Twenty-seven consultants from the UK and Ireland contributed 928 patients to a multicentre randomised trial to compare laparoscopic hernia repair with currently used open repairs. The laparoscopic group developed less wound haematomas (7.6% vs. 15.7%; 99% CI: -14.3 to -2.0), but there was no difference in the incidence of wound infection or general complications such as urinary retention. The laparoscopic group reported lower levels of post-operative pain and this was reflected in significantly better 'Short Form 36' functional scores at one week. By one month the only significant difference between groups was a better score for physical function in the laparoscopic group, and by three months there was no significant difference in any of the 'Short Form 36' domains. The early functional advantages for the laparoscopic repair were reflected in an earlier return to normal activities (10 days vs. 14 days; p<0.01) and work (28 days vs. 42 days; p=0.001). A simulator was constructed to measure the ability to perform an emergency stop following totally extraperitoneal or open prosthetic inguinal hernia repaid. Measurements were made pre-operatively and at one, three and six days post-operatively. The laparoscopic group did not demonstrate any increase in reaction times following hernia repair. The open group had significantly prolonged reaction times on days one and three, but had returned to pre-operative levels by day six. Therefore, laparoscopic repair does not impair driver reaction times, and open prosthetic repair appears to allow an earlier return to driving than the ten days previously recommended for open sutured repair.

Pericardial bioprosthetic valves have shown good long-term clinical follow-up results over a period of 13 years with a low incidence of thrombo-embolism and calcification, and good haemodynamic function. However, doubts remain about the long-term durability of these valves and a significant incidence of primary tissue failure has been reported and this has been observed in our clinical series in Glasgow. I have identified tears in leaflets of explanted valves close to the edge of the cloth-covered stent which have caused prolapsed leaflets and large regurgitation. The performances of four pericardial valves, the Ionescu-Shiley Standard, Ionescu-Shiley Low Profile, Hancock and Mitral Medical pericardial valves have been evaluated in my test apparatus in an attempt to gain understanding of the mechanisms of these primary tissue failures. A hydrodynamic function test apparatus has been developed which allowed pressure difference, regurgitation and energy loss across the valve to be measured, and leaflet dynamics to be studied. Durability tests were carried out with Rowan Ash accelerated fatigue testers. The valve function and leaflet dynamics were dependent on the method of leaflet fixation, and the leaflet geometries and the coaption sutures used to close the leaflets together at the top of the posts. These could also affect the durability of the valves. However, accelerated fatigue test results showed premature failure for all four types of valves with tears in the leaflets caused by abrasion at the edge of the cloth-covered frames. In the Ionescu-Shiley Standard valve, tears were also seen at the commissure stitches. Although in these laboratory tests the mechanism of failure was abrasion and thinning of the leaflets as they were pulled over the edge of the cloth-covered frame, care has to be taken when extrapolating these results to clinical practice as biological effects, such as blood deposits on the cloth and tissue ingrowth, can reduce the abrasion to the leaflets at the edge of the frame. These processes are variable and leaflet abrasion on the cloth-covered frames remains the major cause of primary tissue failure in clinically explanted valves. The new three leaflet pericardial valve which I have developed has improved durability and comparable function in vitro to existing valves. The valve is based on a unique twin frame design. The inner support frame is covered with a single piece of bovine pericardium to reduce abrasion to the leaflets at the edge of the frame and has an array of radially-projecting pins and studs onto which the leaflets are mounted. The outer frame is covered with polyester cloth and this is located over the same radial pins to retain the leaflets in position. The assembled valve is secured with a fine locking ring in the base of the valve. The sewing ring is constructed from polyester cloth and can be positioned towards the inflow aspect of the valve in the aortic position to give a supra-annular configuration and away from the inflow aspect in the mitral position to reduce the length of post projecting into the ventricle. The posts on the outer frame are rounded to reduce the risk of damage of the ventricular wall, and a protective suture can be placed across the top of the posts to reduce the risk of suture-snaring during implantation in the mitral position. The mechanical properties of the pericardial tissue used for the leaflets have been investigated and fixation conditions analysed to produce uniform cross-linking throughout the tissue. Prototype valves have been tested with different leaflet geometries and differing methods of leaflet fixation, and an optimal leaflet geometry has been developed. The flexing position of the leaflet was moulded during fixation in a shape defined by two cylindrical surfaces which intersect in a spherical surface in the centre of the leaflet. This gave a stable closed position with deep coaption between the leaflets and synchronous movement of the leaflets to a uniform open position. Prototype valves have been manufactured in sizes 19 to 31 mm. Hydrodynamic tests on the prototype valves have shown comparable pressure difference, regurgitation and energy loss to other pericardial valves. Accelerated fatigue testers have shown greatly improved durability with eight out of nine valves cycled to over 400 million cycles, the equivalent of 10 years without failure. Implantation of size 25 mm valves in the mitral position in seven sheep for over three months has shown good short-term in vivo function. A randomised clinical trial is planned comparing a porcine valve with this improved pericardial valve.

