Despite the scientific, technological and surgical improvements of the past 50 years organ dysfunction following elective paediatric cardiac surgery utilising cardiopulmonary bypass continues to account for increased complications, often leading to a protracted course in hospital with a longer stay in intensive care and the potential for irreversible organ damage long term. Furthermore, paediatric cardiac surgeons are routinely undertaking more complex operations with a shift from palliation to early correction. This has resulted in younger children being subjected to longer periods on the bypass machine with increased effects on vital organs. This thesis describes two clinical studies designed to further assess and characterise peri-operative cardiac, renal and pulmonary function in children undergoing elective cardiac repair at a tertiary referral centre in Scotland, UK. In the first instance a prospective, observational study was undertaken in forty-five children to examine the use of tissue Doppler imaging in the assessment of peri-operative cardiac function, its relationship to myocardial injury and clinical outcome. Tissue Doppler parameters were obtained using a Vivid 7 ultrasound scanner with a 7-MHz probe pre-operatively, on admission to paediatric intensive care and on day one. Myocardial injury was assessed using Troponin-I on the first post-operative day by a commercially available chemiluminescent immunoassay. In twenty children within this group peri-operative renal function was also investigated using standard estimates of glomerular filtration rate, namely creatinine clearance measured by the kinetic Jaffe method during the first and second twelve hour post-operative periods, in comparison to serum creatinine and the novel biomarker cystatin C. Routine plasma retained pre-operatively and on days 0, 1, 2 and 3 post-operatively was used to measure serum cystatin C and creatinine using a particle-enhanced nephelometric immunoassay and the Roche Creatinine Plus enzymatic assay respectively. The association between cystatin C and recorded perfusion parameters including bypass duration, pump flow, haematocrit, oxygen delivery and Troponin-I was investigated. Peri-operative pulmonary function was evaluated through a phase IV, randomised, double-blind, placebo controlled trial. In total, twenty four children were randomised to receive oral sildenafil or equivalent volume placebo four times the day before surgery. Blood samples were collected peri-operatively to measure serum cyclic guanosine monophosphate with a commercially available competitive enzyme immunoassay. Haemodynamic data and echocardiography were acquired at two and twenty four hours post-operatively including pulmonary vascular resistance index and bi-ventricular contractility. Post-operative oxygenation was also determined at the same time by oxygen delivery and oxygenation index. In Chapter 2, peri-operative cardiac function as assessed by tissue Doppler imaging was examined. The results of this study demonstrated that pre-operatively, bi-ventricular systolic function in the study group was reduced compared with normal controls, displaying a significant step-wise decrease with increasing complexity of lesion. This picture persisted post-operatively predominantly in the right ventricle and was significantly associated with the extent of myocardial injury. Impaired peri-operative left ventricular function correlated with clinical outcomes. In Chapter 3, peri-operative renal function as assessed by cystatin C and its association with parameters of perfusion was examined. The results of this study demonstrated that in comparison to serum creatinine, cystatin C had a superior correlation with glomerular filtration rate in the early post-operative period. An elevated level of this biomarker was significantly associated with bypass duration, minimum pump flow and post-operative myocardial injury. Haematocrit was not directly linked to renal dysfunction in this study although evidence of a critical dysoxic threshold within the kidney was suggested indirectly through oxygen delivery calculations. In Chapter 4, peri-operative pulmonary function and vascular reactivity in association with the pre-operative administration of oral sildenafil (0.5mg/kg, six hourly) was examined. The results of this trial demonstrated that compared to placebo, pre-operative sildenafil resulted in modest elevations of serum cyclic guanosine monophosphate, limited effects on pulmonary vascular resistance index, significant reductions in peri-operative bi-ventricular contractility, significant reductions in post-operative oxygen delivery and a trend for increasing ventilatory support. In summary, the current thesis has demonstrated that in children undergoing corrective cardiac surgery peri-operative bi-ventricular function can be accurately assessed by tissue Doppler imaging which to date has had limited use in this patient group. With regards to renal function, cystatin C was shown to be a better estimate of glomerular filtration rate and a more sensitive marker of early renal dysfunction in children after surgery. Furthermore, cystatin C identified a transient post-operative renal impairment, the magnitude of which was associated with duration of bypass, pump flow and myocardial injury. In relation to pulmonary function, this research identified that pre-operative administration of oral sildenafil to children undergoing cardiac surgery produced limited effects on pulmonary vascular resistance but was associated with reduced ventricular contractility and post-operative oxygenation raising significant concerns over its routine clinical use.

