Advancing microfluidic diagnostic chips into clinical use: a review of current challenges and opportunities.

Microfluidic diagnostic (μDX) technologies miniaturize sensors and actuators to the length-scales that are relevant to biology: the micrometer scale to interact with cells and the nanometer scale to interrogate biology's molecular machinery. This miniaturization allows measurements of biomarkers of disease (cells, nanoscale vesicles, molecules) in clinical samples that are not detectable using conventional technologies. There has been steady progress in the field over the last three decades, and a recent burst of activity catalyzed by the COVID-19 pandemic. In this time, an impressive and ever-growing set of technologies have been successfully validated in their ability to measure biomarkers in clinical samples, such as blood and urine, with sensitivity and specificity not possible using conventional tests. Despite our field's many accomplishments to date, very few of these technologies have been successfully commercialized and brought to clinical use where they can fulfill their promise to improve medical care. In this paper, we identify three major technological trends in our field that we believe will allow the next generation of μDx to have a major impact on the practice of medicine, and which present major opportunities for those entering the field from outside disciplines: 1. the combination of next generation, highly multiplexed μDx technologies with machine learning to allow complex patterns of multiple biomarkers to be decoded to inform clinical decision points, for which conventional biomarkers do not necessarily exist. 2. The use of micro/nano devices to overcome the limits of binding affinity in complex backgrounds in both the detection of sparse soluble proteins and nucleic acids in blood and rare circulating extracellular vesicles. 3. A suite of recent technologies that obviate the manual pre-processing and post-processing of samples before they are measured on a μDX chip. Additionally, we discuss economic and regulatory challenges that have stymied μDx translation to the clinic, and highlight strategies for successfully navigating this challenging space.