Design and evaluation of novel microencapsulation technologies to enhance delivery of Ciclosporin

Drug delivery systems influence the various processes of release, absorption, distribution and elimination of drug. Conventional delivery methods administer drug through the mouth, the skin, transmucosal areas, inhalation or injection. However, one of the current challenges is the lack of effective and targeted oral drug administration. Development of sophisticated strategies, such as micro- and nanotechnology that can integrate the design and synthesis of drug delivery systems in a one-step, scalable process is fundamental in advancing the limitations of conventional processing techniques. Thus, the objective of this thesis is to evaluate novel microencapsulation technologies in the production of size-specific and target-specific drug-loaded particles. The first part of this thesis describes the utility of PDMS and silicon microfluidic flow focusing devices (MFFDs) to produce PLGA-based microparticles. The formation of uniform droplets was dependent on the surface of PDMS remaining hydrophilic. However, the durability of PDMS was limited to no more than 1 hour before wetting of the microchannel walls with dichloromethane and subsequent swelling occurred. Critically, silicon MFFDs revealed very good solvent compatibility and was sufficiently robust to withstand elevated fluid flow rates. Silicon MFFDs facilitated experiments to run over days with continuous use and re-use of the device with a narrower microparticle size distribution, relative to conventional production techniques. The second part of this thesis demonstrates an alternative microencapsulation technology, SmPill® minispheres, to target CsA delivery to the colon. Characterisation of CsA release in vitro and in vivo was performed. By modulating the ethylcellulose:pectin coating thickness, release of CsA in-vivo was more effectively controlled compared to current commercial CsA formulations and demonstrated a linear in-vitro in-vivo relationship. Coated minispheres were shown to limit CsA release in the upper small intestine and enhance localised CsA delivery to the colon.

A benchmark comparison between reconfigurable, intelligent and autonomous wireless inertial measurement and photonic technologies in rehabilitation

Advanced sensory systems address a number of major obstacles towards the provision for cost effective and proactive rehabilitation. Many of these systems employ technologies such as high-speed video or motion capture to generate quantitative measurements. However these solutions are accompanied by some major limitations including extensive set-up and calibration, restriction to indoor use, high cost and time consuming data analysis. Additionally many do not quantify improvement in a rigorous manner for example gait analysis for 5 minutes as opposed to 24 hour ambulatory monitoring. This work addresses these limitations using low cost, wearable wireless inertial measurement as a mobile and minimal infrastructure alternative. In cooperation with healthcare professionals the goal is to design and implement a reconfigurable and intelligent movement capture system. A key component of this work is an extensive benchmark comparison with the 'gold standard' VICON motion capture system.

A simulation-based design method to transfer surface mount RF system to flip-chip die implementation

The flip-chip technology is a high chip density solution to meet the demand for very large scale integration design. For wireless sensor node or some similar RF applications, due to the growing requirements for the wearable and implantable implementations, flip-chip appears to be a leading technology to realize the integration and miniaturization. In this paper, flip-chip is considered as part of the whole system to affect the RF performance. A simulation based design is presented to transfer the surface mount PCB board to the flip-chip die package for the RF applications. Models are built by Q3D Extractor to extract the equivalent circuit based on the parasitic parameters of the interconnections, for both bare die and wire-bonding technologies. All the parameters and the PCB layout and stack-up are then modeled in the essential parts' design of the flip-chip RF circuit. By implementing simulation and optimization, a flip-chip package is re-designed by the parameters given by simulation sweep. Experimental results fit the simulation well for the comparison between pre-optimization and post-optimization of the bare die package's return loss performance. This design method could generally be used to transfer any surface mount PCB to flip-chip package for the RF systems or to predict the RF specifications of a RF system using the flip-chip technology.