Introduction: 12,000 infrainguinal bypass grafts are performed annually in the UK. Despite improvements in surgical technique, outcomes remain suboptimal: 20% of above knee grafts require intervention to maintain patency by 3 years. Only antiplatelet agents have been demonstrated thus far to improve graft survival. 80% of graft failure is as a result of intimal hyperplasia, an inflammatory process characterised by the proliferation and migration of vascular smooth muscle cells. Toll Like Receptors (TLR), part of the innate immune system, have been implicated in atherosclerosis formation but not investigated in a model of infrainguinal graft failure. When a vein is used as a conduit for infrainguinal bypass graft it has been exposed to ischaemic and hypoxic conditions: preliminary data has demonstrated that ischaemic vascular smooth muscle cell explants are hyperproliferative. Phospholipase C γ (PLC γ) is a signalling pathway with potential links to innate immune pathways and pathways induced by hypoxia and ischaemia. Methods: Human vein tissue was obtained from patients undergoing amputation and coronary artery bypass surgery and used for immunohistochemistry and to obtain vascular smooth muscle cells by explant method. Immunohistochemistry was used to determine the presence of TLR4 and PLC γ in human vein tissue. Specific TLR Ligands were used to determine the functional response of TLR’s in vascular smooth muscle cells as measured by Interleukin 8 ELISA. Radiolabelled Thymidine incorporation was used to measure proliferation of vascular smooth muscle cells in response to TLR4 activation, hypoxia and PLC γ inhibition. Results: TLR4 was demonstrated to be present in human vein tissue, and functionally active in human vascular smooth muscle cells. Furthermore stimulation with the specific ligand of TLR4 caused enhanced proliferation of vascular smooth muscle cells. Hypoxia (5% and 10% Oxygen) significantly enhanced proliferative responses of vascular smooth muscle cells. PLC γ was demonstrated to be present in human vein tissue, and inhibition, using U73122 in vascular smooth muscle cells reduced proliferation. Conclusion: TLR activation and hypoxia appear to enhance the proliferative responses of human vascular smooth muscle cells, a key cellular pathway of intimal hyperplasia formation and infrainguinal graft failure. Inhibition of PLC γ reduces proliferative responses. Further research is required to confirm that PLC γ is a key common pathway mediating enhances of proliferation caused by TLR activation and hypoxia.

If the intrinsic control of the liver is responsible for these changes it would be important to show that the liver is more metabolic as the changes occur. An intervention to lower the metabolic demand on the liver is difficult and may not be ethical given that the normal response to injury or infection is an acute phase response. One area where this could be said to have been performed is the tight control of blood glucose in intensive care medicine which reduces the demand on the liver to perform gluconeogenesis. While there are other benefits of lower serum glucose levels this may contribute to the reported improved outcome in such patients. Clinically, measurement of hepatic arterial and portal venous blood flow has been shown to be feasible in the critically ill patient and may be used as a non-invasive measurement of the liver response to a drug or therapy.

