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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 0.35µm, to compensate for a threshold voltage variation of ±10.5V and provide a pH sensitivity of 200mV/pH.

This demonstration presents the first bio-inspired approach to glucose management of type-1 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.

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 paper introduces Chemical Bionics in which the biochemical physiology of cells in the body are implemented in VLSI to make novel bio-inspired therapeutic devices. As an example, the glucose dependant electrophysiology of the pancreatic beta cell is implemented in silicon to form a novel bio-inspired prosthetic for glucose homeostasis of Type I diabetes. For this, the Ion Sensitive Field Effect Transistor (ISFET) is shown as a suitable chemical sensing front end, which allows CMOS monolithic implementation, as well as low power weak-inversion operation.

This paper presents a batch encapsulation technique for CMOS based chemical sensors. SU-8 photoresist is employed as the encapsulant while the sensing membrane of the sensor is directly exposed to the solution. This approach is based on standard photolithographic techniques and thus can be used for processing multiple dies containing chemical sensors in a single step.

This paper presents a biologically-inspired 'silicon neural link', encompassing a neurochemical sensor array, an asynchronous artificial-neural bus and an interleaved biphasic stimulus generator. The proposed system is intended for neuroprosthetic application; employing an array of ISFET-based spiking neurons to convey measured neuronal data across a damaged neural pathway to a target stimulation site. A 48 dB dynamic range is achieved by encoding the neural signal in the time-domain, using accumulating address-events to modulate the biphasic waveform. The electrical stimulation is delivered via a bipolar electrode configuration in a continuous interleave sampling strategy. This has been implemented in a commercially available 035mum CMOS technology.

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 0.25mum CMOS technology.

A spiking chemical sensor (SCS) is presented for detection of neurogenic ion concentration associated with active nerve fibres in nerve bundles. Based on the "integrate-and-fire" circuit, the SCS uses a chemically-modified ISFET front end encoding the sense data in the spike domain. Used in an array, it provides a spatio-temporal map of chemical activity around the nerve bundle which may be relayed off chip using low power asynchronous communication hardware. The circuit is shown to be tunable to yield a linear relation with either pH or actual hydrogen ion concentration. Furthermore, its compact pixel footprint in addition to efficient use of the sensing surface, makes it ideal for use in neuro-chemical imaging.

An ISFET-based integrate and fire neuron, forming the front-end of a chemical pixel sensor, is introduced. With the sense data being encoded in the spike domain, i.e. asynchronous/continuous time and discrete value, it is directly compatible with asynchronous communication hardware, e.g. address event representation. The circuit is shown to be tunable to yield a linear relation with both pH and actual hydrogen ion concentration, with a peak power consumption of 35 muW. Furthermore, its compact pixel footprint of under 6500 mum 2 , makes it ideal for use in arrayed architectures with application in biochemical imaging

The polymer gel-magnetic resonance imaging (MRI) dosimetry technique was used to evaluate the mechanical and dose delivery accuracy in Leksell gammaknife stereotactic radiosurgery for the treatment of multiple targets. Two different polymer gel dosimeter formulations reported in the literature were prepared inhouse. A plan for the treatment of four brain metastases ( targets) was generated. It involved the delivery of four 8-mm collimator shots using different prescription isodose lines and different prescription doses for each target, keeping the maximum dose constant for all targets. A sample of each gel formulation was irradiated using a custom-made phantom with an experimental procedure capable of testing the increased nominal mechanical accuracy of stereotactic radiosurgery. The irradiated dosimeters were evaluated using a clinical 1.5 T MR imager. Result manipulation in 3D allowed for the determination of the mechanical accuracy in the delivery of each shot through the comparison of measured versus planned shot center coordinates. Dose delivery accuracy was also evaluated by comparison of maximum dose values measured at the center of each shot as well as dose distribution measurements, with corresponding treatment-planning calculations. Polymer gel dosimetry was found capable of verifying the complete chain of radiosurgery treatment in gamma-knife applications involving the irradiation of multiple targets.

