Electrochemical Biochip for Applications to Wireless and Batteryless Monitoring of Free-Moving Mice

A multi-sensing platform for applications in wireless and batteryless monitoring of free-moving small animals is presented in this paper. The proposed platform hosts six sensors: four biosensors for sensing of both disease biomarkers and therapeutic compounds, and two further sensors (T and pH) for biosensor calibration. Electrodeposition of Multi-Walled Carbon Nanotubes (MWCNTs) and the subsequent functionalization with proper enzymes is used to assure sensitivity and specificity in electrochemical biosensing. The realized sensors are demonstrated to be capable of measuring several parameters: lactate with a sensitivity of 77±26 μA/mM· cm2 and a limit of detection (LOD) of 4±1 μM; glucose with a sensitivity of 63±15 μA/mM· cm2 and a LOD of 8±2 μM; Etoposide (a well known anti-cancer agent) with a sensitivity of 0.15±0.04 mA/mM· cm2 and a LOD of 4±1 μM; Open Circuit Potential (OCP) measurements are used on a Pt/IrOx junction to sense pH with a sensitivity of around -75±5 mV/pH; while a Pt resistive thermal device is used to measure physiological temperature-range with an average sensitivity of 0.108±0.001 kΩ/°C

Implantable Multi-panel Platform for Continuous Monitoring of Exogenous and Endogenous Metabolites for Applications in Personalized Medicine

Nowadays, scientific advances are leading to the discovery of newer, better, more targeted treatments that will improve the human health. However, despite the promising results and the major advantages in treatments offered to patients, these personalized medical treatments are limited to few cases. Translational medicine research with animals is needed to find innovative, safe and life-saving solutions for patients, especially in drug development. Although technological improvements may lead one day to the end of animal testing, today those strategies are not sufficient, due to the complexity of living organisms. The living conditions of these animals are of primary importance because high stress levels can affect the experimental results. In this respect, the monitoring of the animals in a small living space by means of a fully implantable device, can contribute to minimize the human intervention, increasing the comfort for the animals. The objective of this thesis is the design and characterization of a fully implantable biosensor array for the real-time detection of endogenous and exogenous metabolites, for the monitoring of small caged animals in drug development, and for future applications in personalized medicine. The fully implantable device consists of: a passive sensing platform consisting of an array of four independent electrochemical biosensors, together with a pH sensor and a temperature sensor for the optimization of the sensing performances in different physiological conditions; integrated circuits capable of performing multiple electrochemical measurements; a coil for remote powering of the integrated circuit and the short-range data transmission to an external device; a membrane packaging ensuring measurements with high signal-to-noise ratio, biocompatibility and selectivity against possible interfering molecules in biological fluids. ⢠In vitro monitoring of four anti-cancer drugs and an anti-inflammatory drug within the pharmacological ranges in undiluted human serum; ⢠Demonstration of the in vitro functionality of the complete system, showing that the external powering system correctly operate the device, and receive the data from the sensors; ⢠In vivo biocompatibility tests of the packaging, showing after 30 days a significant reduction of the inflammatory response in time, suggesting normal host recovery; ⢠In vivo continuous monitoring of an anti-inflammatory drug, demonstrating the proof of-concept of the system for future personalized medicine applications

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

AN INTEGRATED MICROSYSTEM FOR BACTERIAL BIOFILM DETECTION AND TREATMENT

Bacterial biofilms cause severe infections in clinical fields and contamination problems in environmental facilities. Due to the unique complex structure of biofilms that comprise diverse polysaccharides and bacteria, traditional antibiotic therapies require a thousand times higher concentration compared to non-biofilm associated infections. The early detection of biofilms, before their structures are fully established in a given host/environment, is critical in order to eradicate them effectively. Also, the development of a new innovative biofilm treatment method that can be utilized with a low dose of antibiotic would be extremely important to the medical community. In this dissertation, a biofilm sensor and a new biofilm treatment method were independently developed to detect and treat biofilm communities, respectively. Furthermore, an integrated microsystem was demonstrated as a single platform of the sensor with the treatment method. The sensor was based on the surface acoustic wave (SAW) detection mechanism, which isn extremely sensitive for biofilm monitoring (hundreds of bacterial population detection limit) and consumes very low power (~100 µW). A piezoelectric ZnO layer fabricated by a pulsed laser deposition process was a key material to induce homogeneous acoustic waves. Reliable operation of the sensor was achieved using an Al2O3 film as a passivation layer over the sensor to protect ZnO degradation from the growth media. The sensor successfully demonstrated real-time monitoring of biofilm growth. The new biofilm treatment was developed based on the principles of the bioelectric effect that introduces an electric field along with antibiotics to biofilms, demonstrating significant biofilm inhibition compared to antibiotic treatment alone. Specifically, the new bioelectric effect was implemented with a superpositioned (SP) electric field of both alternating and direct current (AC and DC) and the antibiotic gentamicin (10 µg/mL). With the SP field treatment, significant biofilm reduction was demonstrated in total biomass (~ 71 %) as well as viable bacterial density (~ 400 times respected to the only antibiotic therapy) of the treated biofilms. This method was transferred to a microfluidic system using microfabricated planar electrodes. The microsystem-level implementation of the bioelectric effect also showed enhanced biofilm reduction (~ 140 % total biomass reduction improvement). The integrated system was based on the SAW sensor with the addition of coplanar thin electrodes to apply electric signals for the biofilm treatment. The chip was tested with two bacterial biofilms (Escherichia coli and Pseudomonas aeruginosa) that are clinically relevant strains. In both biofilm experiments, the integrated system demonstrated successful real-time biofilm monitoring and effective biofilm inhibition. This systematic integration of a continuous monitoring method with a novel effective treatment technique is expected to advance the state of the art in the field of managing clinical and environmental biofilms