Abstract: Detecting small-molecules and other biologically important targets, such as signaling molecules, drugs, toxins, and oligonucleotides, presents unique challenges in complex native environments and at low target concentrations. We developed field-effect transistors (FETs) coupled with nucleic-acid receptors, i.e., aptamers, for sensing in situ. Rare aptamer sequences are identified via solution-phase SELEX thereby circumventing target tethering and epitope masking. Rigorous counter-SELEX against similarly structured metabolites and interferents yields aptamers with high target selectivity. Oligonucleotide libraries are designed for stem closure and adaptive loop-binding upon target recognition. Target-induced conformational rearrangements of stem-loop aptamers are transduced into conductance changes at nanometer-thin In2O3 FET semiconductor surfaces. Portions of the conformational changes in highly negatively charged nucleic acid backbones occur within the Debye length (<1 nm in physiological fluids) to enable direct target quantification over 5-6 orders of magnitude and at concentrations well below aptamer-target dissociation constants. We have demonstrated selective sensing of small-molecule neurotransmitters in brain tissue, e.g., serotonin, dopamine,^1-2 and nutrients in blood, e.g., glucose, phenylalanine. Via hybridization, we detect and differentiate single-nucleotide polymorphisms sans amplification. Paths to temporally resolved in vivo sensing and other key applications will be illustrated. Metal-oxide thin-film FETs fabricated via sol-gel processing, chemical-vapor deposition, standard and novel low-cost chemical patterning methods,^3-4 and on flexible substrates⁵ enable multiplexed sensing with wide accessibility and applicability.

1. Kim, J. et al., Fabrication of high-performance ultrathin In2O3 film field-effect transistors and biosensors using chemical lift-off lithography. ACS Nano 2015, 9:4572.
2. Nakatsuka, N. et al., Aptamer–field-effect transistors overcome Debye length limitations for small-molecule sensing. Science 2018, 362:319.
3. Liao, W. S. et al., Subtractive patterning via chemical lift-off lithography. Science 2012, 337:1517.
4. Zhao, C. et al., Large-area, ultrathin metal-oxide semiconductor nanoribbon arrays fabricated by chemical lift-off lithography. Nano Lett. 2018, 18:5590.
5. Rim, Y. S. et al., Printable ultrathin metal oxide semiconductor-based conformal biosensors. ACS Nano 2015, 9:12174.