Validation and Demonstration of Point-of-Care Sensor for Multi-Metal Exposure Assessment

描述（由申请人提供）：金属在环境中无处不在，长期以来一直被认为对人体健康构成重大威胁。在许多对照研究中，血铅（Pb）一直与智商和学业成绩的缺陷有关。锰（Mn）是一种必需元素，但过量会产生神经毒性，能够穿过血脑屏障并在大脑中积累。目前测量此类暴露的方法成本高昂，包括大量劳动力、设备和耗时的实验室程序，而且往往需要很长的周转时间。因此，迫切需要改进技术，以定量评估这些暴露的水平并确定其不利后果。我们的初步数据显示了用即时传感器测量锰和铅金属的可行性。因此，我们建议对儿童手指刺血中的锰和铅金属进行快速、即时、多分析物评估。在R21阶段，我们将展示传感器在全血金属分析中的有效性和可用性。该传感器的可行性在我们前期的工作中已经得到了证实。在目标1中，我们将首先展示在现实世界条件下准确可靠地测量血液中Mn和Pb金属的能力，并具有适当的特异性和灵敏度。然后，我们将展示在R33阶段扩大传感器制造的能力。在目标2中，我们将开发一个简化的、用户友好的软件界面。最后，我们将通过寻求专家和研究人员的反馈来评估传感器的可用性和支持文件。我们将展示传感器在最小监督下使用的能力，并建立数据分析和部署策略。R33阶段将进一步展示其附加的科学价值。在Aim 3中，我们将在青少年儿童纵向队列中部署传感器，以评估传统和新型金属（Mn和Pb）内剂量标记物与神经运动表现之间的关系。我们将评估新的假设，即锰和铅将显著影响青少年队列的功能步态和静态和动态平衡。此外，我们提出了一个高风险/高效益的目标来评估全血中未结合或游离锰作为一种新的锰生物标志物的临床意义。在目标4中，我们将开发有效的参与者报告机制来返回血金属结果。R33阶段将以制定道德策略为高潮，以建立有效的机制，将测量结果报告给研究参与者。相对迅速、同步地评估重金属暴露，最终减少成本和周转时间，将有利于国家和国际的儿科公共卫生。事实上，我们的长期目标是使用传感器将血液分析从实验室转移到临床环境，在几分钟内提供结果。

DESCRIPTION (provided by applicant): Metals are ubiquitous in the environment and have long been recognized to pose significant threats to hu- man health. Blood lead (Pb) has been consistently associated with deficits in IQ and academic achievement in numerous controlled studies. Manganese (Mn) is an essential element, yet neurotoxic in excess, capable of crossing the blood-brain barrier and accumulating in the brain. Current approaches for measuring such exposures suffer from high costs including extensive labor, equipment and time-consuming laboratory procedures, and often, demonstrate long turnaround times. Hence, there is a critical need for improved technology to quantitatively assess levels and identify adverse consequences of these exposures. Our preliminary data show feasibility of measuring of Mn and Pb metals with point-of-care sensors. We therefore propose to demon- strate rapid, point-of-care, multi-analyte assessment of Mn and Pb metals in a finger prick of blood from children. In the R21 phase, we will demonstrate sensor validity and usability for metal analysis in whole blood. The feasibility of the sensor has been established in our prior work. In Aim 1, we will firs demonstrate ability to ac- accurately and reliably measure Mn and Pb metals in blood under real-world conditions with appropriate specific- ty and sensitivity. Then, we will demonstrate ability to scale-up manufacturing of sensors for the study in the R33 phase. In Aim 2, we will develop a streamlined, user-friendly software interface. Finally, we will assess usability of the sensor and supporting documentation by seeking feedback from experts and study staff. We will demonstrate the ability for sensors to be used with minimal oversight and establish strategies for data analysis and deployment. The R33 phase will further demonstrate the added scientific value. In Aim 3 we will deploy the sensor in longitudinal cohort of adolescent children to evaluate the relationship between traditional and novel internal dose markers of metals (Mn and Pb) and neuromotor performance. We will evaluate the novel hypothesis that Mn and Pb will significantly impact functional gait and static and dynamic balance in an adolescent cohort. Additionally, we propose a high risk/high benefit aim to evaluate the clinical significance of unbound or free Mn in whole blood as a novel biomarker for Mn. In Aim 4 we will develop effective participant report-back mecha- nisms to return blood metal results. The R33 phase will culminate with the development of ethical strategies for effective mechanisms for reporting measurement results back to study participants. A relatively swift, simultaneous assessment of heavy metal exposure, which ultimately reduces costs and turnaround times, would benefit pediatric public health nationally and internationally. Indeed, our long-term goal is to use sensors to move blood analysis from the laboratory to the clinical setting, providing results within minutes.