This experimental study was designed to assess the effects of different surgical repair techniques on the process of flexor tendon healing. In particular, it aimed to evaluate the effects of incorporating a novel biocompatible, biodegradable ‘wrap’ into the process of tendon repair. This inorganic polymer wrap, Controlled Release Glass (Giltech Limited, Ayr, Scotland, UK) was composed of a combination of sodium and calcium cations with phosphate and oxide anions and degraded into simple ionic substances normally found in tissue fluid. The hypothesis to be tested stated that ‘the addition of this potentially anti-adhesiogenic substance to the process of flexor tendon repair would result in no difference in musculoskeletal function or tendon characteristics after recovery’. Tenotomy and primary repair of the ovine Flexor Digitorum Superficialis (Pars Superficialis slip) was performed using a variety of different repair methods, involving combinations of the following elements of repair; modified Kessler core suture, circumferential epitenon suture, CRG wrap, triamcinolone paste. Eleven experimental groups of twelve cases were set-up and evaluated in two time cohorts; six weeks and six months after surgery. A control group of twelve non-operated cases was also assessed. Results of statistical analyses showed that for the experimental groups which incorporated CRG wrap, the proliferative vascular response to injury was diminished toward ‘normal’ range at six weeks and within ‘normal’ range by six months after repair. This occurred in the absence of any significant difference in superficial blood flow beyond the site of repair or in the strength of these groups of repaired tendons. Also, at six weeks after operation these experimental groups showed a reduction in fibrous tissue at the sites of tendon repair without any other significant differences in morphological features of the healing tendon. The implications for clinical practice of these findings are discussed.

The experiments presented in this thesis are a study in which the use of biodegradable glass wrap was compared with microsurgical epineurial suturing as a means of repairing cleaning divided median nerves in a sheep model. Twelve sheep were used in a control group and in each of four repair groups in which the following procedures were carried out: 1. Neurotmesis and repair using microsurgically placed epineurial sutures of 10/0 polyamide; 2. Neurotmesis and repair by entubulation with the biodegradable glass wrap secured by 6/0 polyglactin macrosutures; 3. Neurotmesis and repair by entubulation with the biodegradable glass wrap secured by fibrin (Tisseel) glue; 4. Neurotmesis and repair by entubulation with the biodegradable glass wrap secured with polycaprolactone glue. No gap was left between the proximal and distal stumps. Electrophysiological tests on the median nerve, flexor carpi radialis muscle and flexor digitorum longus muscle were carried out seven months after the repair and a portion of the median nerve distal to the repair site was excised for morphometric examination after all electrophysiological testing had been completed. The main conclusions of the present study were: 1. Nerves repaired with the biodegradable glass wrap and fibrin glue displayed distal neuronal regeneration that was not found to be significantly different from that which occurred after a tensionless microsurgical epineurial suture. This biodegradable glass wrap, secured with fibrin (Tisseel) glue, could therefore be used in humans to repair simple nerve divisions; 2. Using the wrap in nerve repair is simple and is quicker and less expensive than microsurgical epineurial suture; 3. Nerve regeneration after nerve repair could be assessed in humans by measuring <i>maximum conduction velocity (CV_max) </i>(m s^-1) and <i>transcutaneous stimulated jitter (TSJ) </i>.

