A multiscale biomechanical investigation of bone fragility in Type-2 Diabetes using a Zucker Diabetic Fatty (ZDF) rat
Monahan, Genna
Monahan, Genna
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Publication Date
2024-04-18
Type
Thesis
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Abstract
Patients with type-2 diabetes (T2D) face an elevated risk of bone fracture, despite often exhibiting normal or increased bone mineral density (BMD). The prevailing theory suggests that the hyperglycaemic environment in T2D leads to an accumulation of non-enzymatic Advanced Glycation End-Products (AGEs) in the collagen matrix, resulting in a more brittle behaviour. Yet, no causal relationship has been established suggesting that other mechanisms may be responsible for bone fragility in T2D. The objective of this thesis is to elucidate the underlying biological, biophysical and biomechanical mechanisms that contribute to bone fragility in T2D using a multiscale approach in a 46-week longitudinal study with a Zucker Diabetic Fatty (ZDF) (fa/fa) rat model, by investigating geometrical, compositional and mechanical alterations of the ulnar bone in ZDF rats. It was found that longitudinal alterations in bone growth and reduced bone strength was better correlated with altered mineral properties rather than AGEs. This led to the conclusion that bone fragility in ZDF (fa/fa) rats occurs through a multifactorial process, prompting further investigation into various biological, biophysical, and biomechanical factors that contribute to bone fragility. A detailed investigation of the sequence of events from cellular- to tissue- to the whole-bone biomechanical-level in femoral bones of ZDF (fa/fa) rats was conducted on femoral tissue. It was found that the diabetic state disrupted bone metabolism and cell activity, which showed downstream effects on the mineral and organic components of the bone matrix. Together, these sub-tissue alterations coincided with deterioration of the fracture resistance, with biomechanical testing showing significantly reduced cracking toughness and work-to-fracture in 46-week diabetic (fa/fa) rats, compared to lean, healthy controls. Finally, impaired longitudinal bone growth was investigated by assessing regional alterations in bone composition and tissue-level mechanical properties using site-matched Raman spectroscopy, nanoindentation and micro-pillar compression testing. Regional differences were mainly found in the periosteal region of the control and ZDF (fa/fa) rats. In particular, the mineral composition was found to be altered in the ZDF (fa/fa) rats indicating a regional interplay in bone formation and resorption during growth. Despite compositional changes, tissue-level mechanical properties, did not significantly differ between strains in both regions, contributing valuable insights into the complex dynamics of tissue composition, mechanics, and disease progression in the growth and maintenance of cortical bone in ZDF (fa/fa) rats with T2D. Overall, the findings in this thesis reveal that bone fragility in the ZDF rats occurs through a complex process that was not solely attributed to AGE accumulation in the collagen matrix, but instead arose due to altered bone cellular metabolism and its subsequent effects on bone growth, microstructure and the spatial and temporal alterations to the mineral phase of the bone matrix.
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Publisher
NUI Galway