Semiconductor genetics is now disrupting the field of healthcare owing to the rapid parallelization and scaling of DNA sensing using ion-sensitive field-effect transistors (ISFETs) fabricated using commercial complementary metal -oxide semiconductor technology. The enabling concept of DNA reaction monitoring introduced by Toumazou has made this a reality and we are now seeing relentless scaling with Moore's law ultimately achieving the $100 genome. In this paper, we present the next evolution of this technology through the creation of the gene-sensitive integrated cell (GSIC) for label-free real-time analysis based on ISFETs. This device is derived from the traditional metal-oxide semiconductor field-effect transistor (MOSFET) and has electrical performance identical to that of a MOSFET in a standard semiconductor process, yet is capable of incorporating DNA reaction chemistries for applications in single nucleotide polymorphism microarrays and DNA sequencing. Just as application-specific integrated circuits, which are developed in much the same way, have shaped our consumer electronics industry and modern communications and memory technology, so, too, do GSICs based on a single underlying technology principle have the capacity to transform the life science and healthcare industries.

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 $166\pm 39$ to $150\pm 16$ in the adult populations ( $p=0.03$ ) and from $167\pm 25$ to $162\pm 23$ 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.

Proposed is an ISFET readout scheme with minimum analogue components to minimise parasitic and noise effects in large-scale chemical sensing arrays. For each array pixel, a pair of complementary ISFETs shares the same floating gate in an inverter configuration. An additional electrical input is capacitively coupled to the same floating gate with a periodic reference signal input. In this way, the conventional ISFET analogue output is replaced by a chemically controlled pulse width modulated signal. Theoretical analysis and experimental results show a pulse width pH sensitivity of around 6%, of the input reference signal period, per pH. This is achieved along with ±1 V offset suppressing capability.

Presented is an overview of how semiconductor technology is now being used for early detection on therapy of disease. Specifically two areas are described, which are currently utilising CMOS technology with tremendous benefit in healthcare. The first is in genomics, whereby advances in CMOS-based ISFET technology is now allowing implementation of point-of-care diagnostic systems as well as genetic sequencing systems which are scalable, miniature and fabricated at low cost, and the second is in bioinspired prosthetics, whereby low-power CMOS-based systems can be designed to replicate biology to provide implantable and portable devices for personalised therapy of conditions such as diabetes.

This article presents a personal account of the life and scientifi c journey of Professor Piet Bergveld, the inventor and founding father of the Ion-Sensitive Field Effect Transistor (ISFET). The interview gives a unique overview of how ISFET technology has evolved over the years, and the challenges faced during the development from its initial use in neuronal sensing to the technology we see today, which has huge potential in the current era of genetic technology.

Presented is an ion-sensitive field-effect transistor (ISFET) based circuit capable of continuous analogue computation of the urea:creatinine ratio, a marker important for the prediction of pre-renal failure. The designed circuit utilises the weak-inversion of operation to derive sensor currents directly related to the urea and creatinine concentrations, as well as to implement linear division at extremely low power by using a translinear cell.

A report on the use of programmable gate-ion sensitive field effect transistors (PG-ISFETs) to form DNA-logic gates for reaction monitoring is presented. A PG-ISFET sensor is integrated with standard MOSFETs to form a chemical-inverter that switches when a chemical reaction reaches a certain threshold. By employing feedback to the electrical gate rapid switching is achieved for changes in pH as low as 0.1 units, overcoming limitations of voltage division owing to passivation capacitance of CMOS based ISFETs. Using this, DNA-logic arrays can be synthesised to carry out highly parallel chemical processing functions for applications such as DNA sequencing.

The use of hot-electron injection as a method for programming the threshold voltages of CMOS based ion-sensitive field-effect transistors (ISFETs) in standard pH buffer solution is presented. This method allows compensation of large threshold voltage variations generally seen with ISFETs fabricated in unmodified CMOS due to the presence of trapped charge, enabling operation of the device using nominal supply voltage as well as reduction of mismatch between devices when fabricating ISFET arrays. Fabricated in a 0.35 m CMOS process, threshold voltage shifts of up to 2.8 V have been achieved in a pH 7 buffer solution.

Presented is a chemical log-domain filter in which an ion sensitive field effect transistor (ISFET) is used to expand a naturally log-compressed chemical signal to derive a chemically-dependent lossy-integrator, whose gain and bandwidth are functions of ion concentration. This is used to integrate small chemical signals or have a filter adaptable to changes in chemical concentration.

