Optical coherence tomography: applications and developments for imaging in vivo biological tissue

In this thesis the design and build of a high-speed, video-rate optical coherence tomography (OCT) imaging system is described. The system was designed for the purpose of imaging human skin in vivo, particularly that of patients suffering from conditions such as systemic sclerosis. Component selection and design decisions are discussed in the context of the intended final application. Initial test images from the system are presented. In the context of building an OCT system, a supercontinuum light source was characterised and tested for its suitability for use in the OCT environment. Parameters such as coherence length were measured using simple interferometry techniques, while practical considerations such as portability and ease of system integration were also considered.Several applications of OCT imaging techniques were also investigated, using two commercially-available OCT systems from Thorlabs, Inc. A liquid-based skin and blood flow model was constructed using narrow glass capillary tubes, pumped through with scattering solutions of Intralipid or suspensions of polystyrene microspheres. The concentration of the solutions was tuned by dilution in order to best model the scattering parameters of blood. The model also used similar liquid solutions to model static tissue surrounding the blood vessels. Doppler OCT images of the model under various conditions were recorded, and velocity profiles of the flowing liquids were extracted.Using the same commercial OCT systems, imaging over two separate wavelength regions was also performed on the skin of several different species of neo-tropical tree frog, some of which have interesting reflective properties due to the presence of a pigment called pterorhodin. Cross-sectional OCT images of the skin are presented, and averaged depth profiles extracted from them. This is the first time that OCT imaging has been applied to this problem.A clinical study of skin thickening and microvascular function in patients with systemic sclerosis compared to healthy controls was also carried out, again involving a Thorlabs, Inc. commercial OCT system. This study was carried out at Salford Royal Hospital under the supervision of the rheumatology research group. Skin thickness was assessed using OCT and high-frequency ultrasound imaging. Microvascular function was measured using nailfold cappilaroscopy and laser Doppler imaging. Images from the study are presented here.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Intra-and inter-observer reliability of nailfold videocapillaroscopy - A possible outcome measure for systemic sclerosis-related microangiopathy

OBJECTIVES: Our aim was to assess the reliability of nailfold capillary assessment in terms of image evaluability, image severity grade ('normal', 'early', 'active', 'late'), capillary density, capillary (apex) width, and presence of giant capillaries, and also to gain further insight into differences in these parameters between patients with systemic sclerosis (SSc), patients with primary Raynaud's phenomenon (PRP) and healthy control subjects.METHODS: Videocapillaroscopy images (magnification 300×) were acquired from all 10 digits from 173 participants: 101 patients with SSc, 22 with PRP and 50 healthy controls. Ten capillaroscopy experts from 7 European centres evaluated the images. Custom image mark-up software allowed extraction of the following outcome measures: overall grade ('normal', 'early', 'active', 'late', 'non-specific', or 'ungradeable'), capillary density (vessels/mm), mean vessel apical width, and presence of giant capillaries.RESULTS: Observers analysed a median of 129 images each. Evaluability (i.e. the availability of measures) varied across outcome measures (e.g. 73.0% for density and 46.2% for overall grade in patients with SSc). Intra-observer reliability for evaluability was consistently higher than inter- (e.g. for density, intra-class correlation coefficient [ICC] was 0.71 within and 0.14 between observers). Conditional on evaluability, both intra- and inter-observer reliability were high for grade (ICC 0.93 and 0.78 respectively), density (0.91 and 0.64) and width (0.91 and 0.85).CONCLUSIONS: Evaluability is one of the major challenges in assessing nailfold capillaries. However, when images are evaluable, the high intra- and inter-reliabilities suggest that overall image grade, capillary density and apex width have potential as outcome measures in longitudinal studies

Coral reef ecology in the Anthropocene

We are in the Anthropocene—an epoch where humans are the dominant force of planetary change. Ecosystems increasingly reflect rapid human-induced, socioeconomic and cultural selection rather than being a product of their surrounding natural biophysical setting. This poses the intriguing question: To what extent do existing ecological paradigms capture and explain the current ecological patterns and processes we observe? We argue that, although biophysical drivers still influence ecosystem structure and function at particular scales, their ability to offer predictive capacity over coupled social–ecological systems is increasingly compromised as we move further into the Anthropocene. Traditionally, the dynamics of coral reefs have been studied in response to their proximate drivers of change rather than their underlying socioeconomic and cultural drivers. We hypothesise this is limiting our ability to accurately predict spatial and temporal changes in coral reef ecosystem structure and function. We propose “social–ecological macroecology” as a novel approach within the field of coral reef ecology to a) identify the interactive effects of biophysical and socioeconomic and cultural drivers of coral reef ecosystems across spatial and temporal scales; b) test the robustness of existing coral reef paradigms; c) explore whether existing paradigms can be adapted to capture the dynamics of contemporary coral reefs; and d) if they cannot, develop novel coral reef social–ecological paradigms, where human dynamics are part of the paradigms rather than the drivers of them. Human socioeconomic and cultural processes must become embedded in coral reef ecological theory and practice as much as biophysical processes are today if we are to predict and manage these systems successfully in this era of rapid change. This necessary shift in our approach to coral reef ecology will be challenging and will require truly interdisciplinary collaborations between the natural and social sciences. A plain language summary is available for this article

