(351a) Ionic Memristors and Nonlinear Ionic Circuits for Future Massively Multiplexed Liquid Biopsy Electrochemical Biosensor Arrays

Recent discoveries of a multitude of protein, microRNA, ctDNA and other molecular biomarkers for cancer suggest that early screening and dynamic therapy management would soon be possible to significantly increase cancer survival rate. However, the screening tests for these biomarkers are only effective if they are applied frequently and outside laboratories ---- a turn-key liquid biopsy technology needs to be developed to detect and quantify a large number of molecular biomarker targets from a small volume of blood sample. I will review my current progress in developing such a platform and describe some future plans/challenges.

I have developed micro/nanofluidic circuit components that allow precise measurement and control of ion and biomolecule transport in physiological buffers. I intend to synthesize these fluidic circuit units into large-scale fluidic-based ionic circuits, including multiplexed active electrochemical sensor arrays, for cancer liquid biopsy. The ionic circuits require a robust flip-flop latch element to digitize and memorize the ionic signals and to enable robust sequential operations. They also require a high-flux switching/amplifying element to individually address each sensing/memory unit and to sustain the long-range ionic signal propagation. I have focused on the development of these two elements in my PhD work.

A bistable ionic memristor based on a reversible redox reaction on a silicon microelectrode is the basis of my ionic latch element [Sun et al, Small, 11, 5206-5213 (2015)]. The memory of ions transporting across the silicon/solution interface is due to the electrochemical formation of an interfacial nanoscale oxide film on the silicon microelectrode under anodic polarization. While under cathodic bias, the hydride formation decomposes the thin oxide layer. Combining these two processes we produce a reversible and history dependent interfacial resistance of the silicon microelectrode, which gives this ionic memristor distinct on-off current states. The electrochemical oxide film growth and decomposition together with their contribution to the resistive switching are studied by X-ray photoelectron spectroscopy. By designing an optimal latching operation protocol and appropriate impedance matching with the surrounding microfluidic ionic channel, we are able to realize a robust flip-flop memory action with a more than 10 on/off ratio and a 1s short switching time. The ion current signal can hence be sampled and digitized into the ionic memristor electrochemically.

To realize the switching/amplifying element, a high-flux ionic transistor and amplifier based on non-equilibrium ion transport through an ion-selective nanoporous membrane is then designed which allows a small normal gating voltage signal to control a large draining ionic cross current. It can allow for individual addressing of the ionic memristor and help synthesize multiplexed electrochemical sensors with ionic memristors into large-scale electrochemical circuits [Sun et al, LabChip,16, 1171-1177 (2016)]. Because of the charge selectivity, asymmetric concentration polarization occurs across such a membrane upon the application of a normal electric field. By coupling the ion-selective membrane with a tangential microfluidic channel adjacent to the membrane, I utilized coion flux balance to produce a depletion front in the microchannel that is sensitive to the gating voltage, thus creating an ionic transistor with significant conductance amplification. The optimal membrane ionic transistor we have designed based on this non-equilibrium flux balance principle is able to achieve a transconductance of more than 12 µS, which is larger than previous reported for ionic transistors by a factor of 40. It corresponds to a voltage amplification factor of 10.

I will report my preliminary result on controlling a single ionic memristor by the ionic transistor and using the ion current amplifier to improve a single nucleic acid electrochemical membrane sensor [Slouka et al, Annu Rev Anal Chem, 7, 317 (2014)]. The ionic transistor will be shown to enhance the electrochemical membrane sensor by orders of magnitude with fM sensitivity. It can also mediate the communication between the membrane sensor and the ionic memristor to selectively register the sensing result to the ionic latch or to read out the sensing result. I will then discuss my plan to scale up the control-memory electrochemical circuit architecture to massively multiplexed smart electrochemical sensor arrays with a parallel operation paradigm. Advantages and challenges of this future biopsy platform for microRNA profiling against the current lab-bound micro-array and rtPCR technologies will also be discussed [Egatz-Gomez et al, Biomicrofluidics, 10, 032902 (2016)]. More details of the ion current amplification design for improving electrochemical molecular sensing will be presented in Session T9002 and Session T3003.