Background Lateral epicondylalgia (LE) also known as tennis elbow is an overuse tendinopathy of the common extensor tendon at the lateral elbow causing persistent pain and disability. Current pathophysiological models have highlighted that local tendon structural abnormalities and sensory system changes are key factors associated with LE, however, the exact nature of the inter-relationship between these pathophysiological characteristics is largely unknown. In particular, there are notable knowledge gaps on the inter-relationship between local tendon pathology, sensory system changes and their relative contribution to pain and disability in LE. It is important to evaluate the inter-relationship between these pathophysiological factors to model the mechanisms underpinning the clinical presentation and recovery profile in people with LE. While the mechanism underlying the pathogenesis of persistent pain necessitates further exploration, it is equally important to determine the optimal treatment for improving tendon structure and sensory function in LE. Conservative treatments such as manual therapy/exercise and prolotherapy injections have been recognised as potentially effective treatment options for improving pain and function in LE. However, the effects of prolotherapy injections and manual therapy/exercise used, either singly or in combination, on improving tendon structural and sensory abnormalities are largely unknown. Furthermore, it is not clear whether the baseline presence of tendon abnormalities can influence the short- and long-term outcomes of prolotherapy injections and manual therapy/exercise in LE. The aims of this dissertation were (i) to explore the inter-relationship between tendon structural abnormalities, sensory abnormalities and clinical outcomes over time; (ii) investigate the effectiveness of prolotherapy injections, manual therapy/exercise, both singly and in combination in improving tendon structural and sensory abnormalities over time; and (iii) examine the prognostic indicators of short- and long-term outcomes of these interventions for LE. Methods The sample for the thesis was 120 participants with a clinical diagnosis of lateral epicondylalgia, aged 18 to 70 years who enrolled in a single-blinded randomised clinical trial (RCT) of prolotherapy injections and manual therapy/exercise used singly and in combination with a 52-week follow-up. Ultrasound (US) examination, Quantitative Sensory Testing and clinical assessments (e.g., Patient-Reported Tennis Elbow Evaluation; PRTEE) were performed at baseline and at 6, 12, 26 and 52 weeks follow-up. The five studies of the current thesis studies include: 1) an inter-rater reliability study of scoring tendon structural abnormalities from static and dynamic US images by a non-radiologist using a composite scale score; 2) a cross-sectional study investigating the association between tendon structural abnormalities, sensory and clinical characteristics; 3) an RCT assessing the comparative effectiveness of prolotherapy injections and manual therapy/exercise in improving tendon structural and clinical outcomes over time; 4) an RCT investigating the effects of prolotherapy injections and manual therapy/exercise in improving sensory outcomes over time; and 5) a study investigating prognostic factors associated with short- and long-term clinical outcomes following prolotherapy injections and manual therapy/exercise in LE. Results The results of this thesis demonstrate that i) the composite US scoring method has good inter-and intra-rater reliability in grading tendon abnormalities in LE ii) US described tendon structural abnormalities has minimal association with sensory system changes iii) prolotherapy injections and manual therapy/exercise are effective in improving tendon structure, sensory and pain and function over time, with no significant differences between treatment conditions. Also, tendon structural abnormalities assessed using composite US score was significantly associated with pain and disability (PRTEE) at 6, 12, 26 and 52 weeks following interventions. iv) the baseline presence of tendon structural abnormalities was associated with PRTEE at 12 and 52 weeks. Discussion Findings for the US image rating scale used in the study support the reliability of non-experienced US observer for grading tendon abnormalities in LE. Given the poor vascular supply to the common extensor tendon, the presence of neovascularity can be considered a weak clinical indicator of cold hyperalgesia. Individuals exhibiting tendon thickness on the US images reported poor vibration detection threshold. Adding prolotherapy injections with manual therapy/exercises is beneficial in improving tendon and sensory abnormalities in LE. US evaluation of tendon abnormalities using a composite score can be a useful method for predicting treatment outcomes for LE.