Colorectal cancer is the second most common cause of cancer death in the Western world but the factors that determine disease progression remain poorly understood. At the outset of this thesis it was recognised that tumour growth and metastases were determined by complex interactions between tumour and host. It was evident that a systemic inflammatory response was associated with poor prognosis in colorectal cancer while a strong local immune cell response conferred a favourable outcome. This thesis investigated this topic by examining the factors responsible for activating, maintaining and regulating these inflammatory responses and drew the following conclusions: Chapter 3 concluded that abnormal patient physiology, in particular the presence of anaemia and cardiac disease, was strongly associated with a systemic inflammatory response in patients with colorectal cancer. Targeting specific physiological parameters may therefore be a novel way to improve a patients’ inflammatory status. Chapter 5 used CT image analysis to confirm a strong relationship between systemic inflammation and reduced skeletal muscle mass in patients with colorectal cancer. This offered insight into the underlying basis of cancer-related weight loss and suggested attenuation of the host inflammatory response may be a therapeutic target in cancer cachexia. Chapter 6 built on these results with a detailed examination of the relative importance of pre-, intra- and post-operative factors in patients undergoing surgery for colorectal cancer. Rather than being the cause of disease recurrence, surgical complications appeared to be a consequence of pre-existing physiological disturbance and systemic inflammation, supporting a concept whereby pre-operative status is of paramount importance to long-term cancer outcomes. Chapter 7 investigated possible links between the local and systemic inflammatory responses. The pathological feature of tumour necrosis was confirmed as both an independent prognostic indicator in colorectal cancer and the first documented link between local and systemic inflammation. A model was proposed whereby failure of local anti-tumour control leads to rapid growth, tissue hypoxia and cellular necrosis, triggering the host to initiate a systemic inflammatory response. The local inflammatory response in colorectal cancer was then considered. Chapter 8 confirmed that, while a strong local response was primarily the result of lymphocyte infiltration, the examination of individual cell types did not add prognostic value compared to an overall grade of peritumoural inflammation. Chapter 9 built on this knowledge to examine the clinical utility of the local inflammatory response in colorectal cancer. It was clear that the density of cellular infiltrate was more important than the type or location of individual immune cells. After comparing a number of methodologies, an overall grade of peritumoural inflammation, using the Klintrup-Makinen (K-M) criteria, was established as the preferred technique for assessing the local inflammatory response in colorectal cancer.

A novel technique to manufacture porous Poly-Ether-Ether-Ketone (PEEK) scaffolds via a tapped-packing route of fabrication incorporating rounded salt beads had been investigated. The conventional salt leaching technique has been improved via the tapping-route in manufacturing porous PEEK structure that possesses adequate structural and mechanical properties. Three types of PEEK, Vicote, LT3 and LT1 were used as main material and rounded salt as a porogen. PEEK powder and the rounded salt were mixed in 6:1 mass ratio by applying tapping to 22 mm cylindrical die. 5 g of PEEK/salt beads mixture was packed through 8000 taps. Alternative mixing techniques also involved wet (using sprayed water) and dry mixing routes prior to the compaction. To solidify the PEEK and to obtain free-salt PEEK scaffolds, then sintering, dissolving and drying were applied. The results show that only a combination of the tapping route and the LT1 PEEK could secure porous PEEK scaffolds with acceptable and required characteristics in associated with the pore size range (main pores of (560 + 180) µm and windows of (204 + 41) µm) and shape, good interconnectivity, and homogenous and high porosity > 80%. It was also successfully integrated into a viable spinal PEEK cage implant via injection moulding.

