Fully Integrated Biochip Platforms for Advanced Healthcare

Recent advances in microelectronics and biosensors are enabling developments of innovative biochips for advanced healthcare by providing fully integrated platforms for continuous monitoring of a large set of human disease biomarkers. Continuous monitoring of several human metabolites can be addressed by using fully integrated and minimally invasive devices located in the sub-cutis, typically in the peritoneal region. This extends the techniques of continuous monitoring of glucose currently being pursued with diabetic patients. However, several issues have to be considered in order to succeed in developing fully integrated and minimally invasive implantable devices. These innovative devices require a high-degree of integration, minimal invasive surgery, long-term biocompatibility, security and privacy in data transmission, high reliability, high reproducibility, high specificity, low detection limit and high sensitivity. Recent advances in the field have already proposed possible solutions for several of these issues. The aim of the present paper is to present a broad spectrum of recent results and to propose future directions of development in order to obtain fully implantable systems for the continuous monitoring of the human metabolism in advanced healthcare applications

Molecular Microfluidic Bioanalysis: Recent Progress in Preconcentration, Separation, and Detection

This chapter reviews the state-of-art of microfluidic devices for molecular bioanalysis with a focus on the key functionalities that have to be successfully integrated, such as preconcentration, separation, signal amplification, and detection. The first part focuses on both passive and electrophoretic separation/sorting methods, whereas the second part is devoted to miniaturized biosensors that are integrated in the last stage of the fluidic device

Strategies for Multiplexed Electrochemical Sensor Development

Detection of multiple biomarkers for disease diagnosis or treatment monitoring has received a lot of attention due to their potential impact on clinical decision making. Electrochemical biosensors have become one of the preferred detection approaches, due to the simplicity of the accompanying instrumentation. This chapter will explore how electrochemical sensors can be utilized for detection of multiple analytes by integration of sensors into microfluidic microsystems. Some key fabrication technologies for such devices will be presented utilizing polymer microfabrication, paper-based approaches, and the use of printed circuit boards. Next, the use of electrode arrays will be presented along with some commercial platforms, outlining plausible paths towards a successful electrochemical multiplexed sensor. Novel approaches based on microbeads and various labels will then be introduced along with various strategies and technologies utilized to achieve ultrasensitive multiplexed detection

Integration of virus-like particle macromolecular bioreceptors in electrochemical biosensors

Rapid, sensitive and selective detection of chemical hazards and biological pathogens has shown growing importance in the fields of homeland security, public safety and personal health. In the past two decades, efforts have been focusing on performing point-of-care chemical and biological detections using miniaturized biosensors. These sensors convert target molecule binding events into measurable electrical signals for quantifying target molecule concentration. However, the low receptor density and the use of complex surface chemistry in receptors immobilization on transducers are common bottlenecks in the current biosensor development, adding to the cost, complexity and time. This dissertation presents the development of selective macromolecular Tobacco mosaic virus-like particle (TMV VLP) biosensing receptor, and the microsystem integration of VLPs in microfabricated electrochemical biosensors for rapid and performance-enhanced chemical and biological sensing. Two constructs of VLPs carrying different receptor peptides targeting at 2,4,6-trinitrotoluene (TNT) explosive or anti-FLAG antibody are successfully bioengineered. The VLP-based TNT electrochemical sensor utilizes unique diffusion modulation method enabled by biological binding between target TNT and receptor VLP. The method avoids the influence from any interfering species and environmental background signals, making it extremely suitable for directly quantifying the TNT level in a sample. It is also a rapid method that does not need any sensor surface functionalization process. For antibody sensing, the VLPs carrying both antibody binding peptides and cysteine residues are assembled onto the gold electrodes of an impedance microsensor. With two-phase immunoassays, the VLP-based impedance sensor is able to quantify antibody concentrations down to 9.1 ng/mL. A capillary microfluidics and impedance sensor integrated microsystem is developed to further accelerate the process of VLP assembly on sensors and improve the sensitivity. Open channel capillary micropumps and stop-valves facilitate localized and evaporation-assisted VLP assembly on sensor electrodes within 6 minutes. The VLP-functionalized impedance sensor is capable of label-free sensing of antibodies with the detection limit of 8.8 ng/mL within 5 minutes after sensor functionalization, demonstrating great potential of VLP-based sensors for rapid and on-demand chemical and biological sensing

An integrated circuit to enable electrodeposition and amperometric readout of sensing electrodes

This paper presents the design of an integrated circuit (IC) for (i) electrochemical deposition of sensor layers on the on-chip pad openings to form sensing electrodes, and (ii) amperometric readout of electrochemical sensors. The IC consists of two main circuit blocks: a Beta-multiplier based current reference for galvanostatic electrodeposition, and a switch-capacitor based amperometric readout circuit. The circuits are designed and simulated in a 180-nm CMOS process. The reference circuit generates a stable current of 99 nA with a temperature coefficient of 141 ppm/°C at best and 170 ppm/°C on average (across corners) over a supply voltage range of 1.2-2.4 V, and a line regulation of 0.7 %/V. The readout circuit measures current within pm 2 mu mathrmA with 99.9% linearity and a minimum integrated input-referred noise of 0.88 pA

Nucleic Acid-based Detection of Bacterial Pathogens Using Integrated Microfluidic Platform Systems

The advent of nucleic acid-based pathogen detection methods offers increased sensitivity and specificity over traditional microbiological techniques, driving the development of portable, integrated biosensors. The miniaturization and automation of integrated detection systems presents a significant advantage for rapid, portable field-based testing. In this review, we highlight current developments and directions in nucleic acid-based micro total analysis systems for the detection of bacterial pathogens. Recent progress in the miniaturization of microfluidic processing steps for cell capture, DNA extraction and purification, polymerase chain reaction, and product detection are detailed. Discussions include strategies and challenges for implementation of an integrated portable platform

