Roger Cornwall, MD: A Breakthrough Discovery in Neuromuscular Contracture Treatment

The two most common causes of childhood paralysis are cerebral palsy (CP), a brain dysfunction that causes loss of muscle control); and brachial plexus birth injury (BPBI), a nerve damage in the neck during delivery that leads to paralysis of the arm. These conditions occur in a combined five per 1,000 live births. While both conditions initially cause muscle weakness, it is the secondary loss of muscle flexibility, or muscle contractures, that limit joint motion and become the primary driver of physical disability. Furthermore, these muscle contractures in childhood alter the physical forces on the growing skeleton, leading to progressive deformity and dislocation of joints such as the shoulder in BPBI and the hip in CP. The majority of rehabilitative and surgical interventions these children must undergo aim treatment to the effects of these muscle contractures. However, none of the existing therapies can actually cure the contractures because the cause of these contractures has long been unknown.

In our laboratory at Cincinnati Children’s Hospital Medical Center, we elucidated the cause of these muscle contractures, and we identified a revolutionary therapeutic strategy based on this discovery. By developing a mouse model of BPBI, we discovered the cause of contractures is the impairment of longitudinal muscle growth, resulting from loss of normal nerve input (denervation) during a critical neonatal window of muscle development. More specifically, we identified that muscle fails to grow normally after denervation because proteins that are being made at normal rates are being broken down at abnormally high rates. Using our mouse model, we discovered that by delivering a drug to specifically target the molecular mechanism responsible for this elevated protein break-down, we can prevent muscle contractures from developing after neonatal denervation. This discovery constitutes a major advance in the treatment of neuromuscular contractures, as the first ever pharmacologic strategy to prevent contractures by correcting the causative molecular mechanisms underlying contracture development. Along with this important clinical advance, our research also shed light on how muscle grows normally, a process that is not well understood, expanding the implications of our findings to a wide array of childhood muscle problems.

James J. McCarthy, MD: Mission Impossible

Over the past year, the Division of Orthopaedics director, Dr. James McCarthy, MD, MHCM, formed a panel of international experts with the objective to successfully develop guidelines for the surgical management of pediatric patients with cerebral palsy utilizing a combination of best available evidence and expert opinion to establish consensus. The creation of this group is to address the absence of standardized indications for such procedures in this population.

The group will utilize the RAND-UCLA Appropriateness Method, a modified Delphi process. The development of this method is to specifically integrate scientific and clinical knowledge to develop guidelines to measure the appropriateness of medical care, including major medical and surgical procedures. Physicians must make decisions on a daily basis about procedures that lack robust scientific evidence regarding benefits and outcomes. Consequently, this method combines the best available scientific evidence with the collective judgment of experts to yield guidelines regarding the appropriateness of performing a procedure at the level of patient-specific symptoms, medical history and test results.

Beyond the significant goal of creating standards for such a complex patient population, there is hope this research will allow for future evaluation of long-term outcomes. The results from this study will allow for more informed evaluation of practice and form the basis for future improvement efforts to standardize surgical recommendations nationally.

Patrick Whitlock, MD: Musculoskeletal Regenerative Medicine

This year, the Musculoskeletal Regenerative Medicine Research laboratory (MRMRL), continued its progress on the treatment of large osteochondral defects with funding from the Angela Kuo Award from the Pediatric Orthopaedic Society of North America (POSNA).

In collaboration with Dr. James Lin and Stacey Gruber, PhD candidate in biomedical engineering, along with post-doctoral research associate, Dr. Paulomi Ghosh, our research continues to progress and resulted in a publication in the journal Biofabrication. We continue to present this research at meetings of the Orthopaedic Research Society, Tissue Engineering and Regenerative Medicine International Society, and an upcoming podium presentation at the Annual Meeting of the Biomedical Engineering Society by our new post-doctoral research associate, Dr. Sumit Murab, who joined us this year.

We are completing in vitro optimization of our tissue engineered osteochondral scaffolds for upcoming studies in an animal model later this year. We also recently secured a new lab space which will house all of our current molecular, cellular, and materials testing equipment as well as two new 3D printers, one capable of printing cells within 3D matrices. We continue to seek a better solution to large osteochondral defects that we may translate clinically to our young patients.