Integrated Electronics to Control and Readout Electrochemical Biosensors for Implantable Applications

Biosensors can effectively be used to monitor multiple metabolites such as glucose, lactate, ATP and drugs in the human body. Continuous monitoring of these metabolites is essential for patients with chronic or critical conditions. Moreover, this can be used to tune the dosage of a drug for each individual patient, in order to achieve personalized therapy. Implantable medical devices (IMDs) based on biosensors are emerging as a valid alternative for blood tests in laboratories. They can provide continuous monitoring while reduce the test costs. The potentiostat plays a fundamental role in modern biosensors. A potentiostat is an electronic device that controls the electrochemical cell, using three electrodes, and runs the electrochemical measurement. In particular the IMDs require a low-power, fully-integrated, and autonomous potentiostats to control and readout the biosensors. This thesis describes two integrated circuits (ICs) to control and readout multi-target biosensors: LOPHIC and ARIC. They enable chronoamperometry and cyclic voltammetrymeasurements and consume sub-mW power. The design, implementation, characterisation, and validation with biosensors are presented for each IC. To support the calibration of the biosensors with environmental parameters, ARIC includes circuitry to measure the pHand temperature of the analyte through an Iridiumoxide pH sensor and an off-chip resistor-temperature detector (RTD). In particular, novel circuits to convert resistor value into digital are designed for RTD readout. ARIC is integrated into two IMDs aimed for health-care monitoring and personalized therapy. The control and readout of the embedded sensor arrays have been successfully achieved, thanks to ARIC, and validated for glucose and paracetamol measurements while it is remotely powered through an inductive link. To ensure the security and privacy of IMDs, a lightweight cryptographic system (LCS) is presented. This is the first ASIC implementation of a cryptosystem for IMDs, and is integrated into ARIC. The resulting system provides a unique and fundamental capability by immediately encrypting and signing the sensor data upon its creation within the body. Nano-structures such as Carbon nanotubes have been widely used to improve the sensitivity of the biosensors. However, in most of the cases, they introduce more noise into the measurements and produce a large background current. In this thesis the noise of the sensors incorporating CNTs is studied for the first time. The effect of CNTs as well as sensor geometry on the signal to noise ratio of the sensors is investigated experimentally. To remove the background current of the sensors, a differential readout scheme has been proposed. In particular, a novel differential readout IC is designed and implemented that measures inputcurrents within a wide dynamic range and produces a digital output that corresponds to the -informative- redox current of the biosensor

Psychotic experiences in patients with obsessive compulsive disorder. A cross sectional clinical study

Background: Obsessive-compulsive disorder (OCD) is associated with heterogeneous and diverse symptoms. A diagnosis is challenging when patients experience psychotic symptoms. This study aimed to evaluate the pattern of psychotic symptoms in patients with OCD. Methods: Using semi-structured clinical interviews, 185 patients meeting the DSM-IV diagnostic criteria for OCD were selected. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Scale for the Assessment of Positive/Negative Symptoms (SAPS/SANS) were used to measure the OCD severity and insight levels and the pattern of psychotic symptoms, respectively. Characteristics of patients with and without psychotic experiences were compared. Results: A total of 38 patients (20.5%) displayed psychotic symptoms. Delusions were observed in 63.2% of these patients, while in 13.2% of them, delusions were accompanied with negative symptoms. Men, those aged between 18 and 34 years, less educated, and singles displayed significantly higher rates of psychotic symptoms. The mean Y-BOCS score (26.42 +/- 5.07) was significantly higher in patients with psychotic symptoms than in those without (24.97 +/- 6.38). Conclusion: The results showed that in OCD patients, psychotic symptoms are more common in young

A Configurable IC to Control, Readout and Calibrate an Array of Biosensors

We present a novel integrated circuit for a biosensing data acquisition chain. The circuit controls and reads out five bimolecular sensors as well as pH and temperature sensors for biosensor calibration. The IC supports both chronoamperometry (CA) and cyclic voltammetry (CV) measurements, which are commonly used in biosensing. Different voltage waveforms are generated to control CV by using a single configurable waveform generator and programmable constant voltage levels are produced to enable CA. To reduce the area and power consumption of the interface electronics, a unified circuit is designed for CV, CA and pH readout. The biosensors produce currents that are converted by a 13.5-bit sigma delta analog to digital converter. The circuit has been designed and realized in 0.18 μm technology. It consumes 711 μW from a 1.8 V supply voltage, making it suitable for remotely powered and implantable applications

A Current-Mode Potentiostat for Multi-Target Detection Tested with Different Lactate Biosensors

Real-time and multi-target detection by wireless implantable devices is of increasing interest for chronic patients. In this work, electrode sharing is proposed to minimize the size of the implantable device when several three-electrode-based sensing sites are needed. An integrated potentiostat and readout circuit for a multi-target biosensor is presented. To realize this, the circuit reads out the sensor current through each working electrode in a current-mode scheme. The maximum detectable current is 8 μA and the simulated input referred current noise of the circuit is 125 pA/pHz at 1 Hz. The circuit was fabricated in 0.18 μm technology and tested for two lactate biosensors fabricated with a commercial lactate oxidase and an engineered one. Chronoamperometry experiments performed with the circuit agree well with a commercial equipment for lactate detection up to 1 mM

