Portable Bio-Devices: Design of Electrochemical Instruments from Miniaturized to Implantable Devices

The integration of biosensors and electronic technologies allows the development of biomedical systems able to diagnose and monitoring pathologies by detecting specific biomarkers. The chapter presents the main modules involved in the development of such devices, generically represented in Fig. 1, and focuses its attention on the essential components of these systems to address questions such as: how is the device powered? How does it communicate the measured data? What kind of sensors could be used?, and What kinds of electronics are used

Micromachined three-dimensional electrode arrays for in-vitro and in-vivo electrogenic cellular networks

This dissertation presents an investigation of micromachined three-dimensional microelectrode arrays (3-D MEAs) targeted toward in-vitro and in-vivo biomedical applications. Current 3-D MEAs are predominantly silicon-based, fabricated in a planar fashion, and are assembled to achieve a true 3-D form: a technique that cannot be extended to micro-manufacturing. The integrated 3-D MEAs developed in this work are polymer-based and thus offer potential for large-scale, high volume manufacturing. Two different techniques are developed for microfabrication of these MEAs - laser micromachining of a conformally deposited polymer on a non-planar surface to create 3-D molds for metal electrodeposition; and metal transfer micromolding, where functional metal layers are transferred from one polymer to another during the process of micromolding thus eliminating the need for complex and non-repeatable 3-D lithography processes. In-vitro and in-vivo 3-D MEAs are microfabricated using these techniques and are packaged utilizing Printed Circuit Boards (PCB) or other low-cost manufacturing techniques. To demonstrate in-vitro applications, growth of 3-D co-cultures of neurons/astrocytes and tissue-slice electrophysiology with brain tissue of rat pups were implemented. To demonstrate in-vivo application, measurements of nerve conduction were implemented. Microelectrode impedance models, noise models and various process models were evaluated. The results confirmed biocompatibility of the polymers involved, acceptable impedance range and noise of the microelectrodes, and potential to improve upon an archaic clinical diagnostic application utilizing these 3-D MEAs.Ph.D.Committee Chair: Mark G. Allen; Committee Member: Elliot L. Chaikof; Committee Member: Ionnis (John) Papapolymerou; Committee Member: Maysam Ghovanloo; Committee Member: Oliver Bran

A Novel Cell-Based Hybrid Acoustic Wave Biosensor with Impedimetric Sensing Capabilities

A novel multiparametric biosensor system based on living cells will be presented. The biosensor system includes two biosensing techniques on a single device: resonant frequency measurements and electric cell-substrate impedance sensing (ECIS). The multiparametric sensor system is based on the innovative use of the upper electrode of a quartz crystal microbalance (QCM) resonator as working electrode for the ECIS technique. The QCM acoustic wave sensor consists of a thin AT-cut quartz substrate with two gold electrodes on opposite sides. For integration of the QCM with the ECIS technique a semicircular counter electrode was fabricated near the upper electrode on the same side of the quartz crystal. Bovine aortic endothelial live cells (BAECs) were successfully cultured on this hybrid biosensor. Finite element modeling of the bulk acoustic wave resonator using COMSOL simulations was performed. Simultaneous gravimetric and impedimetric measurements performed over a period of time on the same cell culture were conducted to validate the device\u27s sensitivity. The time necessary for the BAEC cells to attach and form a compact monolayer on the biosensor was 35∼45 minutes for 1.5 × 104 cells/cm2 BAECs; 60 minutes for 2.0 × 104 cells/cm2 BAECs; 70 minutes for 3.0 × 104 cells/cm2 BAECs; and 100 minutes for 5.0 × 104 cells/cm2 BAECs. It was demonstrated that this time is the same for both gravimetric and impedimetric measurements. This hybrid biosensor will be employed in the future for water toxicity detection

Wideband Fully-Programmable Dual-Mode CMOS Analogue Front-End for Electrical Impedance Spectroscopy

