PIK3CA p.E545K mutation is a well-studied breast cancer biomarker with a clinical significance as a therapeutic target, particularly with the use of the small molecule inhibitor Alpelisib. An issue with detecting this mutation and other mutations in this exon is that 98% of its sequence homology is identical to a pseudogene, a non-functional non-coding gene found in chromosome 22. This paper aims to use ISFET enabled Lab-on-Chip (LoC) technology, coupled with a well-studied isothermal amplification method (LAMP), as a means to distinguish wild-type (WT), mutant (MT) and pseudogene (PG) copies of DNA. In an age where affordability and accessibility of diagnostic tests is of crucial importance, the use of CMOS technology offers a great potential as an alternative for regular near-patient molecular testing using liquid biopsies. Bespoke primer design is tested and optimised with synthetic DNA to achieve high specificity and low sensitivity (100 copies). The primer efficiencies were also tested on our in-house LoC system showing near identical results to those obtained from a qPCR instrument. Spiking experiments were also conducted, where mixed populations of WT and MT were tested to assess the primers' abilities to estimate the variant allele frequency (VAF) of p.E545K and to mimic clinical scenarios. The results continue to depict how LoC technology in partnership with LAMP detection can be used in a liquid biopsy setting to detect blood DNA biomarkers to assist better patient stratification.

In this paper we present the design of a new point-of-care device for protein quantification. The proposed design is based on a novel aptamer-mediated methodology and real time polymerase chain reaction (RT-PCR), a robust and ultrasensitive method for DNA amplification, which we employ for very sensitive quantification of proteins. In addition, we have also developed an algorithm for the processing of raw fluorescence data from the portable RT-PCR device. The algorithm leads to better linearity than a proprietary software from a commercially available RT-PCR machine. The modular nature of the system allows for easy assembly and adjustment towards a variety of biomarkers for applications in disease diagnosis and personalised medicine.

Custom-made, point-of-care PCR platforms are a necessary tool for rapid, point-of-care diagnostics in situations such as the current Covid-19 pandemic. However, a common issue faced by them is noisy fluorescence signals, which consist of a drifting baseline or noisy sigmoidal curve. This makes automated detection difficult and requires human verification. In this paper, we have tried to use nonlinear fitting for automated classification of PCR waveforms to identify whether amplification has taken place or not. We have presented several novel signal reconstruction techniques based on nonlinear fitting which will enable better pre-processing and automated differentiation of a valid or invalid PCR amplification curve. We have also tried to perform this classification at lower PCR cycles to reduce decision times in diagnostic tests.

This paper presents a method for detection of ESR1 p.E380Q, a common Breast Cancer (BC) mutation, using an ISFET (Ion-Sensitive Field-Effect Transistor) based Lab-on-Chip (LoC) platform. The LoC contains an ISFET array that can detect pH changes during DNA amplification, specifically Loop-Mediated Isothermal Amplification (LAMP). Synthetic ESR1 DNA was detected in a comparison pH-LAMP assay, carried out on the LoC platform as well as a conventional qPCR instrument. Positive detection of the allele arises due to bespoke allele-specific primers that target one base-pair difference between the wild-type and mutant alleles. The LoC and qPCR demonstrate comparable results detecting the mutant allele with mutant primers in around 25 minutes. The sensing microchip technology coupled with the molecular methods of isothermal chemistries and primer design allow this platform to be tested at a Point-of-Care setting for breast cancer patients, offering mutational tracking platform of circulating tumour DNA in liquid biopsies to assist patient stratification and allow tailored treatments.

Primers carry unique genetic information that allows them to be used as specific probes in various applications in the field of diagnostics and particularly in cancer, where the need for accurate treatment selection is crucial. Rapid and affordable detection of cancer specific targets, such as allele-specific single-nucleotide mutational changes, are of great need to improve treatment efficacy and guide clinical use. Detecting these mutations in isothermal conditions creates the opportunity to develop cost-efficient diagnostic platforms for cancer treatment. In this paper, a novel python script was constructed to develop a simple and personalised software tool that could automate the design of allele-specific primers in isothermal conditions using design parameters, such as free energies and annealing temperatures. The scripts' primers were compared to manually designed probes that were experimentally tested on a variant (ESR1 p.E380Q), commonly present in metastatic breast cancer, showcasing the applicability of the method and the potential for the script to be used as part of an automated software to design allele-specific assays for Lab-on-Chip platforms in cancer diagnostics.

Neural activity results in chemical changes in the extracellular environment such as variation in pH or potassium/sodium ion concentration. Higher signal to noise ratio make neurochemical signals an interesting biomarker for closed-loop neuromodulation systems. For such applications, it is important to reliably classify pH signatures to control stimulation timing and possibly dosage. For example, the activity of the subdiaphragmatic vagus nerve (sVN) branch can be monitored by measuring extracellular neural pH. More importantly, gut hormone cholecystokinin (CCK)-specific activity on the sVN can be used for controllably activating sVN, in order to mimic the gut-brain neural response to food intake. In this paper, we present a convolutional neural network (CNN) based classification system to identify CCK-specific neurochemical changes on the sVN, from non-linear background activity. Here we present a novel feature engineering approach which enables, after training, a high accuracy classification of neurochemical signals using CNN.

Intensive attention on personalised skin-health solutions is on account of incomparable love of skin and an urgent need for effective treatment. In the meanwhile, people have great expectations on how to utilise genetic knowledge of our body to provide a precise solution for different individuals, such as daily use of skin-health products, since the rapid development of genetic test services and skin-health science. However, the complexity of multi-modal data, the establishment of correlations between consumer genetic data and product ingredients are the main obstacles encountered today. Determining to settle such obstacles, a personalised recommendation expert system for selecting optimised skin-health product within the category based upon genetic phenotypes for each consumer was introduced in this article. Random Forests were implemented to achieve automatic product categorisation, the performance discussed and compared with SVM and Logistic Regression. Lastly, categorised skin-health product suggestion was made with an optimised recommendation model based on associated genetic phenotype information. Potential changes (up to 71.0% more phenotypic relevant ingredients) from experiments using real product data were demonstrated and compared with imitated cases of real-life human selections.

