Portable Bio-Devices: Design of Electrochemical Instruments from Miniaturized to Implantable Devices

The integration of biosensors and electronic technologies allows the development of biomedical systems able to diagnose and monitoring pathologies by detecting specific biomarkers. The chapter presents the main modules involved in the development of such devices, generically represented in Fig. 1, and focuses its attention on the essential components of these systems to address questions such as: how is the device powered? How does it communicate the measured data? What kind of sensors could be used?, and What kinds of electronics are used

Design of a Customized multipurpose nano-enabled implantable system for in-vivo theranostics

The first part of this paper reviews the current development and key issues on implantable multi-sensor devices for in vivo theranostics. Afterwards, the authors propose an innovative biomedical multisensory system for in vivo biomarker monitoring that could be suitable for customized theranostics applications. At this point, findings suggest that cross-cutting Key Enabling Technologies (KETs) could improve the overall performance of the system given that the convergence of technologies in nanotechnology, biotechnology, micro&nanoelectronics and advanced materials permit the development of new medical devices of small dimensions, using biocompatible materials, and embedding reliable and targeted biosensors, high speed data communication, and even energy autonomy. Therefore, this article deals with new research and market challenges of implantable sensor devices, from the point of view of the pervasive system, and time-to-market. The remote clinical monitoring approach introduced in this paper could be based on an array of biosensors to extract information from the patient. A key contribution of the authors is that the general architecture introduced in this paper would require minor modifications for the final customized bio-implantable medical device

Integrated CMOS Capacitance Sensor And Microactuator Control Circuits For On-Chip Cell Monitoring

"Cell Clinics," CMOS/MEMS hybrid microsystems for on-chip investigation of biological cells, are currently being engineered for a broad spectrum of applications including olfactory sensing, pathogen detection, cytotoxicity screening and biocompatibility characterization. In support of this effort, this research makes two primary contributions towards designing the cell-based lab-on-a-chip systems. Firstly it develops CMOS capacitance sensors for characterizing cell-related properties including cell-surface attachment, cell health and growth. Assessing these properties is crucial to all kinds of cell applications. The CMOS sensors measure substrate coupling capacitances of anchorage-dependent cells cultured on-chip in a standard in vitro environment. The biophysical phenomenon underlying the capacitive behavior of cells is the counterionic polarization around the insulating cell bodies when exposed to weak, low frequency electric fields. The measured capacitance depends on a variety of factors related to the cell, its growth environment and the supporting substrate. These include membrane integrity, morphology, adhesion strength and substrate proximity. The demonstrated integrated cell sensing technique is non-invasive, easy-to-use and offers the unique advantage of automated real time cell monitoring without the need for disruptive external forces or biochemical labeling. On top of the silicon-based cell sensing platform, the cell clinics microsystem comprises MEMS structures forming an array of lidded microvials for confining single cells or small cell groups within controllable microenvironments in close proximity to the sensor sites. The opening and closing of the microvial lids are controlled by actuator hinges employing an electroactive polymer material that can electrochemically actuate. In macro-scale setups such electrochemical actuation reactions are controlled by an electronic instrument called potentiostat. In order to enable system miniaturization and enhance portability of cell clinics, this research makes its second contribution by implementing and demonstrating a CMOS potentiostat module for in situ control of the MEMS actuators

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

Fabrication and Characterization of Polypyrrole/Gold Bilayer Microactuators for Bio-Mems Applications

