Influence of mechanical stimulation on strain environment and patterns of gene expression during fracture healing.

Abstract

Fracture repair is a complex process involving many different cellular processes that must be coordinated temporally and spatially to ensure proper regeneration of bone. While the majority of fractures heal with minimal intervention, a meaningful percentage result in complications such as nonunion or delayed union, which can have significant consequences of morbidity and mortality, particularly in the elderly. This has led the clinical and scientific communities to search for strategies to accelerate or augment bone repair. The rate and efficacy of bone healing can vary tremendously depending on environmental and systemic conditions, including the mechanical environment, which can be influenced by method of fixation, rehabilitation protocol, and the geometry and location of the fracture itself. This dissertation aims to understand the relationship between the mechanical environment of a healing fracture and the cellular processes of proliferation, differentiation, and gene expression that eventually influence the efficacy, rate, and mechanisms of bone healing. A rat model of osteotomy repair under applied mechanical stimulation in bending is used to examine three specific aspects of fracture healing in depth: tissue formation, cellular differentiation, and revascularization. Factors that influence these processes are temporally and spatially localized within the regenerating tissue. These patterns are then compared with predictions of local strains determined by finite element modeling techniques. In addition, patterns and levels of expression are compared between mechanically stimulated and control fractures. Results from this study indicate that, in general, high tensile strains promote chondrogenesis after the stimulation period, despite a local increase in vascular density, which is followed by rapid endochondral ossification and increased bony bridging of the fracture gap. Compressive strains result in decreased bone formation and may shift osteogenesis to an intramembranous pathway. These effects may be mediated by altered expression patterns and levels of bone morphogenetic proteins in response to the applied mechanical environment. These results will hopefully contribute to the current understanding of bone regeneration and its response to altered environmental conditions, as well as provide insight into the mechanism of skeletal adaptation to physical forces.