Closed loop neuromodulation, where the stimulation is controlled autonomously based on physiological events, has been more effective than open loop techniques. In the few existing closed loop implementations which have a feedback, indirect non-neurophysiological biomarkers have been typically used (e.g. heart rate, stomach distension). Although these biomarkers enable automatic initiation of neural stimulation, they do not enable intelligent control of stimulation dosage. In this paper, we present a novel closed loop neuromodulation System-on-Chip (SoC) based on a dual signal mode that is detecting both electrical and chemical signatures of neural activity. We use vagus nerve stimulation (VNS) as a design case here. Vagal chemical (pH) signal is detected and used for initiating VNS and vagal compound nerve action potential (CNAP) signals are used to determine the stimulation dosage and pattern. Although we used the paradigm of appetite control and neurometabolic therapies for developing the algorithms for neurostimulation control, the SoC described here can be utilised for other types of closed loop neuromodulation implants.

A trapped charge compensation scheme for ISFET based translinear circuits is presented, as part of a system for prediction of cancer risk, based on DNA methylation. Each pixel is able to measure a DNA methylation ratio through pH-based measurements and by using in-pixel comparison to a tunable threshold, to output a result which indicates percentage of methylation used as a cancer score. The developed system was designed in a 0.35 μm CMOS technology and uses a novel trapped charge compensation scheme for ISFETs used in translinear circuits. The output scheme was able to compensate trapped charge of up to 380mV, with a ratio error below 5%, in a range of ratios between 50% and 80% which is generated from pH-based DNA methylation reactions.

An integrated circuit for real-time, simultaneous recording of electrical and chemical(pH) signatures of neural activity is presented. It consists of six recording channels, three for electrical and three for chemical signals. Each channel has a low-noise amplifier which utilizes a new and optimized technique of flicker noise suppression. Our approach is based on a modified switched bias current technique. Both electrical and chemical amplifiers use the same circuit topology and have a common footprint, but the type of amplifier is reconfigured by controlling the bias current, which controls the bandwidth of the amplifier. The chip was fabricated using an AMS 0.35μm and four metal double poly CMOS technology. Measured noise reduction depends on the switching frequency. Bench tests have shown that our technique achieves up to 60% intrinsic 1/f noise suppression by determining an optimal switching frequency, without additional circuit complexity or an increase in transistor and chip area. The amplifier was designed to exhibit a 60 dB closed loop gain for electrical neural signals, and a 20 dB closed loop gain neurochemical signals. Each channel within the design occupied an area of 3.66mm2. This circuit design will be used as an integrated circuit for a real-time bimodal recording of neural activity for closed-loop neuromodulation therapies.

We demonstrate a novel custom designed multichannel amplifier for simultaneous electrical and chemical neural signal recording. The demonstration platform includes the chip, a dedicated printed circuit board and a Graphical User Interface (GUI). The amplifiers are low-noise, low-power, based on switching bias technique for reducing the flicker noise. This allows for much improved sensitivity for both chemical and low-frequency electrical signals. The demonstration is based on externally generated signals derived from our experiments on vagus nerve and uses a Data Acquisition (DAQ) instrumentation, which also outputs a broad spectrum signal to aid the visitor's experience. The GUI allows interaction with the amplifiers and adjustment of parameters such as switching frequency, demonstrating the implemented technique which is a physics driven fundamental approach to noise suppression.

OBJECTIVE: Vagus Nerve Stimulation (VNS) has shown great promise as a potential therapy for a number of conditions, such as epilepsy, depression and for Neurometabolic Therapies, especially for treating obesity. The objective of this study was to characterize the left ventral subdiaphragmatic gastric trunk of vagus nerve (SubDiaGVN) and to analyze the influence of intravenous injection of gut hormone cholecystokinin octapeptide (CCK-8) on compound nerve action potential (CNAP) observed on the same branch, with the aim of understanding the impact of hormones on VNS and incorporating the methods and results into closed loop implant design. METHODS: The cervical region of the left vagus nerve (CerVN) of male Wistar rats was stimulated with electric current and the elicited CNAPs were recorded on the SubDiaGVN under four different conditions: Control (no injection), Saline, CCK1 (100[Formula: see text]pmol/kg) and CCK2 (1000[Formula: see text]pmol/kg) injections. RESULTS: We identified the presence of A[Formula: see text], B, C1, C2, C3 and C4 fibers with their respective velocity ranges. Intravenous administration of CCK in vivo results in selective, statistically significant reduction of CNAP components originating from A and B fibers, but with no discernible effect on the C fibers in [Formula: see text] animals. The affected CNAP components exhibit statistically significant ([Formula: see text] and [Formula: see text]) higher normalized stimulation thresholds. CONCLUSION: This approach of characterizing the vagus nerve can be used in closed loop systems to determine when to initiate VNS and also to tune the stimulation dose, which is patient-specific and changes over time.

We demonstrate a diagnostics platform which integrates an ISFET array and a temperature control loop for isothermal DNA detection. The controller maintains a temperature of 63°C to perform nucleic acid amplification which is detected by the on-chip sensors. The 32×32 ISFET array is first calibrated to cancel trapped charge and then measures the change in the pH of the reaction. The sensor data is sent to a microcontroller and the reaction is monitored in real-time using a MATLAB interface. Experiments confirm a change of 0.9 pH when tested for the presence of RNA associated with the Zika virus.

This paper presents a pH-based System-on-Chip DNA methylation quantification platform for real time monitoring of DNA methylation ratio in target genes. The architecture forms a novel autonomous system, capable of providing diagnostic information on the progression of a disease, notably cancer. The system is equipped with drift and trapped charge compensation schemes based on differential measurements and an auto-calibration algorithm. The simulated system in 0.35μm CMOS technology achieves a power consumption of 0.997mW, with a DNA methylation ratio output sensitivity of 0.1%. The ISFET-based detection platform occupies a total of 901μm2and allows the calculation of DNA methylation ratio in pH-monitored DNA methylation based reactions.

