Detection of a multi-disease biomarker in Saliva with Graphene Field Effect Transistors

Abstract

Human carbonic anhydrase 1 (CA1) has been suggested as a biomarker for identification of several diseases including cancers, pancreatitis, diabetes, and Sjogren's syndrome. However, the lack of a rapid, cheap, accurate, and easy-to-use quantification technique has prevented widespread utilization of CA1 for practical clinical applications. To this end, we present a label-free electronic biosensor for detection of CA1 utilizing highly sensitive graphene field effect transistors (G-FETs) as a transducer and specific RNA aptamers as a probe. The binding of CA1 with aptamers resulted in a positive shift in Dirac voltage V D of the G-FETs, the magnitude of which depended on target concentration. These aptameric G-FET biosensors showed the binding affinity (K D ) of ∼ 2.3 ng/ml (70 pM), which is four orders lower than that reported using a gel shift assay. This lower value of K D enabled us to achieve a detection range (10 pg/ml -100 ng/ml) which is well in line with the clinically relevant range. These highly sensitive devices allowed us to further prove their clinical relevance by successfully detecting the presence of CA1 in human saliva samples. Utilization of this label-free biosensor could facilitate the early stage identification of various diseases associated with changes in concentration of CAs.

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“…30 Liquid gated G-FET sensors significantly lower the required voltage (below 2 V) as well as keep the probes and analytes in their original size and conformation. Our prior work, as well as others 38,39 , show liquid gating is a reliable approach with less complex electronics required for backgated FET. In this work, we utilized our upgraded G-FET platform having on-chip coplanar Pt side gate electrodes which provides a miniaturized G-FET platform and allows upscaling of the number of devices on the same chip while measuring them simultaneously (see Figure 1).…”

“…To obtain a resistance vs liquid gate voltage plot, the measurements were performed in 0.01x PBS to minimize the Debye screening effect. 38 Figure 3c shows the shift in Dirac voltage ( V D ) after successive functionalization with PBASE linker and NX-aptamers. Further shift in V D was observed upon incubation of NX target at concentrations of 1 nM and 10 nM while saturating when measured with 100 nM.…”

“…28–33 The electrical resistance of graphene is highly sensitive to the target bio-analytes (or the conformal changes of the probe), enabling direct and rapid readout. 28,30,34,35,36,37 In our recent work, we demonstrated a highly sensitive G-FET for the detection of biomarkers such as CA-I (oral diseases biomarker) in saliva, 38 and antibiotic resistant bacteria, both at clinically relevant concentrations. 39 However, the G-FET design in our prior work was limited to detection of a single target, with each chip functionalized with a single probe, provided minimal passivation, and required a platinum (Pt) wire as a separate reference electrode.…”