Lab-on-CMOS Sensors and Real-time Imaging for Biological Cell Monitoring

Monitoring biological cell growth and viability is essential for in vivo biomedical diagnosis and therapy, and in vitro studies of pharmaceutical efficacy and material toxicity. Conventional monitoring techniques involve the use of dyes and markers that can potentially introduce side effects into the cell culture and often function as end-point assays. This eliminates the opportunity to track fast changes and to determine temporal correlation between measurements. Particularly in drug screening applications, high-temporal resolution cell viability data could inform decisions on drug application protocols that could lead to better treatment outcomes. This work presents development of a lab-on-chip (LoC) sensor for real-time monitoring of biological cell viability and proliferation, to provide a comprehensive picture of the changes cells undergo during their lifecycle. The LoC sensor consists of a complementary metal-oxide-semiconductor (CMOS) chip that measures the cell-to-substrate coupling of adherent cells that are cultured directly on top. This technique is non-invasive, does not require biochemical labeling, and allows for automated and unsupervised cell monitoring. The CMOS capacitance sensor was designed to addresses the ubiquitous challenges of sensitivity, noise coupling, and dynamic range that affect existing sensors. The design includes on-chip digitization, serial data output, and programmable control logic in order to facilitate packaging requirements for biological experiments. Only a microcontroller is required for readout, making it suitable for applications outside the traditional laboratory setting. An imaging platform was developed to provide time-lapse images of the sensor surface, which allowed for concurrent visual and capacitance observation of the cells. Results showed the ability of the LoC sensor to detect single cell binding events and changes in cell morphology. The sensor was used in in vitro experiments to monitor chemotherapeutic agent potency on drug-resistant and drug-sensitive cancer cell lines. Concentrations higher than 5 μM elicited cytotoxic effects on both cell lines, while a dose of 1 μM allowed discrimination of the two cell types. The system demonstrates the use of real-time capacitance measurements as a proof-of-concept tool that has potential to hasten the drug development process

A Low-Power Silicon-Photomultiplier Readout ASIC for the CALICE Analog Hadronic Calorimeter

The future e + e − collider experiments, such as the international linear collider, provide precise measurements of the heavy bosons and serve as excellent tests of the underlying fundamental physics. To reconstruct these bosons with an unprecedented resolution from their multi-jet final states, a detector system employing the particle flow approach has been proposed, requesting calorimeters with imaging capabilities. The analog hadron calorimeter based on the SiPM-on-tile technology is one of the highly granular candidates of the imaging calorimeters. To achieve the compactness, the silicon-photomultiplier (SiPM) readout electronics require a low-power monolithic solution. This thesis presents the design of such an application-specific integrated circuit (ASIC) for the charge and timing readout of the SiPMs. The ASIC provides precise charge measurement over a large dynamic range with auto-triggering and local zero-suppression functionalities. The charge and timing information are digitized using channel-wise analog-to-digital and time-to-digital converters, providing a fully integrated solution for the SiPM readout. Dedicated to the analog hadron calorimeter, the power-pulsing technique is applied to the full chip to meet the stringent power consumption requirement. This work also initializes the commissioning of the calorimeter layer with the use of the designed ASIC. An automatic calibration procedure has been developed to optimized the configuration settings for the chip. The new calorimeter base unit with the designed ASIC has been produced and its functionality has been tested

