Ultrasound to Diagnose and Treat Heterotopic Ossification

The proposed research addresses two FY20 Musculoskeletal Health topic areas: a) research to develop diagnostic tools or increase the understanding of the cause, prevention, and/or treatment of compartment syndrome, sarcopenia/cachexia, or other skeletal muscle specific diseases and conditions; and b) research to better understand tissue-specific diseases or injuries (e.g., bone, cartilage, tendon, and/or muscle) with a focus on treatment, recovery, or regeneration. Heterotopic ossification (HO), or the presence of bone in soft tissues where bone does not normally exist, occurs in over half of musculoskeletal injuries caused by blasts or explosions. HO has also been found to occur in up to 90% of patients after surgical musculoskeletal injury. After trauma, the earliest symptoms of HO of fever and swelling take 3-12 weeks to appear; however, the calcifications are not visible on x-ray or computed tomography for at least 7 weeks post-injury. The ultrasound twinkling artifact has been shown to highlight kidney stones with rapidly changing color. In preliminary studies in the lab, researchers have shown that the twinkling artifact also appears on bone deposited by cells. In this proposal, the twinkling artifact will be investigated and optimized to detect the earliest bone deposits in HO. Different ultrasound parameters will be tested in a cellular model of HO known to produce bone in 2-4 weeks. Then, the best ultrasound parameters will be evaluated in a mouse model of HO to ensure twinkling will detect early bone with high sensitivity. However, early detection is only important if an effective therapy exists to treat early HO. Current therapies for HO include medications, radiation therapy, surgical removal, or extracorporeal shock wave therapy; however, these therapies have mixed success rates with the potential for severe side effects. Further, doctors often wait more than a year for HO to mature before treatment to reduce the risk of recurrence. Histotripsy is a form of therapeutic ultrasound that uses bubbles to liquefy tissues; it has also been explored to break up kidney stones. In this proposal, histotripsy will be investigated to break up early HO in cellular and mouse models of early and mature HO. As recurrence is of concern when treating early HO, mice will be survived for several weeks to ensure the treatment of early HO with ultrasound does not increase the likelihood that HO will return. This innovative study evaluates new ultrasound modalities to identify and treat early HO, which has the potential to change the clinical paradigms for the diagnosis and treatment of HO. If successful, the proposed work will provide proof of concept for the detection and disruption of HO with ultrasound, enabling research to progress to larger animal models of HO in muscles and in joints before translating to humans. Long term, this research is expected to significantly reduce the societal impact of HO by speeding recovery times and reducing the pain and loss of joint mobility from HO. For military Service members, this means faster return to active duty.