A low-noise transimpedance amplifier for BLM-based ion channel recording

High-throughput screening (HTS) using ion channel recording is a powerful drug discovery technique in pharmacology. Ion channel recording with planar bilayer lipid membranes (BLM) is scalable and has very high sensitivity. A HTS system based on BLM ion channel recording faces three main challenges: (i) design of scalable microfluidic devices; (ii) design of compact ultra-low-noise transimpedance amplifiers able to detect currents in the pA range with bandwidth >10 kHz; (iii) design of compact, robust and scalable systems that integrate these two elements. This paper presents a low-noise transimpedance amplifier with integrated A/D conversion realized in CMOS 0.35 µm technology. The CMOS amplifier acquires currents in the range ±200 pA and ±20 nA, with 100 kHz bandwidth while dissipating 41 mW. An integrated digital offset compensation loop balances any voltage offsets from Ag/AgCl electrodes. The measured open-input input-referred noise current is as low as 4 fA/Root Hz at ±200 pA range. The current amplifier is embedded in an integrated platform, together with a microfluidic device, for current recording from ion channels. Gramicidin-A, alpha-haemolysin and KcsA potassium channels have been used to prove both the platform and the current-to-digital converter

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

Design of custom CMOS amplifiers for nanoscale bio-interfaces

The miniaturization of electronics is a technique that holds a lot of potential in improving system performance in a variety of applications. The simultaneous miniaturization of sensors into the nano-scale has provided new ways to probe biological systems. Careful co-design of these electronics and sensors can unlock measurements and experiments that would otherwise be impossible to achieve. This thesis describes the design of two such instrumentation amplifiers and shows that significant gains in temporal resolution and noise performance are possible through careful optimization. A custom integrated amplifier is developed for improving the temporal resolution in nanopore recordings. The amplifier is designed in a commercial 0.18 μm complementary metal-oxide-semiconductor (CMOS) process. A platform is then built with the amplifier at its core that integrates glass-passivated solid-state nanopores to achieve measurement bandwidth over an order of magnitude greater than the state of the art. The use of wavelet transforms for denoising the data and further improving the signal-to-noise ratio (SNR) is then explored. A second amplifier is designed in a 0.18 μm CMOS process for intracellular recordings from neurons. The amplifier contains all the compensation circuitry required for canceling the effects of the electrode non-idealities. Compared to equivalent commercial systems and the state of the art, the amplifier performs comparably or better while consuming orders of magnitude lower power. These systems can inform the design of extremely miniaturized application-specific integrated amplifiers of the future

Single-molecule DNA detection in nanopipettes using high-speed measurements and surface modifications

Inspired by transmembrane pores found in cell membranes and the operating principle of the Coulter counter used for cell counting, nanopore biosensors have emerged as a tool for single-molecule detection. This thesis describes single-molecule DNA detection through resistive pulse sensing using nanopipettes, a novel subclass of solid-state nanopores. In the first part of this thesis, double-stranded (ds) DNA-nanopipette surface interactions were probed in 1 M KCl electrolyte using DNA molecules with lengths ranging from 48.5 to 4 kilobase pair (kbp). A custom-built current amplifier was employed for low-noise and high-bandwidth measurements. Results from these experiments were used to theoretically rationalise DNA-surface interactions and suggest that dsDNA adsorption to the nanopipette surface prior to translocation through the pore is likely to be an important factor in the process. Subsequently, initial investigations to probe DNA-surface interactions were carried out by modifying the surface charge of nanopipettes using silanes. Additionally, experiments were performed to detect shorter dsDNA lengths. In 1 M KCl electrolyte, 200 base pair (bp) long dsDNA was successfully detected using the low-noise and high-bandwidth current amplifier. However detection of 100 bp long dsDNA required the use of 2 or 4 M LiCl electrolyte. Attention was finally shifted to the detection of 100 bp dsDNA in 1 M KCl electrolyte using functionalised lipid bilayer coated nanopipettes. Additional techniques were employed to prepare and characterise the lipid bilayers, including atomic force microscopy (AFM) and dynamic light scattering (DLS). The promising preliminary results provide a framework for further experiments using functionalised lipid bilayers to coat nanopipettes. Overall, results of the aforementioned research presented in this thesis demonstrate high-speed single-molecule detection of DNA and provide novel insights into the translocation dynamics of DNA molecules in nanopipettes and the sensing capabilities of nanopipettes.Open Acces

A compact high gain opamp for Bio-medical applications in 45nm CMOS technology

In this paper a low opamp compensation technique suitable for the bio-medical application has been proposed and intuitive explained the existing compensation techniques. The Present technique relies on the passive damping factor control rather power hungry damping. Implemented in 45nm CMOS technology and simulated with Spectre. Simulation results shows that 100dB dc gain, well compensated 25MHz bandwidth opamp while driving a 1pF capacitive load. Draws with 12uW power consumption from 1V supply and occupying 0.004875mm2 silicon area

Electrochemical noise limits of femtoampere-sensing, CMOS-integrated transimpedance amplifiers