This paper presents a multi-channel dual-mode CMOS analogue front-end (AFE) for electrochemical and bioimpedance analysis. Current-mode and voltage-mode readouts, integrated on the same chip, can provide an adaptable platform to correlate single-cell biosensor studies with large-scale tissue or organ analysis for real-time cancer detection, imaging and characterization. The chip, implemented in a 180-nm CMOS technology, combines two current-readout (CR) channels and four voltage-readout (VR) channels suitable for both bipolar and tetrapolar electrical impedance spectroscopy (EIS) analysis. Each VR channel occupies an area of 0.48 mm 2 , is capable of an operational bandwidth of 8 MHz and a linear gain in the range between -6 dB and 42 dB. The gain of the CR channel can be set to 10 kΩ, 50 kΩ or 100 kΩ and is capable of 80-dB dynamic range, with a very linear response for input currents between 10 nA and 100 μ A. Each CR channel occupies an area of 0.21 mm 2 . The chip consumes between 530 μ A and 690 μ A per channel and operates from a 1.8-V supply. The chip was used to measure the impedance of capacitive interdigitated electrodes in saline solution. Measurements show close matching with results obtained using a commercial impedance analyser. The chip will be part of a fully flexible and configurable fully-integrated dual-mode EIS system for impedance sensors and bioimpedance analysis

Smartphone as a Portable Detector, Analytical Device, or Instrument Interface

The Encyclopedia Britannia defines a smartphone as a mobile telephone with a display screen, at the same time serves as a pocket watch, calendar, addresses book and calculator and uses its own operating system (OS). A smartphone is considered as a mobile telephone integrated to a handheld computer. As the market matured, solid-state computer memory and integrated circuits became less expensive over the following decade, smartphone became more computer-like, and more more-advanced services, and became ubiquitous with the introduction of mobile phone networks. The communication takes place for sending and receiving photographs, music, video clips, e-mails and more. The growing capabilities of handheld devices and transmission protocols have enabled a growing number of applications. The integration of camera, access Wi-Fi, payments, augmented reality or the global position system (GPS) are features that have been used for science because the users of smartphone have risen all over the world. This chapter deals with the importance of one of the most common communication channels, the smartphone and how it impregnates in the science. The technological characteristics of this device make it a useful tool in social sciences, medicine, chemistry, detections of contaminants, pesticides, drugs or others, like so detection of signals or image