Much has been written about the various factors which cause or are thought to cause "cross infection" of wounds in hospital. In most investigations an individual problem such as theatre ventilation or the sterilisation of blankets has been studied in detail. The introduction of one such measure, although a step in the right direction, is unlikely to produce dramatic or permanent results. When, however, all the preventive measures which are known or thought to minimise "cross infection" are introduced simultaneously in one hospital one might expect a reduction in the incidence of infection of clean surgical wounds. By improving theatre facilities, ward facilities and by providing sterile materials for operations and ward procedures, the incidence of infection of clean wounds has been reduced from 6.7% to 0.7 %. It would appear that infection is most frequently introduced in theatre. If money is limited, priority should be given to theatre improvements and to the supply of sterile theatre instruments, dressings and fabrics. A comparison of the results achieved in three surgical units would indicate that the "human element" is very important. One cannot eliminate bacteria unless the surgeon and his assistants can mentally visualise them. The incidence of infection in surgical wounds must be recorded accurately. Phage typing of all staphylococcal infections will make the early detection and prevention of an epidemic of wound sepsis easier. Prevention of wound sepsis is a team responsibility involving the entire hospital staff. Pathogenic bacteria cannot be eliminated from hospital. The war against sepsis cannot end. The team's effort must be planned, vigorous and continuous.

Torso haemorrhage remains one of the leading causes of preventable morbidity and mortality from trauma particularly in the prehospital setting. Early identification of the haemorrhage source is essential in order to improve outcomes and an effective imaging modality may help to establish the diagnosis. This thesis examines how to improve abdominal haemorrhage identification in the prehospital setting in order to achieve rapid haemorrhage control. The current literature is appraised and a national questionnaire distributed to frontline trauma care physicians. For haemorrhage identification research into ultrasound is recommended and for haemorrhage control novel procedures such as Resuscitative endovascular balloon occlusion of the Aorta (REBOA) are valued. FAST (Focused abdominal sonography for trauma) is considered the most appropriate modality for haemorrhage identification in the prehospital setting but it is associated with a steep learning curve. In order to improve training, a face, content and construct validation of a FAST simulator model is undertaken. Furthermore to better understand an ideal performance, an ergonomic analysis of experts’ workspace and force during a FAST scan is conducted. From this, an expert set of metrics is derived of the ideal ultrasound probe position and force for each FAST region. A learning curve study is implemented to assess two randomised groups of novices one trained with the expert metrics and the other trained using a standardised curriculum. The expert metrics group are faster and more accurate at performing a FAST scan than the control. This is also the case in a prospective validity study. REBOA is being investigated as a novel technique for prehospital haemorrhage control. Accurate inflation of the balloon catheter within the correct zone is critical to gain control of bleeding and prevent adverse effects, particularly in the prehospital setting. A feasibility study identifies that ultrasound guidance and balloon insufflation with contrast agent enhances catheter placement within Zone III. Subsequently, two groups of physicians are randomised to perform REBOA with and without ultrasound guidance. The former are faster and more precise than the latter group hence supporting the robustness of the ultrasound imaging technique. Overall this thesis enhances prehospital abdominal haemorrhage identification by improving FAST training and augments haemorrhage control through accurate REBOA placement with the use of ultrasound and contrast agent.

Advances in surgery have had a significant impact on cancer treatment and management. Recurrence, however, is still a major issue, and is often associated with incomplete tumour removal. Thus far, histopathological examination is still the “gold standard” for assessing tumour resection completeness. However, it is operator-dependent and too slow for intraoperative use. Recently developed endomicroscopy techniques enable the acquisition of high resolution images at a cellular level in situ, in vivo, thus significantly extending the information content available intraoperatively. The miniaturised imaging probes incorporate flexible fibre bundles and allow the ease of integration with surgical instruments. However, manual control of these probes is challenging, particularly in terms of maintaining consistent tissue contact and performing large area surveillance of complex, deformable, 3D structures. This thesis explores the use of surgical robots and robotically-assisted probe manipulation to provide stable, precise, consistent and dexterous manipulation of endomicroscopy probes for surgical applications. Following a discussion of image enhancement techniques, a first approach towards robotically-assisted probe manipulation using existing surgical robotic platforms is demonstrated in the form of multi-purpose, pick-up probes. They also incorporate novel force adaptive mechanisms for consistent tissue contact. The development of bespoke, mechatronically-enhanced robotic devices is then presented. Firstly, a handheld robotic scanning device is proposed for breast conserving surgery, allowing accurate, high speed scanning over wide deformable tissue areas. An energy delivery fibre is integrated into the scanning mechanism for image-guided ablation or intraoperative marking of tumour margins. Secondly, a dexterous 5-degree-of-freedom robotic instrument is proposed for use in endoluminal microsurgeries. The instrument offers increased flexibility and by using a master-slave control scheme, we demonstrate how efficient, large area scanning over curved endoluminal surfaces can be performed. Finally, the fusion of ultrasound imaging with endomicroscopy is investigated through the development of a robotically-actuated articulated instrument for multi-modality image fusion.

