Sean Fischer

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MSEE, Stanford University, 2015
BSEE, University of Connecticut, 2013
Email: seanrf@stanford.edu

Potentiostat Array for Molecular Diagnostics

The ability to probe the contents of our blood accurately, rapidly, and cheaply is essential for effective medical practice and research. The typical assay converts the concentration of a target protein into a signal which can be measured optically [1], electronically [2], or mechanically [3]. These assays share the need for a binding element which selectively captures the target protein and fixes it to a surface, allowing the undesired proteins to be washed away. Although affinity assays represent the workhorse of the billion dollar molecular diagnostics industry [4], they suffer from the need to maintain expensive chemical reagents and perform chemical processing in the laboratory. More fundamentally, binding elements are not always available for the protein of interest and can be difficult to develop and reproduce [5]. We are working in collaboration with Roger T. Howe to develop a protein assay which does not use a binding element.

seanrf2016 labeled assays.jpg

Our assay is based on the vibrational theory of olfaction [6], which argues that olfactory receptors are activated by electron transfer assisted by the molecular vibrations of odorant molecules. We use a three electrode electrochemical cell in place of an olfactory receptor, measuring electron transitions between a working electrode and redox active species in an electrolyte. We argue the small signal conductance of the working interface should increase in the presence of vibrationally assisted electron transfer [7]. Cyclic voltammetry of the working interface shows discrete steps in electrode current (Is) at electrode potentials (Vs) which change with the analyte dissolved in the electrolyte, without the need for affinity probes to bind with the target analyte. Our goal is to show these feature-rich current-voltage characteristics can be used to identify proteins and infer their concentration.

seanrf2016 qtep assay.jpg

The electronic circuit responsible for implementing cyclic voltammetry measurements is called a potentiostat. Experiments show that the discrete steps in the current of the electrochemical cell disappear when the noise associated with the voltage bias Vs is large. We reason this electronic noise also assists electron transfer at the interface, but electron transfer is assisted at any bias since the noise energy is distributed over a broad frequency spectrum. My work focuses on the implementation of a low-noise potentiostat to interface with an array of electrochemical olfactory sensors. The specifications of a single channel of the potentiostat are shown below. The proposed potentiostat architecture is based on a mixed-signal feedback loop utilizing an incremental delta sigma analog to digital converter multiplexed among multiple channels in the array. With this architecture, the dominant sources of low-frequency noise can be attenuated by gain, attenuated through filter reset, and modulated out of band through chopping.   


seanrf2016 proposed hardware.jpg

References

[1] Voller, A, A Bartlett, and D E Bidwell. “Enzyme Immunoassays with Special Reference to ELISA Techniques.” Journal of Clinical Pathology 31.6 (1978): 507–520.

[2] Hall DA, Gaster RS, Makinwa K, Wang SX, Murmann B. A 256 pixel magnetoresistive biosensor microarray in 0.18μm CMOS. IEEE journal of solid-state circuits. 2013;48(5):1290-1301.

[3] Arlett, J.L., E.B. Myers, and M.L. Roukes. “Comparative Advantages of Mechanical Biosensors.” Nature nanotechnology 6.4 (2011).

[4] http://www.grandviewresearch.com/industry-analysis/molecular-diagnostics-market

[5] J. Wang. Development of novel technologies for discovery of high performance affinity reagents. ProQuest Dissertations and Theses pp. 104. 2013.

[6] Solov'yov, Ilia A., Po-Yao Chang, and Klaus Schulten. "Vibrationally assisted electron transfer mechanism of olfaction: myth or reality?." Physical Chemistry Chemical Physics 14.40 (2012): 13861-13871.

[7] C. Gupta, R. M. Walker, R. Gharpuray, M. M. Shulaker, Z. Zhang, M. Javanmard, R.W. Davis, B. Murmann, and R. T. Howe, “Electrochemical quantum tunneling for electronic detection and characterization of biological toxins,” Proceedings of SPIE, vol. 8373, p. 837303 (14pp), 2012.

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