A CMOS-based PG-ISFET (programmable gate-ion sensitive field effect transistor) is presented, which compensates for large threshold voltage and device mismatch observed with ISFETs fabricated in an unmodified 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 the device to operate within a tolerable gate voltage range. Fabricated in a 0.35 µm CMOS process, the device shows good weak-inversion operation for low-power chemical sensing.

The increasing prevalence of antimicrobial resistance is a serious threat to global public health. One of the most concerning trends is the rapid spread of Carbapenemase-Producing Organisms (CPO), where colistin has become the last-resort antibiotic treatment. The emergence of colistin resistance, including the spread of mobilized colistin resistance (mcr) genes, raises the possibility of untreatable bacterial infections and motivates the development of improved diagnostics for the detection of colistin-resistant organisms. This work demonstrates a rapid response for detecting the most recently reported mcr gene, mcr−9, using a portable and affordable lab-on-a-chip (LoC) platform, offering a promising alternative to conventional laboratory-based instruments such as real-time PCR (qPCR). The platform combines semiconductor technology, for non-optical real-time DNA sensing, with a smartphone application for data acquisition, visualization and cloud connectivity. This technology is enabled by using loop-mediated isothermal amplification (LAMP) as the chemistry for targeted DNA detection, by virtue of its high sensitivity, specificity, yield, and manageable temperature requirements. Here, we have developed the first LAMP assay for mcr−9 - showing high sensitivity (down to 100 genomic copies/reaction) and high specificity (no cross-reactivity with other mcr variants). This assay is demonstrated through supporting a hospital investigation where we analyzed nucleic acids extracted from 128 carbapenemase-producing bacteria isolated from clinical and screening samples and found that 41 carried mcr−9 (validated using whole genome sequencing). Average positive detection times were 6.58 ± 0.42 min when performing the experiments on a conventional qPCR instrument (n = 41). For validating the translation of the LAMP assay onto a LoC platform, a subset of the samples were tested (n = 20), showing average detection times of 6.83 ± 0.92 min for positive isolates (n = 14). All experiments detected mcr−9 in under 10 min, and both platforms showed no statistically significant difference (p-value > 0.05). When sample preparation and throughput capabilities are integrated within this LoC platform, the adoption of this technology for the rapid detection and surveillance of antimicrobial resistance genes will decrease the turnaround time for DNA detection and resistotyping, improving diagnostic capabilities, patient outcomes, and the management of infectious diseases.

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.

We present here a robust microfluidic cell perifusion device for in vitro primary tissue cell secretion studies. This system increases the sample concentration to perifusion volume ratio by an order of magnitude compared with standard multi-well plate static incubation assays. Further, this device achieves physiologically relevant flow rates, pressures, and temperature. It has been manufactured with typical machining facilities, principally drilling and milling. No specialist clean room equipment is required to replicate it. We show its capability here with hormone perifusion experiments on primary pancreatic tissue from mice. This device can increase cell secretion concentrations by up to a factor of 20, allowing for the first time the direct measurement of islet glucagon using mass spectrometry.

Over the last decade, the way people communicate with each other has been changing astonishingly. The extensive new plethora of media has given to customers more options to gather and provide information about products and services. This study attempted to identify and measure the degree to which Social Networking Sites influence people's professional lives, their social skills and work productivity and ultimately boost effectiveness. Quantitative and qualitative methodologies were used for this research. The results reveal that Social Networking Sites play an essential role in employees‟ relations with customers, that Instant Messaging (IM) services offered by Social Networking Sites can be a crucial element for organizations in disseminating information, enabling knowledge sharing, increasing productivity and promoting teamwork. It seems that customer engagement and Customer Relationship Management (CRM) are vital tools for organizational effectiveness, not only to maintain loyal clients but also to survive and keep maintaining profitability. Keywords: Social Media, Social Commerce, Social Networking, CRM, Instant Messaging (IM), Web 2.0, Facebook, Instagram, Linked In, Twitter, Marketing, Social Media Marketing, Cyprus.