Low-noise operational amplifiers are an important tool in the life sciences. Biosensor measurements typically rely on low-noise transimpedance amplifiers to record biological signals. Two different techniques were used to leverage the advantages of low-noise circuitry for bioelectronics. A CMOS-integrated system for measuring redox-active substrates using electrochemical read-out at very low noise levels is presented. The system incorporates 112 amplifier channels capable of current sensing with noise levels below 1 fArms in a 3.5-Hz bandwidth. The amplifier is externally connected to a gold microelectrode with a radius of 15 µm. The amplifier enables measurement of redox-couples such as potassium ferrocyanide/ferricyanide with concentrations down to 10 nM at current levels of only 300 fA. The electrochemical noise that sets the limits of detection is also measured and analyzed based on redox mass transfer equation and electrochemical impedance spectroscopy. Secondly, CMOS-integrated low noise junction field-effect transistors (JFETs) were developed in a standard 0.18-µm CMOS process. These JFETs reduce input referred flicker noise power by more than a factor of 10 when compared with equally sized n-channel MOS devices by eliminating oxide interfaces in contact with the channel. We show that this improvement in device performance translates into a factor-of-10 reduction in the input-referred noise of integrated CMOS operational amplifiers when JFET devices are used at the input

Ultra-Low-Power Sensors and Receivers for IoT Applications

The combination of ultra-low power analog front-ends and CMOS-compatible transducers enable new applications, such as environmental monitors, household appliances, health trackers, etc. that are seamlessly integrated into our daily lives. Furthermore, wireless connectivity allows many of these sensors to operate both independently and collectively. These techniques collectively fulfil the recent surge of internet-of-things (IoT) applications that have the potential to fundamentally change daily life for millions of people.In this dissertation, the circuit and system design of wireless receivers and sensors is presented that explores the challenges of implementing long lifespan, high accuracy, and large coverage range IoT sensor networks. The first is a wake-up receiver (WuRX), which continuously monitors the RF environment to wake up a higher-power radio upon detection of a predetermined RF signature. This work both improves sensitivity and reduces power over prior art through a multi-faceted design featuring an impedance transformation network with large passive voltage gain, an active envelope detector with high input impedance to facilitate large passive voltage gain, a low-power precision comparator, and a low-leakage digital baseband correlator.Although pushing the prior WuRX performance boundary by orders of magnitude, the first work shows moderate sensitivity, inferior temperature robustness, and large area with external lumped components. Thus, the second work shows a miniaturized WuRX that is temperature-compensated, yet still consumes only nano-watt power and millimeter area while operating at 9 GHz. To further reduce the area, a global common-mode feedback is utilized across the envelope detector and baseband amplifier that eliminates the need for off-chip ac-coupling components. Multiple temperature-compensation techniques are proposed to maintain constant bandwidth of the signal path and constant clock frequency. Both WuRXs operate at 0.4 V supply, consume near-zero power and achieve ~-70 dBm sensitivity.Lastly, the first reported CMOS 2-in-1 relative humidity and temperature sensor is presented. A unified analog front-end interfaces on-chip transducers and converts the inputs into a frequency vis a high-linearity frequency-locked loop. An incomplete-settling switched-capacitor-based Wheatstone bridge is proposed to sense the inputs in a power-efficient fashion

