Mechanobiological Origins of Osteoporosis
Verbruggen, Stefaan W.
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The osteocyte is believed to act as the primary sensor of mechanical stimulus in bone, controlling signalling for bone growth and resorption in response to changes in the mechanical demands placed on bones throughout life. Alterations in local bone tissue composition and structure arising during osteoporosis likely disrupt the local mechanical environment of these mechanosensitive bone cells, and may thereby initiate a mechanobiological response. However, due to the difficulties in directly characterising the mechanical environment of bone cells in vivo, the mechanical stimuli experienced by osteoporotic bone cells are not known. The global aim of this thesis is to discern the in vivo mechanical environment of the osteocyte, both in healthy bone tissue and during the disease of osteoporosis. The first study of this thesis involved the development of 3D finite element models of osteocytes, including their cell body and the surrounding pericellular matrix (PCM) and extracellular matrix (ECM), using confocal images of the lacunar-canalicular network. These anatomically representative models demonstrated the significance of geometry for strain amplification within the osteocyte mechanical environment. A second study employed fluid-structure interaction (FSI) modelling to investigate the complex multi-physics environment of osteocytes in vivo. These models built upon the anatomically representative models developed in the first study, and FSI methods were used to simulate loading-induced interstitial fluid flow through the lacunar-canalicular network. Interestingly, the in vivo mechanical stimuli (strain and shear stress) predicted using these computational approaches were above thresholds known to elicit osteogenic responses from osteoblastic cells in vitro, and thereby provide a novel insight into the complex multi-physics mechanical environment of osteocytes in vivo. The third study of this thesis sought to experimentally characterise the strain environment of osteoblasts and osteocytes under physiological loading conditions in healthy and osteoporotic bone, using a rat model of osteoporosis. A custom-designed loading device compatible with a confocal microscope was constructed to apply strains to fluorescently stained femur samples from normal and ovariectomised rats. Confocal imaging was performed simultaneously during loading and digital image correlation techniques were used to characterise cellular strains from the images acquired. These results suggested that the mechanical environment of osteoblasts and osteocytes is altered during early-stage osteoporosis, and it is proposed that a mechanobiological response restores the homeostatic mechanical environment by late-stage osteoporosis. A final study applied these results as inputs for the developed computational models to investigate whether changes in tissue properties, lacunar-canalicular architecture or amplification mechanisms during osteoporosis could explain the altered mechanical stimulation of osteocytes observed. The findings of this study shed new light on the osteocyte mechanical environment in both healthy and osteoporotic bone, elucidating a possible mechanobiological relationship between increases in strain stimulation of the osteocyte and subsequent increases in mineralisation of bone tissue as key events in the progression of osteoporosis. Together, the studies in this thesis provide a novel insight into the closed mechanical environment of the osteocyte. Using both computational and experimental methods, the mechanical stimuli that osteocytes experience under physiological loading in vivo, in both healthy and osteoporotic bone, were elucidated. In particular, the research in this thesis provides a missing mechanobiological link in the temporal development of post-menopausal osteoporosis, and the information gained from this body of work may inform future treatments for osteoporosis.
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