Full System for Translational Studies of Personalized Medicine with Free-Moving Mice (invited)

A full remotely powered system for metabolism monitoring of free-moving mice is presented here. The fully implantable sensing platform hosts two ASICs, one off-the-shelf micro-controller, four biosensors, two other sensors, a coil to receive power, and an antenna to transmit data. Proper enzymes ensure specificity for animal metabolites while Multi-Walled Carbon Nanotubes ensure the due sensitivity. The remote powering is indeed provided by inductive coils located under the floor of the mouse' cage. Two different approaches were investigated to ensure freedom of movement to the animal. The application to studies for personalized medicine is demonstrated by showing continuous monitoring of both glucose and paracetamol

Low-power Wearable Healthcare Sensors

Advances in technology have produced a range of on-body sensors and smartwatches that can be used to monitor a wearer’s health with the objective to keep the user healthy. However, the real potential of such devices not only lies in monitoring but also in interactive communication with expert-system-based cloud services to offer personalized and real-time healthcare advice that will enable the user to manage their health and, over time, to reduce expensive hospital admissions. To meet this goal, the research challenges for the next generation of wearable healthcare devices include the need to offer a wide range of sensing, computing, communication, and human–computer interaction methods, all within a tiny device with limited resources and electrical power. This Special Issue presents a collection of six papers on a wide range of research developments that highlight the specific challenges in creating the next generation of low-power wearable healthcare sensors

Remote Powering and Communication of Implantable Biosensors Through Inductive Link

Nowadays there is an increasing interest in the field of implantable biosensors. The possibility of real-time monitoring of the human body from inside paves the way to a large number of applications and offers wide opportunities for the future. Within this scenario, the i-IronIC project aims to develop an implantable, low cost, health-care device for real-time monitoring of human metabolites. The contribution of this research work to the i-IronIC project consists of the design and realization of a complete platform to provide power, data communication and remote control to the implantable biosensor. High wearability of the transmitting unit, low invasivity of the implanted electronics, integration of the power management module within the sensor, and a reliable communication protocol with portable devices are the key points of this platform. The power is transmitted to the implanted sensor by exploiting an inductive link. Simulations have been performed to check the effects of several variables on the link performance. These simulations have finally confirmed the possibility to operate in the low megahertz range, where tissue absorption is minimum, even if a miniaturized receiving inductor is used. A wearable patch has been designed to transmit power through the body tissues by driving an external inductor. The same inductive link is used to achieve bidirectional data communication with the implanted device. The patch, named IronIC, is powered by lithium-ion polymer batteries and can be remotely controlled by means of a dedicated Android application running on smartphones and tablets. Long-range communication between the patch and portable devices is performed by means of Bluetooth protocol. Different typologies of receiving inductors have been designed to minimize the size of the implantable device and reduce the discomfort of the patience. Multi-layer, printed spiral inductors and microfabricated spiral inductors have been designed, fabricated and tested. Both the approaches involve a sensibly smaller size, as compared to classic “pancake” inductors used for remote powering. Furthermore, the second solution enables the realization of the receiving inductor directly on the silicon substrate hosting the sensor, thus involving a further miniaturization of the implanted device. An integrated power module has been designed and fabricated in 0.18 μm CMOS technology to perform power management and data communication with the external patch. The circuit, to be merged with the sensor readout circuit, consists of an half-wave voltage rectifier, a low-dropout regulator, an amplitude demodulator and a load modulator. The module receives the power from the implanted inductor and provides a stable voltage to the sensor readout circuit. Finally, the amplitude demodulator and the load modulator enable short-range communication with the patch

Integrated Electronics to Control and Readout Electrochemical Biosensors for Implantable Applications

