Fabrication of μ-pH Biosensor for Implantable Medical Devices and Applications in Detecting Post-Operative Complications

The monitoring of the pH milieu inside the body is critical to the functions associated with implantable medical devices. By monitoring the variation of pH in real-time inside the body, we are capable of identifying the body’s response to the implant, the probability of infection, calibrating sensors and monitoring complications such as internal bleeding or anastomotic leakage. In this work, a pH sensor is presented consisting of a working electrode, a counter electrode and reference Ag/AgCl fabricated to allow the signals to be collected and compared to a reference value. For the working electrode, we chose Polyaniline (PANI) as the sensing material. Upon exposure to different pH solutions, PANI (the active sensing material) acts as an ion-selective membrane, the concentration gradient of ions across the membrane generates a potential difference that can be measured. We first fabricate microscale interdigitated electrodes by photolithography, e-beam deposition, etching, and liftoff. Then we coated a conducting hydronium-sensitive layer of PANI or PU by electropolymerization onto the active electrode. Then we placed the second electrode into a solution of KCl to apply a thin layer of AgCl on the Ag electrode, creating the Ag/AgCl reference electrode. The potential for the polymerization to provide the most stable active layer and the Nernstian potential was optimized. Moreover, the porosity of the active layers has been modified to allow the highest concentration of hydronium ions to diffuse to the electrodes, maximizing the signal stability. This bio-compatible electrodeposited polymer layer also protects the electrode from cellular attacks and biofouling. The fabricated device was used to monitor changes in pH in biological fluids such as gastric juice, simulated blood, and peritoneal fluid. The device was capable of monitoring changes in pH with a Nernstian potential of 68mV/pH. In addition, the active layer demonstrated an active lifetime of five weeks where the electrodes were capable of collecting data continuously during the active period

Robust low power CMOS methodologies for ISFETs instrumentation

I have developed a robust design methodology in a 0.18 [Mu]m commercial CMOS process to circumvent the performance issues of the integrated Ions Sensitive Field Effect Transistor (ISFET) for pH detection. In circuit design, I have developed frequency domain signal processing, which transforms pH information into a frequency modulated signal. The frequency modulated signal is subsequently digitized and encoded into a bit-stream of data. The architecture of the instrumentation system consists of a) A novel front-end averaging amplifier to interface an array of ISFETs for converting pH into a voltage signal, b) A high linear voltage controlled oscillator for converting the voltage signal into a frequency modulated signal, and c) Digital gates for digitizing and differentiating the frequency modulated signal into an output bit-stream. The output bit stream is indistinguishable to a 1st order sigma delta modulation, whose noise floor is shaped by +20dB/decade. The fabricated instrumentation system has a dimension of 1565 [Mu] m 1565 [Mu] m. The chip responds linearly to the pH in a chemical solution and produces a digital output, with up to an 8-bit accuracy. Most importantly, the fabricated chips do not need any post-CMOS processing for neutralizing any trapped-charged effect, which can modulate on-chip ISFETs’ threshold voltages into atypical values. As compared to other ISFET-related works in the literature, the instrumentation system proposed in this thesis can cope with the mismatched ISFETs on chip for analogue-to-digital conversions. The design methodology is thus very accurate and robust for chemical sensing

Ultra-thin and flexible CMOS technology: ISFET-based microsystem for biomedical applications

