Research motivation: Bone tissue scaffolds offer a way forward in a strategy to change from tissue replacement to tissue regeneration. Bone tissue scaffolds are a combination of a physical construct, with clearly defined three-dimensional spatial properties, and biological cells. The microstructure of this construct is the bridge between the physicochemical properties of the scaffold and the cellular processes responsible for tissue regeneration. Gap statement: A formal design methodology has yet to be applied for the design of bone tissue scaffolds Aims and objectives: The aim of this research thesis is to select and apply design methods to the design of bone tissue scaffolds. The objectives are: 1. Review the current state of the art in design theory and methodologies for successful applications of design methods 2. Identify which design techniques are currently implemented in bone tissue scaffold design 3. To apply appropriate design methods to the design of bone tissue scaffolds 4. To validate the design outputs via a survey of expert opinion Methodologies: The following design methodologies were applied; Quality Function Deployment (QFD) and Theory of Inventive Problem Solving (TRIZ), an expanded house of quality, three-dimensional relationship technology chart (3DRTC) and Axiomatic Design (AD).Results: The multi-tiered literature review for design methodologies, firstly, identified the above design methods and, secondly, found no reason to exclude them for consideration as design methods for bone tissue scaffolds. The second literature review identified extensive computer-image-based-design as the current most advanced design method in the domain for bone tissue scaffolds. No formal design methods were in use. The first Quality Function Deployment method identified conflicts in the design which were used as inputs into TRIZ to generate potential solutions. The second QFD approach identified an extensive list of design requirements along with target engineering metrics. The three-dimensional relationship technology chart proposed how to organise design requirements into a scaffold design based upon differing scaffold design strategies. In Axiomatic Design, two approaches were followed: the first based upon percolation theory and the second based upon time-dependent behaviour. These models proposed designs at a higher level of abstraction for scaffold designers, rather than the providing the more practical solutions achieved by the QFD and 3DRTC approaches. Validation: The output of the design methodologies were validated by a survey of expert opinion. The responses indicated that both Axiomatic Design and an expanded house of quality tool offered innovation, and enhancement to, the field of bone tissue scaffold design. Conclusion: Formal design methodologies such as Axiomatic Design and Quality Function Deployment provide design solutions which offer innovation, and enhancement to, the field of bone tissue scaffold design.

Medical devices are an essential part of the human healthcare system. However, one of the major issues associated with their use is the development of medical device related infections (MDRIs) following bacterial colonisation and subsequent biofilm formation on the surface of the device. Different medical device coatings have been designed to help inhibit biofilm development. Antibacterial coatings include those that are contact active, antibacterial drug eluting or those with altered surface energies. The aim of this research was to develop strategies, which can be used to prevent the initial attachment and proliferation of microorganisms on biomaterial surfaces. Multiple linear regression (MLR) analysis was used to investigate the relationship between various drug physicochemical parameters and drug release from different hydrogel networks, which can be used alone or as a coating on medical devices such as urinary catheters. Models generated from this analysis were capable of accurately predicting the time for specific percentage release of drugs not used to derive the original models. An antibacterial quaternary ammonium compound (QAC) with thiol functionality was covalently immobilised on the surface of PVC. This created an anti-infective surface capable of preventing the adherence of two clinically important pathogens. A series of nature inspired slippery liquid infused porous surfaces were fabricated on the surface of PVC using textured silver coatings infused with different ionic liquids. As well as altering the PVC surface energy microbial adherence studies showed these materials were also capable of reducing, or in some cases preventing bacterial attachment and subsequent biofilm formation. The proposed techniques and materials developed in this thesis could be extremely useful in the fight against MDRIs.