Ultrasonic cutting has existed in surgery since the 1950s. However, it was not until the end of the 20th century that advances in ultrasonic tool design, transduction and control allowed commercially viable ultrasonic cutting devices to enter the market. Ultrasonic surgical devices, like those in other power ultrasonic applications such as drilling and welding, require devices to be driven at high power to ensure sufficient output motion is produced to fulfil the application it is designed to perform. With the advent of novel surgical techniques surgeons require tuned ultrasonic tools which can reduce invasiveness while giving access to increasingly difficult to reach surgical sites. To fulfil the requirements of novel surgical procedures new tuned tools need to be designed. Meanwhile, it is well documented that power ultrasonic devices, whilst driven at high power, are inherently nonlinear and, if no attempt is made to understand and subsequently control these behaviours, it is likely that these devices will suffer from poor performance or even failure. The behaviour of the commercial ultrasonic transducer used in bone surgery (Piezosurgery® Device) is dynamically characterised through finite element and experimental methods whilst operating in conjunction with a variety of tuned inserts. Finite element analysis was used to predict modal parameters as well as stress levels within the tuned devices whilst operating at elevated amplitudes of vibration, while experimental modal analysis validated predicted resonant frequencies and mode shapes between 0-80kHz. To investigate the behaviour of tuned devices at elevated vibrational amplitudes near resonance, responses were measured whilst the device was excited via the burst sine sweep method. In an attempt to provide an understanding of the effects that geometry, material selection and wavelength of tuned assemblies have on the behaviour of an ultrasonic device, tuned inserts consisting of a simple rod horn design were characterised alongside more complex cutting inserts which are used in maxillofacial and craniofacial surgery. From these results the aim will be to develop guidelines for design of tuned inserts. Meanwhile, Langevin transducers, commonly known as sandwich or stack transducers, in their most basic form generally consist of four parts; a front mass, a back mass, a piezoceramic stack and a stud or bolt holding the parts together under a compressive pre-load. It is traditionally proposed that the piezoceramic stack is positioned at or close to the vibrational nodal point of the longitudinal mode, however, this also corresponds with the position of highest dynamic stress. It is also well documented that piezoceramic materials possess a low linear stress threshold, therefore this research, in part, investigates whether locating the piezoceramic stack away from a position of intrinsic high stress will affect the behaviour of the device. Through experimental characterisation it has been observed that the tuned devices under investigation exhibited; resonant frequency shifts, jump amplitudes, hysteretic behaviour as well as autoparametric vibration. The source of these behaviours have been found to stem from device geometry, but also from heating within the piezoceramic elements as well as joints with different joining torques.

