Full System for Translational Studies of Personalized Medicine with Free-Moving Mice (invited)

A full remotely powered system for metabolism monitoring of free-moving mice is presented here. The fully implantable sensing platform hosts two ASICs, one off-the-shelf micro-controller, four biosensors, two other sensors, a coil to receive power, and an antenna to transmit data. Proper enzymes ensure specificity for animal metabolites while Multi-Walled Carbon Nanotubes ensure the due sensitivity. The remote powering is indeed provided by inductive coils located under the floor of the mouse' cage. Two different approaches were investigated to ensure freedom of movement to the animal. The application to studies for personalized medicine is demonstrated by showing continuous monitoring of both glucose and paracetamol

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

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

Biocompatible Packagings for Fully Implantable Multi-Panel Devices for Remote Monitoring of Metabolism

This paper compares three different biocompatible packagings suitable to support full implantation of multi-panel sensors for remote monitoring of metabolism. The three packagings have been designed, realized and implanted in mice for 30 days. ATP and neutrophil concentrations have been measured at the implant site after the device was explanted, to assess the level of biocompatibility of the device

A Novel Power-Efficient Wireless Multi-channel Recording System for the Telemonitoring of Electroencephalography (EEG)

This research introduces the development of a novel EEG recording system that is modular, batteryless, and wireless (untethered) with the supporting theoretical foundation in wireless communications and related design elements and circuitry. Its modular construct overcomes the EEG scaling problem and makes it easier for reconfiguring the hardware design in terms of the number and placement of electrodes and type of standard EEG system contemplated for use. In this development, portability, lightweight, and applicability to other clinical applications that rely on EEG data are sought. Due to printer tolerance, the 3D printed cap consists of 61 electrode placements. This recording capacity can however extend from 21 (as in the international 10-20 systems) up to 61 EEG channels at sample rates ranging from 250 to 1000 Hz and the transfer of the raw EEG signal using a standard allocated frequency as a data carrier. The main objectives of this dissertation are to (1) eliminate the need for heavy mounted batteries, (2) overcome the requirement for bulky power systems, and (3) avoid the use of data cables to untether the EEG system from the subject for a more practical and less restrictive setting. Unpredictability and temporal variations of the EEG input make developing a battery-free and cable-free EEG reading device challenging. Professional high-quality and high-resolution analog front ends are required to capture non-stationary EEG signals at microvolt levels. The primary components of the proposed setup are the wireless power transmission unit, which consists of a power amplifier, highly efficient resonant-inductive link, rectification, regulation, and power management units, as well as the analog front end, which consists of an analog to digital converter, pre-amplification unit, filtering unit, host microprocessor, and the wireless communication unit. These must all be compatible with the rest of the system and must use the least amount of power possible while minimizing the presence of noise and the attenuation of the recorded signal A highly efficient resonant-inductive coupling link is developed to decrease power transmission dissipation. Magnetized materials were utilized to steer electromagnetic flux and decrease route and medium loss while transmitting the required energy with low dissipation. Signal pre-amplification is handled by the front-end active electrodes. Standard bio-amplifier design approaches are combined to accomplish this purpose, and a thorough investigation of the optimum ADC, microcontroller, and transceiver units has been carried out. We can minimize overall system weight and power consumption by employing battery-less and cable-free EEG readout system designs, consequently giving patients more comfort and freedom of movement. Similarly, the solutions are designed to match the performance of medical-grade equipment. The captured electrical impulses using the proposed setup can be stored for various uses, including classification, prediction, 3D source localization, and for monitoring and diagnosing different brain disorders. All the proposed designs and supporting mathematical derivations were validated through empirical and software-simulated experiments. Many of the proposed designs, including the 3D head cap, the wireless power transmission unit, and the pre-amplification unit, are already fabricated, and the schematic circuits and simulation results were based on Spice, Altium, and high-frequency structure simulator (HFSS) software. The fully integrated head cap to be fabricated would require embedding the active electrodes into the 3D headset and applying current technological advances to miniaturize some of the design elements developed in this dissertation

A Closed-Loop Bidirectional Brain-Machine Interface System For Freely Behaving Animals

A brain-machine interface (BMI) creates an artificial pathway between the brain and the external world. The research and applications of BMI have received enormous attention among the scientific community as well as the public in the past decade. However, most research of BMI relies on experiments with tethered or sedated animals, using rack-mount equipment, which significantly restricts the experimental methods and paradigms. Moreover, most research to date has focused on neural signal recording or decoding in an open-loop method. Although the use of a closed-loop, wireless BMI is critical to the success of an extensive range of neuroscience research, it is an approach yet to be widely used, with the electronics design being one of the major bottlenecks. The key goal of this research is to address the design challenges of a closed-loop, bidirectional BMI by providing innovative solutions from the neuron-electronics interface up to the system level. Circuit design innovations have been proposed in the neural recording front-end, the neural feature extraction module, and the neural stimulator. Practical design issues of the bidirectional neural interface, the closed-loop controller and the overall system integration have been carefully studied and discussed.To the best of our knowledge, this work presents the first reported portable system to provide all required hardware for a closed-loop sensorimotor neural interface, the first wireless sensory encoding experiment conducted in freely swimming animals, and the first bidirectional study of the hippocampal field potentials in freely behaving animals from sedation to sleep. This thesis gives a comprehensive survey of bidirectional BMI designs, reviews the key design trade-offs in neural recorders and stimulators, and summarizes neural features and mechanisms for a successful closed-loop operation. The circuit and system design details are presented with bench testing and animal experimental results. The methods, circuit techniques, system topology, and experimental paradigms proposed in this work can be used in a wide range of relevant neurophysiology research and neuroprosthetic development, especially in experiments using freely behaving animals