Portable High Throughput Digital Microfluidics and On-Chip Bacteria Cultures

An intelligent, portable, and high throughput digital microfluidic (DMF) system is developed. Chapter 1 introduces microfluidics and DMF systems. In Chapter 2, a low-cost and high resolution capacitive-to-digital converter integrated circuit is used for droplet position detection. A field-programmable gate array FPGA is used as the integrated logic hub of the system for highly reliable and efficient control of the circuit. In this chapter a fast-fabricating PCB (printed circuit board) substrate microfluidic system is proposed. Smaller actuation threshold voltages than those previously reported are obtained. Droplets (3 µL) are actuated using 200 V, 500 Hz DC pulses. Droplet positions can be detected and displayed on a PC-based 3D animation in real time. The actuators and the capacitance sensing circuits are implemented on one PCB to reduce the size of the system. In Chapter 3, an intelligent EWOD (electrowetting on dielectric) top plate control system is proposed. The dynamic top plate is controlled by a piezoelectric (PZT) cantilever structure. A high resolution laser displacement sensor is used to monitor the deflection of the top plate. The gap height optimization and the harmonic vibration significantly improve the droplet velocity and decrease the droplet minimum threshold actuation voltage. The top plate vibration induced actuation improvement is magnitude and frequency dependent. 100 µm and 200 µm vibrations are tested at 25 Hz. Vibration frequencies at 5 Hz, 10 Hz, and 20 Hz are tested while the magnitude is 200 µm. Results show greater improvements are achieved at larger vibration magnitudes and higher vibration frequencies. With a vibrated top plate, the largest reduction of the actuation voltage is 76 VRMS for a 2.0 µl DI water droplet. The maximum droplet instantaneous velocity is around 9.3 mm/s, which is almost 3 times faster than the droplet velocity without top plate vibration. Liquid that has different hysteresis such as acetonitrile with various concentrations are used as a control to show its compatibility with the proposed DMF chip. Contact line depinning under top plate vibration is observed, which indicates the underlying mechanism for the improvements in actuation velocity and threshold voltage. The top plate control technique reported in this study makes EWOD DMF chips more reliable for point of care diagnostics. In Chapter 4, the mechanisms of the improvements were investigated by observing the detailed changes in the contact angle hysteresis using both parallel and nonparallel top plates. In Chapter 5, on-chip cell cultures are used for anti-biotic resistant bacteria detection. The passively dispensed on-chip cell cultures realize the isolated micro environment electrochemistry measurement, shorten the culturing time, and reduce the required sample volume. The design of the next generation ultra-portable DMF system is covered in the Appendix. Detailed technical notes and hardware design is covered in the Appendix. The proposed portable and high throughput DMF system with on-chip cell cultures have a great potential to change the standards for micro-environment culturing technologies, which will significantly improve the efficiency of actuation, sensing, and detecting performance of the DMF systems

Battery-less near field communications (nfc) sensors for internet of things (iot) applications

L’ implementació de la tecnologia de comunicació de camp proper (NFC) en els telèfons intel·ligents no para de créixer degut a l’ús d’aquesta per fer pagaments, això, junt amb el fet de poder aprofitar l’energia generada pel mòbil no només per la comunicació, sinó també per transmetre energia, el baix cost dels xips NFC, i el fet de que els telèfons tinguin connectivitat amb internet, possibilita i fa molt interesant el disseny d’etiquetes sense bateria incorporant-hi sensors i poder enviar la informació al núvol, dins del creixent escenari de l’internet de les coses (IoT). La present Tesi estudia la viabilitat d’aquests sensors, analitzant la màxima distància entre lector i sensor per proveir la potència necessària, presenta tècniques per augmentar el rang d’operació, i analitza els efectes de certs materials quan aquests estan propers a les antenes. Diversos sensors han estat dissenyats i analitzats i son presentats en aquest treball. Aquests son: Una etiqueta que mesura la humitat de la terra, la temperatura i la humitat relativa de l’aire per controlar les condicions de plantes. Un sensor per detectar la humitat en bolquers, imprès en material flexible que s’adapta a la forma del bolquer. Dues aplicacions, una per estimació de pH i una altre per avaluar el grau de maduració de fruites, basats en un sensor de color. I, per últim, s’estudia la viabilitat de sensors en implants per aplicacions mèdiques, analitzant l’efecte del cos i proposant un sistema per augmentar la profunditat a la que aquests es poden llegir utilitzant un telèfon mòbil. Tots aquests sensors poden ser alimentats i llegits per qualsevol dispositiu que disposin de connexió NFC.La implementación de la tecnología de comunicaciones de campo cercano (NFC) en los teléfonos inteligentes no para de crecer debido al uso de esta para llevar a cabo pagos, esto, junto con el hecho de poder aprovechar la energía generada por el móvil no sólo para la comunicación, sino también para transmitir energía, el bajo coste de los chips NFC, i el hecho que los teléfonos tengan conectividad a internet, posibilita y hace muy interesante el diseño de etiquetas sin batería que incorporen sensores i poder enviar la información a la nube, enmarcado en el creciente escenario del internet de las cosas (IoT). La presente Tesis estudia la viabilidad de estos sensores, analizando la máxima distancia entre lector i sensor para proveer la potencia necesaria, presenta técnicas para aumentar el rango de operación, y analiza los efectos de ciertos materiales cuando estos están cerca de las antenas. Varios sensores han sido diseñados y analizados y son presentados en este trabajo. Estos son: Una etiqueta que mide la humedad de la tierra, la temperatura y la humedad relativa del aire para controlar las condiciones de plantas. Un sensor para detectar la humedad en pañales, impreso en material flexible que se adapta a la forma del pañal. Dos aplicaciones, una para estimación de pH y otra para evaluar el grado de maduración de frutas, basados en un sensor de color. Y, por último, se estudia la viabilidad de sensores en implantes para aplicaciones médicas, analizando el efecto del cuerpo y proponiendo un sistema para aumentar la profundidad a la que estos se pueden leer usando un teléfono móvil. Todos estos sensores pueden ser alimentados y leídos por cualquier dispositivo que disponga de conexión NFC.The implementation of near field communication (NFC) technology into smartphones grows rapidly due the use of this technology as a payment system. This, altogether with the fact that the energy generated by the phone can be used not only to communicate but for power transfer as well, the low-cost of the NFC chips, and the fact that the smartphones have connectivity to internet, makes possible and very interesting the design of battery-less sensing tags which information can be sent to the cloud, within the growing internet of things (IoT) scenario. This Thesis studies the feasibility of these sensors, analysing the maximum distance between reader and sensor to provide the necessary power, presents techniques to increase the range of operation, and analyses the effects of certain materials when they are near to the antennas. Several sensors have been designed and analysed and are presented in this work. These are: a tag that measures the soil moisture, the temperature and the relative humidity of the air to control the conditions of plants. A moisture sensor for diapers, printed on flexible material that adapts to the diaper shape. Two applications, one for pH estimation and another for assessing the degree of fruit ripening, based on a colour sensor. And finally, the feasibility of sensors in implants for medical applications is studied, analysing the effect of the body and proposing a system to increase the depth at which they can be read using a mobile phone. All of these sensors can be powered and read by any NFC enabled device