The overall aims of this thesis are: to determine the cellular response to ET-1 and effects of receptor antagonism on proliferation, migration and contraction of colonic fibroblasts and cancer cell lines. At the molecular level to identify novel genes that are regulated by ET-1 and whether antagonists including ZD4054 have potentially beneficial effects by blocking expression of these genes. Finally to determine ET-1 binding distribution by autoradiography in patient tumour sections and delineate binding characteristics of ET-1 and its receptor antagonists (Bmax, Kd and IC50). To investigate ET-1 and its antagonistic effects at the cellular level, colorectal cancer cell lines and colonic fibroblasts (isolated from patient colorectal cancer specimens) were studied. They were incubated with ET-1 with/without BQ123, zibotentan (ETAR antagonists) and/or BQ788 (ETBR antagonist). Growth was measured by methylene blue uptake; migration by scratch wound assay and contraction in collagen gels. To identify novel key genes regulated by ET-1, Illumina micro-arrays determined differential gene expression post-ET-1 stimulation of 3 colorectal cancer cell lines and the 4 human colonic fibroblast strains. To confirm expression of genes of interest, we examined time point induction mRNA levels (conventional RT-PCR; quantitative real-time RT-PCR). ETA (Zibotentan, BQ123) and ETB (BQ788) antagonistic effects were measured at the mRNA and protein levels (Immunoblotting). Silencing (SiRNA) was also used to confirm receptor involvement in regulation of these key genes. ET-1 receptor distribution and binding characteristics (Kd; Bmax) were determined using in vitro autoradiography on patient sections, tissue homogenates, CRC cell lines and colonic fibroblasts. Effects of the ETAR specific antagonist zibotentan (ZD4054) on ET-1 receptor binding (IC50) were evaluated against laboratory-standard compounds. Immunohistochemistry (IHC) was used to identify stromal structures and receptor distribution (vascular CD31; Thy-1 fibroblasts; collagen type XI; ETA and ETB). Study was awarded ethical approval, REC No. 08/H0720/162, University College London Hospitals.

A qualitative systematic review was conducted to assess the performance of tools which have been validated for the prediction of morbidity and/or mortality, in heterogeneous cohorts of surgical (non-cardiac, non-neurological) patients. The Portsmouth- Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (P-POSSUM) and the Surgical Risk Scale (SRS) were found to be the most widely validated and accurate risk stratification tools. The POSSUM, P-POSSUM and SRS were then validated in a population of patients who had major non-cardiac surgery in a metropolitan UK hospital. Their accuracy (discrimination) was compared against two novel predictors - the additive POSSUM score and the POSSUM physiology score. P-POSSUM and the additive POSSUM score predicted short-term mortality with high-moderate accuracy. The POSSUM Physiology score was moderately accurate and therefore worthy of further evaluation. Both POSSUM and P-POSSUM were poorly calibrated for this population. The relationships between perioperative risk, postoperative morbidity (measured using the Post Operative Morbidity Survey, POMS), postoperative length of hospital stay, and short-term mortality, were explored in a series of univariate analyses. There were differences in short-term mortality, and the patterns and prevalence of POMS-defined morbidity between surgical specialities. Cox Proportional Hazards Modelling, using time-dependent covariates, was undertaken to explore the independent relationship between perioperative risk, postoperative morbidity and long-term survival. POMS-defined neurological morbidity (prevalence 2.9%) was independently associated with reduced long-term survival. Prolonged postoperative morbidity, defined as the presence of POMS-defined morbidity on Day 15 post-surgery (prevalence 15.6%), conferred a relative hazard for death in the first 12 months post surgery of 3.52 (p<0.001; 95% C.I. 2.23-5.43) and for the next two years of 2.33 (p<0.001; 95% C.I. 1.56-3.50). Postoperative morbidity is a significant public health issue and poses a risk to longer-term survival; it would be an important measure of the quality of perioperative healthcare.