Hazard and early warning analysis based on domain specific modeling technologies

An aim of proactive risk management strategies is the timely identification of safety related risks. One way to achieve this is by deploying early warning systems. Early warning systems aim to provide useful information on the presence of potential threats to the system, the level of vulnerability of a system, or both of these, in a timely manner. This information can then be used to take proactive safety measures. The United Nation’s has recommended that any early warning system need to have four essential elements, which are the risk knowledge element, a monitoring and warning service, dissemination and communication and a response capability. This research deals with the risk knowledge element of an early warning system. The risk knowledge element of an early warning system contains models of possible accident scenarios. These accident scenarios are created by using hazard analysis techniques, which are categorised as traditional and contemporary. The assumption in traditional hazard analysis techniques is that accidents are occurred due to a sequence of events, whereas, the assumption of contemporary hazard analysis techniques is that safety is an emergent property of complex systems. The problem is that there is no availability of a software editor which can be used by analysts to create models of accident scenarios based on contemporary hazard analysis techniques and generate computer code that represent the models at the same time. This research aims to enhance the process of generating computer code based on graphical models that associate early warning signs and causal factors to a hazard, based on contemporary hazard analyses techniques. For this purpose, the thesis investigates the use of Domain Specific Modeling (DSM) technologies. The contributions of this thesis is the design and development of a set of three graphical Domain Specific Modeling languages (DSML)s, that when combined together, provide all of the necessary constructs that will enable safety experts and practitioners to conduct hazard and early warning analysis based on a contemporary hazard analysis approach. The languages represent those elements and relations necessary to define accident scenarios and their associated early warning signs. The three DSMLs were incorporated in to a prototype software editor that enables safety scientists and practitioners to create and edit hazard and early warning analysis models in a usable manner and as a result to generate executable code automatically. This research proves that the DSM technologies can be used to develop a set of three DSMLs which can allow user to conduct hazard and early warning analysis in more usable manner. Furthermore, the three DSMLs and their dedicated editor, which are presented in this thesis, may provide a significant enhancement to the process of creating the risk knowledge element of computer based early warning systems.

Energy harvesting system design and optimization for wireless sensor networks

Wireless sensor networks (WSN) are becoming widely adopted for many applications including complicated tasks like building energy management. However, one major concern for WSN technologies is the short lifetime and high maintenance cost due to the limited battery energy. One of the solutions is to scavenge ambient energy, which is then rectified to power the WSN. The objective of this thesis was to investigate the feasibility of an ultra-low energy consumption power management system suitable for harvesting sub-mW photovoltaic and thermoelectric energy to power WSNs. To achieve this goal, energy harvesting system architectures have been analyzed. Detailed analysis of energy storage units (ESU) have led to an innovative ESU solution for the target applications. Battery-less, long-lifetime ESU and its associated power management circuitry, including fast-charge circuit, self-start circuit, output voltage regulation circuit and hybrid ESU, using a combination of super-capacitor and thin film battery, were developed to achieve continuous operation of energy harvester. Low start-up voltage DC/DC converters have been developed for 1mW level thermoelectric energy harvesting. The novel method of altering thermoelectric generator (TEG) configuration in order to match impedance has been verified in this work. Novel maximum power point tracking (MPPT) circuits, exploring the fractional open circuit voltage method, were particularly developed to suit the sub-1mW photovoltaic energy harvesting applications. The MPPT energy model has been developed and verified against both SPICE simulation and implemented prototypes. Both indoor light and thermoelectric energy harvesting methods proposed in this thesis have been implemented into prototype devices. The improved indoor light energy harvester prototype demonstrates 81% MPPT conversion efficiency with 0.5mW input power. This important improvement makes light energy harvesting from small energy sources (i.e. credit card size solar panel in 500lux indoor lighting conditions) a feasible approach. The 50mm × 54mm thermoelectric energy harvester prototype generates 0.95mW when placed on a 60oC heat source with 28% conversion efficiency. Both prototypes can be used to continuously power WSN for building energy management applications in typical office building environment. In addition to the hardware development, a comprehensive system energy model has been developed. This system energy model not only can be used to predict the available and consumed energy based on real-world ambient conditions, but also can be employed to optimize the system design and configuration. This energy model has been verified by indoor photovoltaic energy harvesting system prototypes in long-term deployed experiments.

Usability-enhanced coordination design of geovisualisations to communicate coastal flood risk information

For at least two millennia and probably much longer, the traditional vehicle for communicating geographical information to end-users has been the map. With the advent of computers, the means of both producing and consuming maps have radically been transformed, while the inherent nature of the information product has also expanded and diversified rapidly. This has given rise in recent years to the new concept of geovisualisation (GVIS), which draws on the skills of the traditional cartographer, but extends them into three spatial dimensions and may also add temporality, photorealistic representations and/or interactivity. Demand for GVIS technologies and their applications has increased significantly in recent years, driven by the need to study complex geographical events and in particular their associated consequences and to communicate the results of these studies to a diversity of audiences and stakeholder groups. GVIS has data integration, multi-dimensional spatial display advanced modelling techniques, dynamic design and development environments and field-specific application needs. To meet with these needs, GVIS tools should be both powerful and inherently usable, in order to facilitate their role in helping interpret and communicate geographic problems. However no framework currently exists for ensuring this usability. The research presented here seeks to fill this gap, by addressing the challenges of incorporating user requirements in GVIS tool design. It starts from the premise that usability in GVIS should be incorporated and implemented throughout the whole design and development process. To facilitate this, Subject Technology Matching (STM) is proposed as a new approach to assessing and interpreting user requirements. Based on STM, a new design framework called Usability Enhanced Coordination Design (UECD) is ten presented with the purpose of leveraging overall usability of the design outputs. UECD places GVIS experts in a new key role in the design process, to form a more coordinated and integrated workflow and a more focused and interactive usability testing. To prove the concept, these theoretical elements of the framework have been implemented in two test projects: one is the creation of a coastal inundation simulation for Whitegate, Cork, Ireland; the other is a flooding mapping tool for Zhushan Town, Jiangsu, China. The two case studies successfully demonstrated the potential merits of the UECD approach when GVIS techniques are applied to geographic problem solving and decision making. The thesis delivers a comprehensive understanding of the development and challenges of GVIS technology, its usability concerns, usability and associated UCD; it explores the possibility of putting UCD framework in GVIS design; it constructs a new theoretical design framework called UECD which aims to make the whole design process usability driven; it develops the key concept of STM into a template set to improve the performance of a GVIS design. These key conceptual and procedural foundations can be built on future research, aimed at further refining and developing UECD as a useful design methodology for GVIS scholars and practitioners.