Biosensors can effectively be used to monitor multiple metabolites such as glucose, lactate, ATP and drugs in the human body. Continuous monitoring of these metabolites is essential for patients with chronic or critical conditions. Moreover, this can be used to tune the dosage of a drug for each individual patient, in order to achieve personalized therapy. Implantable medical devices (IMDs) based on biosensors are emerging as a valid alternative for blood tests in laboratories. They can provide continuous monitoring while reduce the test costs. The potentiostat plays a fundamental role in modern biosensors. A potentiostat is an electronic device that controls the electrochemical cell, using three electrodes, and runs the electrochemical measurement. In particular the IMDs require a low-power, fully-integrated, and autonomous potentiostats to control and readout the biosensors. This thesis describes two integrated circuits (ICs) to control and readout multi-target biosensors: LOPHIC and ARIC. They enable chronoamperometry and cyclic voltammetrymeasurements and consume sub-mW power. The design, implementation, characterisation, and validation with biosensors are presented for each IC. To support the calibration of the biosensors with environmental parameters, ARIC includes circuitry to measure the pHand temperature of the analyte through an Iridiumoxide pH sensor and an off-chip resistor-temperature detector (RTD). In particular, novel circuits to convert resistor value into digital are designed for RTD readout. ARIC is integrated into two IMDs aimed for health-care monitoring and personalized therapy. The control and readout of the embedded sensor arrays have been successfully achieved, thanks to ARIC, and validated for glucose and paracetamol measurements while it is remotely powered through an inductive link. To ensure the security and privacy of IMDs, a lightweight cryptographic system (LCS) is presented. This is the first ASIC implementation of a cryptosystem for IMDs, and is integrated into ARIC. The resulting system provides a unique and fundamental capability by immediately encrypting and signing the sensor data upon its creation within the body. Nano-structures such as Carbon nanotubes have been widely used to improve the sensitivity of the biosensors. However, in most of the cases, they introduce more noise into the measurements and produce a large background current. In this thesis the noise of the sensors incorporating CNTs is studied for the first time. The effect of CNTs as well as sensor geometry on the signal to noise ratio of the sensors is investigated experimentally. To remove the background current of the sensors, a differential readout scheme has been proposed. In particular, a novel differential readout IC is designed and implemented that measures inputcurrents within a wide dynamic range and produces a digital output that corresponds to the -informative- redox current of the biosensor

Implantable Multi-panel Platform for Continuous Monitoring of Exogenous and Endogenous Metabolites for Applications in Personalized Medicine

Nowadays, scientific advances are leading to the discovery of newer, better, more targeted treatments that will improve the human health. However, despite the promising results and the major advantages in treatments offered to patients, these personalized medical treatments are limited to few cases. Translational medicine research with animals is needed to find innovative, safe and life-saving solutions for patients, especially in drug development. Although technological improvements may lead one day to the end of animal testing, today those strategies are not sufficient, due to the complexity of living organisms. The living conditions of these animals are of primary importance because high stress levels can affect the experimental results. In this respect, the monitoring of the animals in a small living space by means of a fully implantable device, can contribute to minimize the human intervention, increasing the comfort for the animals. The objective of this thesis is the design and characterization of a fully implantable biosensor array for the real-time detection of endogenous and exogenous metabolites, for the monitoring of small caged animals in drug development, and for future applications in personalized medicine. The fully implantable device consists of: a passive sensing platform consisting of an array of four independent electrochemical biosensors, together with a pH sensor and a temperature sensor for the optimization of the sensing performances in different physiological conditions; integrated circuits capable of performing multiple electrochemical measurements; a coil for remote powering of the integrated circuit and the short-range data transmission to an external device; a membrane packaging ensuring measurements with high signal-to-noise ratio, biocompatibility and selectivity against possible interfering molecules in biological fluids. ⢠In vitro monitoring of four anti-cancer drugs and an anti-inflammatory drug within the pharmacological ranges in undiluted human serum; ⢠Demonstration of the in vitro functionality of the complete system, showing that the external powering system correctly operate the device, and receive the data from the sensors; ⢠In vivo biocompatibility tests of the packaging, showing after 30 days a significant reduction of the inflammatory response in time, suggesting normal host recovery; ⢠In vivo continuous monitoring of an anti-inflammatory drug, demonstrating the proof of-concept of the system for future personalized medicine applications

Redesigning chemical analysis: transducing information from chemical into digital