This paper presents an ISFET-based front-end to detect DNA homopolymerisms in ion-semiconductor sequencing. This is realised using a novel ISFET-based switched current integrator which provides discrete output levels proportional to the number of nucleotides incorporated by integrating signals from DNA polymerase reactions in real time. The output response is maintained for noise comparable to the input signal at 0.01pH peak to peak. The proposed circuit has a gain of 2.4μA/pH, σ ± 50nA at 5Hz sampling frequency and 1μA bias current.

People with type 1 diabetes (T1D) rely on exogenous insulin in order to bring blood glucose levels back to healthy levels after a meal. The amount of bolus insulin needed depends on various parameters and recent research has been focused on providing decision support for calculating clinically safe insulin doses. In this demonstration we present a mobile `Advanced Bolus Calculator for Diabetes' for insulin dosing decision support and its operation and notification service through a connected smartwatch. The smartwatch can be used to display glucose information, log diabetes related events and request insulin dose recommendations.

This paper presents the architecture and initial usability results of an advanced insulin bolus calculator for diabetes (ABC4D), which provides personalized insulin recommendations for people with diabetes by differentiating between various diabetes scenarios and automatically adjusting its parameters over time. The proposed platform comprises two main components: a smartphone-based patient platform allowing manual input of glucose and variables affecting blood glucose levels (e.g., meal carbohydrate content and exercise) and providing real-time insulin bolus recommendations; and a clinical revision platform to supervise the automatic adaptations of the bolus calculator parameters. The system implements a previously in silico validated bolus calculator algorithm based on case-based reasoning, which uses information from similar past events (i.e., cases) to suggest improved personalized insulin bolus recommendations and automatically learns from new events. Usability of ABC4D was assessed by analyzing the system usage at the end of a six-week pilot study (n = 10). Further feedback on the use of ABC4D has been obtained from each participant at the end of the study from a usability questionnaire. On average, each participant requested 115 ± 21 insulin recommendations, of which 103 ± 28 (90%) were accepted. The clinical revision software proposed a total of 754 case revisions, where 723 (96%) adaptations were approved by a clinical expert and updated in the patient platform.

This paper presents an advanced insulin bolus advisor for people with diabetes on multiple daily injections or insulin pump therapy. The proposed system, which runs on a smartphone, keeps the simplicity of a standard bolus calculator while enhancing its performance by providing more adaptability and flexibility. This is achieved by means of applying a retrospective optimization of the insulin bolus therapy using a novel combination of run-to-run (R2R) that uses intermittent continuous glucose monitoring data, and case-based reasoning (CBR). The validity of the proposed approach has been proven by in-silico studies using the FDA-accepted UVa-Padova type 1 diabetes simulator. Tests under more realistic in-silico scenarios are achieved by updating the simulator to emulate intrasubject insulin sensitivity variations and uncertainty in the capillarity measurements and carbohydrate intake. The CBR(R2R) algorithm performed well in simulations by significantly reducing the mean blood glucose, increasing the time in euglycemia and completely eliminating hypoglycaemia. Finally, compared to an R2R stand-alone version of the algorithm, the CBR(R2R) algorithm performed better in both adults and adolescent populations, proving the benefit of the utilization of CBR. In particular, the mean blood glucose improved from 166 ± 39 to 150 ± 16 in the adult populations (p = 0.03) and from 167 ± 25 to 162 ± 23 in the adolescent population (p = 0.06). In addition, CBR(R2R) was able to completely eliminate hypoglycaemia, while the R2R alone was not able to do it in the adolescent population.

This paper presents the concept of a ratiometric approach for DNA methylation detection using the “Methylation Cell” for the indication of epigenetic abnormalities related to cancer. The “Methylation Cell” allows real-time detection of pH signals resulting from DNA based reactions using ISFET sensors, performing continuous computation of the ratio of DNA methylation, giving a discrete output signal when DNA methylation exceeds a certain predefined percentage. Fabricated in a typical 0.35μm CMOS process, it uses current-mode translinear circuits to perform computation in low power. Experimental results are presented, demonstrating its capabilities through an integration in a Lab-on-Chip (LoC) set-up using a microfluidic assembly.

This paper presents a novel scalable readout-converter operating in weak inversion with a least significant bit resolution of 0.015pH change. The readout-converter eliminates the effect of temperature on measurements and suppresses the influence of sensing membrane buffer capacity as well as the transistor slope factor variation when in weak inversion. With the ISFET floating-gate resetting, there is no limit on dynamic range while maintaining its linearity. The system is scalable for higher resolutions and ranges without any compromise on performance. While the readout-converter can be used separately, a reference pixel is used here to eliminate the effect of any possible common mode signals in measurements with a common mode rejection ratio of 83.5dB. The system operates in continuous time and does not require any clock signal.

The objective of any cell culturing platform is to decipher the in vivo functionality of native tissue in order to deliver reliable cell models for disease and pharmacological studies and eventually in patient-specific tissue engineering. We present a new perspective in lab-on-chip implementations for cell culturing, emphasizing on a versatile technology for cell micropatterning that can integrate electrical and pH monitoring modalities to record extracellular activity. We employ Parylene C, a highly biocompatible material, as a flexible culture substrate that controls the cellular microtopography and promotes a more in vivo-like morphology of neonatal rat ventricular myocytes. Moreover, we transfer the patterning technology on commercially available Multi-Electrode arrays to highlight the potential of integration with products customly used for extracellular electrical recordings. Finally, we implement flexible Parylene sensors for spatiotemporal pH monitoring, using the material both as a support medium and as a sensing membrane. Integration of these three attributes may deliver a compact solution with high scientific and commercial impact.

