Fabrication and Testing of a Micro-scalable pH Sensor for Implanted Biomedical Use

Biosensors have recently moved into the arena of implantable devices. This incredible capability,to continuously monitor physiological parameters in-situ, allows for earlier and fundamentallymore accurate measurements. As pH is one of the most important biological factors, implantabledevices to measure pH are of great interest. Unfortunately, current pH sensors exhibit signal driftand require regular recalibration. Since this is impractical for implanted devices, much work isneeded in order to extend the working life of the pH sensor. The present work implemented threetechniques for fabricating a pH sensor based on an iridium oxide sensing layer that are compatiblewith micro-fabrication techniques and implantable devices. They are the oxidation of pure iridium,reactive sputtering of iridium in an oxygen environment, and anodic electrodeposition of iridiumoxide. The response of the sensors based on these indicating layers to tests in buer solution revealeda high degree of linearity. Slopes of the response were in agreement with those found in theliterature. Life tests were performed to characterize the signal drift over 20 hours of continuoususe. The established processes for fabricating the pH sensors provide a vehicle for further investigationinto techniques for extending life, specifically, by using microfluidic devices. Preliminarytests were done to show that interruption of the electrochemical circuit slows signal drift. This canbe accomplished in microscale devices using a microfluidic switching mechanism proposed here

Digital CMOS ISFET architectures and algorithmic methods for point-of-care diagnostics

Over the past decade, the surge of infectious diseases outbreaks across the globe is redefining how healthcare is provided and delivered to patients, with a clear trend towards distributed diagnosis at the Point-of-Care (PoC). In this context, Ion-Sensitive Field Effect Transistors (ISFETs) fabricated on standard CMOS technology have emerged as a promising solution to achieve a precise, deliverable and inexpensive platform that could be deployed worldwide to provide a rapid diagnosis of infectious diseases. This thesis presents advancements for the future of ISFET-based PoC diagnostic platforms, proposing and implementing a set of hardware and software methodologies to overcome its main challenges and enhance its sensing capabilities. The first part of this thesis focuses on novel hardware architectures that enable direct integration with computational capabilities while providing pixel programmability and adaptability required to overcome pressing challenges on ISFET-based PoC platforms. This section explores oscillator-based ISFET architectures, a set of sensing front-ends that encodes the chemical information on the duty cycle of a PWM signal. Two initial architectures are proposed and fabricated in AMS 0.35um, confirming multiple degrees of programmability and potential for multi-sensing. One of these architectures is optimised to create a dual-sensing pixel capable of sensing both temperature and chemical information on the same spatial point while modulating this information simultaneously on a single waveform. This dual-sensing capability, verified in silico using TSMC 0.18um process, is vital for DNA-based diagnosis where protocols such as LAMP or PCR require precise thermal control. The COVID-19 pandemic highlighted the need for a deliverable diagnosis that perform nucleic acid amplification tests at the PoC, requiring minimal footprint by integrating sensing and computational capabilities. In response to this challenge, a paradigm shift is proposed, advocating for integrating all elements of the portable diagnostic platform under a single piece of silicon, realising a ``Diagnosis-on-a-Chip". This approach is enabled by a novel Digital ISFET Pixel that integrates both ADC and memory with sensing elements on each pixel, enhancing its parallelism. Furthermore, this architecture removes the need for external instrumentation or memories and facilitates its integration with computational capabilities on-chip, such as the proposed ARM Cortex M3 system. These computational capabilities need to be complemented with software methods that enable sensing enhancement and new applications using ISFET arrays. The second part of this thesis is devoted to these methods. Leveraging the programmability capabilities available on oscillator-based architectures, various digital signal processing algorithms are implemented to overcome the most urgent ISFET non-idealities, such as trapped charge, drift and chemical noise. These methods enable fast trapped charge cancellation and enhanced dynamic range through real-time drift compensation, achieving over 36 hours of continuous monitoring without pixel saturation. Furthermore, the recent development of data-driven models and software methods open a wide range of opportunities for ISFET sensing and beyond. In the last section of this thesis, two examples of these opportunities are explored: the optimisation of image compression algorithms on chemical images generated by an ultra-high frame-rate ISFET array; and a proposed paradigm shift on surface Electromyography (sEMG) signals, moving from data-harvesting to information-focused sensing. These examples represent an initial step forward on a journey towards a new generation of miniaturised, precise and efficient sensors for PoC diagnostics.Open Acces

