CAREER: Integrated Optofluidic Chips towards Label-Free Detection of Exosomal MicroRNA Biomarkers

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Cancer is a major global cause of morbidity and mortality. With the increasing heterogeneity and complexity observed in cancers, the need for accurate diagnosis and molecular monitoring of disease progression has become more important than ever. Liquid biopsy of microscopic vesicles from our cells circulating in human bodily fluids is a promising, inexpensive, and minimally invasive approach for cancer diagnosis and personalized medical treatment. Particularly, detecting the biomolecules carried by these vesicles, including nucleic acids encoding genetic information, has emerged as a promising strategy for early diagnosis. However, the existing diagnostic tools for such technologies lack the needed sensitivity, specificity, speed, and cost-effectiveness necessary to become clinically viable. This CAREER proposal fully exploits the cutting-edge development in small-scale technologies such as nanophotonics, nanofluidics, and biosensing to provide novel solutions for the detection of diagnostic nucleic acids from clinical samples with an improved sensitivity, reduced sample volume, and decreased analysis time. The success of the proposed technology will have significant impact on early-stage diagnosis as well as prognosis and management of diseases, including cardiovascular diseases, autoimmune syndromes, neurodegenerative disorders, and infectious diseases. By integrating research and education, the project will promote public awareness of the importance of nanobiotechnology in health care, and to cultivate the next-generation of scientists and engineers in nanotechnology and biosensing to address grand challenges in affordable and portable disease diagnosis. Further, this project aims to attract the participation of K-12 students and underrepresented individuals (e.g., female and Native American students) in STEM careers. The research objective of this CAREER proposal is to validate the hypothesis that an integrated and multiplexed optofluidic platform can accurately detect exosomal miRNAs. In pursuit of this goal, a nanofluidic chip (ExoMiRChip) will be designed to functionally integrate label-free exosome purification, on-chip exosomal miRNA extraction, and plasmonic miRNA sensing. Theories and experiments will be combined to address fundamental challenges in achieving high-resolution and high-throughput exosome nanoparticle sorting, high-sensitivity and high-specificity miRNA detection, and multi-functional integration of nanofluidic systems. This project will explore scientific unknowns in exosome nanoparticle fluidic dynamics at the nanometer scale, and aim to comprehensively elucidate the limiting factors in on-chip exosome purification. The project will innovate optically coupled ultrasensitive plasmonic nanosensors functionalized with sequence-specific locked nucleic acid (LNA) probes, and use them to identify the critical factors affecting accurate detection of exosomal miRNA, including the plasmonic sensor design, nanostructure fabrication, miRNA molecular concentration, and the miRNA selectivity. Successful nanofluidic integration on the ExoMiRChip will significantly reduce sample volume in diagnosis (from milliliters to microliters), minimize bias and contamination, improve diagnosis speed (estimated from days/weeks to hours), and potentially enable multiplexed biomarker detection. We expect the project to be transformative in future biosensing and applicable to a wide variety of biomolecules.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.