Short-term synaptic plasticity (STP) is a mechanism identified in brain systems according to which the effective connection strength (synaptic strength) between two neurons varies dynamically with recent communication history. As a consequence, the amplitude of the post-synaptic potential in response to a single pre-synaptic event, so-called “spike”, may increase (short-term facilitation) or decrease (short-term depression) with consecutive presynaptic stimulation. However, in contrast to Long-term Synaptic plasticity, these changes are temporary and are typically restored in the absence of input. Interestingly, however, a single neuron which receives input via both facilitating and depressing synapses has improved discrimination capability, distinguishing, for instance, between a sequence of events and a sequence of the same events presented in the reversed order. We, therefore, studied the memory mechanisms in emerging non-CMOS devices with a view to application in temporal pattern recognition and detection, inspired by the STP mechanisms. In particular, we demonstrate that memristors can exhibit a resembling behavior to STP due to an inherent volatility and hysteresis. When stimulated by closely spaced pulse waves, the conductance of the device decreases similar to what a depressing synapse would do if presented with consecutive pre-synaptic spikes. This work paves the way for employing memristors in solving spatio-temporal sequence learning problems.

In-pixel differential measurement with calibration for chemical reaction occurrence detection, particularly for pH-based Single Nucleotide Polymorphism (SNP) detection and genotyping arrays is presented. The proposed work adjusts the offset of upto 130mV between the ISFETs and the REFET in a calibration step and cancels out common mode noise by differential pairs with a 63.5dB CMRR. Conventionally in such arrays Ion-sensitive Field-effect Transistors were used as sensors with interface circuitry, requiring conversion of the signal prior to processing. In this system they form part of the conditioning circuitry, improving the signal-to-noise ratio and easing the design constraints of intelligent large scale system-on-chips.

This paper describes a novel integrated electrode interface for multi-polar stimulation of multi-electrode arrays. This interface allows for simultaneous stimulation using multiple electrodes configured as source or sink with different phase and amplitudes in order to perform field shaping inside the tissue. The system is designed in an high voltage 0.18 μm CMOS process with 8 channels. It features an output voltage swing of 16V and current up to 0.5mA for electrode impedences of up to 30kΩ which is suitable for cuff and cortical grid arrays. This electrode interface comprise a digital module which stores stimulation settings and operates the different electrode channels. Here we present the full system architecture and simulation results.

This paper introduces a CMOS based system that has been designed to allow parallel comparison of fragmented DNA sequences for on-chip assembly. The compatibility of different existing PC-based algorithms for implementation in CMOS is compared and the overlap-layout-consensus approach is found to be the most suitable one. The designed system comprises a scalable processing array capable of parallel computation, which allows identification of overlaps in DNA fragments in addition to error tolerance through dynamic programming. Analysis shows that there is a “pixel area vs computation time” trade-off when implementing such a parallel architecture. Results from a hypothetical assembly confirm good overlap detection and error tolerance, with up to 94% similarity in the detected overlaps, when the error is as much as 10%.

The ISFET chemical current conveyor (CCCII+) was first reported by the authors at ISCAS 2008. In this paper a new application of the CCCII+ is presented, namely to provide a direct means of measuring cell and bacterial activity. The measurement system is based on an array of unmodified ISFET CCCII+ sensors each of which when operated in weak inversion gives an output corresponding to the time derivative of hydrogen ions. Combining each of the CCCII+ time derivative outputs in the array using the analog computational versatility of the CCCII+ current output stage provides a signal corresponding to cell and bacterial activity. The design has been fully simulated using Triple-well 0.18-μm CMOS technology and the results presented in this paper show that a viable system for direct measurement of cell and bacterial activity can be obtain, further confirming the utility of the CCCII+ for another biochemical sensing application.

This preliminary study reports on the combined use of wireless accelerometers and wireless EMG sensors for monitoring walking patterns. The sensor data was analyzed in frequency domain through FFT, PSD and time-frequency spectrogram analysis. Accelerometer spectra was found to shift towards lower frequencies (;50 Hz) during asymmetric walking. Median frequency was used to quantify the spectral shifts. The combined wireless accelerometer/EMG system showed potential for discrimination between the normal and asymmetric walking.

This paper presents a CMOS-based lab-on-chip platform for combined magnetic manipulation and opto-chemical sensing. Within each pixel, a Programmable Gate (PG) ISFET chemical sensor is combined with an active pixel sensor, and is encompassed within an inductive coil. The integrated pixel is tesselated to form an 8 × 8 array. Fabricated in a commercially available 0.35 μm CMOS technology, the system can be used for simultaneous optical imaging and pH sensing, and includes auto- calibration mechanisms for eliminating sensor non-idealities. A spatiotemporal magnetic field pattern generator has also been embedded for micro-scale magnetic manipulation. Controlled via a MATLAB based graphical user interface, the system achieves real time data acquisition at 6 fps, a pH sensitivity of 57 mV/pH and demonstrates magnetic manipulation of micro-beads.

In this paper, we present a novel, ultra-long-time-constant analogue integrator for a PID controller in Lab-on-Chip (LOC) applications. A time constant of up to 5 seconds is achievable using a capacitance of only 18pF by exploiting transconductance reduction techniques involving current splitting and gm-attenuated OTA. Additionally, this architecture provides the ability to digitally tune the time constant from 200ms to 5s with 4-bit programmability. The design achieves a temperature dependance of 1.2% over the range from 0°C to 100°C with micropower consumption.

This paper describes a mixed signal subsystem for the inductive transfer of power and data to a fully-implantable medical device. The design includes circuits for the inductive power recovery and energy storage (charging), in addition to data recovery and demodulation. The data link is used to upload (at a data rate of up to 180Kbps) calibration and configuration data to the implanted device and integrates both error detection and correction on the recovered bitstream. The system incorporates an implanted Li-Ion micro-battery with supporting charging hardware to provide an uninterrupted power supply for autonomous deployment. This is to provide continuous operation without the requirement for an externally worn unit and additionally ensures registry (i.e. patient calibration) settings are maintained. The circuit has been implemented in a commercially available 0.35µm CMOS technology without requiring high-voltage device options.

