Design and Implementation of an Integrated Biosensor Platform for Lab-on-a-Chip Diabetic Care Systems

Recent advances in semiconductor processing and microfabrication techniques allow the implementation of complex microstructures in a single platform or lab on chip. These devices require fewer samples, allow lightweight implementation, and offer high sensitivities. However, the use of these microstructures place stringent performance constraints on sensor readout architecture. In glucose sensing for diabetic patients, portable handheld devices are common, and have demonstrated significant performance improvement over the last decade. Fluctuations in glucose levels with patient physiological conditions are highly unpredictable and glucose monitors often require complex control algorithms along with dynamic physiological data. Recent research has focused on long term implantation of the sensor system. Glucose sensors combined with sensor readout, insulin bolus control algorithm, and insulin infusion devices can function as an artificial pancreas. However, challenges remain in integrated glucose sensing which include degradation of electrode sensitivity at the microscale, integration of the electrodes with low power low noise readout electronics, and correlation of fluctuations in glucose levels with other physiological data. This work develops 1) a low power and compact glucose monitoring system and 2) a low power single chip solution for real time physiological feedback in an artificial pancreas system. First, glucose sensor sensitivity and robustness is improved using robust vertically aligned carbon nanofiber (VACNF) microelectrodes. Electrode architectures have been optimized, modeled and verified with physiologically relevant glucose levels. Second, novel potentiostat topologies based on a difference-differential common gate input pair transimpedance amplifier and low-power voltage controlled oscillators have been proposed, mathematically modeled and implemented in a 0.18μm [micrometer] complementary metal oxide semiconductor (CMOS) process. Potentiostat circuits are widely used as the readout electronics in enzymatic electrochemical sensors. The integrated potentiostat with VACNF microelectrodes achieves competitive performance at low power and requires reduced chip space. Third, a low power instrumentation solution consisting of a programmable charge amplifier, an analog feature extractor and a control algorithm has been proposed and implemented to enable continuous physiological data extraction of bowel sounds using a single chip. Abdominal sounds can aid correlation of meal events to glucose levels. The developed integrated sensing systems represent a significant advancement in artificial pancreas systems

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

IEEE Trans Instrum Meas

This paper introduces a novel compact low-power amperometric instrumentation design with current-to-digital output for electrochemical sensors. By incorporating the double layer capacitance of an electrochemical sensor's impedance model, our new design can maintain performance while dramatically reducing circuit complexity and size. Electrochemical experiments with potassium ferricyanide, show that the circuit output is in good agreement with results obtained using commercial amperometric instrumentation. A high level of linearity (R| = 0.991) between the circuit output and the concentration of potassium ferricyanide was also demonstrated. Furthermore, we show that a CMOS implementation of the presented architecture could save 25.3% of area, and 47.6% of power compared to a traditional amperometric instrumentation structure. Thus, this new circuit structure is ideally suited for portable/wireless electrochemical sensing applications.20192021-05-01T00:00:00ZR01 ES022302/ES/NIEHS NIH HHS/United StatesR01 OH009644/OH/NIOSH CDC HHS/United States32292210PMC7156046759

Carbon and Platinum Nanostructured Electrodes on Miniaturized Devices for Biomedical Diagnostics

Nowadays, medical devices face several limitations concerning rapid, reliable and simultaneous quantification of a set of ions and metabolites from a micro-nanoliter volume of undiluted samples. The development of minimally-sized devices is, therefore, of key importance. In such a context, electrochemical sensors are particularly advantageous because of the simple, low cost and reproducible fabrication procedures and the rapid analytical measurements. Moreover, they provide easy possibilities for continuous monitoring. However, sensitive and selective detection of molecules in the physio-pathological concentration range is very challenging when conventional electrochemical devices are employed, especially for long-term use. Nanostructured electrodes are considered as one of the most promising strategies to overcome issues of sensitivity because of their large surface area and their excellent electrocatalytic properties. They could also address in part the problem of selectivity due to shifts in potential of the measured Faradic currents. In addition, nanomaterials could provide stable and reproducible potential responses when used as solid-contact materials of ion-selective electrodes. Inappropriate nanointegration methods could decrease the sensor performance so that the development of tailored nanostructuration protocols is extremely important to boost the sensor sensitivity, selectivity and stability over time. Objective of this thesis was to design and electrochemical characterise novel carbon and metal nanostructures for medical sensors. First of all, the integration of carbon nanomaterials on specific sensing sites of a microfabricated sensor was considered. Time-consuming, expensive and hardly-reproducible nanostrucuturation approaches contemplate the co-immobilization of carbon nanomaterials and additives whose presence inevitably masks the nanomaterial promising properties and compromises the time-stability in aqueous environments. The selective CVD growth of carbon nanomaterials was considered as a promising method to enable the coupling nanomaterial-electrode. Deposition parameters were optimised to make the process compatible with CMOS temperatures. Then, new protocols based on rapid electrodeposition methods were developed to integrate differently shaped and sized Pt and Pt-Au nanostructures on electrochemical platforms. Template-free electrodeposition was selected because of the durably-anchored and the contaminant-free coatings resulting after the process. Both nanostructuration approaches generated highly-sensitive electrodes to detect human metabolites as compared with the bare counterparts. Unprecedented sensing performance were obtained by both direct and enzyme-mediated detection mechanisms. Selective sensing was achieved thanks to the capability of the proposed nanostructured electrodes to discriminate the detection potentials of biomarkers from those of interfering species. The developed nanostructures were also excellent solid contacts between an electrode and an ion-selective membrane resulting in stable and reliable solid-contact ion-selective electrodes. To prove their stability and reproducibility for long operating lifetimes, these ion-selective electrodes have been successfully used as standard for continuous acute cell death monitoring