Hernia surgery remains one of the most common operations carried out by general surgeons worldwide with more than 800,000 repairs performed in the USA alone in 2003. Advancement in surgical technique has meant fewer recurrences are now encountered with figures dropping to less than 2% using the laparoscopic approach. Yet despite the progress achieved in securing the repair, post operative pain remains an issue with many authors reporting figures of 30% in patients following groin hernia repair 1,2, 3% of patients report sever pain that limits their daily activities and renders them off work. Many patients with inguinal hernia have very little in the way of symptoms and even some of them are asymptomatic, having noticed their hernia by accident or by their general practitioner. In order to clarify two issues (the first being the incidence of acute hernia presentation, its management and subsequent outcome, while the second was the management of patients with an asymptomatic inguinal hernia) 4 studies were carried out: The first study was a prospective observational study looking at all patients presenting to our unit with an acute hernia, the aim of the study was to prospectively assess the presentation and management of acute hernias in light of recent changes in hernia management. Data on all patients admitted with an acute hernia between 2001 and 2004 was collected prospectively. During the 3 year study period 91 patients were admitted with an acute hernia. 46 had a previous medical assessment either as an acute admission (12) at a surgical clinic (22) or by a General Practitioner (12). Eighteen had been declared unfit for operation at that assessment, 10 were ASA4, 5 ASA3 and 3 ASA2. Eleven patients were on the waiting list for operation 3 of whom had a previous acute hospital admission. For 30 patients this hospital admission was the first indication that they had a hernia while the remainder refused operation or did not seek medical advice. Five patients died, 2 while being assessed for operation and 3 postoperatively, 3 were ASA4 while 2 were ASA3. The number of patients undergoing operation for an acute hernia amounted to 8.4% (80 of 952) of all hernia operations carried-out during the study period. This study concluded that despite advances in hernia surgery there was still room for improvement, to ensure that all suitable patients presenting with an acute hernia receive an operation during their acute hospital admission. The second study was a prospective study of all patients presenting with subacute bowel obstruction in one teaching hospital between 2003 and 2004. The aim of the study was to identify the most frequent causes of strangulation in patients presenting with small bowel obstruction. During the study one hundred and sixty-one patients with symptoms and signs of small bowel obstruction were admitted. Eighty-nine were confirmed with contrast studies. The male: female ratio was 1:1.6. The aetiology of obstruction was hernia in 29 (18%), adhesions in 97 patients (60.2%), and miscellaneous in 35 (21.8%) Operative procedures were performed on 74 patients (46%), 31 of them (42%) with adhesions, 25 (34%) with hernias and 18 (24%) due to other causes. Strangulated bowel occurred in 15 patients (9.3%); 12 had hernias whilst three had adhesions (P < 0.0001). Of the strangulated hernias, ten were femoral, one was inguinal and one was paraumbilical. Our conclusion was that whilst adhesions are the most common cause of small bowel obstruction, femoral and not inguinal hernias remain the most frequent cause of strangulation. The third and main study was a prospective randomized trial comparing surgery and no intervention for asymptomatic inguinal hernias. The aim of the study was to compare operation with a wait and see policy in patients with an asymptomatic hernia. 160 male patients 55 years or older were randomly assigned to observation or operation. Patients were assessed clinically and sent questionnaires at 6 months and 1 year. The primary endpoint was pain and general health status at 12 months; other outcome measures included costs to the health service and the rate of operation for a new symptom or complication. At 12 months there were no significant differences between the randomised groups of observation or operation, in visual analogue pain scores at rest, 3.7mm versus 5.2mm (P=0.34), or on moving, 7.6mm versus 5.7mm (P=0.39). Also the number of patients who recorded pain on moving 29 versus 24 (P=0.31), and the number taking regular analgesia, 9 versus 17, (P=0.14) was similar. At 6 months there were significant improvements in most of the dimensions of the SF-36 for the operation group, while at 12 months although the trend remained the same the differences were only significant for change in health (P=0.039). The rate of crossover from observation to operation was 23 patients at a median follow-up of 574 days, this was higher than predicted. The observation group also suffered 3 serious hernia related adverse events compared to none in the operation group. Finally a sub study was generated from the non randomised patients within the asymptomatic trial. The aim here was to assess the outcome of patients opting for no surgery in terms of need for surgery and outcome. There were 72 patients (58 opting for observation and 14 wanting an operation), 13 patients (22.4%) in the observation group became symptomatic and required an operation, 9 patients had died at the time of data analysis, all of which were due to co morbid illnesses. The final 2 studies concluded that repair of an asymptomatic inguinal hernia did not affect the rate of long-term chronic pain and might be beneficial to patients in improving overall health and reducing potentially serious morbidity.

