Following the publication of two large-scale randomised controlled trials in the early 1990s, little doubt remains about the efficacy of carotid endarterectomy as a means of preventing stroke in selected sub-groups of patients. However, the effectiveness and cost-effectiveness of this intervention as a stroke prevention strategy are uncertain, as are the public health implications when this strategy is applied to a population. This thesis focuses on the effectiveness and cost-effectiveness of carotid endarterectomy as a stroke prevention strategy in the Scottish population. The variation in uptake of carotid endarterectomy by hospital and region between 1981 - 1996 is described by analysing a unique set of patient linked data on hospital use and outcome following carotid surgery for 2892 patients. Stroke-free survival and overall survival before and after the publication of the trial results for this cohort are also assessed. A systematic overview of studies addressing the costs and benefits of carotid endarterectomy is conducted by critically appraising the methodology and interpretation of previous cost and cost-effectiveness estimates. Unlike previous studies, this thesis considers the resource implications of carotid endarterectomy by estimating not only the procedure cost of carotid endarterectomy but also the overall NHS work-up costs for a large cohort of patients with transient ischaemic attack referred to a Scottish teaching hospital for carotid endarterectomy assessment, investigation and surgery. Finally, as part of the analysis of cost-effectiveness estimates for Scottish patients, a novel use of the European Carotid Surgery Trial data has enabled assessment of the transferability of efficacy results obtained in a randomised controlled trial to a setting outside trial conditions.

The present study was designed to investigate factors which could influence the regeneration of peripheral nerves which had been cut and repaired using a variety of grafting techniques. These methods were: repair with a microwaved muscle autograft, a freeze-thawed muscle autograft, and several groups where repair involved a controlled release biodegradable glass tube containing a variety of factors which have been shown to influence nerve regeneration. Assessment of all of these experimental groups involved the use of established electrophysiological and morphometric techniques but also the development of new techniques for measuring the conduction velocity of the lowest fibres and the variability of reinnervation at the neuromuscular junction (stimulated jitter). The experiments revealed that the microwave muscle graft provided the structural support needed for regeneration, however difficulties in preparing the graft made its use in the clinical setting doubtful. The controlled release glass tube did not interfere with regeneration an supported similar levels of regeneration when compared with an established surgical technique. Jitter proved to be an excellent and highly discriminatory test for assessment of the progression and quality of reinnervation of skeletal muscle. The potential for using these techniques in the experimental and clinical settings is discussed.

Current trends in surgical intervention favour a minimally invasive (MI) approach, in which complex procedures are performed through increasingly small incisions. Specifically, in neurosurgery, there is a need for minimally invasive keyhole access, which conflicts with the lack of maneuverability of conventional rigid instruments. In an attempt to address this fundamental shortcoming, this thesis describes the concept design, implementation and experimental validation of a novel flexible and steerable probe, named “STING” (Soft Tissue Intervention and Neurosurgical Guide), which is able to steer along curvilinear trajectories within a compliant medium. The underlying mechanism of motion of the flexible probe, based on the reciprocal movement of interlocked probe segments, is biologically inspired and was designed around the unique features of the ovipositor of certain parasitic wasps. Such insects are able to lay eggs by penetrating different kinds of “host” (e.g. wood, larva) with a very thin and flexible multi-part channel, thanks to a micro-toothed surface topography, coupled with a reciprocating “push and pull” motion of each segment. This thesis starts by exploring these foundations, where the “microtexturing” of the surface of a rigid probe prototype is shown to facilitate probe insertion into soft tissue (porcine brain), while gaining tissue purchase when the probe is tensioned outwards. Based on these findings, forward motion into soft tissue via a reciprocating mechanism is then demonstrated through a focused set of experimental trials in gelatine and agar gel. A flexible probe prototype (10 mm diameter), composed of four interconnected segments, is then presented and shown to be able to steer in a brain-like material along multiple curvilinear trajectories on a plane. The geometry and certain key features of the probe are optimised through finite element models, and a suitable actuation strategy is proposed, where the approach vector of the tip is found to be a function of the offset between interlocked segments. This concept of a “programmable bevel”, which enables the steering angle to be chosen with virtually infinite resolution, represents a world-first in percutaneous soft tissue surgery. The thesis concludes with a description of the integration and validation of a fully functional prototype within a larger neurosurgical robotic suite (EU FP7 ROBOCAST), which is followed by a summary of the corresponding implications for future work.