Performance of the CMS Tracker Optical Links and Future Upgrade Using Bandwidth Efficient Digital Modulation

The Compact Muon Solenoid (CMS) experiment at the Large Hadron Collider (LHC) particle accelerator will begin operation in 2007. The innermost CMS subdetector, the Tracker, comprises ~10 million detector channels read out by ~40 000 analog optical links. The optoelectronic components have been designed to meet the stringent requirements of a high energy physics (HEP) experiment in terms of radiation hardness, low mass and low power. Extensive testing has been performed on the components and on complete optical links in test systems. Their functionality and performance in terms of gain, noise, linearity, bandwidth and radiation hardness is detailed. Particular emphasis is placed on the gain, which directly affects the dynamic range of the detector data. It has been possible to accurately predict the variation in gain that will be observed throughout the system. A simulation based on production test data showed that the average gain would be ~38% higher than the design target at the Tracker operating temperature of -10°C. Corrective action was taken to reduce the gains and recover the lost dynamic range by lowering the optical receiver's load resistor value from 100Ω to 62Ω. All links will have gains between 0.64 and 0.96V/V. The future iteration of CMS will be operated in an upgraded LHC requiring faster data readout. In order to preserve the large investments made for the current readout system, an upgrade path that involves reusing the existing optoelectronic components is considered. The applicability of Quadrature Amplitude Modulation (QAM) in a HEP readout system is examined. The method for calculating the data rate is presented, along with laboratory tests where QAM signals were transmitted over a Tracker optical link. The results show that 3-4Gbit/s would be possible if such a design can be implemented (over 10 times the equivalent data rate of the current analog links, 320Mbits/s).(Abridged version) The CMS experiment at the LHC will begin operation in 2007. The CMS Tracker sub-detector, comprises ~10 million detector channels read out by ~40 000 analog optical links. The optoelectronic components have been designed to meet the stringent requirements of a HEP experiment in terms of radiation hardness, low mass and low power. Extensive testing has been performed on the components and on complete optical links in test systems. Their functionality and performance in terms of gain, noise, linearity, bandwidth and radiation hardness is detailed. Particular emphasis is placed on the gain, which directly affects the dynamic range of the detector data. It has been possible to accurately predict the variation in gain that will be observed throughout the system. A simulation based on production test data showed that the average gain would be ~38% higher than the design target at the Tracker operating temperature of -10{\deg}C. Corrective action was taken to reduce the gains and recover the lost dynamic range by lowering the optical receiver's load resistor value from 100{\Omega} to 62{\Omega}. All links will have gains between 0.64 and 0.96V/V. The future iteration of CMS will be operated in an upgraded LHC requiring faster data readout. In order to preserve the large investments made for the current readout system, an upgrade path that involves reusing the existing optoelectronic components is considered. The applicability of Quadrature Amplitude Modulation (QAM) in a HEP readout system is examined. The method for calculating the data rate is presented, along with laboratory tests where QAM signals were transmitted over a Tracker optical link. The results show that 3-4Gbit/s would be possible if such a design can be implemented (over 10 times the equivalent data rate of the current analog links, 320Mbits/s)

