A Novel In Vivo Synchrotron Radiation Micro-CT Imaging Platform For The Direct Tracking Of Remodeling Events In Cortical Bone
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.009 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".