Cincinnati Children's Brachial Plexus Center is Awarded Multi-Year Funding for Novel Collaborative Efforts on Two Innovative Clinical Research Studies

The Cincinnati Children’s Brachial Plexus Center is a world-renowned destination center for treatment of children with brachial plexus birth injury (BPBI), a traumatic, delivery-related injury to the nerves of the upper limb that occurs in 1-3 per 1000 live births. Approximately 30% of affected children experience permanent paralysis and secondary musculoskeletal complications. However, no treatments can restore normal function, and many treatments require sacrificing certain functions to achieve others. Ideally, projected long-term functional impact would be the basis for prioritization of treatments in infancy and childhood. However, it remains unknown how BPBI and its treatments impact the many aspects of physical, psychological and social health throughout childhood and into adulthood.

Recognizing this critical knowledge gap, clinicians and researchers at Cincinnati Children's formed an international group of brachial plexus experts, Plexus Nexus, to identify the top research priorities for improving the outcomes of BPBI and to develop teams to address them. Through this group, the top two priorities for research are: (1) identifying the many ways in which BPBI impacts overall health and quality of life throughout childhood, and (2) determining the impact of BPBI into adulthood. Two collaborative studies designed to study these two priorities recently received awards of multi-year research grants, enabling our center to lead of the most important research for this condition.

The first study, Growing Up with Brachial Plexus Birth Injury (GUPI), brings together four leading North American pediatric brachial plexus centers to prospectively and holistically examine the physical, psychological, and social impact of BPBI throughout childhood, from the patient and family perspective. This project, the first of its kind for this condition, received an award of a multi-year registry grant from the Pediatric Orthopaedic Society of North America. Led by clinicians and researchers at Cincinnati Children's, together with an adult patient with BPBI, herself a healthcare provider is a second study: Lived Experience of Adults with Brachial Plexus Birth Injury (LEAP) . This team partnered with two large, international, online patient social media groups to study the long term impact of this pediatric condition into adulthood. This study, which utilizes innovative mixed-methods (qualitative and quantitative) research methodology, received the multi-year Place Outcomes Research Award from the Cincinnati Children’s Research Foundation. With these new partnerships and funding, the Cincinnati Children's Brachial Plexus Center is poised to lead the care of BPBI into a new era, focusing on the outcomes that truly matter to patients and families.

James J. McCarthy, MD, MHCM, Mission Impossible SUCCESS

Following McCarthy’s successful formation of a 16 international expert panel with over 300 years of combined orthopaedic experience in 2019, the collaboration quickly proved productive and effective in 2020. The initial objective was to successfully develop guidelines, where there was an absence of standardized indications, for the surgical management of pediatric patients with cerebral palsy utilizing a combination of best available evidence and expert opinion to establish consensus.

Through their dedicated efforts, the Journal of Children’s Orthopaedics published their paper, "Establishing surgical indications for hamstring lengthening and femoral derotational osteotomy in ambulatory children with cerebral palsy" in early 2020. These are the first guidelines for medial hamstring lengthening (MHL) and femoral derotational osteotomy (FDO). Expert consensus concluded that a majority of the surgeons used instrumented 3D movement analysis in tandem with their physical exams to better inform their surgical decisions for both procedures. The group cautioned against performing a medial hamstring lengthening if the fixed knee flexion contracture is greater than 10°, as well as, against vigorous testing of the popliteal angle while the patient is under anaesthesia (even gently) or after the MHL, as it could lead to a sciatic nerve stretch injury. Consensus from the panel indicating performing an FDO reliably when the internal rotation was greater than 15° on instrumented 3D movement analysis or a femoral neck angle (anteversion) of greater than 30° and internal rotation of greater than 60° degrees on physical examination, especially with limited external rotation. Several members also commented on incorporating mild overcorrection (rotation) for the osteotomy, especially in younger patients. This collected and analyzed data used the RAND-UCLA Appropriateness Method, developed specifically to integrate scientific and clinical knowledge to develop guidelines to measure the appropriateness of medical care.

