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Nanomaterials are increasingly being developed for applications in biotechnology, including the delivery of therapeutic drugs and vaccine antigens. However, there is a lack of screening systems that can rapidly assess nanoparticle uptake and their consequential effects on cells. Established analytical in vitro approaches are often carried out on single time points, rely on time-consuming bulk measurements and are based primarily on populations of immortalised cell lines. As such, these procedures provide averaged results, do not guarantee precise control over the delivery of nanoparticles to cells and cannot easily generate information about the dynamic nature of nanoparticle-cell interactions and/or nanoparticle-mediated compound delivery. The present work addresses these issues by combining microfluidics, nanotechnology and imaging techniques into a high-throughput microfluidic platform to monitor nanoparticle uptake and intracellular processing in real-time and at the single-cell level. For this, a microfluidic device and protocols for cell trapping and live-cell monitoring were developed. In parallel, specific formulations of gold nanorods were produced, tested and optimised for intracellular multimodal imaging. Subsequently, controlled nanorod delivery to cells trapped in the microfluidic array was achieved across a range of concentrations, with intracellular nanorod signal detected using both fluorescence microscopy and surface-enhanced Raman scattering spectroscopy. Furthermore, on-chip measurement of specific cellular responses to nanorod delivery was also demonstrated. As a proof-of-concept application, the potential of the developed platform for understanding nanovaccine delivery and processing was investigated. Controlled delivery of ovalbumin-conjugated gold nanorods to primary dendritic cells was demonstrated, followed by real-time monitoring of nanoparticle uptake and antigen processing across a range of concentrations over several hours on hundreds of single-cells. This system represents a novel application of single-cell microfluidics for nanomaterial screening, providing a general platform for studying the dynamics of cell-nanomaterial interactions and representing a cost-saving and time-effective screening tool for many nanomaterial formulations and cell types.

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Ankle-foot orthoses are commonly prescribed amongst subjects with diplegic cerebral palsy as a conservative orthotic intervention. Multi-articular and bi-articular muscles are more severely involved in subjects with diplegic cerebral palsy. Appropriate clinical assessment including assessment of these muscles enables optimum ankle-foot orthosis footwear combination (AFO-FC) prescription and any required adjunct therapy. The overarching aim of this thesis was to investigate the effect of optimisation of the temporal midstance shank kinematics with the use of an AFO- FC on several variables including shank kinematics, thigh kinematics, vertical component of ground reaction force (FZ2) and ground reaction force (GRF) alignment in relation to hip and knee joint in temporal midstance to late stance. The understanding of the implication of, and the tools used to conduct assessment procedures and measurement processes were tested in the assessment of bi-articular muscles (specifically rectus femoris), to ascertain if results were predictive of presenting gait deviations and hence provide information to optimise treatment. The results of initial study suggested that a positive influence on the shank kinematics, thigh kinematics, FZ2 and GRF alignment in relation to hip and knee joint in temporal midstance to late stance was observed with the use of an AFO-FC. The results of a further study illustrated that a dominance relationship of the catch angle/length of rectus femoris (RF) measured using the Duncan-Ely with the knee or the hip joints varies at different gait points/periods. Additionally, the effect of dynamic shortness of4the RF differed on gait from the effect of true shortness. The results of series of studies testing the feasibility of using a 2-dimensional analysis system (PnO Clinical Movement Data) for hip, knee and ankle sagittal plane passive joint range of motion measurement during physical assessment confirmed the reliability and accuracy of this system.

The majority of prosthetic feet used in low-income countries suffer from a limited lifespan and limited durability. The aim of this project is to design a prosthetic foot suited to use in low-income countries that incorporates both durability and a high level of function. A review of the literature was carried out which included examining the form and function of the anatomical human foot and the existing prosthetic systems used in low-income countries as well as their limitations and successes. Also reviewed were methods of assessment of a prosthetic foot. A Product Design Specification (PDS) was created to outline the requirements of a prosthetic foot for use in a low-income country based on the information detailed in the literature review. An existing design of Strathclyde foot was tested statically according to the ISO 10328 standard. The design was modified to improve performance in identified areas followed by an evaluation of layered manufacturing processes. Having identified a potential manufacturing method for prototypes testing of materials was carried out to determine the suitability of these materials for testing. Samples of the new design were tested statically according to ISO 10328. The foot design was then further modified based on the test results, confirmed by the use of FEA at which point new prototypes were made and static testing was again carried out. A comparison of the Strathclyde foot to other feet used in low-income countries took place. The second redesign of the Strathclyde foot was assessed via force plate trials by a non-amputee subject wearing prosthetic stilts. Finally, conclusions were drawn with respect to achieving the PDS and further work was recommended to improve upon the existing design and reach the requirements of the PDS. Appendix A gives details of the roll-over shape testing carried out on a range of prosthetic feet while Appendix B details the FEA work carried out to support design modification.