Thiophene Determination in Liquid Hydrocarbons by In-line Acoustic Measurements

Introduction. Petroleum is a complex mixture of hydrocarbons. Sulphur is the most common heteroatom in pe-troleum and petroleum products. Its content in oil can reach 14 %. The determination of sulphur in oil and its removal is of great importance, since sulphur compounds adversely affect the quality of petroleum products and pollute the environment. Desulphurization of hydrocarbons is important in the processing of petroleum products, which needs in usage of accurate and simple methods for the sulphur-containing components determination. Most of developed methods are difficult to apply for flow online analysis, which can create difficulties in using them to monitor the content of sulphur-containing heteroatomic components in real time. Acoustic sensors are one of the possible solutions. In term of sensing of flammable liquids, the use of the acoustic methods is attractive since the analyte is not a part of an electrical measuring circuit and it is only acoustically coupled that prevents an occurrence of a spark.Objective. The purpose of the work is to study the possibilities of online flow analysis of sulphur-containing heteroatomic components using acoustic measurements. The challenge is the development of a resonator system integrated with the pipe.Materials and methods. Thiophene and oil fraction with the boundary boiling point of 100–140 oC were used to prepare the mixtures. Thiophene is a representative of sulphur-containing components, which may be included in the composition of petroleum and its derivatives. Experimental measuring equipment includes impedance analyzer, a developed sensor structure integrated with a liquid-filled pipe, a pump and a tank with a measured liquid. A theoretical analysis of sensor structure was carried out on the basis of numerical simulation using COMSOL Multiphysics software.Results. The sensor structure was designed as a combination of 2D and 1D pipe periodic arrangements to achieve high Q-factor of acoustic resonance in the flow system. The eigenmodes of the sensor structure with a liquid analyte were carried out. The characteristic of sensor structure is determined. The sensor shows good sensitivity to the thiophene content with high resolution in-line analysis. This result is achieved by limiting the energy losses of acoustic resonance in radiation along the pipe by creating a periodic structure.Conclusion. The study of acoustic properties of solutions prepared on the basis of thiophene and oil fraction with boundary boiling point 100–140 °C was performed. It shows that methods based on acoustic spectroscopy make it possible to accurately determine the concentration of heteroatomic components in gasoline mixtures, since the presence of heteroatomic components leads to a change in mechanical properties of liquid hydrocarbons mixtures. Possible applications for developed acoustic sensor are flow analysis for monitoring the quality of oil products. Introduction. Petroleum is a complex mixture of hydrocarbons. Sulphur is the most common heteroatom in pe-troleum and petroleum products. Its content in oil can reach 14 %. The determination of sulphur in oil and its removal is of great importance, since sulphur compounds adversely affect the quality of petroleum products and pollute the environment. Desulphurization of hydrocarbons is important in the processing of petroleum products, which needs in usage of accurate and simple methods for the sulphur-containing components determination. Most of developed methods are difficult to apply for flow online analysis, which can create difficulties in using them to monitor the content of sulphur-containing heteroatomic components in real time. Acoustic sensors are one of the possible solutions. In term of sensing of flammable liquids, the use of the acoustic methods is attractive since the analyte is not a part of an electrical measuring circuit and it is only acoustically coupled that prevents an occurrence of a spark.Objective. The purpose of the work is to study the possibilities of online flow analysis of sulphur-containing heteroatomic components using acoustic measurements. The challenge is the development of a resonator system integrated with the pipe.Materials and methods. Thiophene and oil fraction with the boundary boiling point of 100–140 oC were used to prepare the mixtures. Thiophene is a representative of sulphur-containing components, which may be included in the composition of petroleum and its derivatives. Experimental measuring equipment includes impedance analyzer, a developed sensor structure integrated with a liquid-filled pipe, a pump and a tank with a measured liquid. A theoretical analysis of sensor structure was carried out on the basis of numerical simulation using COMSOL Multiphysics software.Results. The sensor structure was designed as a combination of 2D and 1D pipe periodic arrangements to achieve high Q-factor of acoustic resonance in the flow system. The eigenmodes of the sensor structure with a liquid analyte were carried out. The characteristic of sensor structure is determined. The sensor shows good sensitivity to the thiophene content with high resolution in-line analysis. This result is achieved by limiting the energy losses of acoustic resonance in radiation along the pipe by creating a periodic structure.Conclusion. The study of acoustic properties of solutions prepared on the basis of thiophene and oil fraction with boundary boiling point 100–140 °C was performed. It shows that methods based on acoustic spectroscopy make it possible to accurately determine the concentration of heteroatomic components in gasoline mixtures, since the presence of heteroatomic components leads to a change in mechanical properties of liquid hydrocarbons mixtures. Possible applications for developed acoustic sensor are flow analysis for monitoring the quality of oil products

Development of a novel high resolution and high throughput biosensing technology based on a Monolithic High Fundamental Frequency Quartz Crystal Microbalance (MHFF-QCM). Validation in food control