Angiogenesis and vasculogenesis are essential neovascularisation processes. Various cell types and growth factors are involved, with vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2 identified as key components. The PhD project “In vitro vasculogenesis in 3D” tested the effect of parameters such as support cells, matrix composition and physiological hypoxia on the morphology and aggregation of ECs in 3D collagen hydrogels. Different aggregation patterns were identified depending on the culture conditions tested, and these were found to reflect the different developmental pathways that ECs take to form different sized tubular structures. ECs formed contiguous sheets in collagen only hydrogels, analogous to the ‘wrapping’ pathway in development. In contrast, in co-cultures in 3D collagen-laminin cultures, end-to-end networks formed, mimicking cord hollowing and cell hollowing. A relationship between matrix composition, growth factors and VEGF receptor levels in 3D collagen hydrogels was shown for the first time in this study. Results showed a key linkage between integrin expression on ECs and their uptake of VEGF, regulated by VEGFR2, resulting in end-to-end network aggregation in HBMSC-HUVEC co-cultures. The effect of physiological hypoxia on EC aggregation was also tested by lowering the oxygen tension to 5% O2 using a controlled culture environment. Angiogenic growth factors were quantified using ELISA and their levels were correlated to EC morphological progression within 3D collagen hydrogels. Overall, the findings here showed how different parameters affected EC morphology and aggregation in 3D in vitro collagen hydrogels. The study provides an understanding of how these individual parameters influence EC morphology and show the mechanisms of how this is achieved in 3D in vitro.

No description available.

Upright Pedalling (UP) exercise offers opportunities for stroke survivors to participate in functional, repetitive lower limb activity with similarities to walking. Such functional activity is required to enhance the brain changes underlying recovery of motor function after stroke. UP might also offer opportunities for assessment and measurement of lower limb impairment during functionally-relevant activity. A systematic review using Cochrane methodology investigated effects of reciprocal pedalling (RP) on lower limb motor function after stroke. Despite some beneficial, though not definitive, effects, it was not possible to make clinical recommendations supporting or refuting RP after stroke, due to inter-study heterogeneity, wide confidence intervals around effect sizes and risks of potential biases. A feasibility study investigated participation in Upright Pedalling (UP) by people in the first month after stroke, with substantial weakness and not able to walk, and explored characterisation of lower limb movement during UP. 84.6 % (n=11) of people tested were able to participate in UP. Smooth, reciprocal pedalling was evident in stroke survivors with substantial weakness, using heterogeneous patterns. Though 84.2% (n=16) of those approached consented to participate, attrition was high due to service reorganisation, with 2.2% (n=9 of 411) of those screened actually randomised. A prospective measurement study explored the reliability and discriminative ability of impairment measures derived during instrumented UP (smoothness of pedalling, muscle activation timing, reciprocity of muscle activity). Results indicated that instrumented UP could be used to discriminate between stroke survivors and healthy age-matched volunteers for timing of onset and offset muscle activation (multi-variate ANOVA, difference in activity according to wheel position, p=0.034) and reciprocal activation (two sample t-test, difference -0.249 (CI: -0.491, -0.010; p=0.044)) for quadriceps. It was not possible to establish definitive test-retest repeatability with sufficient precision to make clinical recommendations. UP is a new, promising technology for assessment, rehabilitation and measurement that is worthy of future investigation.