Electronic Implants: Power Delivery and Management

A power delivery system for implantable biosensors is presented. The system, embedded into a skin patch and located directly over the implantation area, is able to transfer up to 15 mW wirelessly through the body tissues by means of an inductive link. The inductive link is also used to achieve bidirectional data communication with the implanted device. Downlink communication (ASK) is performed at 100 kbps; uplink communication (LSK) is performed at 66.6 kbps. The received power is managed by an integrated system including a voltage rectifier, an amplitude demodulator and a load modulator. The power management system is presented and evaluated by means of simulations

Empirical Study of Noise Dependence in Electrochemical Sensors

We report the experimental study of noise in electrochemical biosensors as related to voltage and concentration. A comparison with experiments is performed for H2O2 and Ferrocyanide with bare sensors and with sensors functionalized with Multi-Walled Carbon Nanotubes (MWCNT) modified electrodes. Chronoamperometry measurements at different voltages were carried out, followed by fast Fourier transform analysis of noise at different concentration of analyte to understand the effect of concentration and voltage on the noise Power Spectral Density (PSD) and the Signal over Noise (SNR) ratio. Experimental results demonstrate the presence of 1/f noise and its dependence on the state variables. The parameters of 1/f noise i.e. the amplitude coefficient and frequency power coefficients are extracted by curve fitting, and are characterized by comparing the coefficient in different molecules, electrodes, voltages and concentration

Fully Integrated Biochip Platforms for Advanced Healthcare

Recent advances in microelectronics and biosensors are enabling developments of innovative biochips for advanced healthcare by providing fully integrated platforms for continuous monitoring of a large set of human disease biomarkers. Continuous monitoring of several human metabolites can be addressed by using fully integrated and minimally invasive devices located in the sub-cutis, typically in the peritoneal region. This extends the techniques of continuous monitoring of glucose currently being pursued with diabetic patients. However, several issues have to be considered in order to succeed in developing fully integrated and minimally invasive implantable devices. These innovative devices require a high-degree of integration, minimal invasive surgery, long-term biocompatibility, security and privacy in data transmission, high reliability, high reproducibility, high specificity, low detection limit and high sensitivity. Recent advances in the field have already proposed possible solutions for several of these issues. The aim of the present paper is to present a broad spectrum of recent results and to propose future directions of development in order to obtain fully implantable systems for the continuous monitoring of the human metabolism in advanced healthcare applications

Nano-Sensor and Circuit Design for Anti-Cancer Drug Detection

The development of new technologies to monitor drugs concentration directly in patient’s blood is absolutely required to succeed in personalized drug therapies. In this study, Etoposide - a well-known anti-cancer drug - has been chosen as model for cyclic voltammetry detection of drugs. Carbon nanotubes are chosen as electron-transfer mediators to enhance the system sensitivity. A very low frequency and low slope triangular-wave potential is required to acquire cyclic voltammograms. Cyclic voltammograms are definitely needed for a correct identification and quantification of the drug concentration in the patient serum. The aim of the paper is to investigate the feasibility of VLSI fully-integration of cyclic voltammetry measurements as a tool to develop a low-cost chip for drug monitoring in personalized therapy. A triangular wave generator CMOS circuit is proposed by using Direct Digital Synthesis (DDS) method. The circuit is implemented in 0.18 μm technology and it presents the possibility of changing the slope of the triangular voltage in a wide range of 10 to 100mV/s

Design, fabrication, and test of a sensor array for perspective biosensing in chronic pathologies

Biosensing for chronic pathologies requires the simultaneous monitoring of different parameters such as drug concentrations, inflammation status, temperature and pH. In this paper we discuss the design, fabrication and test of a sensor array hosting five biosensor platforms, a pH electrode and a temperature sensor. Different and reproducible nano-bio- functionalization can be obtained with high spatial resolution via selective electrodeposition of chitosan/MWCNT/enzyme solutions at the various electrodes. The array, completely fabricated with biocompatible materials, can be integrated with a CMOS integrated circuit and a remote powering coil for the realization of a fully implantable device

Sub-mW Reconfigurable Interface IC for Electrochemical Sensing

The IronIC project has the aim of developing a fully implantable and remotely powered platform for the real- time monitoring of human metabolites. In this paper we present a mixed-signal interface IC for the electrochemical sensing data acquisition chain. The IC controls and reads out up to five biomolecular sensors, by receiving commands from a standard interface to conduct chronoamperometry (CA) and cyclic voltammetry (CV). Different voltage profiles are generated by using a single fully on-chip reconfigurable waveform generator, while the measured data are digitized. The IC is realized in 0.18 μm CMOS technology. Electrical measurements show that the linear readout current range is ±1650 nA with 8-bit resolution. The cyclic voltammetry of potassium ferricyanide and the chronoamperometry of hydrogen peroxide have been successfully performed with the interface. The IC consumes 0.92 mW from 1.8 V supply voltage, making it suitable for remotely powered and implantable applications