Biosensor system with an integrated CMOS microelectrode array for high spatio-temporal electrochemical imaging, A

2019 Fall.Includes bibliographical references.The ability to view biological events in real time has contributed significantly to research in life sciences. While optical microscopy is important to observe anatomical and morphological changes, it is equally important to capture real-time two-dimensional (2D) chemical activities that drive the bio-sample behaviors. The existing chemical sensing methods (i.e. optical photoluminescence, magnetic resonance, and scanning electrochemical), are well-established and optimized for existing ex vivo or in vitro analyses. However, such methods also present various limitations in resolution, real-time performance, and costs. Electrochemical method has been advantageous to life sciences by supporting studies and discoveries in neurotransmitter signaling and metabolic activities in biological samples. In the meantime, the integration of Microelectrode Array (MEA) and Complementary-Metal-Oxide-Semiconductor (CMOS) technology to the electrochemical method provides biosensing capabilities with high spatial and temporal resolutions. This work discusses three related subtopics in this specific order: improvements to an electrochemical imaging system with 8,192 sensing points for neurotransmitter sensing; comprehensive design processes of an electrochemical imaging system with 16,064 sensing points based on the previous system; and the application of the system for imaging oxygen concentration gradients in metabolizing bovine oocytes. The first attempt of high spatial electrochemical imaging was based on an integrated CMOS microchip with 8,192 configurable Pt surface electrodes, on-chip potentiostat, on-chip control logic, and a microfluidic device designed to support ex vivo tissue experimentation. Using norepinephrine as a target analyte for proof of concept, the system is capable of differentiating concentrations of norepinephrine as low as 8µM and up to 1,024 µM with a linear response and a spatial resolution of 25.5×30.4μm. Electrochemical imaging was performed using murine adrenal tissue as a biological model and successfully showed caffeine-stimulated release of catecholamines from live slices of adrenal tissue with desired spatial and temporal resolutions. This system demonstrates the capability of an electrochemical imaging system capable of capturing changes in chemical gradients in live tissue slices. An enhanced system was designed and implemented in a CMOS microchip based on the previous generation. The enhanced CMOS microchip has an expanded sensing area of 3.6×3.6mm containing 16,064 Pt electrodes and the associated 16,064 integrated read channels. The novel three-electrode electrochemical sensor system designed at 27.5×27.5µm pitch enables spatially dense cellular level chemical gradient imaging. The noise level of the on-chip read channels allow amperometric linear detection of neurotransmitter (norepinephrine) concentrations from 4µM to 512µM with 4.7pA/µM sensitivity (R=0.98). Electrochemical response to dissolved oxygen concentration or oxygen partial pressure (pO2) was also characterized with deoxygenated deionized water containing 10µM to 165 µM pO2 with 8.21pA/µM sensitivity (R=0.89). The enhanced biosensor system also demonstrates selectivity to different target analytes using cyclic voltammetry to simultaneously detect NE and uric acid. In addition, a custom-designed indium tin oxide and Au glass electrode is integrated into the microfluidic support system to enable pH measurement, ensuring viability of bio-samples in ex vivo experiments. Electrochemical images confirm the spatiotemporal performance at four frames per second while maintaining the sensitivity to target analytes. The overall system is controlled and continuously monitored by a custom-designed user interface, which is optimized for real-time high spatiotemporal resolution chemical bioimaging. It is well known that physiological events related to oxygen concentration gradients provide valuable information to determine the state of metabolizing biological cells. Utilizing the CMOS microchip with 16,064 Pt MEA and an improved three-electrode system configuration, the system is capable of imaging low oxygen concentration with limit of detection of 18.3µM, 0.58mg/L, or 13.8mmHg. A modified microfluidic support system allows convenient bio-sample handling and delivery to the MEA surface for sensing. In vitro oxygen imaging experiments were performed using bovine cumulus-oocytes-complexes cells with custom software algorithms to analyze its flux density and oxygen consumption rate. The imaging results are processed and presented as 2D heatmaps, representing the dissolved oxygen concentration in the immediate proximity of the cell. The 2D images and analysis of oxygen consumption provide a unique insight into the spatial and temporal dynamics of cell metabolism

Topical Workshop on Electronics for Particle Physics

The purpose of the workshop was to present results and original concepts for electronics research and development relevant to particle physics experiments as well as accelerator and beam instrumentation at future facilities; to review the status of electronics for the LHC experiments; to identify and encourage common efforts for the development of electronics; and to promote information exchange and collaboration in the relevant engineering and physics communities