Tesis por compendio[ES] La sociedad actual demanda un mayor control en la seguridad y calidad de los alimentos que se consumen. Esta preocupación se ve reflejada en los diferentes planes estatales y europeos de investigación científica, los cuales, plantean la necesidad de innovar y desarrollar nuevas técnicas analíticas que cubran los requerimientos actuales. En el presente documento se aborda el problema de la presencia de residuos químicos en la miel. El origen de los mismos se debe, fundamentalmente, a los tramientos veterinarios con los que se tratan enfermedades y parásitos en las abejas, y a los tratamientos agrícolas con los que las abejas se ponen en contacto cuando recolectan el néctar en cultivos próximos a las colmenas. La Agencia Europea de Seguridad Alimentaria (EFSA) confirma esta realidad al notificar numerosas alertas sanitarias en la miel. En los últimos años, los métodos de análisis basados en inmunosensores piezoeléctricos se han posicionado como la base de una técnica de cribado muy prometedora, la cual puede ser empleada como técnica complementaria a las clásicas de cromatografía, gracias a su sencillez, rapidez y bajo coste. La tecnología de resonadores High-Fundamental Frequency Quartz Crystal Microbalance with Dissipation (HFF-QCMD) combina la detección directa en tiempo real, alta sensibilidad y selectividad con un fácil manejo y coste reducido en comparación con otras técnicas. Además, está tecnología permite aumentar el rendimiento del análisis mediante el diseño de arrays de resonadores en un mismo sustrato (Monolithic HFF-QCMD). En este documento se presenta el diseño de un array de 24 sensores HFF-QCMD, junto con un cartucho de micro-fluídica que traza diversos microcanales sobre los diferentes elementos sensores, a los que hace llegar la muestra de miel diluida a analizar. El cartucho actúa también como interfaz para realizar la conexión entre el array de resonadores y el instrumento de caracterización de los mismos. Para obtener el máximo partido del array diseñado, se desarrolla un método de medida robusto y fiable que permite elevar la tasa de adquisición de datos para facilitar la toma de registros eléctricos de un elevado número de resonadores de forma simultánea, e incluso en varios armónicos del modo fundamental de resonancia. La gran sensibilidad de la tecnología HFF-QCMD a los eventos bioquímicos a caracterizar se extiende también a otro tipo eventos externos, como son los cambios de temperatura o presión, lo que es necesario minimizar con el fin de reducir el impacto que estas perturbaciones no deseadas provocan en la estabilidad y fiabilidad de la medida. Con este fin, se desarrolla un algoritmo de procesado de señal basado en la Discrete Transform Wavelet (DTW). Finalmente, todos los desarrollos tecnológicos realizados se validan mediante la implementación de un inmunoensayo para la detección simultánea, en muestras de mieles reales, de residuos químicos de naturaleza química muy diferente, a saber, el fungicida tiabendazol y el antibiótico sulfatiazol.[CA] La societat actual demanda un major control en la seguretat i qualitat dels aliments que es consumeixen. Aquesta preocupació es veu reflectida en els diferents plans estatals i europeus d'investigació científica, els quals, plantegen la necessitat d'innovar i desenvolupar noves tècniques analítiques que cobrisquen els requeriments actuals. En el present document s'aborda el problema de la presència de residus químics en la mel. L'origen dels mateixos es deu, fonamentalment, als tractaments veterinaris amb els quals es tracten malalties i paràsits en les abelles, i als tractaments agrícoles amb els quals les abelles es posen en contacte quan recol·lecten el nèctar en cultius pròxims als ruscos. L'Agència Europea de Seguretat Alimentària (EFSA) confirma aquesta realitat notificant nombroses alertes sanitàries en la mel. En els últims anys, els mètodes d'anàlisis basades en immunosensors piezoelèctrics s'han posicionat com la base d'una tècnica de garbellat molt prometedora, la qual pot ser emprada com a tècnica complementària a les clàssiques de cromatografia, gràcies a la seua senzillesa, rapidesa i baix cost. La tecnologia de ressonadors High-Fundamental Frequency Quartz Crystal Microbalance with Dissipation (HFF-QCMD) combina la detecció directa en temps real, alta sensibilitat i selectivitat amb un fàcil maneig i cost reduït en comparació amb altres tècniques. A més, està tecnologia permet augmentar el rendiment del anàlisi mitjançant el disseny d'arrays de ressonadors en un mateix substrat (Monolithic HFF-QCMD). En aquest document es presenta el disseny d'un array de 24 sensors HFF-QCMD, juntament amb un cartutx de microfluídica que estableix diversos microcanals sobre els diferents elements sensors, als quals fa arribar la mostra de mel diluïda a analitzar. El cartutx actua també com a interfície per a realitzar la connexió entre l'array de ressonadors i l'instrument de caracterització d'aquests. Per a traure el màxim partit a l'array dissenyat, es desenvolupa un mètode de mesura robust i fiable que permet elevar la taxa d'adquisició de dades per a facilitar la presa de registres elèctrics d'un elevat nombre de ressonadors de manera simultània, i fins i tot en diversos harmònics del mode fonamental de ressonància. La gran sensibilitat de la tecnologia HFF-QCMD als esdeveniments bioquímics a caracteritzar s'estén també a un altre tipus esdeveniments externs, com són els canvis de temperatura o pressió, la qual cosa és necessari minimitzar amb la finalitat de reduir l'impacte que aquestes pertorbacions no desitjades provoquen en l'estabilitat i fiabilitat de la mesura. A aquest efecte, es desenvolupa un algorisme de processament de senyal basat en la Discrete Transform Wavelet (DTW). Finalment, tots els desenvolupaments tecnològics realitzats es validen mitjançant la implementació d'un immunoassaig per a la detecció simultània, en mostres de mel reals, de residus químics de naturalesa química molt diferent, a saber, el fungicida tiabendazol i l'antibiòtic sulfatiazol.