Nonlinear Ionic Circuits and Ionic Memristors for Integrated Liquid Biopsy Chips

In recent years, state-of-the-art molecular diagnostic technologies make it possible to accurately detect certain diseases with molecule biomarkers, replacing the traditional culturing-based gold standard. However, most molecular diagnostic techniques are disease/biomarker specific and cannot be used for point-of-care (POC) pan-disease screening of a multitude of molecular biomarkers. They also rely on extensive and expensive experiments in the lab. To solve this problem, we urgently need microfluidic tools to rapidly detect and quantify multiple molecular biomarkers within a minimum amount of clinical sample --- and do so at high throughput so many samples can be processed. In particular, an integrated liquid biopsy chip is desired to profile the irregular expression of a large panel of microRNA (miRNA) biomarkers for early pan-cancer screening. Fluidic-based ionic circuits, as potential tools to integrate such a liquid biopsy chip, have drawn much attention, for they can precisely concentrate, separate and detect molecular biomarkers in a low-cost microfluidic chip. One problem with the current ionic circuit devices is their low throughput and high energy consumption, which makes it impossible for them to sustain enough ion and molecular fluxes and to enable a large-scale integration of multiplex sensors and a rapid detection process.

To overcome aforementioned limitations, I demonstrate three novel ionic circuit devices for high-throughput and multiplex integration of the liquid biopsy chip. In Chapter 1, I review current miRNA technologies and specify the needed ionic circuit technologies. In Chapter 2, by using non-linear electrokinetics in a microfluidic-ion exchange membrane hybrid chip, I develop a versatile, high-flux ionic circuit component that acts as either an ionic diode or an ionic transistor. The proposed device is aimed to rapidly transport molecule biomarkers among different functional modules in the integrated chip so as to eliminate external sample transfer. In Chapter 3, by studying the stable but inhomogeneous ion concentration polarization induced by my ionic transistor, I design an on-chip sample pretreatment module to purify nucleic acid targets from a heterogeneous solution. This pretreatment device is ideal for the integrated liquid biopsy chip to process clinical samples. In Chapter 4, based on a reversible redox reaction on a silicon microelectrode, I invent an ionic memristor to realize an ionic latch that can digitize and memorize ionic current signals transmitted in physiological buffers. Such an ionic latch can integrate multiplex ion current biosensors, laying the foundation of rapid and parallel operation for the integrated liquid biopsy chip. In the last chapter, I discuss the application of the integrated liquid biopsy chip to multiplex miRNA profiling and protein detection, and I also suggest future integration of high-flux ionic circuits to implantable or wearable theranostic platforms.