Wearable System with Integrated Passive Microfluidics for Real-Time Electrolyte Sensing in Human Sweat

Wearable systems embodied as patches could offer noninvasive and real-time solutions for monitoring of biomarkers in human sweat as an alternative to blood testing, with applications in personalized and preventive healthcare. Sweat is considered to be a biofluid of foremost interest for analysis due the numerous biomarkers it contains. Recent studies have demonstrated that the concentration of some of these biomarkers in sweat, such as the electrolytes studied in this work, can be directly correlated to their concentrations in blood, making sweat a trusted biofluid candidate for non-invasive diagnostics. Until now, the biggest impediment to onâbody sweat monitoring was the lack of technology to analyze sweat composition in realâtime and mainly to continuously collect it. The goal of this work was to develop the building blocks of such wearable system for sweat electrolyte monitoring, with main emphasis on the passive microfluidics, the integrated miniaturized quasi-reference electrode and the functionalization of the sensing devices. The basic sensor technology is formed by Ion Sensitive Field Effect Transistors (ISFET) realized in FinFET and ultra-thin body Silicon on Insulator technology. This thesis shows the development of a state-of-the-art microsystem that allows multisensing of pH, Na+, K+ electrolyte concentrations in sweat, with high selectivity and high sensitivities (â50 mV/dec for all electrolytes), in a wearable fashion. The microsystem comprises a biocompatible skin interface that collects even infinitesimal quantities of sweat (of the order of hundreds of picoliters to tenths of nanoliters), which the body produces in periods of low physical effort. One of the main achievements of this work is the integration of Ion Sensing Fully Depleted FETs and zero power consumption microfluidics, enabling low power (less than 50 nWatts/sensor) wearable biosensing. The thesis presents the needed technological processes and optimizations, together with their characterization, in order to achieve a Lab-On-Skin system

Field-Effect Sensors

This Special Issue focuses on fundamental and applied research on different types of field-effect chemical sensors and biosensors. The topics include device concepts for field-effect sensors, their modeling, and theory as well as fabrication strategies. Field-effect sensors for biomedical analysis, food control, environmental monitoring, and the recording of neuronal and cell-based signals are discussed, among other factors

Recent advances in chemical sensors for soil analysis: a review

The continuously rising interest in chemical sensors' applications in environmental monitoring, for soil analysis in particular, is owed to the sufficient sensitivity and selectivity of these analytical devices, their low costs, their simple measurement setups, and the possibility to perform online and in-field analyses with them. In this review the recent advances in chemical sensors for soil analysis are summarized. The working principles of chemical sensors involved in soil analysis; their benefits and drawbacks; and select applications of both the single selective sensors and multisensor systems for assessments of main plant nutrition components, pollutants, and other important soil parameters (pH, moisture content, salinity, exhaled gases, etc.) of the past two decades with a focus on the last 5 years (from 2017 to 2021) are overviewed

Thin Film Based Biosensors for Point of Care Diagnosis of Cortisol

This dissertation explores the different ways to create thin film-based biosensors that are capable of rapid and label-free detection of cortisol, a non-specific biomarker closely linked to stress, within the physiological range of 10pM to 10 uM. Increased cortisol levels have been linked to stress-related diseases, such as chronic fatigue syndrome, irritable bowel syndrome, and post-traumatic stress disorder. It also plays a role in the suppression of the immune system as well. Therefore, accurate measurement of cortisol in saliva, serum, plasma, urine, sweat, and hair, is clinically significance to predict physical and mental diseases. In this dissertation, thin film-based electrochemical immunosensors were fabricated using a self-assembled monolayer (SAM) functionalized by cortisol specific antibodies to detect cortisol at 10 pM level sensitivities in the presence of a redox probe. The fabricated electrochemical cortisol immunosensors were able to detect cortisol in human saliva samples and the outcomes were validated using the standard Enzyme Linked Immuno Sorbent Assay (ELISA) technique. With the aim of improving signal amplification and label-free cortisol detection, copper nanoparticles were incorporated on screen-printed carbon electrodes (SPCE) for the fabrication of electrochemical cortisol immunosensor. This SPCE-based sensor showed a sensitivity of 4.21µA/M and the limit of detection 6.6nM. Both the SAM and SPCE-based immunosensors were not thermally stable due to the instability of antibodies at room temperature. To address this issue, an antibody-free immunosensor was fabricated. Molecular Imprinted Polymer (MIP) was used to template the target cortisol molecule. The MIP-based sensing platform was prepared using polypyrrole, a thermally stable conducting polymer. The conductivity of the polymer ensured good electrical performance. The polypyrrole-based MIP was synthesized by means of electrochemical polymerization and was used to detect cortisol within the physiological range at room temperature. MIP-based sensors exhibited the detection limit of 1 pM, and were cost-effective, easy to fabricate, temperature stable, and reusable. The sensing performance of the resulting sensors was comparable to those of commercially available technologies, such as ELISA. Aiming to perform cortisol sensing at point-of-care (POC), an Extended Gate Field Effect Transistor (EGFET) was integrated with a developed MIP cortisol sensor. The as developed MIP-EGFET sensor was used to detect the cortisol concentration in the range of 1 pM to 100 nM. A few of the major advantages of the developed sensor are its ability to provide a direct readout and simpler electronic systems, which are necessary for miniaturized Point of Care devices