[EN] Currently, society demands greater control over the safety and quality of the food consumed. This concern is reflected in the different states and European plans for scientific research, which establish the necessity to innovate and develop new analytical techniques that meet current requirements. This document addresses the problem of the presence of chemical residues in honey. Its origin is fundamentally due to the veterinary treatments against diseases and parasites in bees, and also to the agricultural treatments with which the bees come into contact when they collect the nectar in crops close to the hives. The European Food Safety Agency (EFSA) confirms this reality by notifying numerous health alerts in honey. In recent years, analysis methods based on piezoelectric immunosensors have been positioned as the basis of a very promising screening technique, which can be used as a complementary technique to the classic chromatography, thanks to its simplicity, speed and low cost. High-Fundamental Frequency Quartz Crystal Microbalance with Dissipation (HFF-QCMD) resonator technology combines direct real-time detection, high sensitivity and selectivity with easy handling and low cost compared to other techniques. In addition, this technology allows increasing the performance of the analysis through the design of resonator arrays on the same substrate (Monolithic HFF-QCMD). This document presents the design of an array of 24 HFF-QCMD sensors, together with a microfluidic cartridge that establish various microchannels on the different sensor elements, to provide them the diluted honey sample to be analyzed. The cartridge also acts as an interface to make the connection between the array of resonators and the characterization instrument. To get the most out of the designed array, a robust and reliable measurement method has been developed that allows increasing the data acquisition rate to facilitate electrical parameters readout from a high number of resonators simultaneously, and even in several harmonics of the fundamental resonance mode. The great sensitivity of the HFF-QCMD technology to the biochemical events to be characterized also is extended to other types of external events, such as changes in temperature or pressure, which must be minimized in order to reduce the impact that these unwanted disturbances cause in the stability and reliability of the measurement. To this end, a signal processing algorithm based on the Discrete Transform Wavelet (DTW) is developed. Finally, all the technological developments carried out are validated through the implementation of an immunoassay for the simultaneous detection, in real honey samples, of chemical residues of very different chemical nature, namely, the fungicide thiabendazole and the antibiotic sulfathiazole.The authors would also like to thank Jorge Martínez from the Laboratory of High Frequency Circuits (LCAF) of the Universitat Politècnica de València (UPV) for assistance with profilometry, and Manuel Planes, José Luis Moya, Mercedes Tabernero, Alicia Nuez and Joaquin Fayos from the Electron Microscopy Services of the UPV for helping with the AFM, and SEM measurements. M.Calero is the recipient of the doctoral fellowship BES-2017-080246 from the Spanish Ministry of Economy, Industry and Competitiveness (Madrid, Spain). This research was funded by Spanish Ministry of Economy and Competitiveness with FEDER funds (AGL 2016-77702-R) and European Commission Horizon 2020 Programme (Grant Agreement number H2020-FETOPEN-2016-2017/737212-CATCH-U-DNA - Capturing non-Amplified Tumor Circulating DNA with Ultrasound Hydrodynamics) for which the authors are grateful. Román Fernández is with the Center for Research and Innovation in Bioengineering (Ci2B), Universitat Politècnica de València, València, Spain and with Advanced Wave Sensors S.L., Paterna, València, Spain. (e-mail: [email protected]); Yolanda Jiménez, Antonio Arnau and María Calero are with the Center for Research and Innovation in Bioengineering (Ci2B), Universitat Politècnica de València, València, Spain; Ilya Reiviakine is with Advanced Wave Sensors S.L., Paterna, Valencia, Spain and with the Department of Bioengineering, University of Washington, Seattle, WA, 98150 USA; María Isabel Rocha-Gaso and José Vicente García are with Advanced Wave Sensors S.L., Paterna, València, Spain.Calero Alcarria, MDS. (2022). Development of a novel high resolution and high throughput biosensing technology based on a Monolithic High Fundamental Frequency Quartz Crystal Microbalance (MHFF-QCM). Validation in food control [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182652TESISCompendi

