  This paper presents a dual-aptamer scheme to cancel the signal drifts from
structure-switching aptamers during long-term monitoring. Electrochemical
aptamer-based (E-AB) biosensors recently demonstrated their great potential for
in vivo continuous monitoring. Nevertheless, the detection accuracy is often
limited by the signaling drifts. Conventionally, these drifts are removed by
the kinetic differential measurements (KDM) when coupled with square-wave
voltammetry. Yet we discover that KDM does not apply to every aptamer as the
responses at different SWV frequencies heavily depend on its
structure-switching characteristics and the redox reporters' electron transfer
(ET) kinetics. To this end, we present a "dual-aptamer" scheme that uses two
aptamers responding differentially to the same molecular target for drift
cancellation. We identify these paired aptamers through (1) screening from the
existing aptamers pool and (2) engineering the signaling behavior of the redox
reporters. We demonstrate their differential signaling to ampicillin and ATP
molecules and show that the aptamer pair bears common drifts in undilute goat
serum. Through cancellation, sensor drift is reduced by 370-fold. Benefiting
from the "differential" signaling, the recording throughput is also doubled
using differential readout electronics. The authors believe the proposed
technique is beneficial for long-term in vivo monitoring.
