汗液传感研究和教育的基础设施。 综合教育计划包括支持大学的本科生研究合作社，他们随后将在PI的合作伙伴联邦实验室实习。

ObjectiveSweat for medical diagnostics has been largely overlooked in comparison to blood, urine, breath, and saliva. Research now reveals that numerous water-soluble biomarkers for health monitoring or diagnosis can be found in sweat at comparable concentrations as in blood. Therefore, medical science is potentially on the verge of a transformative shift in fundamental approaches for non-invasive physiological sensing. Of particular impact would be wearable biomarker sensors providing a fast readout of concentration(s). However, this will require new electrical sensing technology, as current sweat biomarker biosensing is capable of only inorganic ion sensing (hydration, infant cystic fibrosis). Moving toward molecular biosensing in sweat will require sensing of biomarker concentrations in the 1-10 pM range. Preliminary studies of electrical sensing in biofluids suggest that sensing down to pM levels is possible. However, neither sensing in the actual complex sweat sample matrix nor sub-pM sensing have been demonstrated. Demonstrating sub-pM electrical sensing of biomarkers in sweat would provide breakthrough evidence on the viability of wearable sweat bio-sensing products.Intellectual meritThe overall objective for this EAGER proposal is to demonstrate sub-pM electrical impedance spectroscopy detection, in real sweat, of at least 3 biomarkers of significant medical diagnostics. Impedance spectroscopy is chosen because it is highly tunable to the various biorecognition elements that are immobilized on the sensing electrode surface, and it provides multifaceted detection including resistance, capacitance, charge transfer, and voltage responsive shape-change as biomarkers are captured by the biorecognition elements. The proposed biomarker focus will be on those which exist in sweat in at least the 1-10 pM concentration range: (1) pro-inflammatory and anti-inflammatory cytokines; and (2) neurotransmitters. Specific aims leading to sub-pM sensitivity include: (1) frequency matching of interdigitated electrodes to the biomarker / biorecognition element response; (2) discovery of the optimal and highly homogeneous surface-orientation of the biorecognition elements for maximum impedance response; (3) deep investigation of charge-transfer, shape-change, ion-screening, and other factors as a function of finer stimuli such as waveform shape, potential magnitude, electrolyte solution pH, and ionic strength. Success with these aims will then stimulate a surge of interest in sweat biosensing and enable pursuit of a broad array of commercial products. Broader Impacts:It is expected that the Success of the proposed work will lead to lower total health care costs by advancing personalized medicine and preventative care. Broad social impacts include heat-stress management in athletics and firefighters, augmenting alertness in pilots and truckers, soldier PTSD prevention, and health baselining for advanced theranostics. Dissemination plan includes organizing a self-sustaining annual international workshop on the Sensing of Biomarkers in Sweat. This EAGER will enhance infrastructure in research and education for sweat sensing. Integrated education plan includes support of an undergraduate research co-op at the university, who will then later intern at PI's partner federal labs.