Background: The popularity of continuous subcutaneous insulin infusion (CSII), or insulin pump therapy, as a way to deliver insulin more physiologically and achieve better glycemic control in diabetes patients has increased. Despite the substantiated therapeutic advantages of using CSII, its use has also been associated with an increased risk of technical malfunctioning of the device, which leads to an increased risk of acute metabolic complications, such as diabetic ketoacidosis. Current insulin pumps already incorporate systems to detect some types of faults, such as obstructions in the infusion set, but are not able to detect other types of fault such as the disconnection or leakage of the infusion set. Methods: In this article, we propose utilizing a validated robust model-based fault detection technique, based on interval analysis, for detecting disconnections of the insulin infusion set. For this purpose, a previously validated metabolic model of glucose regulation in type 1 diabetes mellitus (T1DM) and a continuous glucose monitoring device were used. As a first step to assess the performance of the presented fault detection system, a Food and Drug Administration-accepted T1DM simulator was employed. Results: Of the 100 in silico tests (10 scenarios on 10 subjects), only two false negatives and one false positive occurred. All faults were detected before plasma glucose concentration reached 300 mg/dl, with a mean plasma glucose detection value of 163 mg/dl and a mean detection time of 200 min. Conclusions: Interval model-based fault detection has been proven (in silico) to be an effective tool for detecting disconnection faults in sensor-augmented CSII systems. Proper quantification of the uncertainty associated with the employed model has been observed to be crucial for the good performance of the proposed approach.

In the daily management of type 1 diabetes (T1D), determining the correct insulin dose to be injected at meal-time is fundamental to achieve optimal glycemic control. Wearable sensors, such as continuous glucose monitoring (CGM) devices, are instrumental to achieve this purpose. In this paper, we show how CGM data, together with commonly recorded inputs (carbohydrate intake and bolus insulin), can be used to develop an algorithm that allows classifying, at meal-time, the post-prandial glycemic status (i.e., blood glucose concentration being too low, too high, or within target range). Such an outcome can then be used to improve the efficacy of insulin therapy by reducing or increasing the corresponding meal bolus dose. A state-of-the-art T1D simulation environment, including intraday variability and a behavioral model, was used to generate a rich in silico dataset corresponding to 100 subjects over a two-month scenario. Then, an extreme gradient-boosted tree (XGB) algorithm was employed to classify the post-prandial glycemic status. Finally, we demonstrate how the XGB algorithm outcome can be exploited to improve glycemic control in T1D through real-time adjustment of the meal insulin bolus. The proposed XGB algorithm obtained good accuracy at classifying post-prandial glycemic status (AUROC = 0.84 [0.78, 0.87]). Consequently, when used to adjust, in real-time, meal insulin boluses obtained with a bolus calculator, the proposed approach improves glycemic control when compared to the baseline bolus calculator. In particular, percentage time in target [70, 180] mg/dL was improved from 61.98 (&plusmn, 13.89) to 67.00 (&plusmn, 11.54, p &lt, 0.01) without increasing hypoglycemia.

