The effect of genetic variance on fracture healing as assessed by callus composition and strength
Wulff, Alexander Christopher
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Bones have a large capacity for repair and regeneration after an injury. 5-10% of the nearly 8 million fractures that occur every year in the United States do not heal properly. Bone repair and regeneration is a complex process that utilizes molecular and cellular interactions to return to its original structure. Phosphate is essential for healthy bone growth and when phosphate deficient it has been shown to impair the process of fracture healing. It is unknown if replenishing phosphate to the diet will help return the injured bone to its original properties. Some of the differences in fracture repair may be due to genetic variability that contributes to morphology of bone and fracture healing. This study was carried out to assess how genetic variability affects the process of fracture healing. To determine how genetic differences interact with phosphate deficiency fractures were generated in three different inbred mouse strain (A/J (AJ), C57BL/6J (B6), C3H/HeJ (C3)) that had previously been shown to have different endochondral bone formation. Animals were placed on a phosphate restricted diet two days prior to fracture, and was maintained for 15 days, which covered the normal duration of endochondral bone development. To determine if replenishing phosphate in the diet could recover the normal healing, phosphate was returned to the diet after 15 days. There was also control groups that were on a regular diet for the entire time of the study, which was used for comparison. Micro-computed tomography (micro-CT), biomechanical torsion testing, and contrast enhanced micro-computed tomography (CECT) were methods used to asses the properties of the callus over the course of fracture healing. Micro-CT and mechanical test results showed that there were significant differences within AJ, B6, and C3 strains of mice at the various post-operative day (POD) time points. Results from micro-CT data showed that as the POD time point increased there was an increase in the amount of mineralized tissue and a decrease in fracture callus. These results were confirmed by with the increase in strength measurements from mechanical testing conclusions. Further, the fracture callus is less rigid at the early time points and as the fracture callus becomes mineralized there is an increase in the rigidity measures. Other measures of mechanical properties showed that there were significant differences in the B6 and C3 strains of mice among the various POD time points and control and phosphate restricted diets. Assessing cartilage content via CECT showed that there were significant differences in the control and phosphate restricted diets at POD 14, however many of these differences were recovered at the later time points. Visualization of the fracture callus using CECT confirmed that there was diminishing cartilage present in the fracture callus. These results provide insight into the fracture healing process and much information about the return of stability and strength to the fractured bone. Taken together, the outcomes of this study indicate that the bones heal and mechanical strength is recovered once the phosphate has been added back into the diet.