The MAKO RIO (MAKO Surgical, Stryker, Mahwah, NJ, USA) is an assistive surgical robotic arm system developed to increase the accuracy of bone cuts in joint replacement surgery. A high-speed cutting burr is mounted on the arm and is manoeuvred by the surgeon. The robotic arm allows free movement of the burr through the calculated cutting volume but restricts movement, and hence cutting, outside of this volume. Localised fatigue anecdotally reported during burring from high output users of the MAKO RIO system is an issue. An ergonomic assessment of the MAKO RIO was carried out to review possible causes of the complaint of discomfort and fatigue. A clinical trial was observed and assessed for typical use of the system. This assessment culminated in a time analysis review of video footage recorded, defining a typical workflow of the surgery and details of its constituent parts. The clinical trial didn't represent a high output use of the system, but a number of users presented discomfort associated with fatigue. After observing fatigue in users of the system, the project explored the biomechanical reasons for potential causes of this fatigue. A testing protocol of optical tracking, EMG and a force transducer was developed to assess users performing repetitive burring stages of the surgery. The output from the assessment showed high levels of muscle activity, poor posture and large forces that ultimately led to fatiguing of muscles in the lower arm. Specifically, the most significant fatigue was seen in the intrinsic muscles of the hand, with the high grip forces being held for extended periods and a splayed hand over the handle of the robotic arm. A new prototype handle was also available for assessment to investigate if this would resolve the issues with the current handle. While there were some improvements in some muscles, extension and grip muscles were still presenting fatigue. The manoeuvring of the burr is still shown to take an extended length of time and require large forces from muscles that eventually cannot be met. Within high output users, either this accumulation of demand on these muscles over the day or the increased probability of a patient with sclerotic bone on a surgical list would lead these users to experience fatigue when working with the MAKO RIO system. Finally, some conceptual ideas for improvements to the system are suggested throughout the thesis. Fundamentally, however, the cutting method of a burr while enabling accurate cuts and ability to create unique shapes in the bone is not suitable for large volume resection of hard, sclerotic bone.

Falls are the leading cause of injuries in older adults. To prevent falls, early identification of individuals at risk is therefore needed. Although gait impairments are among the main risk factors, currently available clinical balance and gait assessments lack sensitivity in identifying risk for falls. Since most falls occur following trips or slips reduced ability to adequately recover from gait perturbations may be indicative of fall risk. The main aim of my industrial doctorate programme was to investigate whether reactive gait assessment can be used to identify risk for falls in older adults I used innovative technology from the company Motek and developed a mixed-perturbation protocol to challenge the individual's gait pattern and measure the recovery responses in a safe, standardized and objective manner. The initial protocol and outcome measures were based on a literature review. Three subsequent phases of development and evaluation were used to deliver a standardized reactive gait assessment. Using this assessment I was able to reveal that older adults with a history of falls were more affected by contralateral sway and deceleration perturbation in terms of continuous trunk motion than those without a history of falls, while no differences between fallers and non-fallers were found in clinical and steady state gait measures. This suggests that reactive gait assessment has added value in fall risk identification in older adults. Therefore, I recommend using the contralateral sway and deceleration perturbations of our developed perturbation protocol and assessing responses by means of continuous trunk motion to further evaluate the use of reactive gait assessment for fall risk identification in older adults. Motek as an industrial company can facilitate this by providing customers with the developed reactive gait assessment and encourage clinically driven research to examine the reproducibility and validity of reactive gait assessment using evidence-based, affordable and easy-to-use technologies.

There is a growing incidence of younger patients contracting joint disease. Osteochondral Autograft Transfer (OAT) remains a widely adopted surgical technique to treat the presence of osteochondral lesions in the knee. In this procedure, grafts of cartilage and bone are harvested from a non-load bearing site and used to replace the damaged tissue, predominately at a load bearing location. However, it is not well understood if a mismatch exists between the mechanical properties of the graft tissues and those of the local environment in which they are placed. To investigate this, a number of the key mechanical properties of cartilage and bone are determined in tibiofemoral and patellorfemoral locations, using a porcine model analogue. These include the strength of the bone but also the aggregate modulus, Poisson‟s ratio and frictional properties of the cartilage. It was discovered significant variations do exist between the sites of interest for many of these parameters and, should this translate to human models, may have implications for the integration and survival of osteochondral grafts. However, some evidence of relative immaturity in the porcine model was found, which may have had an influence on the results. Possible alternatives to OAT include tissue engineering, which has gained substantial momentum in clinical settings, and the use of allograft tissues. However, the health and viability of these osteochondral repair products is highly dependent on the environment in which they are developed (tissue engineered tissues) or stored (allograft tissues). The preliminary design and development stages of a novel bioreactor/joint simulator capable of producing physiologically relevant mechanical stimulus are discussed. It is hoped that this device can eventually be employed to grow site-specific osteochondral tissues or store osteochondral allografts in a mechanically beneficial environment.

Approximately 30% of patients with aortic stenosis over the age of 75 years are refused surgery on the grounds of technical or high risk complications. Following the onset of symptoms, prognosis is very poor if left untreated. Transcatheter aortic valves intervention (TAVI) has paved the way for valve replacement in high risk patients without the need for open heart surgery. The current market approved valves can be delivered percutaneously through the femoral artery or transapically to the beating heart, deployed over the calcified leaflets and begin functioning immediately. Complications with the current TAVI valves include a requirement for a large delivery sheath which leads to major vascular bleeding. Additionally, these valves use pericardial leaflets, which are too thick to collapse into a small catheter and have a propensity to calcify. It is therefore the objective of this thesis to develop an ultra-thin reinforced synthetic leaflet to reduce the delivery profile and facilitate deployment though a peripheral artery. Polyurethane films reinforced with multi-walled carbon nanotubes were solvent cast and tested for changes to the mechanical properties. Dip coated composite valves with varying content of carbon nanotubes were then developed and tested in a high cycle durability tester. The stiffness of composites was found to improve overall with increasing nanotube content. However, fatigue life was found to be compromised, with only the 0.125% MWNT-TPU composite material having similar fatigue life to the neat TPU. The durability of the leaflets was also severely compromised when the thickness was dropped below 50 μm. Leaflet stresses were also reportedly highest at the commissures and the belly region. A valve having sufficiently thin leaflets (130 μm) was developed from a harder grade of polyurethane and has survived 23 million cycles to date. It is believed that a thin and durable leaflet can be achieved using harder grades of polyurethanes reinforced with low carbon nanotube concentrations.