Ultra-sensitive Detection of Nucleic Acids using an Electronic Chip

The detection of particular genetic sequences aids in the early detection and diagnosis of disease; permits monitoring of the health and state of the natural environment; and informs forensic investigations. To date, gene detection has relied on enzymatic amplification followed by optical readout. Though these technologies have advanced dramatically, the instruments and assays are costly and lack portability. The work presented herein addresses an urgent challenge: molecular diagnostics at the point-of-need. This work reports the first electronic chip capable of analyzing - directly, without amplification, and with clinically-relevant sensitivity - multiple genes of interest present in a clinical sample. It reports a dramatic acceleration in sample-to-answer times, with clinically actionable findings in minutes where legacy techniques take hours or days. The key to the sensitivity and speed of the biosensors reported herein lies in their architecture and morphology on multiple lengthscales. It is proven that hybridization-based assays employing a nucleic probe attached to a solid surface can only achieve efficient performance when displayed on a nanotextured surface. It is also discovered that these same sensing elements must reach tens of micrometers into solution to achieve rapid, sensitive detection of nucleic acids in clinical samples. As a result, the materials integrated onto the sensing chip reported herein are engineered on multiple lengthscales - from the nanometers to the tens of micrometers. Engineering is done through a combination of low-cost, convenient top-down photolithographic patterning; combined with hierarchically-designed bottom-up growth of electrodeposited sensing elements. The capstone of this work is a chip that distinguishes among different types of bacteria in an unpurified sample. The chip gives accurate answers in under half an hour when detecting bacteria at a level of 1.5 colony-forming-unit (cfu) per microliter. These speeds and sensitivies enable the application of this technology in point-of-need assays for infectious disease detection. Ultimately, the work showcases the power of bringing together techniques and principles from materials chemistry, biochemistry, applied physics, and electrical engineering to the solution of an important problem relevant to human health.Ph