Integration Of Electrical Impedance Spectroscopy For Multichannel Cell Culture Measurement

ELECTROCHEMICAL IMPEDANCE SPECTROSCOPY (EIS) has been widely used to study the electrical properties of biological material due to its non-invasive nature and experimental reliability. However, most of the precision impedance analyzers used in EIS only provide single- or two-channel measurements which are inadequate for larger-scale multiplexed measurements, such as those found in modern microfluidic cell culture experiments. The Biomedical Microsystems Laboratory has developed a 16-channel cell culture platform with integrated electrode arrays for monitoring cell growth and electrical properties (i.e., the so-called “electrical phenotype”). In this paper, a system consisting of a 16-channel solid-state analog multiplexer (MUX)paired with a low-cost, impedance analyzer is developed to replace high-cost physical relay MUX and impedance analyzer systems. System requirements and design constraints for monitoring biological systems are considered and a prototype device was fabricated. Initial testing was performed on a breadboard to verify the feasibility of the design idea. Results identified measurement errors due to parasitic elements in the system. Software compensation successfully corrected for parasitic capacitance in the analog MUX design. The accuracy of the measurement system was evaluated on a developed Printed Circuit Board Assembly (PCBA) by comparing theoretical values to MUX compensated data. Finally, an EIS experiment was carried out with tap water with the PCBA system, and measurement results were analyzed using an equivalent Circuit Model (ECM). These results successfully captured the dynamics of charge transport in the electrical double layer, consistent with a modified-Randlecell ECM

Multi-channel microfluidic biosensor platform applied for online monitoring and screening of biofilm formation and activity

Bacterial colonization of surfaces and interfaces has a major impact on various areas including biotechnology, medicine, food industries, and water technologies. In most of these areas biofilm development has a strong impact on hygiene situations, product quality, and process efficacies. In consequence, biofilm manipulation and prevention is a fundamental issue to avoid adverse impacts. For such scenario online, non-destructive biofilm monitoring systems become important in many technical and industrial applications. This study reports such a system in form of a microfluidic sensor platform based on the combination of electrical impedance spectroscopy and amperometric current measurement, which allows sensitive online measurement of biofilm formation and activity. A total number of 12 parallel fluidic channels enable real-time online screening of various biofilms formed by different Pseudomonas aeruginosa and Stenotrophomonas maltophilia strains and complex mixed population biofilms. Experiments using disinfectant and antibiofilm reagents demonstrate that the biofilm sensor is able to discriminate between inactivation/killing of bacteria and destabilization of biofilm structures. The impedance and amperometric sensor data demonstrated the high dynamics of biofilms as a consequence of distinct responses to chemical treatment strategies. Gene expression of flagellar and fimbrial genes of biofilms grown inside the microfluidic system supported the detected biofilm growth kinetics. Thus, the presented biosensor platform is a qualified tool for assessing biofilm formation in specific environments and for evaluating the effectiveness of antibiofilm treatment strategies