Optimizing Muscle Function in Composite Tissue Injuries with Segmental Bone Defects
Abstract
The purpose of this research is to determine the best way(s) to treat bone injuries in badly injured extremities to prevent further injury to the surrounding muscle. Our proposal involves using our pig composite tissue injury (CTI) model and directly aligns with the Focus Area Composite Tissue Regeneration: Techniques aimed at improving outcomes following high-energy extremity trauma, with a focus on improving wound healing, neuromuscular recovery following composite tissue loss and segmental bone loss. Composite tissue injury (CTI) is injury to all of the tissues in a limb, including the bone, muscle, nerves, and skin, all of which are at high risk to have poor long-term function that is primarily due to pain and weakness. We have developed a pig CTI model purposefully designed for these studies that can generate evidence that can be rapidly advanced for investigation in human trials. Traditionally, the majority of focus in CTI extremity trauma is to get the bone to heal without infection, as poor bone healing is a clear cause of pain and residual weakness. Researchers and clinicians have determined that the viability of the muscle that surrounds the bone plays an important role in how the bone heals. In our recent work, we have conversely determined that the injury to the underlying bone plays an important role in how the overlying muscle functions and heals. Specifically, we determined that untreated large bone defects, called segmental bone defects (SBDs), cause injury and weakness to the adjacent muscle even when the muscle was uninjured. In this study we will determine how two current clinical methods used at the time of injury to treat an SBD affect adjacent muscle function and composition. In our previous work, we showed that an SBD caused the adjacent muscle to fill with scar tissue that led to loss of 50% of its strength three months after injury. The loss of strength was no different in pigs that had an isolated SBD compared to pigs that had an identical SBD and a direct injury to the muscle. Based on this, we concluded that the SBD was the most important cause of injury and weakness in the adjacent muscle, even more so than the direct muscle injury. Therefore, we designed this study to determine the best way to treat the SBD to minimize collateral muscle injury. We will use our pig model that includes removing a 25-mm (roughly one inch) segment of bone from the middle of the tibia (the shin bone) that is fixed with standardized orthopaedic surgical methods using plates and screws. This model leads to significant injury in the surrounding muscle. In this study, we will create the same SBD. In the first group of pigs, the SBD will be filled with what is done currently in the majority of injuries in humans. The SBD will be filled with a solid spacer made from standard bone cement (the same bone cement we use to secure joint replacements) filled with antibiotics. In a second group of pigs, the SBD will be filled with a bone-morphogenetic protein (BMP-2) which is a protein that speeds up bone healing. Typically, in clinical cases, therapies that accelerate bone healing are withheld until all of the underlying skin and muscle are healed, but it is possible that this may not be the best way to prevent muscle injury. In our initial studies, BMP-2 rapidly accelerated bone healing in the SBD. So, here we will test if immediate treatment to accelerate bone healing is better for the adjacent muscle. In the third group of pigs, the SBD will be untreated to replicate the conditions from our previous study. Strength will be measured monthly for 3 months using a custom pig testing apparatus that measures the peak amount of torque the muscle adjacent to the SBD can produce. The pigs will be euthanized at 3 months, and we will remove the muscle adjacent to the SBD and do testing to determine concentrations of healthy muscle proteins, proteins that show that the nerves in the muscle are working well,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310309
Entities
People
- Roman M Natoli
Organizations
- Indiana University
- United States Army