Aquesta tesi planteja que les xarxes distribuïdes de detecció de substàncies químiques serán eines beneficioses per aconseguir millors resultats de salut com a éssers humans, així com per a guiarnes en el nostre paper autodeterminat con a guardians en l'àmbit ecològic. Tot aixo, des de la perspectiva d’introduir elements de disseny en les eines analítiques. El treball comença amb una introducció a la visió de com els sensors químics s'adapten als contextos més grans de la biologia, la història i la tecnologia. El segon capítol ofereix una base de coneixements sobre els mètodes i principis científics i tecnològics subjacents sobre els quals es basa aquest treball. A continuació, es fa una revisió crítica dels avenços acadèmics cap als sensors electroquímics distribuïts, que divideixen el problema en tres aspectes: rendiment adequat, usabilitat intuïtiva i assequibilitat. Entre aquests, la usabilitat s'identifica com el coll d'ampolla principal en l'adopció generalitzada de sensors químics centrats en l'usuari. Els capítols posteriors ofereixen algunes respostes als reptes, en forma de treball experimental original. Encara que aquest treball es basa en l'electroquímica analítica, s'aborda des d’una metodologia de disseny, amb iteracions d'anàlisi i síntesi incrustades en el procés d'ideació. Les declaracions finals reflexionen sobre el treball com una petita part en una creixent revolució de l'edat de la informació química; com una petita esquerda a la presa que contenia una allau de dades químiques de diagnòstic amb conseqüències imprevisibles, però positives i revolucionàries.Esta tesis postula que las redes distribuidas de detección química serán herramientas beneficiosas para alcanzar mejores resultados de salud como seres humanos, así como para guiarnos en nuestro papel autodeterminado como guardianes en la esfera ecológica. Todo esto desde una perspectiva de introducir elementos de diseño en herramientas analíticas. El trabajo comienza con una introducción a la visión de cómo los sensores químicos se ajustan a los contextos más amplios de la biología, la historia y la tecnología. El segundo capítulo proporciona algunos antecedentes de los métodos y principios científicos y tecnológicos subyacentes en los que se basa este trabajo. Esto es seguido por una revisión crítica de los avances académicos hacia sensores electroquímicos distribuidos, que divide el problema en tres aspectos: rendimiento apropiado, usabilidad intuitiva y asequibilidad. Entre estos, la usabilidad se identifica como el cuello de botella principal en la adopción generalizada de sensores químicos centrados en el usuario. Los siguientes capítulos ofrecen algunas respuestas a los desafíos, en forma de trabajo experimental original. Mientras que este trabajo se arraiga en la electroquímica analítica, se aborda desde una metodología de diseño, con iteraciones de análisis y síntesis integradas en el proceso de ideación. Las declaraciones finales reflejan el trabajo como una pequeña parte en una floreciente revolución de la era de la información química; como una pequeña grieta en la presa que contiene una avalancha de datos químicos de diagnóstico con consecuencias imprevisibles, pero positivas y revolucionarias.This thesis posits that distributed chemical sensing networks will be beneficial tools towards our greater health outcomes as humans, as well as in guiding us in our self-determined role as custodians over the ecological sphere. A perspective of infusing design elements and approaches into analytical tools is shared. The work begins with an introduction presenting a vision of how chemical sensors fit within the greater contexts of biology, history, and technology. The second chapter provides some background to the underlying scientific and technological methods and principles on which this work stands. This is followed by a critical review of the academic advances towards distributed electrochemical sensors, which divides the problem into three aspects of appropriate performance, intuitive usability, and affordability. Amongst these, usability is identified as the principal bottleneck in the widespread adoption of user-centered chemical sensors. The subsequent chapters offer some responses to the challenges, in the form of original experimental work. While rooted in analytical electrochemistry, the work is approached with a design methodology, with iterations of analysis and synthesis embedded in the ideation process. Concluding statements reflect on the work as a small part in a burgeoning revolution of the chemical information age; as a minor crack in the dam holding back a flood of diagnostic chemical data with unforeseeable, yet positive and revolutionary consequences

Can smartphone technology improve patient care?

Introduction The emergence of evidenced-based medicine (EBM) has led to an ever-increasing plethora of guidelines to follow in order to best deliver this high standard of care. Compliance with such guidelines remains sub-optimal and novel methods of guideline dissemination have become popular. Two patient safety areas of major morbidity and, potentially, mortality for patients are venous thromboembolism (VTE) and sepsis. Prophylaxis is available to minimise risk of VTE and early resuscitation bundles for sepsis, such as Sepsis Six have become widely promoted. Both of these areas have local guidelines that should be followed but compliance is poor. At the start of this period of research Sepsis Six had not yet been rolled-out in the surgical department at the RAH, Paisley. This provided a golden opportunity to look at guideline dissemination for one area, using a variety of modalities. Smartphone technology has become ubiquitous in the past few years. The reasons for this are examined and the role for smartphones, and their applications (apps) in delivering assistance to doctors involved in front-line care is discussed. Potential regulatory issues are reviewed. Aims The aims of this thesis are: To assess prevalence of smartphones in the doctor population in a three-site hospital board area and these doctors’ attitudes to smartphone technology for clinical uses. To design and implement novel apps for thromboprophylaxis and Sepsis Six as a supplemental modality for guideline dissemination. To assess the impact of the introduction of these apps on guideline compliance, including assessing for fatiguing of interest. Materials and Methods A SurveyMonkey questionnaire was emailed to all 456 doctors across the three hospitals in the GGC Clyde sector asking about smartphone ownership and usage and their views on the roles of apps for clinical care. Native smartphone apps were designed and developed for both iPhone and android platforms for both VTE prophylaxis and Sepsis Six. Once these had been field-tested, and pre-app audit of current guideline compliance undertaken they were manually deployed to the surgical junior doctors at the Royal Alexandra Hospital, Paisley. Concurrently, while the Sepsis Six app was being developed the concept of Sepsis Six was rolled out using standard posters, presentations and tutorials. After each modality introduction for both VTE prophylaxis and Sepsis Six audit was undertaken both early, and some time later, to try and assess possible fatiguing of interest and compliance. Results There was a good response to the survey, revealing very high smartphone ownership levels at virtually 90%, with 100% ownership in doctors in the early years of training. Further analysis revealed that doctors in the middle of their training, rather than at either extreme, were the most likely to use a smartphone for clinical care. Doctors preferentially own iPhones rather than Android based smartphones which is out-of-keeping with worldwide, and indeed UK statistics, strongly favouring Android. VTE prophylaxis at baseline audit was better than expected. This meant it was difficult to show any improvement on addition of the smartphone app. There were transient improvements in the correct prescribing of anti-embolic stockings however but generally results suggested that the app simply wasn’t being used. Sepsis bundle compliance at baseline was poor but slowly improved over the seven audit points. There were no sharp improvements in Sepsis Six bundle compliance to suggest that either the traditional methods or the app were particularly good at improving guideline compliance. Conclusions Electronic patient care is fast becoming universal and smartphone/ tablet technology will be at the forefront of this. Despite disappointing results here,the use of an app for more complex patient-specific guidelines is likely to become increasingly popular, as long as accuracy of the information provided by the app can be guaranteed