This work presents an electrochemical DNA sensor microarray which supports the detection principles cyclic voltammetry (CV) and Coulometry. The three-electrode system needed for these detection methods is post-processed on the solid-state 5.5 mm x 3 mm CMOS-based chip, which is realized in a 180 nm, 1.8 V and 3.3 V standard CMOS technology. The constellation of an array of 109 working electrodes surrounded by the counter electrode and the reference electrodes is designed to meet stability requirements and structured using layers of gold and silicon nitride. The DNA sensor chip presented in this work has 3 operation modes: a calibration mode, a cleaning mode, and a measurement mode. Every single pixel has an area of 120 µm x 120 µm and consists of one working electrode connected to a readout CMOS circuitry: a 1-bit first order continuous-time ?S modulator. When its reference voltage is varied, the modulator measures its input current while controlling the electrode potential as required for cyclic voltammetry. With a sampling frequency of 10 MHz and an oversampling of 512, the pixel output data rate is around 20 ksamples/s. It allows a maximum input current amplitude of 15.6 nA. Post-layout simulations including transient device noise predict SNR of 63.4 dB and a SNDR of 62.9 dB. The modulator reference voltage is generated by an 8-bit segmented DAC with a full-scale range of 0.63 V. Simulations prove DAC monotonicity with worst-case DNL value of 0.783 LSB. The potentiostat controlling the electrolyte potential is realized as a super class AB amplifier with a peak supply current of 6.5 mA and a quiescent supply current of 0.5 mA. The potentiostat is controlled by an 8-bit segmented DAC with a full-scale output voltage range of 1.39 V. The potentiostat together with its driving DAC achieves voltage steps of ±1 V in 1 µs. Biasing circuits, calibration current sources, bandgap reference, and POR-circuits are designed and implemented on-chip. Thanks to these circuits, the number of chip pads is reduced to 6. A part of this work is dedicated to alternative readout circuit concepts. The alternative architectures are investigated, implemented, and characterized on transistor-level. The basic functionality is verified and key performance parameters are proven to be adequate by means of electrical measurements. In dieser Arbeit wird ein elektrochemischer DNA-Sensor-Microarray präsentiert, welcher die Detektionsprinzipien Zyklovoltammetrie und Coulometrie unterstützt. Ein Dreielektroden-System wird auf dem CMOS-basierten Chip der Größe 5.5 mm x 3 mm postprozessiert. Die Konstellation eines Arrays von 109 Arbeitselektroden umringt von der Gegenelektrode und der Referenzelektrode wurde entworfen, um Stabilitätsanforderungen zu erfüllen. Die Elektroden wurden mittels Gold- und Siliziumnitrid- Schichten strukturiert. Der DNA-Sensor-Chip verfügt über drei Betriebsmodi: einen Kalibriermodus, einen Reinigungsmodus und einen Messmodus. Der Microarray besteht aus 109 Pixeln. Jedes Pixel hat eine Fläche von 120 µm x 120 µm und besteht aus einer Arbeitselektrode, die mit einer CMOS-Messschaltung verbunden ist: Ein 1-bit zeitkontinuierlicher ?S-Modulator erster Ordnung. Wenn seine Referenzspannung variiert wird, kann der Modulator seinen Eingangsstrom messen und dabei das Elektrodenpotential durch seine Rückkopplungsschleife steuern. Schalter-Steuersignale mit einem kleineren Spannungshub von 0.85 V werden durch eine spezielle Schaltung für alle Pixel zentral generiert. Die Abtastfrequenz und die Überabtastrate betragen jeweils 10 MHz und 512. Bei einer Pixel-Ausgangsdatenrate von circa 20 ksamples/s beträgt die maximale Eingangsstrom-Amplitude 15,4 nA. Post-layout Simulationen mit Bauelementen-Rauschen ein SNR von 63,4 dB und ein SNDR von 62,9 dB prognostizieren. Die Modulator Referenzspannung wird durch ein 8-bit segmented DAC generiert, mit einem full-Scale Ausgangsspannungsbereich von 0,63 V. Post-layout Simulationen zeigen, dass der DAC monoton ist, denn der Worst-Case DNL Wert beträgt 0,783 LSB. Der Potentiostat, der das Elektrolytenpotential kontrolliert, wird als ein Super-Class-AB Verstärker realisiert. Der maximale Versorgungsstrom beträgt 6,5 mA, bei einem Ruhe-Versorgungsstrom von 0,5 mA. Der Potentiostat wird von einem 8-bit segmented DAC angesteuert, dessen Full-Scale Ausgangsspannungsbereich 1,39 V. Post-layout Simulationen zeigen eine Worst-Case DNL von 0,23 LSB, während die Worst-Case INL beträgt 0,37 LSB. Bias-Schaltungen, Kalibrierungsstrom-Quellen, eine Current-Mode Bandgap-Referenzschaltung und Power-On-Reset-Schaltungen sind ebenfalls auf dem Chip integriert so, dass die Pad-Anzahl auf nur 6 reduziert wird. Ein Teil dieser Arbeit ist alternativen Konzepten von Ausleseschaltungen gewidmet. Die alternativen Architekturen werden untersucht, implementiert und auf Transistorebene charakterisiert. Die Grundfunktionalität wird für alle implementierten Schaltungsblöcke verifiziert. Außerdem liefern die ersten Messungen angemessene Werte für die wesentlichen Leistungsparameter.