Major surgeries, such as cardiac or orthopaedic procedures in particular, expose the patient to extensive trauma, blood loss, and tissue injury; all of these factors effectively modulate the immune system to ultimately trigger an inflammatory response. Postoperative cognitive dysfunction (POCD), the condition being characterized by impairment of short and long-term memory, is one of common complicates following surgery. Recently, our data have demonstrated that neuroinflammation and microglia activation in the hippocampus following surgery are associated with cognitive decline. The aim of this thesis is to investigate the inflammatory signaling pathways specifically involved with POCD, with a particular interest between systemic inflammation and local inflammation in the brain following surgery. The data presented in this thesis introduce the general concepts and the involvement of inflammation in the etiology of cognitive dysfunctions using a mouse model of POCD. Upon the identification of specific pro-inflammatory markers both systemically and centrally and the delineation of the time course of events that characterize the inflammatory response following aseptic orthopaedic surgery, I describe how specific cellular signal pathways interact, mediate, and sustain this response. Following an initial non-specific approach using a general anti-inflammatory compound to identify whether inflammation plays a role in this scenario, I have exploited this model into a wide range of knockouts animals in the attempt of identifying specific signaling mechanisms and upstream receptors that mediate the behavioral abnormality following surgery. In order to achieve this, I have compared the inflammatory events after aseptic surgery with the response after a defined infectious stimulus, to ultimately joint the two in the context of a postoperative complication. In conclusion, inflammation clearly plays a pivotal role in mediating physiological as well as behavioral changes after surgery and infection. This thesis has started to unmask the signaling pathways involved with surgery and how anti-cytokine therapy can potentially ameliorate the associated cognitive dysfunction.

The increasing demand for organs has stimulated the necessity in xenotransplantion, which promises an unlimited supply of organs for clinical use. However, coagulopathy of xenografts remains a major hurdle to successful pig-to-primate xenotransplantation. The ability to generate pigs expressing a human complement-regulatory protein (hCRP) and/or pigs in which the α1,3-Galactosyltransferase gene has been knocked-out (GT-KO) has largely overcome the barrier of hyperacute rejection (HAR) of a pig organ transplanted into a primate. However, acute humoral xenograft rejection (AHXR), presenting as microvascular thrombosis with/without consumptive coagulopathy (CC), ensures and results in graft failure. The causes of coagulopathy were believed to be humoral response-dependent. Xenoreactive antibodies (Abs) and activation of complement provoke porcine endothelial cells (ECs) from an anticoagulant to a procoagulant phenotype. In this study, I demonstrated that recipient platelets and monocytes were activated to express tissue factor (TF), an initiator of the coagulation cascade, after incubation with porcine ECs through humoral immune response-independent process. These observations were mirrored in the animal studies. Kidneys or livers from GT-KO pigs that express a hCRP transplanted into nonhuman primates were not susceptible to HAR. Nevertheless, most recipients developed CC, even when the grafts were still functioning. Activation of graft ECs and the measurable immune response were minimal. TF expression on recipient platelets plays a pivotal role in initiating CC. Therefore, understanding the interactions between porcine ECs and primate platelets may be crucial to prevent coagulopathy. On the other hand, the generation of GT-KO pigs has directed interest to the role of anti-nonGal Abs in intravascular thrombosis. My study revealed that anti-nonGal Abs activated porcine ECs to express TF, independent of complement activation. I also demonstrated that anti-P-selectin and vWF Abs and some anti-platelet agents, such as clopidogrel and eptifibatide, prevented TF expression on platelets after incubation with porcine ECs. Porcine ECs from pigs that expressed tissue factor pathway inhibitor (TFPI) were resistant to the activation induced by primate serum even with high titre anti-nonGal Abs. Atorvastatin not only inhibited this activation of platelets but also prevented the activation of porcine ECs induced by primate serum. Coagulopathy is increasingly recognized as barriers to successful xenotransplantation, many mechanisms of which are not associated with humoral immune response. Further manipulation of the immune response alone, with the risk of inducing infection and other complications, does not appear likely to resolve the challenge of xenograft coagulopathy. My results provide evidence for further genetic manipulation or systemic pharmaceutical treatment to prevent coagupolpathy seen after pig-primate xenotransplantation.