Cardiovascular disease is the leading cause of death in surgical patients and because of this a number of strategies have been utilised to attempt to predict the cardiac risk of surgery. Theoretically, accurate pre-operative risk stratification would allow patients at low risk to have their surgery expedited efficiently, whilst those at higher risk could have a change made to their treatment plan such as peri-operative cardiac optimisation or in some cases, modification of the operative procedure. Despite this rationale, no guidelines currently exist in the United Kingdom for the management of the surgical patient at high cardiac risk. This may partly reflect the limited methods of risk stratification currently available. Clinical scoring systems are simple and inexpensive but limited by their predictive value. Trans-thoracic echocardiography provides prognostic information but is inconsistent, adding little to clinical information alone. The most accurate methods of pre-operative cardiac risk prediction at the present time are dobutamine stress echocardiography and dipyridamole thallium scanning. However they are expensive, time consuming and have shown poor positive predictive ability, even in high risk cohorts. Few studies have studied the usefulness of biochemical markers in the prediction of post-operative cardiac events. In particular, no information was available in the literature regarding the role of B-type natriuretic peptide (BNP) in the prediction of cardiac events in non-cardiac surgical patients; despite the fact that its measurement has been shown to be an important prognostic tool in both non-surgical and cardiac surgical cohorts. In this thesis the aim was to determine whether pre-operative BNP concentration related to cardiac outcome following non-cardiac surgery; and also to determine whether measurement of other markers such as C- reactive protein (CRP) and cardiac troponin I (CTnI) would be of benefit in pre-operative cardiac risk stratification. To assess the effectiveness of plasma BNP measurement in the prediction of peri-operative cardiac morbidity a pilot study of 41 patients undergoing vascular surgery was conducted. To ensure that any post-operative rise in CTnI was due to operative stress, this was measured pre-operatively along with CRP. Median pre-operative BNP concentration was significantly higher in patients who suffered a post-operative cardiac event (cardiac death, non-fatal myocardial infarction (MI)) than in those who did not (210 (165-380) pg/ml vs. 34.5 (14-70) pg/ml, p<0.001). On the basis of these results a single-centre, prospective, observational cohort study was performed of all patients undergoing non-cardiac surgery. Of the 149 patients recruited to this study, 15 had a cardiac event. The median BNP in those patients having a cardiac event was more than ten-times higher than in those who did not (351 (127-1034) vs. 30.5 pg/ml (11-79.5), p<0.001). A BNP concentration of 108.5pg/ml was the best performing cut-off value having a sensitivity and a specificity of 87%. Although CTnI had originally been measured to ensure that any post-operative rise was due to operative stress, 3 patients had a pre-operative elevation all of whom underwent lower extremity amputation. The amputation group, and in particular those patients who had a raised pre-operative cTnI were therefore analysed further. Amputation patients in general had a high cardiac event rate (23%); however the outcome in those patients who had a raised pre-operative cTnI was particularly poor with 2 suffering a cardiac death post-operatively and one suffering a non-fatal MI. A pre-operative rise in CTnI was the only significant single predictor of peri-operative cardiac events in patients undergoing amputation (p= 0.009). Pre-operative CRP concentration was measured routinely in vascular patients. The concentration in those who had a cardiac event was significantly higher than those who did not (69 (0-260) vs. 12 (0-285), (p=0.003). The cardiac event rate rose with each logarithmic increment in CRP concentration (0-10mg/l (5.7%); 11-100mg/l (22.4%), >100mg/l (55.6%) (p=0.002). Measurement of CRP was of most potential benefit in patients undergoing aortic aneurysm surgery. In conclusion, this thesis has shown that pre-operative measurement of biochemical markers (BNP, CTnI, and CRP) can allow accurate peri-operative risk stratification. BNP concentration in particular was a sensitive and specific predictor of cardiac outcome. Careful case selection using a combination of clinical assessment and the results of these markers may lead to a reduction in the cardiac event rate.