Graphene for Electronics

Graphene is an allotrope of carbon consisting of a single layer of atoms arranged in a two-dimensional (2D) honeycomb lattice. Graphene's unique properties of thinness and conductivity have led to global research into its applications as a semiconductor. With the ability to well conduct electricity at room temperature, graphene semiconductors could easily be implemented into the existing semiconductor technologies and, in some cases, successfully compete with the traditional ones, such as silicon. This reprint presents very recent results in the physics of graphene, which can be important for applying the material in electronics

Design of a multi-sensor platform for integrating extracellular acidification rate with multi-metabolite flux measurement for small biological samples

2019 Spring.Includes bibliographical references.To view the abstract, please see the full text of the document

Multiplexed label-free electrical detection of DNA amplification using field effect transistors

The objective of this research project was to develop a miniaturized DNA amplification biosensor for the detection and identification of pathogenic bacteria. Using tailored loop-mediated isothermal amplification (LAMP) and field effect transistors, we developed a microchip platform for multiplexed screening of samples querying the presence of multiple pathogenicity genes. In our platform, ion-sensitive field effect transistors (ISFETs) detect the incorporation of nucleotides during LAMP by monitoring changes in the solution's acidity. Employing transistors as biosensors enables label-free detection of the reaction, simple multiplexing, and seamless integration with required electronics for data acquisition. These characteristics of the detection system and protocols that we developed will make genotyping analysis simple and readily available for different applications that would benefit from low cost, portability, and ease-of-use. Here, we present a series of studies performed in three experimental setups that are related to the multiplexed electrical detection of LAMP and culminate in a large ISFET sensor array microchip that monitors DNA amplification reactions. A first chip consisted of 30 nL silicon oxide wells that were prepared with dried nucleic acid primers for multiplexed on-chip amplification. This initial study demonstrated the high specificity and low limit of detection of on-chip parallel LAMP when used for the detection of E.coli O157, S.enterica, L. monocytogenes, and non O157 Shiga-toxin producing E.coli of the `big six' group. Then, a second chip with novel individually addressable dual-gated ISFETs was fabricated in collaboration with Taiwan Semiconductor Manufacturing Company (TSMC). These devices were used to evaluate and optimize their pH sensing ability, develop methods to do label-free detection of LAMP, and study the sensor performance when biased with polypyrrole quasi-reference electrodes. The last platform, that demonstrates the impressive scalability of the semiconductor technology, is a chip with over a million ISFET sensors distributed in a 7x7 mm2 area. The use of on-chip decoding and routing circuits enables the parallel operation of 1024x1024 sensors in an array for massively multiplexed biosensing. In this platform we applied methods and systems developed previously to perform parallel electrical detection of foodborne pathogens by monitoring DNA amplification reactions in micro-chambers of 250 nL detecting down to 25 copies/reaction in less than 60 min. We demonstrate that the intrinsic redundancy of the high density ISFET array enabled clear identification of electrical signals resulting from the amplification reaction. This microchip for the detection of DNA and the related protocols on reaction miniaturization, parallelism, and electrical detection are poised to be the basis of new detection systems that bring the impressive advances of the semiconductor industry into biological applications