Research and design of high-speed advanced analogue front-ends for fibre-optic transmission systems

In the last decade, we have witnessed the emergence of large, warehouse-scale data centres which have enabled new internet-based software applications such as cloud computing, search engines, social media, e-government etc. Such data centres consist of large collections of servers interconnected using short-reach (reach up to a few hundred meters) optical interconnect. Today, transceivers for these applications achieve up to 100Gb/s by multiplexing 10x 10Gb/s or 4x 25Gb/s channels. In the near future however, data centre operators have expressed a need for optical links which can support 400Gb/s up to 1Tb/s. The crucial challenge is to achieve this in the same footprint (same transceiver module) and with similar power consumption as today’s technology. Straightforward scaling of the currently used space or wavelength division multiplexing may be difficult to achieve: indeed a 1Tb/s transceiver would require integration of 40 VCSELs (vertical cavity surface emitting laser diode, widely used for short‐reach optical interconnect), 40 photodiodes and the electronics operating at 25Gb/s in the same module as today’s 100Gb/s transceiver. Pushing the bit rate on such links beyond today’s commercially available 100Gb/s/fibre will require new generations of VCSELs and their driver and receiver electronics. This work looks into a number of state‐of-the-art technologies and investigates their performance restraints and recommends different set of designs, specifically targeting multilevel modulation formats. Several methods to extend the bandwidth using deep submicron (65nm and 28nm) CMOS technology are explored in this work, while also maintaining a focus upon reducing power consumption and chip area. The techniques used were pre-emphasis in rising and falling edges of the signal and bandwidth extensions by inductive peaking and different local feedback techniques. These techniques have been applied to a transmitter and receiver developed for advanced modulation formats such as PAM-4 (4 level pulse amplitude modulation). Such modulation format can increase the throughput per individual channel, which helps to overcome the challenges mentioned above to realize 400Gb/s to 1Tb/s transceivers.

Design, fabrication and characterisation of components for microfluidic enzymatic biofuel cells

The concept of a biofuel cell takes inspiration from the natural capability of biological systems to catalyse the conversion of organic matter with a subsequent release of electrical energy. Enzymatic biofuel cells are intended to mimic the processes occurring in nature in a more controlled and efficient manner. Traditional fuel cells rely on the use of toxic catalysts and are often not easily miniaturizable making them unsuitable as implantable power sources. Biofuel cells however use highly selective protein catalysts and renewable fuels. As energy consumption becomes a global issue, they emerge as important tools for energy generation. The microfluidic platforms developed are intended to maximize the amount of electrical energy extracted from renewable fuels which are naturally abundant in the environment and in biological fluids. Combining microfabrication processes, chemical modification and biological surface patterning these devices are promising candidates for micro-power sources for future life science and electronic applications. This thesis considered four main aspects of a biofuel cell research. Firstly, concept of a miniature compartmentalized enzymatic biofuel cell utilizing simple fuels and operating in static conditions is verified and proves the feasibility of enzyme catalysis in energy conversion processes. Secondly, electrode and microfluidic channel study was performed through theoretical investigations of the flow and catalytic reactions which also improved understanding of the enzyme kinetics in the cell. Next, microfluidic devices were fabricated from cost-effective and disposable polymer materials, using the state-of-the-art micro-processing technologies. Integration of the individual components is difficult and multiple techniques to overcome these problems have been investigated. Electrochemical characterization of gold electrodes modified with Nanoporous Gold Structures is also performed. Finally, two strategies for enzyme patterning and encapsulation are discussed. Several protein catalysts have been effectively immobilized on the surface of commercial and microfabricated electrodes by electrochemically assisted deposition in sol-gel and poly-(o-phenylenediamine) polymer matrices and characterised with confirmed catalytic activity.