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Bone cement is required for the majority of implant procedures. The mechanical integrity of cemented implants may be compromised by fatigue failure of the bone cement, mainly due to internal defects or debonding at the implant interfaces; improvements in the mechanical properties of bone cement may therefore be valuable if the implant lifetime of cemented arthroplasties are to be increased and revision rates decreased. The present study investigated the use of synchrotron X-ray microtomography for the observation of internal defects and failure processes that occur during fatigue loading. Initial assessments of fatigue damage processes in in-vitro fatigue test specimens demonstrated the uncertain nature of locating fatigue cracks and other defects, identifying the need for a synthesis of high resolution tomographic imaging with complementary prior damage monitoring methods. This was achieved via a novel amalgamation of acoustic emission, ultrasound and/or microfocus computed tomography scans prior to testing. Location of cracks/defects prior to high resolution tomographic imaging increased the probability of capturing crack initiation, furthering the underlying understanding of crack formation and propagation. Experiments performed at the European Synchrotron Research Facility have shown that the microstructural features of a commercial bone cement are readily imaged using microtomography of short exposure times. Furthermore, interactions (for example crack deflection and ligament formation) have been clearly identified between failure processes and both the cement defect population and internal microstructure. Early stages of crack initiation have also been captured: a new mechanism of crack initiation is proposed where porosity and local BaSO4 distribution are seen to act together to cause resultant crack initiation in the cement matrix rather than directly from pore surfaces. An opportunity for cement enhancement has been identified in the use of carbon nanotubes (CNTs); improved mechanical and physical properties of acrylic bone cement reinforced with CNTs are reported in the literature, although current methods utilised for CNT dispersion in polymers do not immediately lend themselves to surgical deployment. Adding CNTs to bone cement may further provide bio-active and sensing capabilities, beyond the conventional fixation and load-bearing rôle. The present study confirms that CNT-reinforcement (using shear mixing techniques) enhances the fatigue performance of a PMMA matrix and additional acoustic emission parameter based analyses confirm that the presence of CNTs alters the associated failure mechanisms. An insight into the potential capabilities of CNT reinforced cements, using relatively simple preparation techniques suitable for surgical deployment, is provided. These results suggest that enhanced fatigue performance may be achieved by means of CNT reinforcement of the matrix leading to crack shielding mechanisms such as crack bridging. Biologically, the presence of CNTs may reduce local thermal necrosis in the tissue surrounding the cemented construct through a reduction of the peak exothermic polymerisation temperature.

Incorporation of routine biofeedback into the management of patients with rectal cancer who are undergoing anterior resection offers potential for improved anal continence compared with standard management. A multicentre randomised controlled trial was performed to investigate this and 121 participants undergoing major rectal resection were randomly assigned to receive biofeedback training. In the control group participants received standard management. Randomisation was stratified for preoperative radiotherapy exposure. The primary end point was Cleveland Clinic Incontinence (CCI) score at 1 year. Analysis was by intention to treat (ITT). Secondary end points were serial symptom-score, quality of life questionnaires and anorectal physiology measured during the first postoperative year. Follow-up to one year was completed by 89 participants. A mean CCI score of 4 was recorded at 1 year in both groups. Before anterior resection, 15 (17%) participants reported severe anal incontinence. At 3 months after anterior resection, 27% of participants reported severe anal incontinence, which caused a negative impact on their quality of life. Function improved in some participants but 15% complained of severe anal incontinence at one year. Anal continence after anterior resection is a poorly defined problem. Although no advantage was found by the addition of routine biofeedback to standard management, this study establishes a working definition for “Anterior Resection Syndrome” and evaluates methods for measuring the structural and functional abnormalities associated with it. Symptom-score and quality of life questionnaires, anorectal physiology and proctography are frequently used to evaluate pelvic floor patients but are also relevant to assess anterior resection patients. An additional study was carried out to compare Barium (BaP) and MR proctography. BaP reproduced rectal emptying and demonstrated structural abnormalities to a greater extent than MR proctography and would be the best test for assessing structural abnormalities after anterior resection

With an ageing population putting ever increasing demands on the musculoskeletal system there is a growing need for the development of regenerative medical strategies to provide for the healthcare needs of the future. With increasing numbers of joint arthroplasty occurring in younger and younger patients there is likely to be a growing need for therapeutic strategies to replace lost bone stock in the coming decades This thesis aims to explore strategies to enhance the biological and mechanical properties of impaction bone grafting and the effects of skeletal stem cell (SSC) concentration. In order for SSC to be effective in replacing new bone stock new strategies looking to enhance osteogenic differentiation have been examined. Section I: An in vitro Impaction Bone Graft (lBG) model of SSC seeded onto human allograft was used to study the biomechanical effects of altering SSC concentration. The use of concentrated SSC was then used in the treatment of patients with avascular necrosis (AVN) of the femoral head and fracture non union with parallel in vitro analysis of the samples. Section 11: In vitro and murine in vivo analysis of the biomechanical effects of type 1 Collagen and Hydroxyapatite nanoparticles primarily looking at differences in shear strength and osteogenic differentiation compared to plain allograft and basal cultured SSC. Section Ill: An in vitro acetabular model was used to study the effect of vibration IBG compared to standard techniques in revision hip surgery. The graft compaction, force of impaction, fracture risk and rate of subsidence post cyclical loading was assessed. This thesis has demonstrated in vitro and in vivo strategies that are clinically translatable and have demonstrated that: • Skeletal Stem Cell concentration plays a pivotal role in the biomechanical enhancement of Impacted bone graft (IBG) • Translation of these strategies into the successful treatment of fracture non union and Avascular necrosis of the hip. • Type 1 Collagen and Hydroxyapatite nanoparticles both enhance the osteogenic differentiation and shear strength of the IBG / SSC construct • Vibration impaction bone grafting is a novel technique that significantly reduces the intraoperative risk of acetabular fracture or catastrophic subsidence This thesis has demonstrated novel techniques for the biomechanical enhancement of I BG with most techniques being readily transferable to clinical practice with the potential to form part of a surgeon's armament for regenerative medical techniques of the future.