Introduction: Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease associated with sustained ventricular arrhythmias and sudden cardiac death (SCD). Patients at high risk of SCD are currently identified by specific clinical characteristics, as outlined in an algorithm proposed by the American College of Cardiology and European Society of Cardiology in 2003. Patients at high risk of SCD are treated with Implantable Cardioverter Defibrillators (ICD), but the accuracy of the risk stratification algorithm, the long term outcome of ICD recipients and the nature of ventricular arrhythmias are unclear. Objectives: The aims of the thesis were to: a) characterise the electrophysiological nature of ventricular arrhythmias; b) determine long term outcomes post ICD implantation; c) validate the current risk stratification strategy; d) develop a novel clinical risk prediction model for SCD. Methods: Retrospective, observational cohort studies. Results: Monomorphic ventricular tachycardia is the most common ICD-treated ventricular arrhythmia (86%), and premature ventricular complexes are the most common electrical triggers (72%). ICD recipients had an appropriate shock rate of 2.3%/year (none suffered SCD), but experienced inappropriate shocks (4.6%/year), implant complications (5.1%/year) and heart failure death/transplantation (1.7%/year). Cox proportional hazards analysis showed that the risk of SCD increases with the aggregation of risk factors, but the current risk stratification strategy has poor discrimination (time dependent receiver operating characteristic curve c=0.64 at 5 years). An alternative clinical risk prediction model providing more individualised SCD risk estimates is proposed. The risk prediction model was externally validated in an Italian cohort (Harrell’s c=0.78; calibration slope: 0.82). Conclusions: The mode of initiation and morphology of ventricular arrhythmias suggest that underlying mechanism is re-entry. The current risk stratification strategy has limited predictive capabilities, and as a consequence the majority of ICD recipients do not receive appropriate shocks and are exposed to ICD related complications. The novel SCD risk prediction model offers an alternative approach by providing validated SCD risk estimates.

Embryonic stem cells have generated much interest due to their ability to differentiate into any cell type within the body. This ability could potentially allow for scientists and engineers to develop a number of therapies for diseases, which currently have no cure such as Parkinson’s disease, Alzheimer’s disease and diabetes. However, the differentiation process itself is one of the major bottlenecks in developing potential therapies. Currently protocols involve the use of mixtures of growth factors in order to create a suitable soluble microenvironment for differentiation. These growth factors are often expensive, thereby limiting the potential for scale-up of cell bioprocesses. Much interest has thus been generated into other elements of the microenvironment that could improve differentiation efficiency. The field of mechanobiology in particular, has developed rapidly in recent years. The aim of this thesis was to investigate the effect of Young’s modulus on neuronal differentiation of mouse embryonic stem cells (mESC’s). Instead of treating differentiation as one long process, the decision was made to split the process into three stages. The first, involved the formation of neural precursors from mESC’s. This was followed by the formation of immature neurons from neural precursors. The final stage was to allow the immature neurons to develop into a mature neuronal subtype. The impact of Young’s modulus was split into three effects. One was the initial attachment of cells. The second was the expansion of cells into colonies. The third was the effect of Young’s modulus on enrichment of neuronal cells. It was found that physiologically soft materials favoured the formation of all three neuronal cell types (precursor, immature and mature). However, the exact effect of differentiation varied over the course of differentiation. Over the first and second stages, soft substrates favoured the initial attachment of cells without affecting enrichment. Over the final stage, however, soft substrates directly favoured maturation of immature neurons, without having a significant effect upon their attachment. Thus the effect of Young’s modulus on neuronal differentiation changes according to the level of cellular maturity. There have not been any previous studies, which have tried to characterise the effect of the mechanical microenvironment on differentiation in a stage-by-stage manner. These findings have many important implications in terms of regenerative medicine bioprocessing. Firstly the optimal conditions for cellular attachment are not always the same as the optimal conditions for increasing cell enrichment. By carefully fine-tuning the mechanical properties at each stage of differentiation, both cell yields and final enrichment could be increased substantially. Furthermore, different cell types will require different optimisation strategies. Finally, by better understanding the interaction between cells and their mechanical environment, these findings could allow for better future design of tissue engineering biomaterials for implantation of cells into target areas for cell therapies.

If medical products were to possess the qualities of ' desirability' that are commonly associated with jewellery, positive user interaction would be enhanced. The wearer would be able to use medical products with pleasure and confidence, without fear or social stigma, and in doing so retain an element of personal control which might otherwise be lost to them. This research addresses intersections between the two disciplines of craft and science of medicine. It focuses on developing new digital jewellery capable of monitoring the medical parameters of a patient as well as redeveloping specific products such as the Asthma Inhaler, the Diabetic Insulin-Pen, and the Human Immunodeficiency Virus Medication Carrier. The aim in each case was to produce a more effective and user-friendly set of items. This research also facilitates the categorisation of jewellery artefacts which have a medical purpose, evaluating the benefits of devising new designs to ameliorate known problems, such as, iatrophobia (a phobia of seeking medical advice from a doctor or medical expert), or sociophobia (fear of being negatively judged in social situations).

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