TWO-DIMENSIONAL POLYANILINE NANOSTRUCTURES FOR THE DEVELOPMENT OF ULTRASENSITIVE FLEXIBLE BIOSENSORS

The demand for ultrasensitive, inexpensive and wearable biosensors is always strong due to the increasing healthcare related concerns. In this work, field-effect-transistor (FET) biosensors based on two-dimensional (2-D) polyaniline (PANI) nanostructures were developed on both nonflexible (SiO2) and flexible substrates (polyethylene terephthalate and polyimide). The biosensor devices were fabricated through a facile and inexpensive method that combines top-down and bottom-up processes. A low-temperature bilayer process was developed that vastly improved the yield of flexible devices. The chemically synthesized PANI nanostructures showed excellent p-type semiconductor properties as well as good compatibility with flexible designs. With the 2-D PANI nanostructure being as thin as 80 nm and its extremely large surface-area-to-volume (SA/V) ratio due to the intrinsic properties of PANI chemical synthesis, the developed biosensors exhibited outstanding sensing performance in detecting B-type natriuretic peptide (BNP) biomarkers. Excellent reproducibility, and high specificity with the limit of detection as low as 100 pg/mL were achieved for both designs. PANI nanostructure under bending condition was also investigated and showed controllable conductance changes being less than 20% with good restorability which may open up the possibility for wearable applications. In addition, a facile and template-free method is demonstrated to synthesize a new two-dimensional thin film structure: PANI film/nanotubes hybrid. The hybrid is a 100 nm thick PANI film embedded with PANI nanotubes. This well controlled method requires no surfactant or organic acid as well as relatively low concentration of reagents. Synthesis condition studies reveal that aniline oligomers with certain structures are responsible for guiding the growth of the nanotubes. Electrical characterization also indicates that the hybrid nanostructure possesses similar FET characteristics to bare PANI film. With its 20% increased SA/V ratio contributed by surface embedded nanotubes and the excellent p-type semiconducting characteristic, PANI film/nanotubes hybrid shows clear superiority compared with bare PANI film. Such advantages guarantee the hybrid a promising future towards the development of ultra-high sensitivity and low cost biosensors

Biosensors

A biosensor is defined as a detecting device that combines a transducer with a biologically sensitive and selective component. When a specific target molecule interacts with the biological component, a signal is produced, at transducer level, proportional to the concentration of the substance. Therefore biosensors can measure compounds present in the environment, chemical processes, food and human body at low cost if compared with traditional analytical techniques. This book covers a wide range of aspects and issues related to biosensor technology, bringing together researchers from 11 different countries. The book consists of 16 chapters written by 53 authors. The first four chapters describe several aspects of nanotechnology applied to biosensors. The subsequent section, including three chapters, is devoted to biosensor applications in the fields of drug discovery, diagnostics and bacteria detection. The principles behind optical biosensors and some of their application are discussed in chapters from 8 to 11. The last five chapters treat of microelectronics, interfacing circuits, signal transmission, biotelemetry and algorithms applied to biosensing

Strategies for Multiplexed Electrochemical Sensor Development

Detection of multiple biomarkers for disease diagnosis or treatment monitoring has received a lot of attention due to their potential impact on clinical decision making. Electrochemical biosensors have become one of the preferred detection approaches, due to the simplicity of the accompanying instrumentation. This chapter will explore how electrochemical sensors can be utilized for detection of multiple analytes by integration of sensors into microfluidic microsystems. Some key fabrication technologies for such devices will be presented utilizing polymer microfabrication, paper-based approaches, and the use of printed circuit boards. Next, the use of electrode arrays will be presented along with some commercial platforms, outlining plausible paths towards a successful electrochemical multiplexed sensor. Novel approaches based on microbeads and various labels will then be introduced along with various strategies and technologies utilized to achieve ultrasensitive multiplexed detection

Development Of Carbon Based Neural Interface For Neural Stimulation/recording And Neurotransmitter Detection

Electrical stimulation and recording of neural cells have been widely used in basic neuroscience studies, neural prostheses, and clinical therapies. Stable neural interfaces that effectively communicate with the nervous system via electrodes are of great significance. Recently, flexible neural interfaces that combine carbon nanotubes (CNTs) and soft polymer substrates have generated tremendous interests. CNT based microelectrode arrays (MEAs) have shown enhanced electrochemical properties compared to commonly used electrode materials such as tungsten, platinum or titanium nitride. On the other hand, the soft polymer substrate can overcome the mechanical mismatch between the traditional rigid electrodes (or silicon shank) and the soft tissues for chronic use. However, most fabrication techniques suffer from low CNT yield, bad adhesion, and limited controllability. In addition, the electrodes were covered by randomly distributed CNTs in most cases. In this study, a novel fabrication method combining XeF2 etching and parylene deposition was presented to integrate the high quality vertical CNTs grown at high temperature with the heat sensitive parylene substrate in a highly controllable manner. Lower stimulation threshold voltage and higher signal to noise ratio have been demonstrated using vertical CNTs bundles compared to a Pt electrode and other randomly distributed CNT films. Adhesion has also been greatly improved. The work has also been extended to develop cuff shaped electrode for peripheral nerve stimulation. Fast scan cyclic voltammetry is an electrochemical detection technique suitable for in-vivo neurotransmitter detection because of the miniaturization, fast time response, good sensitivity and selectivity. Traditional single carbon fiber microelectrode has been limited to single detection for in-vivo application. Alternatively, pyrolyzed photoresist film (PPF) is a good candidate for this application as they are readily compatible with the microfabrication process for precise fabrication of microelectrode arrays. By the oxygen plasma treatment of photoresist prior to pyrolysis, we obtained carbon fiber arrays. Good sensitivity in dopamine detection by this carbon fiber arrays and improved adhesion have been demonstrated