The panel recently submitted another manuscript to the Journal of Children’s Orthopaedics indicating their guidelines for gastrocsoleus lengthening in ambulatory children with cerebral palsy and is awaiting acceptance. Other procedures in review include: various osteotomy procedures, patella tendon shortening and patella tendon advancement, anterior distal femoral hemiepiphysiodesis, and distal rectus femoris surgery.

Breakthrough Discovery in Neuromuscular Contracture Treatment Earns Top Research Award from American Society for Surgery of the Hand

Following the breakthrough discovery in neuromuscular contracture treatment described below, and the attainment of NIH R01 funding, Roger Cornwall, MD, received the Weiland Medal for Outstanding Research in Hand Surgery. This is the highest research honor bestowed by the American Society for Surgery of the Hand. Additionally, his work received the award for the Best Basic Science Paper at the 2019 Annual Meeting of the Pediatric Orthopaedic Society of North America.

These honors reflect the importance of Cornwall’s discovery of the cause of muscle contractures following a brachial plexus birth injury (BPBI) diagnosis. Furthermore, he was able to identify a revolutionary therapeutic strategy based on this discovery.

By developing a mouse model of BPBI, he discovered that the cause of contractures are by impaired longitudinal muscle growth, resulting from loss of normal nerve input (denervation) during a critical neonatal window of muscle development. More specifically, he 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 a mouse model, he 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. With this new mechanistic understanding and backed by NIH R01 funding, Cornwall’s lab continued to deepen the understanding of how nerves regulate longitudinal muscle growth, and he continues to optimize the dosing and timing of candidate drugs in order to get his discovery closer to clinical trials. Along with this important clinical advance, his research also shed light on how muscle grows normally, a process that is not well understood, expanding the implications of these findings to a wide array of childhood muscle problems, including cerebral palsy.

Continued Funding and Expansion of MRMRL Bioprinting Laboratory Based on Recently Reported Findings

This year, the Musculoskeletal Regenerative Medicine Research Laboratory (MRMRL), completed work on the treatment of large osteochondral defects funded by the Angela SM Kuo Award from the Pediatric Orthopaedic Society of North America (POSNA). Our research continues to progress on the treatment of large osteochondral defects with recent funding obtained from the Musculoskeletal Transplant Foundation with Dr. James Lin. We also continued to publish and present our research at meetings of the Orthopaedic Research Society, Tissue Engineering and Regenerative Medicine International Society, and the Biomedical Engineering Society.

Our new lab space which houses molecular, cellular, and materials testing equipment, as well as two new 3D printers, one capable of printing cells within 3D matrices, is a great addition to the division and will be overseen by newly promoted instructor, Sumit Murab, PhD. We also recently purchased an Instron mechanical testing machine with the capability of testing materials from hydrogels to bones and metallic implants. Additionally, we recently acquired a TA instruments rheometer for studying the rheological properties of bioink formulations, which in conjugation of Cincinnati Children's core facilities, make us a fully equipped and functional BIO-PRINTING laboratory. We continue to seek a better solution to large osteochondral defects that we may translate clinically to our young patients.

Our latest initiative, for which we are currently actively seeking NIH funding, focuses on developing “An injectable / 3-D printable bioink system for the prevention of osteochondral collapse secondary to avascular necrosis (AVN)” using inductive, composite bioinks utilizing our experience in decellularized scaffolds, 3D additive manufacturing, and the development of hydrogel, polymeric systems. We successfully formulated a chemical strategy for chemically re-mineralizing decellularized extracellular matrix that imparts it bio-physical and bi-chemical cues for guiding mesenchymal stem cell differentiation towards bone cells, without compromising on the mechanical properties. The bioink system is both injectable and bio-printable while retaining excellent mechanical properties due to the formation of bone-like hydroxyapatite-matrix nano-composite structure. Our successful, initial work on this effort was recently submitted for publication as well as presentation at national meetings.