A new paradigm of silicon technology is the ultra-thin chip (UTC) technology and the emerging applications. Very thin integrated circuits (ICs) with through-silicon vias (TSVs) will allow the stacking and interconnection of multiple dies in a compact format allowing a migration towards three-dimensional ICs (3D-ICs). Also, extremely thin and therefore mechanically bendable silicon chips in conjunction with the emerging thin-film and organic semiconductor technologies will enhance the performance and functionality of large-area flexible electronic systems. However, UTC technology requires special attention related to the circuit design, fabrication, dicing and handling of ultra-thin chips as they have different physical properties compared to their bulky counterparts. Also, transistors and other active devices on UTCs experiencing variable bending stresses will suffer from the piezoresistive effect of silicon substrate which results in a shift of their operating point and therefore, an additional aspect should be considered during circuit design. This thesis tries to address some of these challenges related to UTC technology by focusing initially on modelling of transistors on mechanically bendable Si-UTCs. The developed behavioural models are a combination of mathematical equations and extracted parameters from BSIM4 and BSIM6 modified by a set of equations describing the bending-induced stresses on silicon. The transistor models are written in Verilog-A and compiled in Cadence Virtuoso environment where they were simulated at different bending conditions. To complement this, the verification of these models through experimental results is also presented. Two chips were designed using a 180 nm CMOS technology. The first chip includes nMOS and pMOS transistors with fixed channel width and two different channel lengths and two different channel orientations (0° and 90°) with respect to the wafer crystal orientation. The second chip includes inverter logic gates with different transistor sizes and orientations, as in the previous chip. Both chips were thinned down to ∼20m using dicing-before-grinding (DBG) prior to electrical characterisation at different bending conditions. Furthermore, this thesis presents the first reported fully integrated CMOS-based ISFET microsystem on UTC technology. The design of the integrated CMOS-based ISFET chip with 512 integrated on-chip ISFET sensors along with their read-out and digitisation scheme is presented. The integrated circuits (ICs) are thinned down to ∼30m and the bulky, as well as thinned ICs, are electrically and electrochemically characterised. Also, the thesis presents the first reported mechanically bendable CMOS-based ISFET device demonstrating that mechanical deformation of the die can result in drift compensation through the exploitation of the piezoresistive nature of silicon. Finally, this thesis presents the studies towards the development of on-chip reference electrodes and biodegradable and ultra-thin biosensors for the detection of neurotransmitters such as dopamine and serotonin

Two-layer Electrospun System Enabling Wound Exudate Management and Visual Infection Response

The spread of antimicrobial resistance calls for chronic wound management devices that can engage with the wound exudate and signal infection by prompt visual effects. Here, the manufacture of a two-layer fibrous device with independently-controlled exudate management capability and visual infection responsivity was investigated by sequential free surface electrospinning of poly(methyl methacrylate-co-methacrylic acid) (PMMA-co-MAA) and poly(acrylic acid) (PAA). By selecting wound pH as infection indicator, PMMA-co-MAA fibres were encapsulated with halochromic bromothymol blue (BTB) to trigger colour changes at infection-induced alkaline pH. Likewise, the exudate management capability was integrated via the synthesis of a thermally-crosslinked network in electrospun PAA layer. PMMA-co-MAA fibres revealed high BTB loading efficiency (>80 wt.%) and demonstrated prompt colour change and selective dye release at infected-like media (pH > 7). The synthesis of the thermally-crosslinked PAA network successfully enabled high water uptake (WU = 1291 ± 48 − 2369 ± 34 wt.%) and swelling index (SI = 272 ± 4 − 285 ± 3 a.%), in contrast to electrospun PAA controls. This dual device functionality was lost when the same building blocks were configured in a single-layer mesh of core-shell fibres, whereby significant BTB release (~70 wt.%) was measured even at acidic pH. This study therefore demonstrates how the fibrous configuration can be conveniently manipulated to trigger structure-induced functionalities critical to chronic wound management and monitoring

Design and development of a miniaturised flow-through measuring device for the in vivo monitoring of glucose and lactate

The aim of this thesis was to develop a (portable) miniaturized device for long-term continuous real time in vivo monitoring of analytes, such as glucose and lactate. Both glucose and lactate are markers for energy metabolism, as glucose is the major energy substrate for the body and lactate is released during oxygen deficiency. Glucose and lactate can be monitored in a wide variety of settings, such as during athletic performance and pathological situations like brain trauma, diabetes and heart failure. Because an interruption in the energy supply to organs, such as the brain and the heart, can quickly lead to lifethreatening situations, the need and potential of these devices have been long recognized in clinical diagnostics. By means of real time continuous in vivo monitoring rapid clinical intervention can be established and, as a consequence, may prevent further damage. Additionally, for large patient groups, such as patients suffering from diabetes mellitus, the quality of life will be improved when frequent finger pricking to control their blood glucose level can be significantly reduced.