Structural Requirements for Dihydrobenzoxazepinone Anthelmintics:Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here, we report a systematic investigation of the structure–activity relationship of the anthelmintic activity of DHB compounds. We synthesized 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQs) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics

Three-dimensional optoacoustic imaging of nailfold capillaries in systemic sclerosis and its potential for disease differentiation using deep learning

From Springer Nature via Jisc Publications RouterHistory: received 2020-05-07, accepted 2020-09-09, registration 2020-09-16, pub-electronic 2020-10-05, online 2020-10-05, collection 2020-12Publication status: PublishedFunder: Helmholtz Association; doi: http://dx.doi.org/10.13039/501100009318; Grant(s): i3 (ExNet-0022-Phase2-3)Funder: University of Manchester; doi: http://dx.doi.org/10.13039/501100000770; Grant(s): MC_PC_16053Funder: Manchester Biomedical Research Centre; doi: http://dx.doi.org/10.13039/100014653Funder: H2020 European Research Council; doi: http://dx.doi.org/10.13039/100010663; Grant(s): No 694968 (PREMSOT)Funder: Arthritis Research UK,United Kingdom; Grant(s): 19465Abstract: The autoimmune disease systemic sclerosis (SSc) causes microvascular changes that can be easily observed cutaneously at the finger nailfold. Optoacoustic imaging (OAI), a combination of optical and ultrasound imaging, specifically raster-scanning optoacoustic mesoscopy (RSOM), offers a non-invasive high-resolution 3D visualization of capillaries allowing for a better view of microvascular changes and an extraction of volumetric measures. In this study, nailfold capillaries of patients with SSc and healthy controls are imaged and compared with each other for the first time using OAI. The nailfolds of 23 patients with SSc and 19 controls were imaged using RSOM. The acquired images were qualitatively compared to images from state-of-the-art imaging tools for SSc, dermoscopy and high magnification capillaroscopy. The vascular volume in the nailfold capillaries were computed from the RSOM images. The vascular volumes differ significantly between both cohorts (0.216 ± 0.085 mm3 and 0.337 ± 0.110 mm3; p < 0.0005). In addition, an artificial neural network was trained to automatically differentiate nailfold images from both cohorts to further assess whether OAI is sensitive enough to visualize anatomical differences in the capillaries between the two cohorts. Using transfer learning, the model classifies images with an area under the ROC curve of 0.897, and a sensitivity of 0.783 and specificity of 0.895. In conclusion, this study demonstrates the capabilities of RSOM as an imaging tool for SSc and establishes it as a modality that facilitates more in-depth studies into the disease mechanisms and progression

Feasibility study of mobile phone photography as a possible outcome measure of systemic sclerosis-related digital lesions

Objective: Clinical trials assessing systemic sclerosis (SSc)-related digital ulcers have been hampered by a lack of reliable outcome measures of healing. Our objective was to assess the feasibility of patients collecting high-quality mobile phone images of their digital lesions as a first step in developing a smartphone-based outcome measure. Methods: Patients with SSc-related digital (finger) lesions photographed one or more lesions each day for 30 days using their smartphone and uploaded the images to a secure Dropbox folder. Image quality was assessed using six criteria: blurriness, shadow, uniformity of lighting, dot location, dot angle and central positioning of the lesion. Patients completed a feedback questionnaire. Results: Twelve patients returned 332 photographs of 18 lesions. Each patient sent a median of 29.5 photographs [interquartile range (IQR) 15-33.5], with a median of 15 photographs per lesion (IQR 6-32). Twenty-two photographs were duplicates. Of the remaining 310 images, 256 (77%) were sufficiently in focus; 268 (81%) had some shadow; lighting was even in 56 (17%); dot location was acceptable in 233 (70%); dot angle was ideal in 107 (32%); and the lesion was centred in 255 (77%). Patient feedback suggested that 6 of 10 would be willing to record images daily in future studies, and 9 of 10 at least one to three times per week. Conclusion: Taking smartphone photographs of digital lesions was feasible for most patients, with most lesions in focus and central in the image. These promising results will inform the next research phase (to develop a smartphone monitoring application incorporating photographs and symptom tracking)