Recent evidence suggests that stem cells are important for cancer metastasis and that the epithelial-to-mesenchymal transition also involves a transition toward stemness. Current thinking suggests that lgr5, a 7-transmembrane spanning G-protein, also marks a certain population of stem cells capable of regenerating an intestinal crypt and that the specialised immune secretory paneth cell, is important for maintenance of the stem cell niche. We implicate fascin in regulating the balance of lgr5 stem cells during acute intestinal inflammation and in regenerating intestinal tissue. Fascin is an actin bundling protein that drives the assembly of filopodia through the cross-linking of actin filaments into straight bundles. Conserved from amoebas to man, fascin was originally purified from extracts of sea urchin oocytes and coelomocytes and later found in Drosophila as the singed gene product. It is involved in the invasion and metastasis of multiple epithelial cancer types through stabilisation of actin in invadopodia, finger like protrusions used by cancer cells to invade into and degrade the extra-cellular matrix. Fascin, whilst normally low or absent from epithelia, localises to the leading edges of migratory cells and is over-expressed in many cancers of the same epithelial origin including lung, colorectal, pancreatic and liver. Fascin has also recently been shown to increase during inflammatory bowel disease (IBD) conditions such as diverticulitis, Crohn’s disease and ulcerative colitis. In this thesis I have investigated the role of fascin in murine models of IBD and have demonstrated that fascin is required for the haematopoietic production of leucocytes, in response to inflammation and that the loss of fascin, in the presence of high Wnt levels, results in enhanced proliferation of intestinal epithelial cells. One of the serious consequences of IBD is the increased lifetime risk of the patient developing an intestinal malignancy secondary to the disease. The exact mechanism underlying the increase in malignancies has not yet been fully established, however it is postulated that chronic inflammation and the effect this has on the major molecular pathways involved in carcinogenesis underlies the transformation from benign to malignant disease. Highest fascin expression has been shown in the dysplastic, pre-malignant cells in human IBD tissues indicating an important role of fascin in the transformation of benign to malignant cells. In this thesis, I have demonstrated that loss of fascin impairs tumour initiation in inflammatory driven and spontaneous intestinal tumourigenesis models, which is likely, in part, to be as a consequence of reduced leucocytes, in particular neutrophils, which may be CXCL2 mediated.

Liver transplantation is a vital medical procedure as it helps to prolong the lives and improve the quality of life for a number of people suffering from end stage liver diseases. Unfortunately though, there is a limit to the number of people that may benefit from the operation due to a shortage in the number of livers that are donated. This shortage, conflicting viewpoints, and a changing mix of patients requiring liver transplantation means that it is important to make sure that the livers which are donated are used to their greatest potential (utility) and allocated in a way which is seen as fair (equity). This thesis considers various transplant assessment rule, allocation rule, demand and supply scenarios, to aid in the understanding of the dynamics of the liver transplantation process, and in identifying situations in which equity and utility improve. Survival and Competing Risks Models identify key patient, donor and transplant attributes which influence a patients’ progression through the system. A Discrete Event Simulation model is developed to assess the equity and utility outcomes for how a particular scenario allocates liver transplants to patients. Parametric distributions generated from relevant Survival and Competing Risks models are used to predict the events a patient will experience and to estimate the times at which they will experience the events. Some of the key insights gained into decision making within the UK Liver Transplantation System, are: (1) the need to implement simple rules and rules which change over time, to obtain the best equity and utility output measures as supply, demand and patient mix change; and (2) it is easier to improve the overall utility in the system than the equity, due to the implications of prioritisation.

