Advances in High-Resolution Microscale Impedance Sensors

Sensors based on impedance transduction have been well consolidated in the industry for decades. Today, the downscaling of the size of sensing elements to micrometric and submicrometric dimensions is enabled by the diffusion of lithographic processes and fostered by the convergence of complementary disciplines such as microelectronics, photonics, biology, electrochemistry, and material science, all focusing on energy and information manipulation at the micro- and nanoscale. Although such a miniaturization trend is pivotal in supporting the pervasiveness of sensors (in the context of mass deployment paradigms such as smart city, home and body monitoring networks, and Internet of Things), it also presents new challenges for the detection electronics, reaching the zeptoFarad domain. In this tutorial review, a selection of examples is illustrated with the purpose of distilling key indications and guidelines for the design of high-resolution impedance readout circuits and sensors. The applications span from biological cells to inertial and ultrasonic MEMS sensors, environmental monitoring, and integrated photonics

Towards Single-Chip Nano-Systems

Important scientific discoveries are being propelled by the advent of nano-scale sensors that capture weak signals from their environment and pass them to complex instrumentation interface circuits for signal detection and processing. The highlight of this research is to investigate fabrication technologies to integrate such precision equipment with nano-sensors on a single complementary metal oxide semiconductor (CMOS) chip. In this context, several demonstration vehicles are proposed. First, an integration technology suitable for a fully integrated flexible microelectrode array has been proposed. A microelectrode array containing a single temperature sensor has been characterized and the versatility under dry/wet, and relaxed/strained conditions has been verified. On-chip instrumentation amplifier has been utilized to improve the temperature sensitivity of the device. While the flexibility of the array has been confirmed by laminating it on a fixed single cell, future experiments are necessary to confirm application of this device for live cell and tissue measurements. The proposed array can potentially attach itself to the pulsating surface of a single living cell or a network of cells to detect their vital signs

High-Density Neurochemical Microelectrode Array to Monitor Neurotransmitter Secretion

Neuronal exocytosis facilitates the propagation of information through the nervous system pertaining to bodily function, memory, and emotions. Using amperometry, an electrochemical technique that directly detects electroactive molecules, the sub-millisecond dynamics of exocytosis are revealed and the modulation of neurotransmitter secretion due to neurodegenerative diseases or pharmacological treatments can be studied. The method of detection using amperometry is the exchange of electrons due to a redox reaction at an electrochemically sensitive electrode. As electroactive molecules, such as dopamine, undergo oxidation, electrons are released from the molecule to the electrode and an oxidation current is generated and recorded. Despite the significance of traditional single-cell amperometry, it is a costly, labor-intensive, and low-throughput, procedure. The focus of this dissertation is the development of a monolithic CMOS-based neurochemical sensing system that can provide a high-throughput of up to 1024 single-cell recordings in a single experiment, significantly reducing the number of experiments required for studying the effects of neurodegenerative diseases or new pharmacological treatments on the exocytosis process. The neurochemical detection system detailed in this dissertation is based on a CMOS amplifier array that contains 1024 independent electrode-amplifier units, each of which contains a transimpedance amplifier with comparable noise performance to a high-quality electrophysiology amplifier that is used for traditional single-cell amperometry. Using this novel technology, single exocytosis events are monitored simultaneously from numerous single-cells in experiments to reveal the secretion characteristics from groups of cells before and after pharmacological treatments which target the modulation of neurotransmitters in the brain, such as drugs for depression or Parkinson\u27s disease

Biologically modified microelectrode sensors provide enhanced sensitivity for detection of nucleic acid sequences from Mycobacterium tuberculosis

