Comprehensive, Near Patient Assessment of Severe Hypoglycemia in Newborns Using Low Blood Volume

摘要 对重度脑功能减退症的全面、近距离患者评估 使用低血容量（快速通道SBIR）的新生儿 低血糖症是新生儿中最常见的代谢紊乱，并且使新生儿处于增加的风险中。 癫痫和永久性脑损伤严重新生儿低血糖症的病因-影响周围 在美国每年有25,000名新生儿--这很复杂，其潜在原因包括高胰岛素血症， 皮质醇和/或生长激素（GH）缺乏，以及糖原代谢缺陷。全面 对这些生理途径的评估对于指导适当、有效的医疗干预是必不可少的。 然而，目前的实验室测定组需要相对大体积（3 mL或更多）的全生物样品。 血液，使新生儿评估具有挑战性，特别是早产儿。更重要的是， 这些化验的周转时间可能是48小时或更长，导致挽救生命治疗的严重延误。 这个快速通道SBIR项目的总体目标是开发一个全面的近患者数字微流体 系统，FINDER，用于快速评估新生儿严重，持续性低血糖症，使用 微量全血。FINDER将接受一次性检测盒，并将对6种检测试剂盒进行多重检测， 胰岛素、皮质醇、生长激素、葡萄糖、β-羟基丁酸和游离脂肪酸的检测，使用< 50 µL的 全血用于所有检测。运行时间约为45分钟。Baebies的团队将与 与新生儿学（Michael Cotten博士）和儿科内分泌学（Michael Freemark）在杜克大学的这个项目上。本文提出的系统解决了关键的未满足的临床问题 需要在低血糖时进行快速检测;最终产品将与 在更低的血容量、更低的成本和更快的结果时间方面，目前基于实验室的测定。 第一阶段的具体目标包括：1）优化检测试剂盒上的干燥和储存; 2） 将六种基于实验室的检测转换为数字微流控盒，并建立初步的分析 性能;和3）证明全血测定组的初步可行性。关键里程碑 进入II期的关键是成功证明使用干 试剂，具有高可靠性和精密度。Aim 3中的一个小型可行性研究将测试我们的分析方法 与临床标准实验室测定相比的性能。第二阶段的具体目标是：1）多路复用， 在同一检测盒上同时进行检测; 2）进行分析验证，以确定器械 性能;和3）低血糖组的初步临床验证：使用FINDER获得的结果 将与在杜克临床实验室获得的标准值进行比较。 在第二阶段结束时，我们将有一个快速，高效和准确的商业化产品 使用微升体积的全血评估新生儿的严重低血糖。我们将寻求FDA 最终产品的批准，最初将在美国医院销售用于儿科患者， 未来的市场将面向其他可能受益于该平台创新功能的患者。

ABSTRACT Comprehensive, Near Patient Assessment of Severe Hypoglycemia in Newborns using Low Blood Volume (Fast-Track SBIR) Hypoglycemia is the most common metabolic disorder in newborns and places the neonate at increased risk of seizures and permanent brain injury. The etiology of severe neonatal hypoglycemia -- which affects around 25,000 newborns each year in the U.S. -- is complex, with underlying causes including hyperinsulinism, cortisol and/or growth hormone (GH) deficiencies, and defects in glycogen metabolism. Comprehensive evaluation of these physiological pathways is essential to guide appropriate, effective medical interventions. However, the current panel of laboratory assays requires relatively large volumes (3 mL or more) of whole blood, making newborn assessment challenging, particularly in preterm newborns. More importantly, routine turnaround times for these assays may be 48 hours or more, leading to critical delays in life-saving treatment. The overall goal of this Fast Track SBIR project is to develop a comprehensive near patient digital microfluidic system, FINDER, for the rapid assessment of severe, persistent hypoglycemia disorders in newborns using microliter volumes of whole blood. FINDER will accept single use cartridges and will multiplex 6 assays for the detection of insulin, cortisol, growth hormone, glucose, β-hydroxybutyrate and free fatty acids using < 50 µL of whole blood for all assays. Run time will be approximately 45 minutes. The team at Baebies will collaborate with leading clinical investigators in Neonatology (Dr. Michael Cotten) and Pediatric Endocrinology (Dr. Michael Freemark) at Duke University on this project. The system proposed herein addresses a critical unmet clinical need for rapid testing at the time of hypoglycemia; the final product will be substantially differentiated from current laboratory based assays in terms of lower blood volume, lower cost and faster time-to-result. The Phase I Specific Aims include: 1) optimize assay-ready reagents for on-cartridge drying and storage; 2) translate six laboratory based assays to the digital microfluidic cartridge and establish preliminary analytical performance; and 3) demonstrate preliminary feasibility of the assay panel on whole blood. The key milestone for progression to Phase II will be the successful demonstration of all individual assays on-cartridge using dry reagents and with high reliability and precision. A small feasibility study in Aim 3 will test our assay performance against clinical standard laboratory assays. The Specific Aims for Phase II are: 1) multiplex all assays to perform simultaneously on the same cartridge; 2) perform analytical validations to determine device performance; and 3) preliminary clinical validation of the hypoglycemia panel: results obtained with FINDER will be compared to standard values obtained in the Duke Clinical Laboratory. At the conclusion of Phase II, we will have a commercializable product for rapid, efficient and accurate assessment of severe hypoglycemia in newborns using microliter volumes of whole blood. We will seek FDA approval of the final product, which will initially be marketed for use in pediatric patients in U.S. hospitals, with a future market towards other patients who may benefit from the innovative features of the platform.