Breast cancer remains the most common malignancy in women and a major cause of morbidity and mortality in the western World, despite the advances in diagnosis and treatment. The main challenge remains to identify new, and improve existing treatment modalities. Understanding the mechanism by which tumours grow and metastasise is key to developing new therapeutic targets Similar to most cancers, the incidence of breast cancer increases with age. Therefore, genes involved in biological ageing and factors affecting genomic integrity, considered critical to cellular senescence and organismal life span, are also relevant to neoplastic transformation and tumour growth. Thus exploring factors associated with biological ageing in cancer may improve our understanding of the disease as an aberration of normal biological ageing and result in new prognostic markers or therapeutic targets. There is increasing evidence for the involvement of sirtuins in biological ageing, along with other essential cellular processes including cell cycle control, DNA damage repair and differentiation. This is suggestive of a possible role for sirtuins in cancer. Therefore, this study was conducted to investigate a potential role for sirtuins in breast cancer disease (including anti-tumour treatment). Firstly, Real time PCR was used to compare the transcriptional expression level of individual sirtuin genes in vivo. The experimental result showed that only SIRT1 and SIRT4 showed an association with age in “normal patients” (normal and non malignant patient grouped together), with decreasing levels of SIRT1 and increasing levels of SIRT4 being associated with increasing chronological age. All sirtuin levels were significantly decreased in malignant tumours, when compared to either normal and/ or non-malignant biopsies. Decreased relative transcriptional expression of SIRT1, SIRT2, SIRT3, SIRT6 and SIRT7 showed significant association with higher tumour grade, when breast cancer patients were divided according to the known histopathological markers. The Kaplan-Meier analysis for cancer specific survival and tumour recurrence was preformed on entire patient cohorts and in patient subgroups selected to have moderate prognosis (ER+ve and NPI between 3.4 and 5.4). The Kaplan-Meier survival analysis showed that higher levels of SIRT6 and SRT7 were associated with a longer survival period in all patient cohorts. Furthermore, higher levels of SIRT6 remained significantly associated with better survival, when breast cancer patients were selected to have intermediate prognosis (ER+ve and NPI between 3.4 and 5.4). Whereas, higher levels of SIRT7 remained significantly associated with longer survival period only in patients with ER+ve tumours. The Kaplan-Meier analysis showed that lower levels of SIRT1 gene expression were associated with longer patient survival and lower tumour recurrence in a patient group, selected by NPI, to have an intermediate clinical prognosis. Multivariate Cox-regression analysis demonstrated that the relative transcriptional level of the SIRT6 gene was independent of tumour size, grade, nodal status, oestrogen receptor status, lymphovascular invasion status, and the NPI in influencing survival. The decreased sirtuin gene expression observed in this study is consistent with an anti-cancer effect and suggests that sirtuins might be implicated in breast cancer pathogenesis. For example, decreased levels of SIRT2 might assist DNA-damaged tumour cells, as indicated by the decreased expression of another sirtuin involved in DNA damage responses, SIRT6, in escaping cell cycle arrest during tumour initiation and progression. Furthermore, The associations between sirtuins and survival period suggest that these sirtuins (especially SIRT6) might be used as an additional prognostic marker in breast cancer patients, especially in those individuals who have equivocal prognostic pathological markers. Therefore, the level of expression of sirtuin genes (SIRT6) might help explaining those breast cancer cases, which behave unexpectedly, according to the known pathological prognostic markers. Secondly, The changes in the relative transcriptional expression levels of the sirtuin genes were investigated in response to adjuvant chemotherapy therapies, commonly used in breast cancer (Tamoxifen and Docetaxel), in breast caner cell lines. The first experiment determining sirtuins changes in response to Docetaxel treatment for 72 hours in ER-ve breast cancer cell line (MDA-MB-231) showed significant increase in the relative transcriptional expression levels of all sirtuins after Docetaxel treatment. These data were consistent with the pro-apoptotic role for SIRT1, SIRT3 and SIRT7, and suggestive of DNA damage involvement at higher doses of Docetaxel, as indicated by increased SIRT6 and XRCC5. Finally, increased SIRT2 levels are suggestive of SIRT2 involvement in the mitotic arrest caused by Docetaxel, through its contribution to microtubule dysfunction. The second experiment, determining sirtuin changes in response to Tamoxifen treatment in ER+ve (MCF-7) and ER-ve (MDA-MB-453) breast cancer cell lines, showed significant increase in the relative transcriptional expression levels of all sirtuins after Tamoxifen treatment. These data were consistent with the pro-apoptotic role for sirtuins. Furthermore, the observed increased levels of SIRT6 are suggestive of DNA damage involvement at higher doses of Tamoxifen. Another noteworthy result of this experiment is the increased levels of SIRT2 in response to Tamoxifen treatment. This might explain the failure of a TAM-treated cell to proceed through the cell cycle, in spite of the increases in transcription factors that promote cell cycle after Tamoxifen treatment. There was no significant difference in sirtuin changes after Tamoxifen treatment between these two cell lines to indicate that sirtuin changes were ER-dependent. In total, the data accumulated from this study demonstrated the involvement of sirtuins in breast cancer disease (pathogenesis and anti-tumour treatment) and suggest the possible use of SIRT6 as a novel, additional and biological prognostic marker. Finally, this study suggests that sirtuins activators, rather than inhibitors, might be beneficial in breast cancer disease and enhance the response to adjuvant chemotherapy.