This paper describes improved sensitivity when using biosensors based on microfabricated microelectrodes to detect DNA, with the goal of progressing towards a low cost and mass manufacturable assay for antibiotic resistance in tuberculosis (TB). The microelectrodes gave a near 20 times improvement in sensitivity compared to polycrystalline macroelectrodes. In addition, experimental parameters such as redox mediator concentration and experimental technique were investigated and optimised. It was found that lower concentrations of redox mediator gave higher signal changes when measuring hybridisation events and, at these lower concentrations, square wave voltammetry was more sensitive and consistent than differential pulse voltammetry. Together, this paper presents a quantifiable comparison of macroelectrode and microelectrode DNA biosensors. The final assay demonstrates enhanced sensitivity through reduction of sensor size, reduction of redox mediator concentration and judicious choice of detection technique, therefore maintaining manufacturability for incorporation into point of care tests and lab-on-a-chip devices

Electrochemical sensor system architecture using the CMOS-MEMS technology for cytometry applications

This thesis presents the development process of an integrated sensor-system-on-chip for recording the parameters of blood cells. The CMOS based device consists of the two flow-through sensor arrays, stacked one on top of the other. The sensors are able to detect the biological cell in terms of its physical size and the surface charge on a cell’s membrane. The development of the measurement system was divided into several stages these were to design and implement the two sensor arrays complemented with readout circuitry onto a single CMOS chip to create an on-chip membrane with embedded flow-through micro-channels by a CMOS compatible post-processing techniques to encapsulate and hermeti-cally package the device for liquid chemistry experiments, to test and characterise the two sensor arrays together with readout electronics, to develop control and data acquisition software and to detect the biological cells using the complete measurement system. Cy-tometry and haematology fields are closely related to the presented work, hence it is envis-aged that the developed technology enables further integration and miniaturisation of the biomedical instrumentation. The two vertically stacked 4 x 4 flow-through sensor arrays, embedded into an on-chip membrane, were implemented in a single silicon chip device together with a readout circuitry for each of the sensor sets. To develop a CMOS-MEMS device the design and fabrication was carried out using a commercial process design kit (0.35 µm 4-Metal, 2-Poly, CMOS) as well as the foundry service. Thereafter the device was post-processed in-house to develop the on-chip membrane and open the sensing micro-apertures. The two types of sensor were integrated on the silicon dice for multi-parametric characterisation of the analyte. To read the cell membrane charge the ion sensitive field effect transistor (ISFET) was utilised and for cell size (volume) detection an impedance sensor (Coulter counter) was used. Both sensors rely on a flow-through mode of operation, hence the constant flow of the analyte sample could be maintained. The Coulter counter metal electrode was exposed to the solution, while the ISFET floating gate electrode maintained contact with the analyte through a charge sensitive membrane constructed of a dielectric material (silicon dioxide) lining the inside of the micro-pore. The outside size of each of the electrodes was 100 µm x 100 µm and the inside varied from 20 µm x 20 µm to 58 µm x 58 µm. The sense aperture size also varied from 10 µm x 10 µm to 16 µm x 16 µm. The two stacked micro-electrode arrays were layed out on an area of 5002 µm2. The CMOS-MEMS device was fit into a custom printed circuit board (PCB) chip carrier, thereafter insulated and hermetically packaged. Microfluidic ports were attached to the packaged module so that the analyte can be introduced and drained by a flow-through mode of operation. The complete microfluidic system and packaging was assembled and thereafter evaluated for correct operation. Undisturbed flow of the analyte solution is es-sential for the sensor operation. This is related to the fact that the electrochemical response of both sensors depends on the analyte flow through the sense micro-apertures thus any aggregation of the sample within the microfluidic system would cause clogging of the mi-cro-pores. The on-chip electronic circuitry was characterised, and after comparison with the simulated results found to be within an error margin of what enables it for reliable sensor signal readout. The measurement system is automated by software control so that the bias parame-ters can be set precisely, it also helped while error debugging. Analogue signals from the two sensor arrays were acquired, later processed and stored by a data acquisition system. Both control and data capture systems are implemented in a high level programming lan-guage. Furthermore both are integrated and operated in a one window based graphical user interface (GUI). A fully functional measurement system was used as a flow-through cytometer for living cells detection. The measurements results showed that the system is capable of single cell detection and on-the-fly data display

