PhD Defense: David Reynolds

Structural and mechanical Analysis from a mouse model of massive bone allografts, and the effect of systemic anabolic parathyroid hormone therapy for graft healing

The use of bone allografts for skeletal reconstructions is commonplace clinically, but they are known to have incomplete healing even years after implantation, and fail to develop union and will fail due to unrepaired fatigue damage. Identifying patients at risk for bone graft failure remains an unmet clinical need. Additionally, developing new ways of enhancing bone healing are in being devised, so there is need for quantitative evaluation of their efficacy. The goals of this dissertation were to evaluate the specific structural qualities that contribute to the mechanical properties of grafted bones in a critically-sized defect in the mouse femur, to generate a novel measure of graft-to-host union, and to evaluate parathyroid hormone (PTH), a systemic anabolic bone therapy, for its impact on bone graft healing.

First, two standard means of grafting were evaluated over time to create a working toolset for evaluating treatments. We compared processed bone allografts, from donor mice which lack any intrinsic healing capacity, with live autografts, whose live periosteum and intrinsic healing capacity make it the gold standard of bone graft materials. Surprisingly, autografts did not produce more bone callus, but the callus was better organized, forming a bridge over the graft entirely. Correlations of the measures of cross sectional geometry and volume of the callus and graft helped to explain up to 44% and 50% of the variation in torsional strength and rigidity, respectively.

We observed that allograft-to-host union was deficient in many samples in this model, which recapitulates the complication found clinically, so we devised an imaging analysis tool to measure the degree of graft-to-host union from the CT images and coined it the Union Ratio. The Union Ratio significantly improved the ability to predict torsional mechanics from CT imaging by 8 to 26%, and was particularly critical in delineating successfully healed allografts at these time points.

PTH has been used to reverse osteoporotic bone loss and has recently been found to significantly enhance fracture healing. In this dissertation, PTH was investigated as a potential adjuvant therapy for bone grafting in this mouse model. It was found to almost double the callus bone volume and the union area on the graft, which resulted in almost doubling the yield torque and rigidity, proving its efficacy.

Lastly, progress towards evaluating persistent non unions from clinical case studies, and measuring the effect of PTH to consolidate these fractures was made.

Together, these results indicate that achieving a high level of union, as measured by the Union Ratio, is an important non invasive biometric in allograft functional strength and can be improved with systemic intermittent PTH therapy during healing.