Label-free single-molecule detection has been achieved so far by funnelling a large number of ligands into a sequence of single-binding events with few recognition elements host on nanometric transducers. Such approaches are inherently unable to sense a cue in a bulk milieu. Conceptualizing cells’ ability to sense at the physical limit by means of highly-packed recognition elements, a millimetric sized field-effect-transistor is used to detect a single molecule. To this end, the gate is bio-functionalized with a self-assembled-monolayer of 1012 capturing anti-Immunoglobulin-G and is endowed with a hydrogen-bonding network enabling cooperative interactions. The selective and label-free single molecule IgG detection is strikingly demonstrated in diluted saliva while 15 IgGs are assayed in whole serum. The suggested sensing mechanism, triggered by the affinity binding event, involves a work-function change that is assumed to propagate in the gating-field through the electrostatic hydrogen-bonding network. The proposed immunoassay platform is general and can revolutionize the current approach to protein detection.

Organic bioelectronic sensors are gaining momentum as they can combine high-performance sensing level with flexible large-area processable materials. This opens to potentially highly powerful sensing systems for point-of-care health monitoring and diagnostics at low cost. Prominent to detect biochemical recognition events, are electrolyte-gated organic field-effect transistors (EGOFETs) and organic electrochemical transistors (OECTs) as they are easily fabricated and operated. EGOFETs are recently shown to be capable of labelfree single-molecule detections, even in serum. This progress report aims to provide a critical perspective through a selected overview of the literature on both EGOFET and OECT biosensors. Attention is paid to correctly attribute them to the potentiometric and amperometric biosensor categories, which is important to set the right conditions for quantification purposes. Moreover, to deepen the understanding of the sensing mechanisms, with the support of unpublished data, focus is put on two among the most critical aspects, namely, the capacitance interplay and the role of Faradaic currents. The final aim is to provide a rationale of the functional mechanisms encompassing both EGOFET and OECT sensors, to improve materials and devices' designs taking advantage of the processes that enhance the sensing response enabling the extremely highperformance level resulting in ultimate sensitivity, selectivity, and fast response.

Immunoglobulin M (IgM) single-molecule and label-free detection is demonstrated, for the first time, by means of an electrolyte-gated thin-film transistor. The sensor integrates a millimeter-wide self-assembled monolayer (SAM) that includes trillions of anti-IgM capturing proteins. This adds generality to the already introduced Single-Molecule with a Transistor (SiMoT) platform. Besides the extremely high sensitivity, the SAM confers to the SiMoT bioelectronic sensor a high selectivity that is here assessed by measuring the differential responses of the IgM or the immunoglobulin G (IgG) cognate biomarkers mutually interacting with anti-IgM or anti-IgG capturing SAMs. At the same time, no response to IgG or IgM is measured with the anti-IgM or anti-IgG SAM, respectively. The SiMoT technology is known to exploit the hydrogen bonding network present in the SAM. In this paper, further elements supporting the model of this network enabling single-molecule sensitivity is provided by demonstrating that, once this electrostatic connecting element is removed, the sensing is suppressed. It also provides a plausible explanation of the wide-field single-molecule sensing mechanism in terms of amplified field-effect response and propagation of electrostatic domains associated with the electrostatic hydrogen bonding network. Future possible applications to low-cost early detection of infection diseases can be envisaged.

The paper provides an overview on the use of photoacoustic sensors based on semiconductor laser sources for the detection of trace gases. We review the results obtained using standard, differential and quartz enhanced photoacoustic techniques.

A systematic comparison between electrochemical and organic bioelectronic sensors reveals a unified rational description for a transistor amplified detection.