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

Biosensors

A biosensor is defined as a detecting device that combines a transducer with a biologically sensitive and selective component. When a specific target molecule interacts with the biological component, a signal is produced, at transducer level, proportional to the concentration of the substance. Therefore biosensors can measure compounds present in the environment, chemical processes, food and human body at low cost if compared with traditional analytical techniques. This book covers a wide range of aspects and issues related to biosensor technology, bringing together researchers from 11 different countries. The book consists of 16 chapters written by 53 authors. The first four chapters describe several aspects of nanotechnology applied to biosensors. The subsequent section, including three chapters, is devoted to biosensor applications in the fields of drug discovery, diagnostics and bacteria detection. The principles behind optical biosensors and some of their application are discussed in chapters from 8 to 11. The last five chapters treat of microelectronics, interfacing circuits, signal transmission, biotelemetry and algorithms applied to biosensing

Re-thinking Analog Integrated Circuits in Digital Terms: A New Design Concept for the IoT Era

A steady trend towards the design of mostly-digital and digital-friendly analog circuits, suitable to integration in mainstream nanoscale CMOS by a highly automated design flow, has been observed in the last years to address the requirements of the emerging Internet of Things (IoT) applications. In this context, this tutorial brief presents an overview of concepts and design methodologies that emerged in the last decade, aimed to the implementation of analog circuits like Operational Transconductance Amplifiers, Voltage References and Data Converters by digital circuits. The current design challenges and application scenarios as well as the future perspectives and opportunities in the field of digital-based analog processing are finally discussed

Developing integrated optical structures, with special respect to applications in medical diagnostics

In my dissertation, I described two label-free optical biosensors based on integrated optical (IO) structures for the sensitive, rapid detection of pathogens - bacterial cells, viral proteins - from fluid samples, which can serve as a basis for rapid clinical tests. These types of devices provide a specific, cost-effective, user-friendly and portable way of detection with sufficient sensitivity by changing the optical signal. Thus, in practice, they could potentially be used as point-of-care (POC) or home rapid diagnostic tests, offering a promising alternative to traditional laboratory assays. Their realization is supported by their integration with microfluidic channels in a lab-on-a-chip (LOC) device, for handling small volumes of fluid. Based on these aspects, biosensors were designed as waveguides, integrated in a microfluidic channel on a glass substrate, performing evanescent-field sensing. The detection method is based on the fact that the light, propagating in the waveguide with total internal reflections, penetrates into the surrounding media at a limited extent, which is called the evanescent field. Material can enter this space and become bound to the surface, which can change the phase of the light, propagating in the structure, or even scatter it into the surrounding medium. These phenomena offer the possibility of specific detection of pathogens, adhering to the surface, pre-coated with a biological recognition element, such as an antibody. As a first application, an electro-optical biosensor was developed with an evanescent field-based detection concept, aiming at label-free, rapid, selective and sensitive detection of bacteria from body fluids. The usability of the measurement principle, based on the processing of light-scattering patterns, caused by evanescent waves, scattered on target cells, was demonstrated by quantitative detection of Escherichia coli bacterial cells from their suspensions. One of the keys to the applicability of biosensors is their sensitivity. To increase it in case of this device, I applied the phenomenon of dielectrophoresis using the polarizability of the target cells. It provides the possibility to selectively collect cells on the surface of electrodes placed close to the waveguide and then detect them based on the evanescent field. To test this, I wanted to sense bacteria in an artificial urine sample containing somatic cells, in this case endothelial cells, mimicking urine in an inflammatory state. By optimizing the parameters of the measurements, a rapid, sensitive bacterial detection of about 10 minutes was achieved. The detection limit of the biosensor was comparable to the characteristic pathogen concentration in body fluids. Furthermore, selective bacterial detection was also achieved from a fluid sample containing somatic cells, mimicking inflammatory urine. In my dissertation, a second application is also presented, in this case a miniature IO Mach-Zehnder interferometer-based biosensor was developed for the specific quantitative detection of viral proteins. Thanks to the interferometric measurement principle, a fast and accurate detection of target proteins can be achieved. With this device, the aim was to investigate the potential neuroinvasion of coronavirus (SARS-CoV-2) infection, from which point of view the pathological effects of viral surface spike proteins on the blood-brain barrier are of great importance in the case of severe symptoms. Furthermore, infection may also cause adverse effects in the intestinal tract. Thus, the specific aim of this application was to evaluate the ability of the S1 subunit of the coronavirus surface spike protein to cross the human in vitro blood-brain barrier and intestinal epithelial biological barrier system models using the biosensor. Experiments were designed to use the sensor for specific, quantitative detection of spike proteins, that may have been passed through permeability assays on biological barrier models prepared by our collaborators. To reach the specific sensing of the target protein, the waveguide surface of the interferometer’s measuring arm was functionalized with specific S1 protein antibody. To achieve optimal, stable measurement conditions, the operating point of the interferometer was adjusted thermo-optically. The results of the experiments with the biosensor were in agreement with the ones of the conventional immunological tests (ELISA) carried out in parallel. It was possible to determine that S1 protein could pass through the two types of barriers in different amounts. The findings of the experiments with the integrated optical Mach-Zehnder interferometer biosensor demonstrate that this detection approach can be used for similar medical diagnostic purposes, and thus can contribute to the investigation of the adverse effects of SARS-CoV-2 on the human body

