Background: Large segmental defects in bone do not heal well. Indeed, beyond a certain critical size they have no ability to heal spontaneously. The success of Kevlar body armor in saving the lives of warriors suffering blast injuries in Afghanistan and Iraq has increased the incidence of large segmental osseous defects; their healing potential is further diminished by extensive damage to the surrounding soft tissues.Objective: The aim of the current research proposal is to improve the speed and efficiency of healing large segmental defects by manipulating the ambient mechanical environment in a controlled and standardized manner. A rat model will be used. We have developed customized external fixators whose stiffness can be deliberately modified, even when attached to a living animal, thereby allowing us to impose selected, calibrated mechanical regimens in a controlled fashion.Specific Aims1) To determine the effect of fixator stiffness upon the healing of a 5mm segmental defect in the rat femur.2) To optimize healing of such defects by altering the mechanical environment at different stages while healing is in progress.3) To determine whether the optimized method accelerates the recovery of full mechanical strength by the healed bone.4) To determine whether the optimized method reduces the amount of rhBMP-2 needed to recover full mechanical strength by the healed bone.Study Design: Customized external fixators will be used to stabilize 5mm defects created in the femora of Fischer rats. The defects do not heal spontaneously, but do so after the implantation of a large amount (11mu g) of recombinant BMP-2. Healing of the defects will be assessed by serial weekly X-ray of living animals, followed by euthanasia 8 weeks after surgery. Femora will then be evaluated by micro-computed tomography, dual energy X-ray absorptiometry, histology, and mechanical testing. In Aim 3, rats will be euthanized at multiple time points prior to 8 weeks.Innovation: Although there is a vast literature describing the effects of mechanical manipulation on the healing of sub-critical size fractures, the refereed literature appears to contain no reports of data from experiments studying the effects of the mechanical environment on healing of critical size segmental defects. The current clinical practice of stabilizing segmental defects with rigid internal fixation is adopted from the literature concerning fracture healing. There is no experimental evidence to support this practice for critical size defects. We will not only be the first to examine this issue experimentally, but also the first to suggest and test the effects of the calibrated modulation of the mechanical environment during the healing of large segmental defects.Military Benefit: Large segmental osseous defects are common sequelae of blast injuries and their treatment is inadequate. This research aims to develop a straightforward, highly effective way to improve healing by purposefully manipulating the ambient mechanical environment. A successful method will also greatly diminish the need for BMP-2 and thus reduce any additional risk of heterotopic ossification. Although this is a rat study, its findings should be readily translatable to humans.Focus AreaThis Idea Development Award application addresses the following focus area:Prevention of complications: Methods of early bone or soft tissue stabilization.
|Effective start/end date||9/30/10 → 10/29/13|
- Congressionally Directed Medical Research Programs: $695,824.00