In this paper, a novel chemical sensor system utilizing an Ion-Sensitive Field Effect Transistor (ISFET) for pH measurement is presented. Compared to other interface circuits, this system uses auto-zero amplifiers with a pingpong control scheme and array of Programmable-Gate Ion-Sensitive Field Effect Transistor (PG-ISFET). By feedback controlling the programable gates of ISFETs, the intrinsic sensor offset can be compensated for uniformly. Furthermore the chemical signal sensitivity can be enhanced due to the feedback system on the sensing node. A pingpong structure and operation protocol has been developed to realize the circuit, reducing the error and achieve continuous measurement. This system has been designed and fabricated in AMS 0.35μm, to compensate for a threshold voltage variation of ±5V and enhance the pH sensitivity to 100mV/pH.

Recently we have completed a system level modelling of the G-protein coupled cascade in Drosophila photoreceptors that converts single photons into transient electrical responses. Many interesting properties were revealed including the underlying mechanisms by which the system generates high quantum efficiency, single photon responses, huge signal amplification and fast recovery, as well as light adaptation to 11 orders of magnitude of light intensities. Now we would like to use this enzymatic cascade model as a design blueprint for a cascade of analogue amplifiers. These circuits can then be used in very sensitive sensory systems such as imaging chips or uncooled infrared detectors and cameras. This paper represents the first phase in this quest, which is establishing the link between the phototransduction model and an engineering design, before we move on to the detailed circuit design realization (phase two).

We report on the fabrication and electrical characterisation of memristors with TiO2/TiO2+xactive layer. This active layer is deposited at room temperature with RF-sputtering and consists of two sub-layers, the top one of which contains excess oxygen atoms. Electrical characterisation of the devices demonstrates similar switching characteristics as previously reported for nano-scale memristors with TiO2/TiO2-xactive cores.

The use of inductors operating in the radio frequency region of 10 MHz to 1 GHz for detection of a change in concentration of ionic species present in a liquid sample is reported here. Liquid samples under constant ionic strength and varying pH along with constant pH and varying ionic strength were used for testing purposes. Y-parameters were extracted and used for data analysis. A change of 15.3 MHz in the resonant frequency of the inductor under varying pH and a change of 20MHz under the constant pH condition was obtained. The results from this study show that inductors can be employed in designing simple, scalable and integrable sensing systems to perform label free analysis without the need for surface activation or perturbing the system under study. This design has the potential in being used for certain applications like monitoring DNA hybridization or gastric juice.

This paper presents an integrated silicon pancreatic islet to be used for the control algorithm of an artificial pancreas. The system replicates the temporal behaviour of the electrophysiology of the alpha and beta cells which are located in the islet of Langerhans in the pancreas, generating signals which can be used to infuse the two regulatory hormones, glucagon and insulin, used for tight glycemic control. The silicon islet can be easily programmed to choose between multiple bursting periods and can thus be tailored to each patients insulin sensitivity. Designed in a 0.35μm process, the system is fully integrated with an on-chip digitally tuned oscillator to drive the system and an algorithmic mode A/D converter to interface to an electrochemical glucose sensor.

Exploding health care demands and costs of aging and stressed populations necessitate the use of more in-home monitoring and personalized health care. Electronics hold great promise to improve the quality and reduce the cost of health care. The speakers in this hot topic session will discuss the field of health care electronics from all aspects. First, the market of health care electronics is described, and realities, trends and hypes will be pointed out. The second presentation describes the engineering challenges in ultra low-power disposable electronics for wireless body sensor applications. Both the sensor aspects, the related signal processing, and business models will be discussed. The third presentation talks about embedded bio-stimulation applications in cochlea implants, thereby highlighting the design challenges in terms of power consumption and extreme reliability of these devices. The final presentation discusses the application of brain stimulation and recording with respect to artifact reduction and field steering, and describes aspects of the modeling and design strategy. In this way, this hot-topic session offers the attendees a complete picture of the field of health-care electronics, ranging from the business to the technological and design aspects.

This paper describes an ASIC developed as part of a neural prosthesis to restore balance to individuals with a dysfunctional vestibular end-organ. The device interfaces with inertia sensors; sensing acceleration in five degrees of freedom (three radial and two linear axis), and then conditions, processes and converts the signals to provide the artificial stimulus to the vestibulocochlear nerve. The IC described herein has been realised as part of a board-level solution, also including the sensors, power source and DC blocking capacitors. It is envisaged that this can be later implemented in a system-in-package (SiP) form to provide a totally implantable solution. We describe the design and implementation of the integrated circuit in a standard 0.35 mum CMOS technology.

This paper presents a novel CMOS based PG-ISFET (programmable gate-ion sensitive field effect transistor) and readout for compensation of large threshold voltages observed with ISFETs fabricated in a standard CMOS process. The proposed device uses a capacitively coupled floating gate to allow tunability of its operating point to counteract the presence of trapped charge, thus allowing operation within a tolerable gate voltage range. By using feedback, an adaptive readout has been designed, which allows integration of the device as well as cancellation of reduced sensitivity due to extra capacitance of the programmable gate. Fabricated in a 0.35 mum CMOS process, the device can compensate for a variation of up to 14.2 V for 1 muA using a 3.3 V supply.

This work is an investigation on the large threshold voltage variation exhibited in CMOS based ISFETs. This irregularity is thoroughly examined and is identified to be caused by mobile ionic charge that is induced in the sensing membrane when the membrane is in contact with the ionic-solution. This auxiliary charge increments the effective capacitance of the sensing membrane, causing irregular shifts in the characteristics of the devices. Several methods for overcoming this issue are addressed.

This paper presents an analogue VLSI circuit which implements three particular receptors of the chemical synapse: AMPA, GABAAand GABAB. The dynamics of postsynaptic receptor is implemented in CMOS current mode circuits. Furthermore with the implementation of chemical sensors in CMOS technology, the possibility of realising complete synapses which model the non-linear electrochemical behaviour of the synapse is now feasible.

