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Title: The biomechanical and biological pathways of tibiofemoral focal cartilage defect pathogenesis and shortfalls of microfracture surgery
Author: Khatib, Nidal
ISNI:       0000 0004 7962 1466
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2018
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Tibiofemoral focal cartilage defects (FCDs) are lesions of the smooth articular surface of the knee caused by maladaptive overload and predispose the knee to osteoarthritis (OA), a major clinical issue. However, the pathways involved in their pathophysiology and progression, particularly in humans, are not well understood. It is clinically useful to characterise this since the outcomes of conventional treatments such as microfracture surgery which aim to repair the lost or damaged cartilage are heterogeneous and less than adequate. This study investigates mechanical and biological pathways of FCD pathogenesis that could be useful in the development of comprehensive treatment strategies, as well as to address the shortfalls of microfracture surgery. Lower limb biomechanical and neuromuscular function was investigated using gait analysis techniques including 3D motion capture analysis, electromyography and principal component analysis of waveforms in a cohort of tibiofemoral medial and lateral compartment FCD subjects relative to healthy control subjects during the performance of level gait. Both medial and lateral knee FCD subjects exhibited biomechanical indicators of increased dynamic loading of the respective affected knee compartment, which was concomitant with dynamic frontal plane knee malalignment. A proportion of FCD subjects, notably medial knee affected types presented adaptive biomechanical gait strategies reflective of pain avoidance that appears to be related to loading of the chondral defect site during gait. Differences in the activation of lower limb muscles during gait was also found, most prominently in medial FCD subjects who abnormally co-contracted their thigh muscles during load bearing, reflective of compensation for knee instability. Longitudinal assessment of biomechanical and neuromuscular function was also carried out six-months following microfracture surgery, which revealed heterogeneous functional outcomes that were independent of subject-perceived outcomes (reduced pain, symptoms and increased functional ability). Some improvement in function was experienced by lateral knee FCD subjects, in contrast to overall worsening function in medial FCD subjects. A total of seventeen biomarkers of bone remodelling, cartilage degradation, bone mechanical loading and inflammation were examined using immunoassays in knee FCD synovial fluid and serum samples relative to knee OA and healthy control samples, respectively. Many synovial fluid biomarkers were reflected poorly in serum, however high levels of bone resorption (CTX-I) and glutamate were found in FCD serum relative to controls, as well as decreasing anti-inflammatory cytokine IL-10 levels concomitant with advancing disease state (i.e. control > FCD > OA). In synovial fluid analysis, inflammatory dysregulation (increased IL-6 and IL-8 and decreased IL-10 and IL-13) and high osteoprotegerin (OPG) levels were found in OA relative to FCD subject joint fluids. Discrete principal component analysis identified distinct phenotypes of FCD and OA fluids relating to sclerostin and anti-inflammatory cytokine levels. Furthermore, follow-up analysis of serum biomarkers six-months following microfracture surgery revealed decreased CTX-I and glutamate, as well as increased anti-inflammatory cytokine levels associated with positive patient-reported outcomes, in contrast to decreased IL-10 and IFN-γ with negative reported outcomes. Finally, associations between biomechanical indicators of altered knee biomechanical loading and synovial fluid biomarkers relating to previous objectives were explored in FCD and OA subjects, whilst controlling for demographic factors. The magnitude of knee peak loading, cumulative loading or degree of knee malalignment significantly predicted pro-inflammatory cytokine and bone resorption activity when combining FCD and OA data. However, in FCD knees alone, dynamic joint malalignment associated with increased bone remodelling (CTX-I and ALP). Furthermore, discrete PCA identified high knee loaders from each group that were associated with high pro-inflammatory activity, increased osteoclast activation (RANKL-OPG) and reduced symptoms. This study provides new evidence of aberrant biomechanical and biological factors associated with FCD pathogenesis and progression, as well as the association between them, that improves our understanding of the heterogeneity of the condition and outcomes to microfracture surgery. The failure of microfracture surgery to address functional and biological deficiencies in some subjects is a critical factor that needs to be addressed in future areas of treatment for optimum outcomes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available