Members of the armed forces in combat are subject to blast injuries. Because of the success of Kevlar body armor, the survival rate after explosions is much higher than in previous conflicts. However, the arms and legs are not protected by such armor and thus sustain major injuries. Indeed, of the 33,000 service members wounded in Iraq and Afghanistan, 60-70% sustain injuries to their bones and joints. Among such injuries is the loss of large pieces of bone, also known as segmental defects. These heal very poorly, partly because they are so large and partly because of extensive damage to the surrounding tissues upon which healing depends. Although orthopaedic surgeons have a number of procedures they can use to replace the lost bone and help the large segmental defects to heal, these are far from ideal. The research described in this grant proposal will explore a new way to improve the healing of large segmental defects in bone. It is based upon the concept that the healing of these defects is very sensitive to their mechanical environment, and that manipulating this environment in a purposeful way will greatly improve healing.

Laboratory rats will be used to test these concepts. To enable this research, we have designed and built very small devices, known as fixators, which fit onto the thigh bones of rats. The stiffness of the devices can be changed at will in a controlled fashion. In the proposed research, sections of bone will be surgically removed from the thigh bones of rats and stabilized with these fixators. In a first series of experiments, fixators of different stiffnesses will be compared. In a second series of experiments the stiffness of the fixator will be changed at different stages of healing to determine whether this gives a better result. Based upon the results of these experiments, we will select the best ("optimized") method for further study. In one further study, we will determine the degree to which the optimized method accelerates healing. In a second further study, we will determine whether the selected method reduces the need for a protein called bone morphogenetic protein-2 (BMP-2). This protein is used to help bones heal, but it is very expensive and is used at very high doses that may increase the chances of getting a serious complication known as "heterotopic ossification." Patients who develop this complication grow new bone in their muscles. This can be very painful and, in amputees, complicate the use of artificial limbs. Reducing the need for BMP-2 will reduce the likelihood of heterotopic ossification. Although these experiments will be performed in rats, the results from the study should be applicable to humans and will lead to better ways of healing damaged bones in our troops.