Bone Fracture Healing and Regeneration in the Context of an Altered Altered Collagenous Extracellular Matrix.

Abstract

This dissertation includes a series of studies into bone imaging and healing. One of the main outcomes utilizes non-destructive micro-computed tomography (μCT) based imaging, so the accuracy of this imaging modality is investigated. The results indicate that proper use of filtration can avoid the beam hardening artifacts that are attributed to changes in material thickness and radiodensity. These artifacts can affect bone densitometry, but the effects can be minimized at the expense of image contrast, noise and scan throughput. The subsequent experiments build on this knowledge and use μCT as a modality in broader investigations of bone fracture healing and regeneration of structural bone allografts. An animal model of osteogenesis imperfecta (OI), a disease which results in a high incidence of bone fractures for the afflicted pediatric patients, is employed in both healing scenarios. OI patients are normally treated with antiresorptive therapies to reduce fracture risk, so the effect of these therapies on the healing of a subsequent fracture is also investigated. The results indicate that these anti-resorptives have a strong affect on fracture healing if they are present in the circulation, but if treatment is stopped at the time of fracture the effect is very minimal. Furthermore, collagen organization in the healing and intact bone are drastically different, resulting in structure biomechanical properties for the healing bone that are markedly improved in comparison to intact OI bone. This collagen matrix serves as the initial conditions in healing of a structural bone allograft, so the final study investigates this healing paradigm. A model of mouse internal fixation was developed to test grafts both with and without mineral because the presence of mineral complicates effects of matrix alterations in bone. In this case, there was variability in the graft healing between animals, between limbs of the same animal, and even within a single limb. The nature of the healing between grafts with and without mineral is quite different, but the chaotic nature of the healing process may indicate that subtleties in matrix alterations are less important than efforts to improve the healing process at all.