A Novel In Vivo Synchrotron Radiation Micro-CT Imaging Platform For The Direct Tracking Of Remodeling Events In Cortical Bone

Throughout life, bone tissue continuously alters its microarchitecture in response to microdamage and other stimuli through remodeling. Specialized cellular groupings, Basic Multicellular Units (BMUs), conduct remodeling through ‘coupling’ bone resorption to formation. Osteoclasts within a BMU’s cutting cone create a localized cylindrical space which osteoblasts concentrically refill, creating a secondary osteon (a.k.a. Haversian system). Continual production of secondary osteons by multitudes of BMUs creates a vast interconnected vascular network that permeates the cortex of bone, and therefore, BMUs are essential components in the overall maintenance of bone health. However, with increasing age or diseased states, such as osteoporosis (OP), remodeling can destabilize where resorbed bone is not entirely replaced (unbalanced) and/or where BMUs become ‘uncoupled’ preventing initiation of the bone formation following resorption. This increases porosity and thins cortices, leading to fragile, brittle bones much more susceptible to fracture. BMU behavior has never been replicated in vitro nor directly observed in vivo. The resorptive characteristics of BMUs, such as Longitudinal Erosion Rate (LER) – the rate of the advance of the cutting cone over time – are particularly poorly understood as our current understanding is inferred from indirect histological assessment of bone formation. Critically, BMUs have never been imaged in 4D (3D over time) due to limitations imposed by the radiation dose associated with conventional absorption-based imaging. This thesis explores in-line phase contrast synchrotron radiation micro- CT (SR micro-CT) as means of overcoming the limitations of conventional imaging. The goal was to develop a novel pre-clinical (animal) platform capable of directly tracking individual BMUs. The specific objectives of my thesis research were: 1) develop an in vivo imaging protocol to target individual BMU remodeling events within rabbit tibiae cortical bone to permit longitudinal imaging, using in-line phase contrast SR micro-CT; 2) Within rabbits, implement OP models of ovariectomy, glucocorticoids, a combination thereof and parathyroid hormone (PTH) to elevate cortical bone remodeling rates and, thus, the ability to observe BMU behavior on a large scale; and 3) directly measure BMU LER in 4D for the first time. A novel SR micro-CT protocol capable of detecting cortical porosity without any apparent radiation impacts was successfully developed on the BioMedical Imaging and Therapy Beamline of the Canadian Light Source. Compared to sham controls, elevated remodeling was found for all the OP models. PTH induced the highest rate of remodeling and it was selected as the model for direct assessment of LER. Through a novel co-registration technique, where in vivo SR micro-CT and follow-up ex vivo micro-CT scans acquired two weeks later were combined, LER (23.79 µm/day) was directly assessed for the first time. This novel platform establishes a means of investigating BMU spatio- temporal behavior and thus has great potential to advance our understanding of the role of remodeling in bone aging, adaptation, and disease.

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