Electrochemical microfluidic multiplexed biosensor platform for point-of-care testing

Early and accurate diagnosis of a specific disease plays a decisive role for its effective treatment. However, in many cases the clinical findings, based on a single biomarker detection alone, are not sufficient for the appropriate diagnosis as well as monitoring of its treatment. Furthermore, it is highly desirable to screen multi-analytes (e.g. various diseases and drugs) at the same time enabling a low-cost, quick and reliable quantification. Thus, multiplexing, simultaneous detection of different analytes from a single sample, has become in recent years essential for diagnostics, especially for point-of-care testing (POCT). This thesis focuses on the scientific issue regarding the sensitivity enhancement of microfluidic biosensor platforms. Simulations, design studies and experiments are employed to investigate the interplay between the immobilization area and the resulting sensitivity. Thereby, a novel concept comprising design rules for microfluidic biosensors using the stop-flow technique has been introduced. In combination with different technical measures it allows the realization of an electrochemical lab-on-a-chip (LOC) platform for the fast, sensitive and simultaneous POCT in clinically relevant samples. This system employs a universally applicable, bioaffinity based biomolecule immobilization along with an amperometric readout. By means of the dry film photoresist technology, the fabrication of disposable microfluidic biosensors is enabled with high yield on wafer-level. The presented LOC platform offers three different biosensors with a microfluidic channel network of two, four or eight discrete immobilization sections, each with a volume of 680  nl. They can be actuated by individual channel inlets allowing a high flexibility in the assay design with respect to its format (e.g. competitive) and its technology (e.g. genomics). The feasibility for multiplexing is successfully demonstrated with DNA-based antibiotic assays for tetracycline and streptogramin, both important growth promoters in livestock breeding. The extensive usage of antibiotics is one of the major causes of the multi-drug-resistant bacteria and so, it has to be kept under surveillance. This platform allows the simultaneous POCT of different antibiotics from human plasma along with a limit of detection of less than 10  ng  ml⁻¹, a wide working range up to 1,600  ng ml⁻¹ and inter-assay precisions of about 10  %. Moreover, the microfluidic LOC system provides a low consumption of reagent and sample, reduces the total assay time drastically with a sample-to-result time of only 10  min. The shelf-life of the biosensors is proven to be at least 3 months at +4  °C. The introduced design concept with specific technical measures facilitates the implementation of microfluidic multiplexed biosensors in a low-cost, compact, and at the same time sensitive manner. This platform targets the POCT in the first place, yet, owing to its multiplexing approach it can be expanded for in vitro diagnostics

Fundamentals of SARS-CoV-2 Biosensors

COVID-19 diagnostic strategies based on advanced techniques are currently essential topics of interest, with crucial roles in scientific research. This book integrates fundamental concepts and critical analyses that explore the progress of modern methods for the detection of SARS-CoV-2