Phosphate based glasses are emerging in the field of biomaterials for their potential to resorb in biological environments, fulfilling applications from the fibre reinforcement of resorbable polymeric matrices to carriers for therapeutic drug delivery. Here we show the optimisation and characterisation of thin film glasses deposited by RF magnetron sputtering onto medical implant materials such as Ti6Al4V to function as ion leaching coatings to promote osseointegration or inhibit bacterial attachment. Vaporisation of the target preform occurred by momentum exchange interactions leading to non stoichiometric transfer to the condensed coating, sputtering in the order Na > Mg > Ca > Fe > P. Structural analyses revealed short range variation between compositionally equivalent glasses such that coatings with 32.5, 34 and 37 mol% P2O5 showed bulk polymerisation increasing in Q2 species by (23% to 45%) versus (9% to 32%) in quenched glasses. P O P bridging oxygens on the surface of coatings formed (PO3) metaphosphates (Q2), compared to (PO4)3 orthophosphates (Q0) and (P2O7)4 pyrophosphates (Q1) in quenched glasses. Quinternary coatings of up to 2.67 μm, containing Fe3+ and Ti4+ intermediate and cross linking elements were degraded in distilled water and phosphate buffered saline. Fe2O3 was increased from 4 to 8 mol% to stabilise dissolution, however an observed increase was attributed to variable condensation energies leading to inequivalent enthalpy and internal stress states. A comparison of a compositionally equivalent condensed and quenched glass suggested that the surface ratios of P O P to (P=O and PO ) were 34.2% to 65.8% versus 20.5% to 79.5% respectively leading to more soluble coating surfaces, exhibiting an exponential degradation dependence in the first 2 h in distilled water, followed by a linear profile. Post deposition heat treatments at 500, 550 and 610 °C were employed to stabilise dissolution and to tailor mechanical properties. All phosphate glass coatings showed interfacial tensile adhesion in excess of 73.6 MPa; surpassing ISO and FDA requirements for HA coatings. The initial exponential degradation from 0 2 h was stabilised via heat treatment. From 2 24 h coatings exhibited linear ion release rates ordering P > Na > Mg > Ca > Fe whilst dissolution rates reduced by factors of 2.44 to 4.55, attributed the formation of crystals and the depletion of hydrophilic P O P bonds within the surface layer. Vapour deposition has shown its ability to condense tailorable compositions of glasses, maintaining their amorphous tetrahedral structures whilst demonstrating exceptional adhesion to Ti6Al4V substrates. Coatings have demonstrated linear ion release capabilities and the ability to accommodate a vast array of potentially therapeutic ions to promote osteogenic or antimicrobial capabilities.

The most important hip post-surgery problem is named Edge Loading (EL). This phenomenon significantly increases the contact pressure on the ball and the socket of the hip prosthesis hence decreasing the lifetime of the hip prosthesis drastically. Nowadays millions of patients cannot go under total hip replacement surgery due to the short lifetime of the hip prostheses. This research mainly focuses on finding solution for reducing the effect of this phenomenon. In this research, reasons of EL are investigated and important factors in designing of the prosthesis are studied. Furthermore, a novel hip prosthesis is proposed. The model has been successfully patented with PCT number: PCT/GB2015/052933 and published with International Publication Number: “WO2016/055783Al”. In this study the proposed design is analysed using three methods and the results are compared with the best available hip prosthesis in the market. The key results of the proposed design are outlined below: -Comparison of the features of the proposed design with those of the available hip prosthesis suggests a promising outcome. This is mostly due to eliminating of the EL causes, in the new design. -According to Hertzian Contact Theory, the proposed design reduces contact pressure during EL by 99.7% in comparison with the best available prosthesis in the market. This represents an upper limit. -Finite element method simulation demonstrates up to 63% reduction (lower limit) of contact pressure during EL and also Neck-Rim/Ring impingement by the proposed design in comparison with the best available prosthesis in the market. Although reduction of contact pressure by the novel design is noticeable, aforementioned methods show different results. This is due to the limitation of every method in this study. In this regard the novel design expecting to reduce contact pressure during EL / Microseparation more than 63% but less than 99.7%. The novel design may open a new path for the total hip replacement surgery, and solve the EL problem forever.