Historically, bone defects resulting from trauma, disease or infection are treated with autograft or allograft. Autograft is bone transplanted from a non-critical area of the skeleton and allograft is bone donated from another member of the same species. The drawbacks with these treatments such as limited availability, donor site morbidity, high cost and disease transmission have driven increasing use of bone graft substitute (BGS) materials. These represent 15% of the £1.6 billion global orthobiologics market. BGS materials available to date are not suitable for use in grafts that are intrinsic to the stability of the skeleton. Thus, the aim for this project was to fabricate an off the shelf and economically viable BGS that will support the skeletal structure whilst healing occurs. This project employed an empirical approach utilising both rapid prototyping (RP) and conventional manufacturing processes to produce novel BGSs. A range of RP techniques were attempted and discovered to be unsuitable as a result of their long build and postprocessing times, poor availability of suitable materials, and undesirable surface finish. Experiments with injection moulding and laser drilling of polylactic acid (PLA) successfully produced 10 mm blocks with a compressive strength of 67 – 80 MPa and compressive modulus of 1.5 – 2.2 GPa. This line of research led to the hypothesis that ceramic extrusion, a process hitherto untested for use in bone tissue engineering (BTE), may be feasible for production of a novel and high strength BGS. In collaboration with an international expert in the manufacture of ceramic monoliths it was possible, for the first time, to manufacture hydroxyapatite (HA) monoliths by adapting the process used for manufacture of automotive exhaust catalysts. These HA monoliths exhibited a compressive strength of 142 – 265 MPa and compressive modulus of 3.2 – 4.4 GPa. The exceptional strength of these monoliths match the properties of cortical bone whilst retaining the high levels of porosity (> 60 %) found in cancellous bone. This combination of strength and porosity will enable treatment of large structural bone defects where the high strength will withstand typical skeletal forces whilst the high porosity allows blood vessels to infiltrate the monolith and begin the healing process. Furthermore, these HA monoliths support the proliferation and differentiation of human osteoblast-like MG63 cells and compare very favourably with a market leading BGS material in terms of their biological performance. It is suggested that this work will result in the development of a new family of high strength and high porosity BGSs for use in challenging clinical situations. The International Preliminary Examination Report for the patent issued to the author (WO 2007/125323) decreed that all 45 claims contained novelty and an inventive step. Two successful applications for research funding have raised nearly £50,000 that helped fund this research effort. Warwick ventures are currently involved in negotiating with medical partners to licence this technology for clinical use.

The potential effects of introducing bone regeneration strategies into environments of disease and damage are often overlooked, despite the fact that many of the signalling pathways in inflammation have effects on bone development and healing. Embryonic stem cells (ESCs) are increasingly being used to develop models of disease and have potential in osteogenic-cell based therapies. Osteogenic differentiation strategies for ESCs are well established, but the response of these cells to tissue damage and inflammation has not yet been investigated, particularly in comparison to primary osteoblasts. Here, proinflammatory cytokines were used as part of an in vitro model to mimic elements of skeletal disease, such as rheumatoid arthritis and non-union fractures. The response of osteogenically differentiated mouse embryonic stem cells (osteo-mESCs) to the proinflammatory cytokines interleukin 1-β (IL-1β), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), was compared to that of primary mouse calvarial osteoblasts, already well-described in literature and used as a “benchmark” in this study. Although histology, immunocytochemistry and PCR showed similarities in osteogenic differentiation of the osteo-mESCs and the primary calvarial cells, over 21 days in culture, there were marked differences in the response to the proinflammatory cytokines. Viability of the osteo-mESCs was maintained in response to cytokines, whereas viability of primary cells was significantly reduced. There were marked increases in nitric oxide (NO) and prostaglandin E2 (PGE2) production in primary calvarial cells over the entire 21-day culture period, but this was not seen with osteo-mESCs until day 21. The study then went on to look at the effects of proinflammatory signalling on the in vitro bone formation of the two cell types. Significant differences in the effects of proinflammatory cytokines on bone nodule formation and matrix production were seen when comparing the osteo-mESCs and the calvarial cells. This study demonstrates that while osteo-mESCs share phenotypic characteristics with primary osteoblasts, there are some distinct differences in their biochemistry and response to cytokines. This is relevant to understanding differentiation of stem cells, developing in vitro models of disease, testing new drugs and developing cell therapies. An additional objective in this investigation was to look at tissue engineering strategies as a means of controlling inflammation in bone disease. The primary calvarial osteoblasts were utilised as an in vitro inflammation model, and used to study the effects of anti-inflammatory mediators. Anti-inflammatory-releasing porous scaffolds were manufactured from poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG). The calvarial osteoblast inflammation model was used successfully to show successful release of diclofenac sodium from the PLGA/PEG scaffolds. This study demonstrates that there is much to consider in the development of regenerative strategies for bone disease, particularly the role that the effect and control of inflammation will play in bone healing.

