Ultrasensitive dopamine detection with graphene aptasensor multitransistor arrays

Abstract

Detecting physiological levels of neurotransmitters in biological samples can advance our understanding of brain disorders and lead to improved diagnostics and therapeutics. However, neurotransmitter sensors for real-world applications must reliably detect low concentrations of target analytes from small volume working samples. Herein, a platform for robust and ultrasensitive detection of dopamine, an essential neurotransmitter that underlies several brain disorders, based on graphene multitransistor arrays (gMTAs) functionalized with a selective DNA aptamer is presented. High-yield scalable methodologies optimized at the wafer level were employed to integrate multiple graphene transistors on small-size chips (4.5 × 4.5 mm). The multiple sensor array configuration permits independent and simultaneous replicate measurements of the same sample that produce robust average data, reducing sources of measurement variability. This procedure allowed sensitive and reproducible dopamine detection in ultra-low concentrations from small volume samples across physiological buffers and high ionic strength complex biological samples. The obtained limit-of-detection was 1 aM (10–18) with dynamic detection ranges spanning 10 orders of magnitude up to 100 µM (10–8), and a 22 mV/decade peak sensitivity in artificial cerebral spinal fluid. Dopamine detection in dopamine-depleted brain homogenates spiked with dopamine was also possible with a LOD of 1 aM, overcoming sensitivity losses typically observed in ion-sensitive sensors in complex biological samples. Furthermore, we show that our gMTAs platform can detect minimal changes in dopamine concentrations in small working volume samples (2 µL) of cerebral spinal fluid samples obtained from a mouse model of Parkinson’s Disease. The platform presented in this work can lead the way to graphene-based neurotransmitter sensors suitable for real-world academic and pre-clinical pharmaceutical research as well as clinical diagnosis.

Recent Advances in Aptamer-Based Sensors for Sensitive Detection of Neurotransmitters

“…In 2022, a group succeeded in quantitating DA using a graphene multi-transistor array (gMTA) functionalised with a selective DNA aptamer [ 65 ]. Micron-sized electrolyte-gated field-effect graphene transistors (EG-gFETs) were functionalised by attaching DNA aptamers and incorporated into graphene multi-transistor arrays (gMTA) ( Figure 4 A).…”

“…( D ) Schematic illustration of the in vivo DA detection and the dot plots showing the in vivo detection performance. With permission from [ 65 ]. Copyright 2022, BMC.…”

Advances in graphene-based nanoplatforms and their application in Parkinson's disease

“…In this context, the graphene-based biosensors for DA detection offer acceptable selectivity and sensitivity in human serum/plasma and urine samples with a LOD ranging from 1 pM to 1.5 M. 73 Combining an array of graphene field-effect transistors with a selective DNA aptamer increased DA detection sensitivity significantly with a LOD of up to 1 aM in biological samples. 74 5- S -Cysteinyl-dopamine, a metabolite of DA oxidation found in PD patients, was suggested to be also a biomarker detectable by graphene sensors for PD diagnosis. 75 Recent studies designed a more complex biosensor that can detect α-syn in real samples towards the early stage diagnosis of PD.…”

Ultrasensitive monolithic dopamine microsensors employing vertically aligned carbon nanofibers

“…Traditional DA detection strategies are enzyme-linked immunosorbent assay (ELISA) or high-performance liquid chromatography (HPLC) associated with various electrical, optical, or mass spectroscopy methods. [27][28][29] However, these strategies involve costly equipment and require rigorous sample preparation, [26,30,31] which make them incompatible with BoC applications. Photonic biosensors have also been investigated in recent years to reduce the device cost and improve data acquisition speed.…”