The thesis reviews the literature regarding the relationship between the local and systemic inflammatory responses and outcome in patients with gastro-oesophageal cancer. The study chapters then examine the relationship between the systemic inflammatory response and survival, in operable and inoperable disease and within, a cohort treated with palliative chemotherapy. The local inflammatory response and its relationship with tumour related factors, the systemic inflammatory response and survival, was examined in patients who underwent potentially curative surgery Also, the clinical utility of a systemic inflammation based score (Glasgow Prognostic Score) as a part of clinical staging, was then examined. The importance of these studies in a scientific and clinical context are discussed. Future work is also discussed.

Introduction: In the past five years chronic post herniorrhaphy pain has become the predominant post operative complication following the common procedure of inguinal hernia repair. However information regarding the precise aetiological factors of this chronic post surgical pain is lacking. To date no previous studies have assessed the long term outcome of patients who report chronic severe pain following inguinal hernia surgery. There are no studies assessing the presence of preoperative pain and the effect of surgical intervention on these pain scores. One factor thought to contribute to post herniorrhaphy chronic pain is the mesh type used by the surgeon. The characteristics of two different mesh types are evaluated with respect to postoperative chronic pain. Aims: The aim of the first study was to assess the outcome of patients who report severe or very severe pain three months after groin hernia repair. The aim of the second study was to quantify patients’ pain from their inguinal hernia prior to surgery and to examine the effect of surgery on this pain. The aim of the third study was to compare the composite partially absorbable and ultimately lighter weight (Vypro 11) mesh with an example of a conventional polyprolene mesh (Atrium) in a tension free repair of an inguinal hernia. Methods: One hundred and twenty five patients were identified as experiencing severe chronic pain at 3 months post herniorrhaphy, from the prospective National Hernia database1 of 5506 patients (97% of total) between 1 April 1998 and 31 march 1999. These 125 patients were assessed at 30 months post-surgery, with the use of the modified SF36 quality of life questionnaire. For the second study, consecutive patients referred for elective inguinal hernia repair between January 1998 and October 2000 completed visual analogue pain scores (VAS) pre- and 1 year post-repair. These patients were Western Infirmary patients who were part of a larger multicentre clinical trial comparing local versus general anaesthesia 2 for inguinal hernia repair. The third study examined patients who were involved in a multicentre trial comparing the incidence and severity of chronic pain following elective inguinal hernia repair, comparing the light weight or partially absorbable (PA) to the standard heavy weight or non-absorbable (NA) mesh. Results: In the first study, of the 125 patients who experienced severe chronic pain at three months post repair, at 30 months post-surgery 25% had persistent, unchanged chronic pain 45% had a reduction in pain to mild or very mild, and 29% were pain-free. In the 25% of patients that had persistence of severe chronic pain, the symptoms had a significant effect on all daily activities and quality of life, for example in measurement of general enjoyment of life, those with mild pain scored 2.32 (1.5-3.13) compared to 7.14 (5.97 - 8.30) in those with persistent severe pain (P<0.05) . In the second study 63% of patients completed VAS scores at follow-up. Prior to surgery the majority of patients had no pain or only mild pain at rest (80.5%) or on movement (58.8%). At 1 year follow-up the mean (SD) VAS score reduced by 2.9 (1.2) at rest, and reduced by 9.2 (1.8) on movement. However the majority of the beneficial effect was seen in those with moderate to high pre=operative pain scores. Those with preoperatively VAS score >10 had a reduction of 22.8 (3.7) at rest, compared to a slight increase in pain (+1.8) in those with no pain pre-operatively (P<0.05). Similar effects were seen on movement (improvement of 32.2 (4.8) in those with preoperative pain score >10, and little change in pain, -0.3 (1.6), in those with no, or only mild, preoperative pain (P<0.05). In the third study 162 patients received the PA mesh and 159 received the NA mesh. The PA mesh was not associated with less pain at 1 year postoperatively, compared to the NA mesh, with the proportion experiencing any pain being 39.5% in the PA group compared to 51.6% in the NA group (P=0.033). The proportion experiencing severe pain was similar, being 3% for the PA group and 4% for the NA group, and the recurrence rate was greater with the PA mesh compared to the NA mesh (4.9% versus 0.6%, P=0.037). Conclusion: Of those with chronic severe pain at 3 months post inguinal hernia repair, the majority will have still have some pain at 30 months post operatively. The greatest benefit in terms of pain reduction in patients undergoing inguinal hernia repair is experienced by those with the more severe preoperative pain. From our data there is no clear overall benefit in using the PA mesh over the standard mesh, as whilst pain scores were slightly lower in the PA group, this was countered by a higher recurrence rate. Further attention to the multiple factors that contribute to pain post-inguinal hernia repair is required, including the development of superior mesh technology.