This paper presents a novel readout circuit for a pH sensitive programmable-gate ion-sensitive field effect transistor (PG-ISFET) to overcome bias issues due to threshold voltage variation and increase output-referred sensitivity. Compared to other commonly-used ISFET readouts, this circuit uses two extra programmable nodes which are driven by a feedback configuration. Using the device in a source follower configuration, one node is used to evaluate and cancel the offset of the intrinsic device while the other tracks and amplifies changes in pH. A sample and hold protocol has been developed to minimize the leakage effects and improve the pH sensing range. The system has been designed and fabricated in AMS 0.35 mum, to compensate for a threshold voltage variation of plusmn10.5 V and provide a pH sensitivity of 200 mV/pH.

This papers presents a front-end circuit for interfacing to differential capacitive sensors, including certain micro- electromechanical systems (MEMS). The system combines a self- resetting, biphasic integrator with a difference timer, producing a word parallel output representing the differential capacitance. The measurable capacitance range is tunable by means of an input current bias and system clock frequency. For an input bias of lOnA and system clock of 128 KHz, the measurable capacitance range is +/-5 pF (to 8 bit resolution) consuming below 26 muW total system power.

This paper describes a novel partial-current-steering stimulation drive for implantable neural prosthetics. The drive hardware momentarily delivers a charge-balanced asymmetric stimulus to a dummy load before steering towards the stimulation electrodes. In this fashion, power is conserved whilst still gaining from the benefits of current steering. The circuit has been designed to be digitally programmable as part of an implantable vestibular prosthesis. The hardware has been implemented in AMS 0.35 mum 2P4M CMOS technology.

A CMOS based ion sensitive chemical imager chip is presented for real time spatio- temporal monitoring of chemical activity. Ion-sensitive field effect transistors (ISFETs) implemented on an unmodified process (AMS 0.35 um) are used as the chemical input to the analogue circuits. A 3 x 11 array has been designed and fabricated for monitoring applications such as cell metabolism and growth. Chemical sensor information is encoded using integrate and fire neurons with address event representation (AER) used to fan out the data. Global adaptive biasing of pixels is used to conserve power and allow automatic functionality in changing buffer concentrations.

This demonstration presents the first bio-inspired approach to glucose management of Type-I diabetic patients using a real-time closed-loop insulin delivery system. The delivery system consists of a glucose biosensor, used with the silicon beta-cell to drive a motorized pump. Glucose-induced bursting of beta cells in the pancreas are used to control the insulin secretion in our bodies. A low-power implementation of these metabolic cells in silicon is achieved resulting in efficient glucose control.

This paper presents a CMOS image sensor intended for a novel optoelectronic retinal prosthesis. Each pixel acts as an independent oscillator, whose frequency is controlled by the incident light intensity. A 9 x 9 pixel array was fabricated in AMS 0.35 mum CMOS Opto Process. Each pixel's area amounts to 25600 mum2with the array occupying 2.89 mm2. Measured results show that the sensor achieves an overall dynamic range of 143 dB (from 34 mHz to 502 KHz) when the controlling bias current value varies from 0.2 pA to 5 muA respectively. Similarly, when the incident light intensity varies from 0.35 muW/cm2to 3.5 mW/cm2, the pixel's oscillation frequency changes from 0.24 Hz to 2.2 KHz respectively. This performance suffices for the optical stimulation of photosensitized RGCs.

The concept of a chemical current-conveyor, or CCCII+, is presented. The device is primarily intended for pH read-out. At its core is an embedded CMOS current-conveyor, type-II, with two ISFETs in the input stage. The CCCII+ is extremely versatile and can easily be configured to give an output voltage, or current, directly proportional to pH value.

We present an adaptive, current-mode analogue neuron circuit (Boahen, 1996), which adapts its spiking output frequency and pulse width relative to the magnitude and vector of the computation of its input nodes. By modulating the pulse width to represent the output vector signed double byte data transfer protocol along a single channel is enabled: doubling output data bandwidth. This artificial neuron consists of a four quadrant current subtraction circuit, a low power current comparator, and an adaptive spiking output circuit, implementing novel, distributed, focal plane image processing, enabling real-time operation. Each cell consumes 15 pico-joules, and takes 20 milliseconds to process an output decision: allowing it to be integrated within large scale arrays. This biologically inspired circuit imitates the spatial image processing at the Bipolar, Ganglion cell nodes of the retina, and has used these cells' functions to define its processing algorithms.

This paper presents novel fractional-rate architectures for FM-to-digital Δ-Σ modulation (FDSM) converters. The adoption of lower clock frequencies translates into reduction in power consumption. The general approach to fractional-rate FDSM architecture is introduced together with a novel two-flip-flop half-rate architecture reducing power consumption by 50%. System theory and supporting simulation results in the ST 90nm CMOS process are presented.

This demonstrator presents an ultra low power mixed-signal implementation of a cochlear prosthesis system. A laptop PC provides an audio stimulus to the cochlear chip. A microcontroller on the demonstrator board monitors the output channels of the chip and returns these to the PC to be displayed as a spectrogram. The audiological settings of the implant chip are controlled via a GUI running on the PC.

This paper proposes a miniaturized optoelectronic system suitable for the optical stimulation of genetically engineered retinal ganglion cells (RGCs) and focuses upon the synthesis and performance characteristics of a key circuit component needed for the programmable stimulator chip of the system: a wide tuning range voltage-controlled oscillator (VCO). The paper elaborates the synthesis and performance of a novel OTA structure which is used for the realisation of the needed wide tuning range VCO. The VCO has been designed and fabricated in AMS 0.35μm CMOS technology. Simulation results reveal a tuning range of more than 6 decades (70mHz to 0.2MHz).