20-50% of patients develop pouchitis following restorative proctocolectomy for ulcerative colitis (UC). Pre-pouch ileitis (PPI) also develops in some of these patients. Bacteria are implicated in the pathogenesis of pouchitis and antibiotics are the mainstay of treatment. Studies were performed to examine the role of bacteria in the pathogenesis of this disease and to develop new treatment. Further studies examined the prevalence and implications of PPI and the efficacy and complications associated with maintenance antibiotic therapy. 16s rRNA sequencing demonstrated an increase in Proteobacteria and a reduction in Bacteroidetes in the UC compared with the familial adenomatous polyposis (FAP) cohort, but only limited differences between the UC non-pouchitis and pouchitis groups. We were unable to identify an individual species or phylotype specifically associated with pouchitis. Treatment with elemental diet produced a symptomatic improvement in 71% of chronic pouchitis patients but none entered clinical remission. Patients with PPI were identified, the prevalence, symptoms and short term outcomes of this group were studied. PPI was identified in 5.7% of patients with UC. All patients had associated pouchitis but not all were symptomatic. PPI was not associated with reclassification to Crohn’s disease. A subgroup of patients with symptomatic pre-pouch ileitis were treated with combination antibiotic therapy and 86% entered remission. Faecal samples from patients with antibiotic resistant pouchitis were grown on agar and sensitivity patterns identified. Following guided antibiotic therapy 80% of patients entered remission. Stool analysis also identified the presence of extended spectrum beta-lactamase (ESBL) resistant coliforms in 35% of patients with chronic pouchitis. Not all were symptomatic. PPI was associated with an increased risk of ESBL. Patients treated with maintenance antibiotic therapy were identified. Pre-pouch ileitis was associated with an increased risk of relapse. Reported side effects were rare and treatment was associated with an improved quality of life.

This thesis presents some image processing tools for plastic surgery planning. In particular, it presents a novel method that combines local and global context in a probabilistic relaxation framework to identify cephalometric landmarks used in Maxillofacial plastic surgery. It also uses a method that utilises global and local symmetry to identify abnormalities in CT frontal images of the human body. The proposed methodologies are evaluated with the help of several clinical data supplied by collaborating plastic surgeons.

Conventional coronary artery bypass surgery requires invasive sternotomy and the use of a cardiopulmonary bypass, which leads to long recovery period and has high infectious potential. Totally endoscopic coronary artery bypass (TECAB) surgery based on image guided robotic surgical approaches have been developed to allow the clinicians to conduct the bypass surgery off-pump with only three pin holes incisions in the chest cavity, through which two robotic arms and one stereo endoscopic camera are inserted. However, the restricted field of view of the stereo endoscopic images leads to possible vessel misidentification and coronary artery mis-localization. This results in 20-30% conversion rates from TECAB surgery to the conventional approach. We have constructed patient-specific 3D + time coronary artery and left ventricle motion models from preoperative 4D Computed Tomography Angiography (CTA) scans. Through temporally and spatially aligning this model with the intraoperative endoscopic views of the patient's beating heart, this work assists the surgeon to identify and locate the correct coronaries during the TECAB precedures. Thus this work has the prospect of reducing the conversion rate from TECAB to conventional coronary bypass procedures. This thesis mainly focus on designing segmentation and motion tracking methods of the coronary arteries in order to build pre-operative patient-specific motion models. Various vessel centreline extraction and lumen segmentation algorithms are presented, including intensity based approaches, geometric model matching method and morphology-based method. A probabilistic atlas of the coronary arteries is formed from a group of subjects to facilitate the vascular segmentation and registration procedures. Non-rigid registration framework based on a free-form deformation model and multi-level multi-channel large deformation diffeomorphic metric mapping are proposed to track the coronary motion. The methods are applied to 4D CTA images acquired from various groups of patients and quantitatively evaluated.