The aim of this thesis was to investigate the impact of the Managed Clinical Network (MCN) for colorectal cancer in the West of Scotland on outcomes for its patients. The alternative hypothesis was that greater changes to patient outcome had occurred over time than those that would have been expected in the absence of a Managed Clinical Network service structure. The study was a retrospective cohort study merging locally derived clinical audit and nationally held Cancer Registry datasets. This facilitated a comprehensive examination of patient characteristics and survival outcomes in varied cohorts of patients suffering from colorectal cancer in the West of Scotland. I employed longitudinal, cross sectional, univariate and multivariate methods of data analysis. Following a review of the current literature a baseline demographic summary of the population was produced. This allowed an examination of temporal changes in both survival and practice in the region in order to evaluate the key determinants underpinning differences before and after the inception of the new service structure. I went on to study specific aspects of patient management on outcome including effects of surgeon specialisation, effects of mechanical bowel preparation on short and long term outcomes and degree of equity of surgical provision for patients with rectal cancer. These aspects of care are thought to be measures of quality in patients with colorectal cancer and could be influenced by the inception of a Managed Clinical Network Evaluation of the current literature regarding effects of Managed Clinical Network on outcomes for colorectal cancer patients demonstrated a paucity of studies investigating the alternative hypothesis. Overall it appears that the introduction of the MCN has lead to improvements in survival for particular groups of patients only. We analysed the records of 37,890 colorectal cancer patients in the West of Scotland over a 25-year period and confirmed expected proportions of colonic to rectal lesions as well as equal sex distribution. We also report a higher ascertainment for data regarding Dukes’ stage when compared to other published series. Trends in relation to volume of work undertaken by surgeons on colorectal cancer patients in the West of Scotland demonstrate that there was increasing specialisation over the period under study. This is evidenced by the increase in proportion of resections performed by higher volume surgeons and is encountered in both colon and, to a lesser extent rectal cancer surgery. It seems that increasing specialisation has had resultant effects on overall survival for colon cancer patients but not for rectal cancer patients thus far. With regard to specific aspects of patient care we were able to show that specialisation has increased with time in our region and that mechanical bowel preparation has no effect on either immediate or long-term outcome in patients undergoing surgery for colon cancer. We also showed that in the West of Scotland we provide a surgical service to rectal cancer patients that is unbiased with regard to sex and degree of socioeconomic deprivation. This contrasts to previous findings in England.

The primary aim of this thesis was to develop more acceptable methods of ballistic neck protection that could replace the existing OSPREY ballistic neck collar. Clinical and post mortem injury analysis, computed tomography interpretation and ergonomics assessments were undertaken, resulting in the recommendation of two prototype designs to the Ministry of Defence. These two prototypes have subsequently been renamed the Enhanced Protection Under Body Armour Combat Shirt and the Patrol collar, and are now issued to all UK armed forces personnel deploying on operations overseas. The secondary aim of this thesis was to develop methods to validate the potential medical effectiveness of future body armour designs. Two new novel injury models have been developed using an anthropometrically accurate three- dimensional representation of cervical anatomical structures. Penetration of representative fragment simulating projectiles through skin and muscle was determined experimentally using physical and animal simulants. The Coverage of Armour Tool is being used in the current Ministry of Defence VIRTUS procurement programme to rule out future body armour designs on medical grounds, thereby greatly reducing the number of prototypes requiring ergonomics assessment.

Kidney Transplantation is the gold standard treatment for patients with end-stage renal failure. Most kidneys used for transplantation are from deceased donors and ensuring successful outcomes depends on many factors. One of these is organ storage. Hypothermic Machine Perfusion (HMP) of deceased donor organs has been shown to have several benefits. However, it has not been widely adopted and the underlying mechanism is poorly understood. The first section of this thesis examines the introduction of HMP into clinical practice. HMP outcomes were similar to those of standard storage techniques but with the additional benefit of increasing safe storage times. This was likely due to inherent benefits of the machine itself, improved recipient preparation and better peri-operative conditions. The second part of this study analysed HMP perfusate using metabolomics (Nuclear Magnetic Resonance) to identify potential predictors of graft outcome. Differences were identified in the metabolic profiles of perfusate from kidneys with immediate and delayed graft function. These may have a future role in viability assessment. Improved understanding of metabolism during storage may help target optimization strategies for deceased donor organs. The final part of this study describes the development of a porcine model of transplantation to test future hypotheses.

