A 12.8 k current-mode velocity-saturation ISFET array for on-chip real-time DNA detection

This paper presents a large-scale CMOS chemical-sensing array operating in current mode for real-time ion imaging and detection of DNA amplification. We show that the current-mode operation of ion-sensitive field-effect transistors in velocity saturation devices can be exploited to achieve an almost perfect linearity in their input-output characteristics (pH-current), which are aligned with the continuous scaling trend of transistors in CMOS. The array is implemented in a 0.35-m process and includes 12.8 k sensors configured in a 2T per pixel topology. We characterize the array by taking into account nonideal effects observed with floating gate devices, such as increased pixel mismatch due to trapped charge and attenuation of the input signal due to the passivation capacitance, and show that the selected biasing regime allows for a sufficiently large linear range that ensures a linear pH to current despite the increased mismatch. The proposed system achieves a sensitivity of 1.03 A/pH with a pH resolution of 0.101 pH and is suitable for the real-time detection of the NDM carbapenemase gene in E. Coli using a loop-mediated isothermal amplification

Wearable, low-power CMOS ISFETs and compensation circuits for on-body sweat analysis

Complementary metal-oxide-semiconductor (CMOS) technology has been a key driver behind the trend of reduced power consumption and increased integration of electronics in consumer devices and sensors. In the late 1990s, the integration of ion-sensitive field-effect transistors (ISFETs) into unmodified CMOS helped to create advancements in lab-on-chip technology through highly parallelised and low-cost designs. Using CMOS techniques to reduce power and size in chemical sensing applications has already aided the realisation of portable, battery-powered analysis platforms, however the possibility of integrating these sensors into wearable devices has until recently remained unexplored. This thesis investigates the use of CMOS ISFETs as wearable electrochemical sensors, specifically for on-body sweat analysis. The investigation begins by evaluating the ISFET sensor for wearable applications, identifying the key advantages and challenges that arise in this pursuit. A key requirement for wearable devices is a low power consumption, to enable a suitable operational life and small form factor. From this perspective, ISFETs are investigated for low power operation, to determine the limitations when trying to push down the consumption of individual sensors. Batteryless ISFET operation is explored through the design and implementation of a 0.35 \si{\micro\metre} CMOS ISFET sensing array, operating in weak-inversion and consuming 6 \si{\micro\watt}. Using this application-specific integrated circuit (ASIC), the first ISFET array powered by body heat is demonstrated and the feasibility of using near-field communication (NFC) for wireless powering and data transfer is shown. The thesis also presents circuits and systems for combatting three key non-ideal effects experienced by CMOS ISFETs, namely temperature variation, threshold voltage offset and drift. An improvement in temperature sensitivity by a factor of three compared to an uncompensated design is shown through measured results, while adding less than 70 \si{\nano\watt} to the design. A method of automatically biasing the sensors is presented and an approach to using spatial separation of sensors in arrays in applications with flowing fluids is proposed for distinguishing between signal and sensor drift. A wearable device using the ISFET-based system is designed and tested with both artificial and natural sweat, identifying the remaining challenges that exist with both the sensors themselves and accompanying components such as microfluidics and reference electrode. A new ASIC is designed based on the discoveries of this work and aimed at detecting multiple analytes on a single chip. %Removed In the latter half of the thesis, Finally, the future directions of wearable electrochemical sensors is discussed with a look towards embedded machine learning to aid the interpretation of complex fluid with time-domain sensor arrays. The contributions of this thesis aim to form a foundation for the use of ISFETs in wearable devices to enable non-invasive physiological monitoring.Open Acces

Molecular methods for the detection of infectious diseases: bringing diagnostics to the point-of-care

Human infectious diseases represent a leading cause of morbidity and mortality globally, caused by human-infective pathogens such as bacteria, viruses, parasites or fungi. Point-of-care (POC) diagnostics allow accessible, simple, and rapid identification of the organism causing the infection which is crucial for successful prognostic outcomes, clinical management, surveillance and isolation. The research conducted in this thesis aims to investigate novel methods for molecular-based diagnostics. This multidisciplinary project is divided into three main sections: (i) molecular methods for enhanced nucleic acid amplification, (ii) POC technologies, and (iii) sample preparation. The application, design and optimisation of loop-mediated isothermal amplification (LAMP) is investigated from a molecular perspective for the diagnostics of emerging infectious pathogens and antimicrobial resistance. LAMP assays were designed to target pathogens responsible for parasitic (malaria), bacterial and viral (COVID-19) infections, as well as antimicrobial resistance. A novel LAMP-based method for the detection of single nucleotide polymorphisms was developed and applied for diagnostics of antimicrobial resistance, emerging variants and genetic disorders. The method was validated for the detection of artemisinin-resistant malaria. Furthermore, this thesis reports the optimisation of LAMP from a biochemical perspective through the evaluation of its core reagents and the incorporation of enhancing agents to improve its specificity and sensitivity. In order to remove cold-chain storage from the diagnostic workflow, the optimised LAMP protocol was designed to be compatible with lyophilisation. Translation of LAMP to the POC demands the development of detection technologies that are compatible with the advantages offered by isothermal amplification. The use of simple, accessible and portable technologies is investigated in this thesis through the development of: (i) a novel colorimetricLAMP detection method for end-point and low cost detection, and (ii) the combination of LAMP with an electrochemical biosensing platform based on ion-sensitive field effect transistors (ISFETs) fabricated in unmodified complementary metal-oxide semiconductor (CMOS) technology for real-time detection. Lastly, current nucleic acid extraction methods are not transferable to be used outside the laboratory. Research of novel methods for low-cost and electricity-free sample preparation was carried out using cellulose matrices. A novel, rapid (under 10 min) and efficient nucleic acid extraction method from dried blood spots was developed. A sample-to-result POC test requires the implementation and integration of molecular biology, cutting-edge technology and data-driven approaches. The work presented in this thesis aims to set new benchmarks for the detection of infectious diseases at the POC by leveraging on developments in molecular biology and digital technologies.Open Acces