The use of minimally invasive techniques can dramatically improve patient outcome from neurosurgery, with less risk, faster recovery, and better cost effectiveness when compared to conventional surgical intervention. To achieve this, innovative surgical techniques and new surgical instruments have been developed. Nevertheless, the simplest and most common interventional technique for brain surgery is needle insertion for either diagnostic or therapeutic purposes. The work presented in this thesis shows a new approach to needle insertion into soft tissue, focussing on soft tissue-needle interaction by exploiting microtextured topography and the unique mechanism of a reciprocating motion inspired by the ovipositor of certain parasitic wasps. This thesis starts by developing a brain-like phantom which I was shown to have mechanical properties similar to those of neurological tissue during needle insertion. Secondly, a proof-of-concept of the bio-inspired insertion method was undertaken. Based on this finding, the novel method of a multi-part probe able to penetrate a soft substrate by reciprocal motion of each segment is derived. The advantages of the new insertion method were investigated and compared with a conventional needle insertion in terms of needle-tissue interaction. The soft tissue deformation and damage were also measured by exploiting the method of particle image velocimetry. Finally, the thesis proposes the possible clinical application of a biologically-inspired surface topography for deep brain electrode implantation. As an adjunct to this work, the reciprocal insertion method described here fuelled the research into a novel flexible soft tissue probe for percutaneous intervention, which is able to steer along curvilinear trajectories within a compliant medium. Aspects of this multi-disciplinary research effort on steerable robotic surgery are presented, followed by a discussion of the implications of these findings within the context of future work.

Advances in Minimally Invasive Surgery (MIS) are driven by the clinical demand to reduce the invasiveness of surgical procedures so patients undergo less trauma and experience faster recoveries. These well documented benefits of MIS have been achieved through parallel advances in the technology and instrumentation used during procedures. The new and evolving field of Flexible Access Surgery (FAS), where surgeons access the operative site through a single incision or a natural orifice incision, is being promoted as the next potential step in the evolution of surgery. In order to achieve similar levels of success and adoption as MIS, technology again has its role to play in developing new instruments to solve the unmet clinical challenges of FAS. As procedures become less invasive, these instruments should not just address the challenges presented by the complex access routes of FAS, but should also build on the recent advances in pre- and intraoperative imaging techniques to provide surgeons with new diagnostic and interventional decision making capabilities. The main focus of this thesis is the development and applications of a flexible robotic device that is capable of providing controlled flexibility along curved pathways inside the body. The principal component of the device is its modular mechatronic joint design which utilises an embedded micromotor-tendon actuation scheme to provide independently addressable degrees of freedom and three internal working channels. Connecting multiple modules together allows a seven degree-of-freedom (DoF) flexible access platform to be constructed. The platform is intended for use as a research test-bed to explore engineering and surgical challenges of FAS. Navigation of the platform is realised using a handheld controller optimised for functionality and ergonomics, or in a "hands-free" manner via a gaze contingent control framework. Under this framework, the operator's gaze fixation point is used as feedback to close the servo control loop. The feasibility and potential of integrating multi-spectral imaging capabilities into flexible robotic devices is also demonstrated. A force adaptive servoing mechanism is developed to simplify the deployment, and improve the consistency of probe-based optical imaging techniques by automatically controlling the contact force between the probe tip and target tissue. The thesis concludes with the description of two FAS case studies performed with the platform during in-vivo porcine experiments. These studies demonstrate the ability of the platform to perform large area explorations within the peritoneal cavity and to provide a stable base for the deployment of interventional instruments and imaging probes.