Microneedles for Transdermal Biosensing: Current Picture and Future Direction

A novel trend is rapidly emerging in the use of microneedles, which are a miniaturized replica of hypodermic needles with length-scales of hundreds of micrometers, aimed at the transdermal biosensing of analytes of clinical interest, e.g., glucose, biomarkers, and others. Transdermal biosensing via microneedles offers remarkable opportunities for moving biosensing technol-ogies and biochips from research laboratories to real-fi eld applications, and envisages easy-to-use point-of-care microdevices with pain-free, minimally invasive, and minimal-training features that are very attractive for both devel-oped and emerging countries. In addition to this, microneedles for trans-dermal biosensing offer a unique possibility for the development of biochips provided with end-effectors for their interaction with the biological system under investigation. Direct and effi cient collection of the biological sample to be analyzed will then become feasible in situ at the same length-scale of the other biochip components by minimally trained personnel and in a minimally invasive fashion. This would eliminate the need for blood extraction using hypodermic needles and reduce, in turn, related problems, such as patient infections, sample contaminations, analysis artifacts, etc. The aim here is to provide a thorough and critical analysis of state-of-the-art developments in this novel research trend, and to bridge the gap between microneedles and biosensors

Design, development and characterization of nanostructured electrochemical sensors

This is a publication-based thesis which focuses on the study of electrochemical microbiosensors for glucose detection. It investigates applications of a series of microfabricated gold electrodes based on several nanostructures in electrochemical biosensing technologies, embracing three major methodologies: direct electro-catalytic detection, enzymatic detection and dual-enzyme cascade detection. The study is described over five main chapters with a sixth providing a summary of the material presented and perspectives for the future. Chapter 1 provides an introduction to the field of the electrochemical biosensors with a specific focus on the chosen nanostructures and miniaturized systems, as well as a brief history of the biosensor. Chapter 2 presents results published in ACS Applied Nanomaterials, 2019, 2, 9, 5878-5889. It demonstrates the enzyme free detection of glucose via a direct electro-catalytic reaction. The miniaturized band array electrodes with specific width, length and inter-electrode-distance were integrated with homogeneously distributed copper foam nano dendrites. Such foam deposits presented for the first time at the micro scale were achieved using the in-situ hydrogen bubble template method. The resulting very high electroactive surface area of the porous foam deposits was one of the major advantages in terms of achieving superior performance from each micro band foam electrode towards glucose detection. Moreover, both sensors also showed a strong resistance to the poisoning effects of chloride ions and displayed excellent stability over a period of three months.Chapter 3 presents the first of t wo sets of results for the enzymatic detection of glucose, results published in Elsevier Electrochimica Acta, 2019, 293, 307-317. Chapter 4 then presents the second set of results on this topic which is published in and Elsevier Electrochimica Acta, 2019, 298, 97-105. The aim of these two chapters is to discuss the effect of miniaturization on the enzymatic biosensor performance which was studied in the presence of a carbon quantum dot (CQD) and gold nanoparticle nanohybrid system. CQDs, are a new class of carbon-based materials and have been used here for the first time as a matrix component integrated onto microfabricated gold electrode surfaces for enzyme immobilization and further miniaturization. The biosensors developed were studied by electrochemistry to investigate the analytical performance of each device. By scaling down the surface area of the biosensor, a 13-times increase in sensitivity was achieved towards glucose. Moreover both sensors-planar, micro disk array- exhibited excellent reproducibility, reusability and operational stability in terms of the performance of biosensors. Chapter 5 presents results published in RSC Analyst, 2020 (DOI: 10.1039/C9AN01664C). It demonstrates the operation of a dual-enzyme cascade which was constructed onto a micro band array electrode based on glucose oxidase and horseradish peroxidase enzymes. To achieve a very high surface area, a porous gold-foam was electrodeposited onto surface and then a second electrodeposition layer of chitosan and multi walled carbon nanotube nano-bio-composite. The micro band cascade scheme developed exhibited the highest sensitivity towards glucose detection in comparison to other systems reported in the literature. Chapter 6 provides an insight into the field of electrochemical biosensing with the support of the achievements presented in this thesis. Thus, by taking advantage of the available system, this chapter discusses the possible future applications of the electrochemical biosensors. The thesis then ends with section 7 which presents some Appendices

An Integrated Circuit for Galvanostatic Electrodeposition of on-chip Electrochemical Sensors

This paper presents the design of an integrated circuit (IC) for (i) galvanostatic deposition of sensor layers on the on-chip pads, which serve as the sensor's base layer, and (ii) amperometric readout of electrochemical sensors. The system consists of three main circuit blocks: the electrochemical cell including a 4×4 electrode array, two Beta-multiplier based current generators and one pA-size current generator for galvanostatic electrodeposition, and a switch-capacitor based amperometric readout circuit for sensor current measurement. The circuits are designed and simulated in a 180-nm CMOS process. The three current reference circuits generate a stable current from 7.2 pA to 88 µA with low process, power supply voltage and temperature (PVT) sensitivity. The pA-size current generator has a temperature coefficient of 517.8 ppm/°C on average (across corners) in the range of 0 to 60°C. The line regulation is 4.4 %/V over a supply voltage range of 0.8-3 V. The feasibility of galvanostatic deposition on on-chip pads is validated by applying a fixed current of 300 nA to electrochemically deposit a gold layer on top of electrodes with nickel/zinc as the adhesive layer for gold. Successful deposition of gold was confirmed using optical microscope images of the on-chip electrodes