Design and Implementation of an Integrated Biosensor Platform for Lab-on-a-Chip Diabetic Care Systems

Recent advances in semiconductor processing and microfabrication techniques allow the implementation of complex microstructures in a single platform or lab on chip. These devices require fewer samples, allow lightweight implementation, and offer high sensitivities. However, the use of these microstructures place stringent performance constraints on sensor readout architecture. In glucose sensing for diabetic patients, portable handheld devices are common, and have demonstrated significant performance improvement over the last decade. Fluctuations in glucose levels with patient physiological conditions are highly unpredictable and glucose monitors often require complex control algorithms along with dynamic physiological data. Recent research has focused on long term implantation of the sensor system. Glucose sensors combined with sensor readout, insulin bolus control algorithm, and insulin infusion devices can function as an artificial pancreas. However, challenges remain in integrated glucose sensing which include degradation of electrode sensitivity at the microscale, integration of the electrodes with low power low noise readout electronics, and correlation of fluctuations in glucose levels with other physiological data. This work develops 1) a low power and compact glucose monitoring system and 2) a low power single chip solution for real time physiological feedback in an artificial pancreas system. First, glucose sensor sensitivity and robustness is improved using robust vertically aligned carbon nanofiber (VACNF) microelectrodes. Electrode architectures have been optimized, modeled and verified with physiologically relevant glucose levels. Second, novel potentiostat topologies based on a difference-differential common gate input pair transimpedance amplifier and low-power voltage controlled oscillators have been proposed, mathematically modeled and implemented in a 0.18μm [micrometer] complementary metal oxide semiconductor (CMOS) process. Potentiostat circuits are widely used as the readout electronics in enzymatic electrochemical sensors. The integrated potentiostat with VACNF microelectrodes achieves competitive performance at low power and requires reduced chip space. Third, a low power instrumentation solution consisting of a programmable charge amplifier, an analog feature extractor and a control algorithm has been proposed and implemented to enable continuous physiological data extraction of bowel sounds using a single chip. Abdominal sounds can aid correlation of meal events to glucose levels. The developed integrated sensing systems represent a significant advancement in artificial pancreas systems

The Boston University Photonics Center annual report 2006-2007

This repository item contains an annual report that summarizes activities of the Boston University Photonics Center in the 2006-2007 academic year. The report provides quantitative and descriptive information regarding photonics programs in education, interdisciplinary research, business innovation, and technology development. The Boston University Photonics Center (BUPC) is an interdisciplinary hub for education, research, scholarship, innovation, and technology development associated with practical uses of light.This annual report summarizes activities of the BUPC over the period of July, 2006 through June, 2007, corresponding to the University’s fiscal year. These activities span the Center’s complementary missions in research, education, technology development, and commercialization. This reporting period included a milestone, as BUPC completed its tenth year of operation in its landmark building in the heart of the University’s Charles River Campus. Faculty research activity reached an all time high when evaluated by the usual metrics of external funding, scholarly publications, honors and awards. The Center’s educational programs were bolstered by two summer programs hosting more than 40 undergraduate interns, and by the launch of a competitive graduate fellowship program sponsoring ten BUPC graduate fellowships. In technology development, the prototype RedOwl sniper detection system pioneered by Center faculty, staff, and industry partners was fieldtested by the US Department of Defense, and has been handed off to industry partners for further pre-commercial development. Three new defense/security prototypes were developed by BUPC to address critical national defense needs in the past year and 13 faculty development projects were supported in collaboration with the Army Research Laboratory to fill the technology pipeline for our future defense-related prototyping efforts. The Center’s business incubator had a transformative year. After revising its core mission and operational strategy in the summer of 2006, the incubator generated significant demand for the intellectual environment, facilities, and expertise available to participating companies. New companies attracted by this revised value proposition now occupy all available space

Characterization and analysis of hybrid electronic materials for molecular based devices