This thesis reports a clinical study designed to assess myocardial, renal and lung outcomes following cardiac surgery. In a single centre, prospective randomized, placebo intervention-controlled trial the effects of intermittent upper limb ischaemia (remote ischaemic preconditioning (RIPC)) were compared in non-diabetic adult patients undergoing on-pump multi-vessel coronary artery surgery. Patients, investigators, anaesthetists, surgeons and critical care teams were all blind to group allocation. Subjects were randomized(1:1) to RIPC(or placebo) stimuli (3x upper limb (or dummy arm) 5 minute cycles of 200mmHg cuff inflation/deflation) during sternotomy and conduit procurement. Anaesthesia, perfusion, cardioplegia and surgical techniques were standardized. Groups were well matched on demographic and operative variables. In contrast to prior smaller studies, RIPC did not reduce troponin T (48 hour area under the curve (AUC); 6hour and peak) release, improve post-operative haemodynamics (cardiac indices; low cardiac output episodes incidence; IABP usage; inotrope and vasoconstrictor use; M mode, 2D contrastenhanced echocardiography and tissue Doppler imaging) or offer antiarrhythmic benefit (de novo left bundle branch block or Q waves; ventricular tachyarrhythmia incidence). RIPC did not afford renal (peak creatinine, AUC urinary albumin-creatinine ratios, dialysis requirement) or lung protection (intubation times, 6hour and 12 hour pO2/FiO2 ratios). Case urgency did not influence RIPC effect.

Poly-ether-ether-ketone (PEEK) is a high performance aromatic thermoplastic with proven biocompatibility. Recently, it has been proposed as a promising bearing material for cervical total disc replacement (TDR). A new bearing combination of PEEK-on-PEEK based self-mating articulation has been used, which may overcome current bearing materials related complications. For ball-on-socket based cervical TDR designs, PEEK based bearing articulation is expected to operate under a boundary lubrication regime regardless of the radial clearance used. The contact stress encountered by the bearing surfaces is insufficient to result in either material yield or fatigue failure. High-cycle fatigue tests were performed on PEEK 450G specimens via three-point flexural bending. The obtained fatigue results (104.1 ± 5.8 MPa) show superiority over the historical polymeric bearing material UHMWPE (31 MPa). Moreover, it demonstrates a good resistance to sterilisation and thermal ageing. Laboratory wear simulation was also conducted, using spine simulators and following ISO 18192-1 standard. For PEEK-on-PEEK self-mating articulation, a steady state wear rate of 1.0 ± 0.9 mg/million cycles is obtained, which is comparable as the historical bearing combination (UHMWPE against CoCrMo). The results of this work suggest that PEEK-on-PEEK based articulation is a possible alternative for future cervical TDR designs.

This thesis evaluates and explores the effectiveness of post discharge physiotherapy exercise following total knee arthroplasty (TKA) for osteoarthritis in three ways. 1. A systematic review evaluated the effectiveness of post discharge physiotherapy exercise on function, walking, range of motion, quality of life and muscle strength, for patients following elective primary TKA. Functional physiotherapy exercise interventions following discharge resulted in short term, but not long term, benefit. Effect sizes were small to moderate for function (0.33). Weighted mean differences were small to moderate for motion (2.9) and small for quality of life (1.66). 2. A randomised clinical trial compared the effectiveness of a post discharge physiotherapy intervention in improving patient function versus usual physiotherapy for patients undergoing primary TKA. No significant statistical differences were observed between the two groups for all outcomes. This early trial was underpowered and impacted upon by some important factors which could potentially have masked any treatment trends occurring in the home visit group. 3. Since blinding procedures are often assumed to indicate trial quality, the feasibility of achieving blind outcome assessment in a pragmatic physiotherapy rehabilitation trial involving older people was explored. Reasons for unblinding were explored and successful blinding rates of 81-91% were achieved.