This paper presents a novel interface for ion-sensitive field effect transistors (ISFET) in which operation at a fixed electrical bias is achieved by voltage clamping. The chosen topology provides pH-dependent current and voltage output signals to drive an appropriate output stage. The circuit can be operated in either strong or weak inversion, depending on the requirements of the application with a pseudo-differential ISFET-REFET topology to allow use of an on-chip reference electrode. Simulation results are shown herein for single-ended and differential implementations. For a single-ended front-end with 1nA bias current, the strong inversion implementation at 2.5V supply has a power consumption of 0.185mW at pH 7 and the weak inversion implementation at 1.5V supply has a power consumption of 13nW at pH 7. The circuit and ISFET-REFET pair have been fabricated in the UMC 0.25μm CMOS technology.

this paper describes the development of a novel physiological platform aiming at the on-line, in-situ, multi-parametric, multi-channel, physicochemical, spatiotemporal monitoring of stem cell cultures. The three main operational components are: a) miniaturized electro-chemical (bio)sensors; b) real-time data acquisition system tailored to the sensor interfacing requirements and c) the bioreactor within which the stem cells are growing. It is believed that the totality of the platform constitutes a novel technological modality for the bioprocess engineer and can contribute to the harnessing of the potential of stem cells by enabling and/or facilitating the identification and classification of their proliferation and differentiation paths. This paper places emphasis upon the electronic hardware and software parts of the proposed "Intelligent Stem Cell Culture Systems" (ISCCS). The hardware of the measurement system is organized into three types of modules each capable of 16-channel real-time data acquisition. The three types of modules correspond to potentiometric, amperometric and ohmic types of sensors. The platform can support an arbitrary combination of such modules up to the number of eight, thus enabling the realization of a flexible and versatile system capable of providing up to 128 data acquisition channels for the physiological monitoring of the stem cell culture process. In other words, the measurement equipment can be configured to interface with up to eight different types of sensors each sensor monitoring a physiological quantity of relevance (e.g. glucose, lactate, ammonia, oxygen, pH etc.

This paper presents the novel concept of adopting bit stream processing at the output stage of a parallel Delta-Sigma FM-to-digital converter. Addition of bit streams by interleaving allows speed to be traded with circuit complexity, chip area and power consumption. The conventional implementation employing a summing tree is substituted by a simple and compact multiplexing tree. The inherent simplicity renders the converter easy to reconfigure. System theory and simulation results are presented

In this work we present an adaptable foveating vision chip. This chip has no physical foveation; all its pixels are in the same uniform pattern. However with a given input signal it is possible to define areas of the chip which act as a fovea, returning high spatial resolution. The surrounding peripheral vision acts to return lower spatial resolution but much higher temporal resolution. Our chip is therefore able to achieve full spatial resolution via scanning of the fovea across the visual field. This operation is analogous to the functioning of the human eye. In the human eye however, the limitations of biology enforce a fixed fovea, while the optomechanics are highly efficient. In our structure, we acknowledge the limitations of physical optomechanics but use the advantages of silicon processing to achieve dynamic foveation. This paper discusses the algorithm, its implementation and simulated results describing its responses and power consumption

A hybrid vision chip is presented for real-time object-based processing for tasks such as positioning and sizing of enclosed objects. This system presents the first artificial silicon retina capable of position and size determination of multiple objects in true parallel fashion. Based on a novel distributed algorithm, this approach uses the input image to enclose a feedback loop to realise a data-driven pulsating action. The fabricated device is shown to achieve a computation-efficiency of at least 725 million instructions per second per milliwatt and capable of processing up to 2000 frames per second

In this paper we present a biologically inspired circuit capable of implementing the membrane potential behaviour of the pancreatic beta cell. This is important as it is correlated with insulin release which is required for regulating blood glucose at a healthy level. Dysfunction of these cells is the main cause of various forms of diabetes. A nano-power glucose biosensor is used to provide a chemical input to the silicon based beta-cell. Measured results of up to 25 mM of glucose concentration are shown, as well as bursting behaviour from the circuit which matches well with physiological results

This paper introduces an automated circuit design system for the evolution and subsequent invention of CMOS amplifiers. The proposed system relies on a mix of genetic programming and a new topology-independent design optimization method referred to as current-flow analysis. Genetic programming evolves new circuit topologies from the collection of primitive devices and basic building blocks. Current-flow analysis screens and corrects circuits using topology-independent design rules. Experimental results show a promising improvement on the design of operational amplifiers that make the automated analog design environment using genetic programming a lot more practical.

A comparative study between switched-capacitors (SC) and switched-current (SI), using speed, power and signal-to-noise-ratio as performance vectors, is presented. To no one's surprise, the analysis suggests that SC outperforms SI considerably for the past and present technologies. However, as processing heads towards lower power supply voltages the performance of SC falls steadily while that of SI remains almost constant. Ultimately, there is a fundamental tendency for the performance gap between SC and SI to steadily reduce and SI performance is expected to match and surpass that of SC during the course of the next decade.

Techniques to enhance the linearity of switched-capacitor circuits utilising MOSFET gate capacitance are presented. Practical aspects limiting accuracy are investigated. With appropriate choice of capacitor technique, all types of switched-capacitor circuit become possible in standard digital CMOS processes. A sample-and-hold amplifier employing the proposed techniques was designed using a standard 0.6 /spl mu/m digital CMOS process, and verified with simulation results to demonstrate significant linearity enhancement.

A four-channel common-emitter (CE) transimpedance amplifier (TIA) array for optical receiver applications is studied in terms of gain, bandwidth, noise, and crosstalk between adjacent channels. The substrate crosstalk is analyzed by using a proposed lumped-element model. HSPICE simulations were conducted by using a 0.8 /spl mu/m Si/SiGe HBT technology, confirming the small signal analysis and the lumped model for crosstalk analysis. A test chip was fabricated and the measured results will be available shortly.

The feasibility of extending a class AB SI configuration to two-step sampling switched-currents is demonstrated. Particular emphasis is given to observing its practical benefits and possibility of reducing supply voltage requirement in comparison to class A S/sup 2/I. As indicated by both theoretical analysis and simulations of memory cells, the use of class AB techniques can enable S/sup 2/I circuits to operate at a lower supply voltage (as low as 2.4 V for a 5 V CMOS process with V/sub t/=0.8 V) while exhibiting approximately 3.5 times figure-of-merit improvement (including SNR, speed and power) over the conventional class A S/sup 2/I approach.

