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), 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, 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 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. With this new mechanistic understanding, and backed by NIH R01 funding, we continue to expand a list of candidate drugs along with optimization of dosing and timing in order to get our discovery closer to clinical trials. Along with this important clinical advance, our research sheds 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.

Creating International Standards for Complex Patient Populations

Over the past year, the Division of Pediatric Orthopaedics director, James McCarthy, MD, MHCM, formed a panel of 16 international experts with over 300 years of combined orthopaedic experience, 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 reason for 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, to examine several surgical procedures including: femoral and tibial derotational procedures, medial hamstring lengthening, and gastrocnemius-soleus lengthening. The development of this method is to specifically integrate cientific and clinical knowledge to create 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 judgement of experts to yield guidelines regarding the appropriateness of performing a procedure at the level of patient-specific symptoms, medical history, and test results.

A paper draft discussing the surgical indications for hamstring lengthening and femoral derotational osteotomy is under review by the other members of the committee. Beyond the significant goal of creating standards for such a complex patient population, the hope is that 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.

National Study Group Devoted to Patellar Instability

The goal of the ‘Justifying Patellar Instability Treatment by Early Results’ (JUPITER) project is to compare the safety and efficacy of non-operative treatment, isolated medial patellofemoral ligament (MPFL) reconstruction, and an “à la carte” surgical approach to treat patellar instability. Using patient reported outcomes and clinical data, the study will compare different surgical treatments with non-surgical treatments in skeletally mature patients versus those who are not.

The JUPITER project is recruiting and enrolling patellar instability patients for two years now. Led by Shital Parikh, MD, FACS, and Beth Shubin Stein, MD, from the Hospital for Special Surgery in New York, there are a total of 12 sites and 25 physicians recruiting patients across the United States. There are a total of over 900 patients enrolled with over 600 of the enrolled receiving surgical treatment for their instability. Researchers follow patients for a minimum of two years after enrollment. With enrollment ongoing until the end of 2020, and an enrollment goal of 1600 participants, the JUPITER research project will be the largest prospective cohort of patients with patella instability. The project receives partial funding through specialty societies.

The data collected from this study will help formulate future treatment plans, analyze risk factors and predictors for patella instability, help predict outcomes and best treatment options for a wide variety of instability types as well as long term prognosis for these patients.

An Injectable 3D Bioink Scaffold for the Prevention of Osteochondral Collapse

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). Our research continues to progress with final work on our last aim of the study scheduled for completion this fall focusing on evaluation of our tissue engineered osteochondral scaffolds in an animal model of osteochondral injury. We continue to publish and present our research at meetings of the Orthopaedic Research Society, Tissue Engineering and Regenerative Medicine International Society, and the Annual Meeting of 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. Co-op engineers, undergraduate biomedical engineers, and summer SURF and medical students conducting research under PhD candidate, Stacey Gruber, and our post-doctoral research associate, Sumit Murab, PhD, will fill the lab this summer. We continue to seek a better solution to large osteochondral defects that we can translate clinically to our young patients.

Our latest initiative, that we are currently actively seeking NIH funding for, focuses on developing “An injectable 3-D bioink scaffold 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. Our successful, initial work on this effort was recently submitted for publication as well as presentation at national meetings.