This work is on developing clean-room processes for the fabrication of electrolyte-gate graphene field-effect transistors at the wafer scale for biosensing applications. Our fabrication process overcomes two main issues: removing surface residues after graphene patterning and the dielectric passivation of metallic contacts. A graphene residue-free transfer process is achieved by using a pre-transfer, sacrificial metallic mask that protects the entire wafer except the areas around the channel, source, and drain, onto which the graphene film is transferred and later patterned. After the dissolution of the mask, clean gate electrodes are obtained. The multilayer SiO2/SiNx dielectric passivation takes advantage of the excellent adhesion of SiO2 to graphene and the substrate materials and the superior impermeability of SiNx. It hinders native nucleation centers and breaks the propagation of defects through the layers, protecting from prolonged exposition to all common solvents found in biochemistry work, contrary to commonly used polymeric passivation. Since wet etch does not allow the required level of control over the lithographic process, a reactive ion etching process using a sacrificial metallic stopping layer is developed and used for patterning the passivation layer. The process achieves devices with high reproducibility at the wafer scale.

Emerging research in biosensors has attracted much attention worldwide, particularly in response to the recent pandemic outbreak of coronavirus disease 2019 (COVID-19). Nevertheless, initiating research in biosensing applied to the diagnosis of diseases is still challenging for researchers, be it in the preferences of biosensor platforms, selection of biomarkers, detection strategies, or other aspects (e.g., cutoff values) to fulfill the clinical purpose. There are two sides to the development of a diagnostic tool: the biosensor development side and the clinical side. From the development side, the research engineers seek the typical characteristics of a biosensor: sensitivity, selectivity, linearity, stability, and reproducibility. On the other side are the physicians that expect a diagnostic tool that provides fast acquisition of patient information to obtain an early diagnosis or an efficient patient stratification, which consequently allows for making assertive and efficient clinical decisions. The development of diagnostic devices always involves assay developer researchers working as pivots to bridge both sides whose role is to find detection strategies suitable to the clinical needs by understanding (1) the intended use of the technology and its basic principle and (2) the preferable type of test: qualitative or quantitative, sample matrix challenges, biomarker(s) threshold (cutoff value), and if the system requires a mono- or multiplex assay format. This review highlights the challenges for the development of biosensors for clinical assessment and its broad application in multidisciplinary fields. This review paper highlights the following biosensor technologies: magnetoresistive (MR)-based, transistor-based, quartz crystal microbalance (QCM), and optical-based biosensors. Its working mechanisms are discussed with their pros and cons. The article also gives an overview of the most critical parameters that are optimized by developing a diagnostic tool.

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Biosensors based on graphene field-effect transistors have become a promising tool for detecting a broad range of analytes. However, they lack the stability and reproducibility required to step into biotechnological and biomedical applications. In this work, we use a controlled in-vacuum physical method for the covalent functionalization of graphene to construct ultrasensitive aptamer-based biosensors (aptasensors) able to detect hepatitis C virus core protein. These devices are highly specific and robust, achieving attomolar detection of the viral protein target in human blood plasma. The improved sensitivity is rationalized by theoretical calculations showing that induced polarization at the graphene interface caused by the proximity of covalently bound probe molecule modulates the charge balance at the graphene/molecule interface. This charge balance causes a net shift of the Dirac cone providing enhanced sensitivity towards the attomolar detection of proteins. Such an unexpected effect paves the way for using this kind of graphene-based platform for real-time diagnostics of different diseases.