Silicon doped hydroxyapatite (SiHA) could be used as a thin film coating on load bearing bone implants to provide a bioactive layer enabling bone to form a direct bond with the implant/bone interface thus increasing implant lifetime by lowering the chances of aseptic loosening. This study has been undertaken to investigate silicon additions to RF magnetron sputtered hydroxyapatite (HA) thin films. Detailed characterisation was carried out on SiHA thin films to establish the structural, chemical, mechanical and compositional properties. Silicon content was altered by adjusting the power density applied to silicon targets in a co-deposition process resulting in SiHA films containing 0.0, 1.8, 4.2 and 13.4 wt.% silicon. All as-deposited thin films were found to be amorphous. After annealing at 600˚C in flowing argon for 2 h, it was found that films exhibited a single phase HA structure. The addition of silicon inhibited HA crystallite growth and acted to lower the stability of HA films in aqueous solutions. The 13.4 wt.% SiHA thin film did not recrystallise until a heat treatment at 800˚C. From the work presented here, it is proposed that, in post-plasma-deposited heat treated films, silicon substitutes as silicate species into the HA lattice. Asdeposited silicon containing thin films were found to be amorphous and have a polymeric silicate configuration, suggesting that, silicate groups may be randomly distributed throughout the amorphous film. After post-deposition annealing silicon containing films were in a monomeric state suggesting silicate groups had substituted for phosphate tetrahedra in the HA lattice. Furthermore, an HA-like phase was found to be present. Contrary to these findings, FTIR analysis did not manifest any silicate-based bands. This may, however, be due to the fact that technique used only samples a very small amount of material and, due to the low doping quantities of silicon in the HA films. Furthermore, Ca/P ratios consistently differed from the stoichiometric value of HA (1.67). This combined evidence raises the question of whether the post-deposition heat-treated films have a true HA-like structure. More work is required in order to truly understand the structures present in heat-treated SiHA thin films. HA thin film composition is commonly measured in terms of the Ca/P ratio. Energy dispersive X-ray analysis (EDX) and XPS were evaluated in terms of accuracy in conjunction with Rutherford backscattering spectroscopy (RBS) to measure the Ca/P ratio of HA thin films to establish the most appropriate technique for accurate compositional analysis. This was was found to the RBS, achieving an accuracy of within 2 %, with EDX averaging 8 % and XPS ranging from 25 - 42%. It was concluded that XPS gave such large differences in values because the top few atomic layers of thin films was of a different composition than the bulk of the coating. A Human osteoblast cell (HOB) model was used to establish the in vitro cellular response of SiHA thin films. Initially, HA and SiHA thin films annealed at 600˚C were compared. Cells attached and proliferated well on HA surfaces compared to SiHA surfaces, however, improved cell growth was seen with increasing silicon content. Dissolution studies showed that SiHA thin films were highly unstable in cell culture media and it is thought that the films dissolved, and where cell adhesion and growth did occur it was because cells adhered to the titanium substrates beneath the films. This was then compared with HA and SiHA thin films annealed at 700˚C. No significant difference was found between the two surfaces in terms of cell growth or protein expression indicating that silicon content and crystallinity play an important role in the cellular response of SiHA thin film.