Towards tactile sensing active capsule endoscopy

Examination of the gastrointestinal(GI) tract has traditionally been performed using tethered endoscopy tools with limited reach and more recently with passive untethered capsule endoscopy with limited capability. Inspection of small intestines is only possible using the latter capsule endoscopy with on board camera system. Limited to visual means it cannot detect features beneath the lumen wall if they have not affected the lumen structure or colour. This work presents an improved capsule endoscopy system with locomotion for active exploration of the small intestines and tactile sensing to detect deformation of the capsule outer surface when it follows the intestinal wall. In laboratory conditions this system is capable of identifying sub-lumen features such as submucosal tumours.Through an extensive literary review the current state of GI tract inspection in particular using remote operated miniature robotics, was investigated, concluding no solution currently exists that utilises tactile sensing with a capsule endoscopy. In order to achieve such a platform, further investigation was made in to tactile sensing technologies, methods of locomotion through the gut, and methods to support an increased power requirement for additional electronics and actuation. A set of detailed criteria were compiled for a soft formed sensor and flexible bodied locomotion system. The sensing system is built on the biomimetic tactile sensing device, Tactip, \cite{Chorley2008, Chorley2010, Winstone2012, Winstone2013} which has been redesigned to fit the form of a capsule endoscopy. These modifications have required a $360^{o}$ cylindrical sensing surface with $360^{o}$ panoramic optical system. Multi-material 3D printing has been used to build an almost complete sensor assembly with a combination of hard and soft materials, presenting a soft compliant tactile sensing system that mimics the tactile sensing methods of the human finger. The cylindrical Tactip has been validated using artificial submucosal tumours in laboratory conditions. The first experiment has explored the new form factor and measured the device's ability to detect surface deformation when travelling through a pipe like structure with varying lump obstructions. Sensor data was analysed and used to reconstruct the test environment as a 3D rendered structure. A second tactile sensing experiment has explored the use of classifier algorithms to successfully discriminate between three tumour characteristics; shape, size and material hardness. Locomotion of the capsule endoscopy has explored further bio-inspiration from earthworm's peristaltic locomotion, which share operating environment similarities. A soft bodied peristaltic worm robot has been developed that uses a tuned planetary gearbox mechanism to displace tendons that contract each worm segment. Methods have been identified to optimise the gearbox parameter to a pipe like structure of a given diameter. The locomotion system has been tested within a laboratory constructed pipe environment, showing that using only one actuator, three independent worm segments can be controlled. This configuration achieves comparable locomotion capabilities to that of an identical robot with an actuator dedicated to each individual worm segment. This system can be miniaturised more easily due to reduced parts and number of actuators, and so is more suitable for capsule endoscopy. Finally, these two developments have been integrated to demonstrate successful simultaneous locomotion and sensing to detect an artificial submucosal tumour embedded within the test environment. The addition of both tactile sensing and locomotion have created a need for additional power beyond what is available from current battery technology. Early stage work has reviewed wireless power transfer (WPT) as a potential solution to this problem. Methods for optimisation and miniaturisation to implement WPT on a capsule endoscopy have been identified with a laboratory built system that validates the methods found. Future work would see this combined with a miniaturised development of the robot presented. This thesis has developed a novel method for sub-lumen examination. With further efforts to miniaturise the robot it could provide a comfortable and non-invasive procedure to GI tract inspection reducing the need for surgical procedures and accessibility for earlier stage of examination. Furthermore, these developments have applicability in other domains such as veterinary medicine, industrial pipe inspection and exploration of hazardous environments

Modern Telemetry

Telemetry is based on knowledge of various disciplines like Electronics, Measurement, Control and Communication along with their combination. This fact leads to a need of studying and understanding of these principles before the usage of Telemetry on selected problem solving. Spending time is however many times returned in form of obtained data or knowledge which telemetry system can provide. Usage of telemetry can be found in many areas from military through biomedical to real medical applications. Modern way to create a wireless sensors remotely connected to central system with artificial intelligence provide many new, sometimes unusual ways to get a knowledge about remote objects behaviour. This book is intended to present some new up to date accesses to telemetry problems solving by use of new sensors conceptions, new wireless transfer or communication techniques, data collection or processing techniques as well as several real use case scenarios describing model examples. Most of book chapters deals with many real cases of telemetry issues which can be used as a cookbooks for your own telemetry related problems

Development of biomedical devices for the extracorporeal real-time monitoring and perfusion of transplant organs

The goal of this Thesis is to develop a range of technologies that could enable a paradigm shift in organ preservation for renal transplantation, transitioning from static cold storage to warm normothermic blood perfusion. This transition could enable the development of novel pre-implantation therapies, and even serve as the foundation for a global donor pool. A low-hæmolysis pump was developed, based on a design first proposed by Nikola Tesla in 1913. Simulations demonstrated the theoretical superiority of this design over existing centrifugal pumps for blood recirculation, and provided insights for future avenues of research into this technology. A miniature, battery-powered, multimodal sensor suite for the in-line monitoring of a blood perfusion circuit was designed and implemented. This was named the ‘SmartPipe’, and proved capable of simultaneously monitoring temperature, pressure and blood oxygen saturations over the biologically-relevant ranges of each modality. Finally, the Thesis details the successful implementation and optimisation of a combined microfluidic and microdialysis system for the real-time quantitation of creatinine in blood or urine through amperometric sensing, to act as a live renal function monitor. The range of detection was 4.3μM – 500μM, with the possibility of extending this in both directions. This work also details and explores a novel methodology for functional monitoring in closed-loop systems which avoids the need for sensor calibration, and potentially overcomes the problems of sensor drift and desensitisation.Open Acces