Microfluidics for Biosensing

There are 12 papers published with 8 research articles, 3 review articles and 1 perspective. The topics cover: Biomedical microfluidics Lab-on-a-chip Miniaturized systems for chemistry and life science (MicroTAS) Biosensor development and characteristics Imaging and other detection technologies Imaging and signal processing Point-of-care testing microdevices Food and water quality testing and control We hope this collection could promote the development of microfluidics and point-of-care testing (POCT) devices for biosensing

Sensors Based on Bio and Biomimetic Receptors in Medical Diagnostic, Environment, and Food Analysis

Analytical chemistry is now developing mainly in two areas: automation and the creation of complexes that allow, on the one hand, for simultaneously analyzing a large number of samples without the participation of an operator, and on the other, the development of portable miniature devices for personalized medicine and the monitoring of a human habitat. The sensor devices, the great majority of which are biosensors and chemical sensors, perform the role of the latter. That last line is considered in the proposed review. Attention is paid to transducers, receptors, techniques of immobilization of the receptor layer on the transducer surface, processes of signal generation and detection, and methods for increasing sensitivity and accuracy. The features of sensors based on synthetic receptors and additional components (aptamers, molecular imprinted polymers, biomimetics) are discussed. Examples of bio- and chemical sensors’ application are given. Miniaturization paths, new power supply means, and wearable and printed sensors are described. Progress in this area opens a revolutionary era in the development of methods of on-site and in-situ monitoring, that is, paving the way from the “test-tube to the smartphone”

Holographic Point-of-Care Diagnostic Devices

Developing non-invasive and accurate diagnostics that are easily manufactured, robust and reusable will provide monitoring of high-risk individuals in any clinical or point-of-care environment, particularly in the developing world. There is currently no rapid, low-cost and generic sensor fabrication technique capable of producing narrow-band, uniform, reversible colorimetric readouts with a high-tuneability range. This thesis aims to present a theoretical and experimental basis for the rapid fabrication, optimisation and testing of holographic sensors for the quantification of pH, organic solvents, metal cations, and glucose in solutions. The sensing mechanism was computationally modelled to optimise its optical characteristics and predict the readouts. A single pulse of a laser (6 ns, 532 nm, 350 mJ) in holographic “Denisyuk” reflection mode allowed rapid production of sensors through silver-halide chemistry, in situ particle size reduction and photopolymerisation. The fabricated sensors consisted of off-axis Bragg diffraction gratings of ordered silver nanoparticles and localised refractive index changes in poly(2-hydroxyethyl methacrylate) and polyacrylamide films. The sensors exhibited reversible Bragg peak shifts, and diffracted the spectrum of narrow-band light over the wavelength range λpeak ≈ 500-1100 nm. The application of the holographic sensors was demonstrated by sensing pH in artificial urine over the physiological range (4.5-9.0), with a sensitivity of 48 nm/pH unit between pH 5.0 and 6.0. For sensing metal cations, a porphyrin derivative was synthesised to act as the crosslinker, the light absorbing material, the component of a diffraction grating, as well as the cation chelating agent. The sensor allowed reversible quantification of Cu2+ and Fe2+ ions (50 mM - 1 M) with a response time within 50 s. Clinical trials of a glucose sensor in the urine samples of diabetic patients demonstrated that the glucose sensor has an improved performance compared to a commercial high-throughput urinalysis device. The experimental sensitivity of the glucose sensor exhibited a limit of detection of 90 µM, and permitted diagnosis of glucosuria up to 350 mM. The sensor response was achieved within 5 min and the sensor could be reused about 400 times without compromising its accuracy. Holographic sensors were also tested in flake form, and integrated with paper-iron oxide composites, dyed filter and chromatography papers, and nitrocellulose-based test strips. Finally, a generic smartphone application was developed and tested to quantify colorimetric tests for both Android and iOS operating systems. The developed sensing platform and the smartphone application have implications for the development of low-cost, reusable and equipment-free point-of-care diagnostic devices