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Integrated microfluidic devices for preterm birth biomarker measurement

用于早产生物标志物测量的集成微流体装置

基本信息

批准号：
9087225
负责人：
Adam Thomas Woolley
金额：
$ 29.77万
依托单位：
BRIGHAM YOUNG UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087225
关键词：
Address Adsorption Affinity Chromatography Biological Assay Biological Markers Birth Blinded Blood Blood specimen Caring Coupling Defensins Development Device or Instrument Development Devices Diagnosis Evaluation Excision Fingers Fluorescence Goals Health Healthcare Hour Human Human Resources Immunoassay Individual Label Lactoferrin Measurement Measures Medical Membrane Methods Microchip Electrophoresis Microfluidic Microchips Microfluidics Nature Neonatal Newborn Infant Peptides Performance Phase Polymers Pregnancy Complications Pregnant Women Premature Birth Preparation Prevalence Preventive measure Process Proteins Pump Reagent Risk Risk Assessment Sampling Serum Severities Solid Specificity System Testing Therapeutic Intervention United States Universities Utah Work design improved instrument medical schools meetings microchip neonatal death operation pressure prevent protein biomarkers research study tool

项目摘要

DESCRIPTION (provided by applicant): Preterm birth (PTB) is the most common complication of pregnancy, with over 500,000 early births annually in the United States. PTB is responsible for the majority of neonatal deaths and newborn illnesses. Unfortunately, the ability to assess PTB risk prior to contractions is not available clinically; this capability would enable therapeutic interventions that prevent or forestall delivery, potentially decreasing PTBs and/or the severity of neonatal complications. This renewal proposal focuses on the development of an integrated microfluidic platform for rapid, sensitive and inexpensive quantitation of serum PTB risk biomarkers (newly discovered peptides and known proteins), weeks before contractions occur. This proposal thus offers a major human health impact, potentially decreasing the prevalence of PTBs and their associated complications. This proposal tests the hypothesis that further development of microfluidic systems, which combine sample preparation, separation and quantitation in a single platform, will enable the direct measurement of PTB biomarkers in serum, allowing risk assessment and preventative measures to occur well before contractions begin. The proposed automated microfluidic platform has three main components: (1) a multiplexed immunoaffinity extraction module to selectively capture unlabeled PTB biomarkers; (2) a purification/labeling module to enrich PTB biomarkers and then allow fluorescence labeling with removal of unreacted tag; and (3) a microchip electrophoresis module to separate the labeled PTB biomarkers, enabling their quantitation. This approach improves significantly over present instrument- and personnel-intensive methods to determine PTB biomarkers, and should offer specificity comparable to sandwich immunoassays that would be problematic to develop for small peptide targets. The goal of this renewal proposal is to further develop integrated microfluidic systems for convenient, inexpensive, rapid and quantitative analysis of serum biomarkers with PTB risk correlation. This objective will be accomplished via three specific aims. In Aim 1 electrokinetically operated microchips to quantify PTB biomarkers will be created and tested, integrating immunoaffinity extraction, solid-phase enrichment, fluorescence labeling, electrophoretic separation and biomarker quantitation. Aim 2 will involve developing PTB biomarker analysis microdevices that use pressure actuation of on-chip valves and pumps to carry out integrated sample preparation operations. Performance of the devices from Aims 1 and 2 will then be compared. In Aim 3 these microfluidic platforms will be used to measure PTB biomarkers in blood samples to establish the feasibility of microchip methods in predicting PTB risk weeks before contractions occur. Importantly, this work addresses the urgent need to diagnose PTB risk when therapeutic intervention is still feasible; however, the general nature of the approach should be applicable well beyond biomarkers for PTB, further exemplifying the large and important health impact of these studies.

描述（由申请人提供）：早产（PTB）是最常见的妊娠并发症，在美国每年有超过50万例早产。多数新生儿死亡和新生儿疾病是由肺结核造成的。不幸的是，临床没有能力在宫缩前评估肺结核风险；这种能力将使预防或提前分娩的治疗干预成为可能，从而可能降低ptb和/或新生儿并发症的严重程度。这项更新建议的重点是开发一个集成的微流控平台，用于在收缩发生前几周快速，敏感和廉价地定量血清PTB风险生物标志物（新发现的肽和已知的蛋白质）。因此，这一建议对人类健康产生重大影响，可能会降低ptb及其相关并发症的患病率。该建议验证了微流体系统的进一步发展，该系统将样品制备，分离和定量结合在一个平台上，将能够直接测量血清中的PTB生物标志物，从而在收缩开始之前进行风险评估和预防措施。提出的自动化微流控平台有三个主要组成部分：(1)一个多路免疫亲和提取模块，选择性地捕获未标记的PTB生物标志物；(2)纯化/标记模块，用于富集PTB生物标志物，然后去除未反应的标记进行荧光标记；(3)微芯片电泳模块，用于分离标记的PTB生物标志物，使其能够定量。这种方法大大改进了现有的仪器和人员密集型方法来确定PTB生物标志物，并且应该提供与三明治免疫分析法相当的特异性，而三明治免疫分析法对于小肽靶标的开发是有问题的。本课题的目标是进一步开发集成微流控系统，方便、廉价、快速、定量地分析与PTB风险相关的血清生物标志物。这一目标将通过三个具体目标来实现。在Aim 1中，将创建并测试用于量化PTB生物标志物的电动操作微芯片，包括免疫亲和提取，固相富集，荧光标记，电泳分离和生物标志物定量。目标2将涉及开发PTB生物标志物分析微设备，该设备使用片上阀门和泵的压力驱动来进行集成的样品制备操作。然后比较目标1和目标2的设备性能。在Aim 3中，这些微流控平台将用于测量血液样本中的PTB生物标志物，以确定微芯片方法在子宫收缩发生前数周预测PTB风险的可行性。重要的是，这项工作解决了在治疗干预仍然可行的情况下诊断PTB风险的迫切需要；然而，该方法的一般性质应该远远超出PTB的生物标志物，进一步例证了这些研究对健康的巨大而重要的影响。