Single Molecule Particle Analysis using Nanotechnology

Nanotechnology is the area of science that involves creation of devices/materials or systems in the nanometer scale. The last few decades have seen an increasing demand for rapid, sensitive, and cheaper diagnostic tools in healthcare. Advances in fabrication technologies have led to more miniaturized systems that are satisfying the promise of “micro total analysis” or “lab-on-chip” systems by facilitating the integration of multiple processing steps into a single device or multiple task-specific devices into a fluidic motherboard (i.e., modular microfluidics). The field of nanotechnology has the ability to revolutionize medical diagnostics by facilitating point-of-care testing with greater sensitivity even at the single molecule level. This allows for the screening of diseases at an early stage by identifying biomarkers of the diseases that are in extremely low concentrations in the blood (i.e., liquid biopsy). To this realization, we have used thermoplastics as our choice of material to fabricate microfluidic/nanofluidic hybrid systems that can evaluate how well a patient responds to chemotherapy, identify single nucleotide polymorphisms that cause major life threatening diseases such as stroke and caner, and development of nanofluidic devices to enumerate SARS CoV-2 viral particles that causes the novel coronavirus of 2019. We developed a high-throughput nanofluidic circuit on which single DNA molecules can be stretched to near their full contour length in nanochannels (<100 nm). Patients with cancer undergoing chemotherapy have more oxidative damage in their DNA compared to a healthy individual, which is an indicator of their response to therapy. We tested the device using calf thymus DNA standards labelled with a bis-intercalating dye and the abasic sites were labelled with another dye. Thus, the DNA molecules that were stretched in the nanochannels were parked and visualized using a fluorescent microscope. The abasic sites that were labelled were identified with their position in the DNA and the number of abasic sites per 105 nucleotides identified. This technique can be effectively used on samples having mass limits (picograms range) and where PCR cannot be utilized. Higher the number of abasic sites, better the response of the patient to chemotherapy, such as doxorubicin for breast cancer patients. While this nanofluidic circuit was used only to visualize the abnormalities in DNA, the next device we developed, called the nanosensor, facilitates the integration of multiple processes into a single device. The nanosensor was used to identify point mutations in DNA or mRNA responsible for diseases such as cancer and stroke, respectively. The device featured 8 pixel array populated with 1 µm pillars, which act as a solid support for Ligase Detection Reactions (spLDR) that can identify a single nucleotide mutation in a DNA from a large majority of wild type DNA. The spLDR can also identify mRNA transcripts from the design of spLDR primers that specifically recognize a unique transcript. The reaction is performed on the pixel arrays and the products are subsequently shuttled into nanometer flight tubes featuring two in-plane nanopores that act as resistive pulse sensors (RPS) to generate a current drop as the products pass through these pores. The time-of-flight (TOF) between the pores in series are used to distinguish between normal and mutated DNA, thus acting as a diagnostic appropriate for the precision medicine initiative. We were able to successfully fabricate the device, run COMSOL simulations to test operation using both hydrodynamic and electrokinetic flows, which were verified via experimentation to establish the functionality of the device to perform the above mentioned processes. The hydrodynamic flow operations used for spLDR was tested using Rhodamine B and the electrokinetic flow to inject the products of the spLDR into the flight tube was tested using oligonucleotides (25mer). Further, plastic-based nanofluidic devices were extended to detect the presence of SARS-CoV-2 viral particles using a nanopore of 350 nm in effective diameter, which has called a nano-coulter Counter (nCC). Briefly, saliva samples containing the viral particles were run through a microfluidic affinity chip containing pillars with surface-immobilized aptamers specific to the SARS-CoV-2 particles. The captured viral particles were released from the microfluidic chip using a blue light and the elute containing only the SARS viral particles were sent to the nCC, which used the RPS technique to count the number of particles. We designed multiple iterations of the nCC and used COMSOL simulations to guide device development. Using the combined principle of hydrodynamic and electrokinetic flow to introduce the viral particles into the nCC, we were able to detect patients with COVID-19 as well as estimate the viral load in SARS CoV-2 standards based on the frequency of the signals generated by correlating the results to a calibration curve. Thus, this combined multi-chip process can diagnose COVID-19 in <20 min thus venturing as an in-home diagnostic kit in the future by automating the operations into a hand-held device

New Architectures and Circuits for Pushing the Dynamic Range and Multiplexing Boundaries of CMOS-Integrated Sensors

Over the last decades, CMOS-integrated sensors have made impressive progress in performance, form-factor, and energy-efficiency for various applications such as imaging, physical/chemical sensing, bio/health monitoring. In the era of the artificial intelligence (AI) and the internet-of-things (IoT), such CMOS-integrated sensors are essential for massive and comprehensive data acquisition, where sensing range (or dynamic range), signal fidelity (or signal-to-noise ratio), and data throughput are key factors. Towards pushing the boundaries of such sensing capabilities, in this dissertation, novel sensing architectures are presented with energy/area-efficient circuit design techniques for multi-channel CMOS optical sensors and neural interfaces. The first topic is a fully-integrated, wide linear dynamic range optical sensor array combining linear and single-photon avalanche diode operation within each pixel. A pulse-counting readout scheme provides in-pixel digitization in an area-efficient manner for both operation modes, enabling fully parallel measurement across the array. The proposed dual-mode optical sensor array alternately requires high-voltage(10-20 V) and low-voltage supply (2-5 V) for reverse bias of the photodiodes, which is provided by a reconfigurable, closed-loop high-voltage charge pump in the same substrate. An 8 x 8 array architecture along with the dual-mode bias generator is fabricated in a general purpose 180 nm CMOS process and demonstrates 129 dB dynamic range while maintaining linear photoresponse operating with a dual-mode frame rate of 20 Hz. The second topic is a new approach for applying code-division multiplexing (CDM) to current-mode and voltage-mode sensor arrays with analog-domain orthogonal encoding directly in a shared, single analog-front-end circuit, which enables simultaneous readout for multiple sensors. The approach is applied to a 8 x 16 array of CMOS-integrated photodetectors and implemented in a general purpose 180 nm CMOS process, where the 16 channel CDM-based oversampling readout achieves an SNR improvement of more than 12 dB compared with time-division multiplexing at the same sampling rate. In addition, a CDM-based neural recording architecture is presented, which offers a significant tolerance to interference that can be injected through long cables

Lab-on-PCB Devices

Lab-on-PCB devices can be considered an emerging technology. In fact, most of the contributions have been published during the last 5 years. It is mainly focussed on both biomedical and electronic applications. The book includes an interesting guide for using the different layers of the Printed Circuit Boards for developing new devices; guidelines for fabricating PCB-based electrochemical biosensors, and an overview of fluid manipulation devices fabricated using Printed Circuit Boards. In addition, current PCB-based devices are reported, and studies for several aspects of research and development of lab-on-PCB devices are described