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.
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