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Title: In vivo and in vitro models of distraction osteogenesis
Author: Chang, Cynthia J.
ISNI:       0000 0004 2723 1079
Awarding Body: Oxford University
Current Institution: University of Oxford
Date of Award: 2011
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Distraction osteogenesis (DO) is a unique process of bone formation used for clinical correction of skeletal deformities. In DO, bone is osteotomised, and the cut ends are slowly pulled apart by mechanical means to induce de novo ossification. Despite the extensive current and historical use of DO, the .mechanisms involved are not well understood. A novel mouse model of DO featuring a custom-developed external fixator was validated and characterised by using radiography, immunohistochemistry, and micro array techniques. The in vivo model was subsequently studied in a whole-transcriptome time course micro array analysis of DO. Genes relevant to osteogenesis, angiogenesis, mechanotransduction, cytoskeletal signalling, and the Wnt pathway were highly expressed. Time course statistical methods applied to the micro array data enabled profiling of global gene expression throughout DO and identification of genes and functions that showed significant differential expression over time. Concurrently, a novel three-dimensional in vitro model of DO was developed to assess the mechanobiological effects of distraction. The system consists of two pieces of hard mineral scaffold held in a rigid distractor. A cell-seeded fibrin clot bridges the scaffold ends to simulate the in vivo distraction gap. Using this in vitro model, the effects of a single application of tensile strain on the model were assessed. Digital image correlation demonstrated that strain patterns in the stretched construct are similar to those in the distraction gap. Additionally, murine osteoblasts were viable and proliferated in the scaffold-fibrin construct. Following a single distraction, cells exhibited elongated morphology, greater alignment, and increased alkaline phosphatase activity. In conclusion, a new mouse model and a novel in vitro model were shown to be useful correlates to clinical DO. Additionally, time course statistical analyses and in situ 3D staining techniques provide new tools for understanding and improving surgical bone lengthening. These findings serve as a promising starting point for future investigations into the key mediators of the regenerative potential unleashed in DO.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available