The proof of concept for conjugated polymer bilayer microactuators had been demonstrated prior to this dissertation with numerous devices, and their advantages in biomedical applications had been recognized. The next step for this technology was implementation in real systems, which required knowledge of the main performance metrics and limitations. In this dissertation, work focused on measuring these metrics for the first time to facilitate the development of cell-clinics, which are microsystems for cell study and for cell-based sensing. The conjugated polymer used throughout the dissertation was polypyrrole doped with dodecylbenzenesulfonate, PPy(DBS), and the second layer in the bilayer was gold. Device fabrication challenges were first identified and addressed, focusing particularly on methods to produce PPy/Au bilayers that did not suffer from delamination. By electroplating Au onto the electrodes or by wet etching them to increase mechanical interlocking, this problem, which had plagued the field for the last decade, was solved. Another important contributor to lifetime, which is a key actuator metric, is loss of electro-activity with extended cycling. This metric was quantified through measurements of the total exchanged charge of PPy(DBS) with cycles of electromechanical redox. This result impacts how these actuators can be used. Two other key metrics on which this work focused were bending angle, analogous to stroke in a linear actuator, and force. It was necessary to determine bending angle as a function of film thickness experimentally because the traditional bilayer beam models could not account for microfabricated bilayer radius of curvature data. Through experimental testing over a wide range of PPy and Au thicknesses, the relationship between PPy:Au thickness ratio and curvature was mapped out. The experimental results demonstrated the existence of strain gradients within the conjugated polymer films, with the material at the surface having greater actuation strain than that at the gold interface. Finally, accurate force measurements had not been done prior to this dissertation research because of the significant challenges involved in developing a method for measuring force in microactuators. This dissertation described the development of such a methodology and provides data for the blocked force as a function of polypyrrole thickness

Novel Current-Mode Sensor Interfacing and Radio Blocks for Cell Culture Monitoring

Since 2004 Imperial College has been developing the world’s first application-specific instrumentation aiming at the on-line, in-situ, physiochemical monitoring of adult stem cell cultures. That effort is internationally known as the ‘Intelligent Stem Cell Culture Systems’ (ISCCS) project. The ISCCS platform is formed by the functional integration of biosensors, interfacing electronics and bioreactors. Contrary to the PCB-level ISCCS platform the work presented in this thesis relates to the realization of a miniaturized cell culture monitoring platform. Specifically, this thesis details the synthesis and fabrication of pivotal VLSI circuit blocks suitable for the construction of a miniaturized microelectronic cell monitoring platform. The thesis is composed of two main parts. The first part details the design and operation of a two-stage current-input currentoutput topology suitable for three-electrode amperometric sensor measurements. The first stage is a CMOS-dual rail-class AB-current conveyor providing a low impedancevirtual ground node for a current input. The second stage is a novel hyperbolic-sinebased externally-linear internally-non-linear current amplification stage. This stage bases its operation upon the compressive sinh−1 conversion of the interfaced current to an intermediate auxiliary voltage and the subsequent sinh expansion of the same voltage. The proposed novel topology has been simulated for current-gain values ranging from 10 to 1000 using the parameters of the commercially available 0.8μm AMS CMOS process. Measured results from a chip fabricated in the same technology are also reported. The proposed interfacing/amplification architecture consumes 0.88-95μW. The second part describes the design and practical evaluation of a 13.56MHz frequency shift keying (FSK) short-range (5cm) telemetry link suitable for the monitoring of incubated cultures. Prior to the design of the full FSK radio system, a pair of 13.56MHz antennae are characterized experimentally. The experimental S-parameter-value determination of the 13.56MHz wireless link is incorporated into the Cadence Design Framework allowing a high fidelity simulation of the reported FSK radio. The transmitter of the proposed system is a novel multi-tapped seven-stage ring-oscillator-based VCO whereas the core of the receiver is an appropriately modified phase locked loop (PLL). Simulated and measured results from a 0.8μm CMOS technology chip are reported

Multisite monitoring of choline using biosensor microprobe arrays in combination with CMOS circuitry

A miniature device enabling parallel in vivo detection of the neurotransmitter choline in multiple brain regions of freely behaving rodents is presented. This is achieved by combining a biosensor microprobe array with a custom-developed CMOS chip. Each silicon microprobe comprises multiple platinum electrodes that are coated with an enzymatic membrane and a permselective layer for selective detection of choline. The biosensors, based on the principle of amperometric detection, exhibit a sensitivity of 157±35 µA mM-1 cm-2, a limit of detection of below 1 µM, and a response time in the range of 1 s. With on-chip digitalization and multiplexing, parallel recordings can be performed at a high signal-to-noise ratio with minimal space requirements and with substantial reduction of external signal interference. The layout of the integrated circuitry allows for versatile configuration of the current range and can, therefore, also be used for functionalization of the electrodes before use. The result is a compact, highly integrated system, very convenient for on-site measurement