The goal of this work is to characterize and to analyze hybrid electronic materials (HEMs) using fluorescence (FL) spectroscopy and conductive probe-atomic force microscopy (CP-AFM) in order to investigate the electrical and optical properties of these materials. Currently, research efforts to characterize novel organic materials for the determination of molecular level transport properties are of great interest.[6] One of the most interesting organic materials is the porphyrin molecule, which exhibits behavior useful for memory applications.[4] Colloidal CdS quantum dots (Q-CdS) capped with dioctyl sulfosuccinate (AOT) and thiol functionalized porphyrin molecules are explored for their potential application to next-generation hybrid electronic systems. Q-CdS capped with AOT self-assembled on various substrates are used to study the effect of electron transport in colloidal quantum dots using FL spectroscopy. In turn, porphyrin molecules chemisorbed onto gold surfaces are used to study the phonon-electron interaction in these molecules due to their metal cations. Maximum fluorescence intensities are obtained at specific angles of incidence, such as 80 and 45 degree with respect to the sample, for Q-CdS and porphyrin molecules, respectively. Emission spectra of Q-CdS absorbed onto different substrates such as gold, GaAs, and mica show a slight but systematic redshift of peak characteristics of spatially confined phonon interactions. The effects of relative quantum dot size, different substrates, and light intensity are discussed in this thesis. As the relative sizes of the quantum dots decrease, the excitonic peaks are slightly blue shifted. In order to study the electron transport mechanism of a single or a few molecules in metal-molecule-metal heterostructures, the electronic characteristics of self-assembled monolayers (SAMs) of n-alkanethiols such as hexanethiol and octanethiol are investigated using CP-AFM. SAMs of alkanethiols on gold surfaces have been shown to form stable surface structures.[21] Studies have shown that thiolated porphyrins readily self-assemble on gold surfaces.[73] The I-V characteristics of self-assembled monothiolated porphyrin molecules on gold substrates are measured under ambient conditions. I-V traces of porphyrin molecules behave sigmoidally according to the Simmons Equation for square barrier tunneling and illustrate that the electron transport mechanism through porphyrin is direct tunneling for the applied bias levels in this study

Development of a Dual-Mode CMOS Microelectrode Array for the Simultaneous Study of Electrochemical and Electrophysiological Activities of the Brain

Medical diagnostic devices are in high demand due to increasing cases of neurodegenerative diseases in the aging population and pandemic outbreaks in our increasingly connected global community. Devices capable of detecting the presence of a disease in its early stages can have dramatic impacts on how it can be treated or eliminated. High cost and limited accessibility to diagnostic tools are the main barriers preventing potential patients from receiving a timely disease diagnosis. This dissertation presents several devices that are aimed at providing higher quality medical diagnostics at a low cost. Brain function is commonly studied with systems detecting the action potentials that are formed when neurons fire. CMOS technology enables extremely high-density electrode arrays to be produced with integrated amplifiers for high-throughput action potential measurement systems while greatly reducing the cost per measurement compared to traditional tools. Recently, CMOS technology has also been used to develop high-throughput electrochemical measurement systems. While action potentials are important, communication between neurons occurs by the flow of neurotransmitters at the synapses, so measurement of action potentials alone is incapable of fully studying neurotransmission. In many neurodegenerative diseases the breakdown in neurotransmission begins well before the disease manifests itself. The development of a dual-mode CMOS device that is capable of simultaneous high-throughput measurement of both action potentials and neurotransmitter flow via an on-chip electrode array is presented in this dissertation. This dual-mode technology is useful to those studying the dynamic decay of the neurotransmission process seen in many neurodegenerative diseases using a low-cost CMOS chip. This dissertation also discusses the development of more traditional diagnostic devices relying on PCR, a method commonly used only in centralized laboratories and not readily available at the point-of-care. These technologies will enable faster, cheaper, more accurate, and more accessible diagnostics to be performed closer to the patient