A novel first order sigma-delta architecture, which also shapes the nonlinearity of the DAC is proposed. Unlike other proposed solutions this topology consists of multibit quantisation noise only so offers enhanced stability and higher-order noise-shaping at the expense of a highly linear analog differentiator. The paper discusses some aspects of a practical realisation and possible extensions to higher order noise-shaping.

This paper describes a new first and second-order delta-sigma modulator (DSM) concept where the first integrator is extracted and implemented by a FM oscillator with the modulating signal as the input. The result is a simple DSM with no need for DACs, allowing straightforward multi-bit quantization. Without the FM oscillator, the modulator becomes a F/D converter with delta-sigma noise shaping.

This article presents a new concept for concurrent self test of switched current circuits based on S/sup 2/I cells as basic building blocks. Six different transistor faults were modelled and the ability to detect the various fault-situations was studied. The fault detection system presented was applied to a simple switched-current integrator in which all the different faults were introduced sequentially in all transistors. The fault coverage was derived and the result shows that a powerful system for detection of transistor faults in an analogue sampled-data system can be realised with a minimum of additional overhead circuitry.

A fully differential operational amplifier operating within a 2 V power supply range is presented. The amplifier was designed using 1.2 /spl mu/m CMOS technology and uses a novel multi-regulation technique to provide a high open loop gain without degrading the open loop phase response. Fully differential techniques are employed so that the amplifier is able to operate over a larger input voltage range. The output voltage swing extends to be within 0.2 V of the lower and upper power supply rails.

A new technique for very fast analogue discrete-time processing is presented. It uses BiCMOS technology and combines the high speed available from bipolar transistors with the storage capability of MOS devices. The technique is based on (nearly) linear building blocks and can equally easily be configured for either current-mode or voltage-mode processing. SPICE simulations on a realistic circuit indicate that a sampling frequency of 2,50 MHz can be achieved in a 0.8 /spl mu/m-BiCMOS process with a maximum NPN transistor f/sub T/ of 10 GHz.

The active-R filter technique attracted much interest in the 1970s as a method for implementing continuous-time analog filters. This technique used the internal capacitance of a voltage op-amp to derive the filter transfer function, and showed potential advantages in terms of high-frequency performance and IC integration. However the main disadvantages of the technique were found to be the strong temperature-dependence of the filter centre-frequency, and the limited dynamic range due to op-amp slew rate limitations. By applying the active-R technique to current-feedback op-amps, it is found that these major disadvantages are overcome. Thus the active-R technique applied to current-feedback op-amps seems a very promising method for the implementation of high-frequency integrated analog filter.

For pt. I see ibid., vol. 14, no. 2, p. 218-38 (1995). This part of the paper is focused on a novel application of Qualitative Reasoning, which allows modifications of a circuit's topology to take place in cases where not all performance specifications are met. Within ISAID, this task of post-simulation circuit correction is carried out by the Circuit Corrector.>

The research presented in this paper is concerned with the automation of analog integrated circuit design and, in particular, with a description of methods and techniques employed by the ISAID design system developed at Imperial College, UK. ISAID is comprised of two modules: the circuit generator and the circuit corrector. The circuit generator is based on newly developed methods that are used to handle hierarchical generation of topologies and size MOS transistors so that the performance of designed circuits compare satisfactorily with their specifications. To avoid long design times, simulation is used only after the generation of an initial circuit topology. Simulated performances may therefore be found to differ from the required. One novel feature of the proposed methodology is that in such cases a circuit corrector is invoked to correct the initial design. The circuit corrector is essentially a novel application of qualitative reasoning, which, without iterative simulation analyses performance trade-offs, thereby selects circuit adjustments-transistor size adjustments or topological modifications-that would improve the problematic performances. Several design examples have demonstrated the benefits of the ISAID design approach.>

Low-power analogue-sampled-data (ASD) signal processing has traditionally relied on the well-known switched capacitor (SC) technique for the implementation of medical implants, hearing instruments and/or interfaces for battery operated instrumentation. In this paper recent advances in the rapidly maturing switched-current (SI) technique are reviewed with respect to their feasibility for application in novel circuit structures that set the foundations of low-power SI for biomedical signal processing (BSP) and other applications. A qualitative comparison is made between class A and AB SI cells and the mode of MOS transistor operation. The authors briefly discuss building blocks for novel continuously tuneable filtering structures that rely on transconductance-ratios rather than capacitor ratios. Biologically inspired implementations of the cochlea illustrate possible applications.>

This paper describes the theoretical basis for a design methodology which enables control of the fundamental tradeoff between speed, dynamic range, and power consumption in switched current cells. The presented methods are applied to the design of a very high dynamic range current memory cell and simulation results are given.>

In this paper, a high-speed 14-bit D/A converter based on. Binary weighted current sources is presented. A full-scale output current of 10-20 mA allows 50/spl Omega/ loads to be driven directly. Matching of small MOSFETs at the low LSB current level allows-only 5-bits accuracy. However, 14-bit accuracy is achieved by the novel architecture which uses digitally-controlled trimmable current sources and one of two self-calibration schemes to automatically adjust the current sources after power-up or when triggered by an external signal.>

A circuit design, whether on first silicon, breadboarded or PCB's will quite often fail to work first time and getting it to work is costly time-consuming, irritating and sometimes very frustrating. If the failure is inevitable, then why are more precautions not taken at the earlier stages of design? What are these mystical failure mechanisms? Human errors, simulation errors, testing errors? etc. The authors attempt to answer some of these questions.>

A new hybrid design approach for high frequency, high gain transconductors is proposed. The idea is based upon the combination of FETs and optical devices. Measured results of a high frequency high Q active filter and a high DC gain FET operational amplifier are presented, employing the optoelectronic approach.>