Research Summary Research topic:
Investigated whether disturbances in muscle satellite cell behavior are responsible for neonatal brachial plexus injury contractures Research results:
An understanding of why there are a disproportionate number of dormant satellite cells in denervated muscles associated with brachial plexus injury contractures, and what cellular processes are missing from or suppressing those cells, preventing them from generating new muscle
Patient care application of results:
Protocols that can be used to treat contracture in neonatal brachial plexus injury patients by adding the missing or reversing the suppressive cellular signals that prevent satellite cells from creating muscle Simplified patient care application:
New treatment protocols for neonatal brachial plexus injury patients that prevent muscle contracture by prompting satellite cells to generate muscle tissue
Unlocking the biology of NBPI
OREF grant recipient probes cellular mechanisms underlying neonatal brachial plexus injury
Neonatal brachial plexus injury (NBPI) is the most common birth injury and the most common cause of paralysis in children.1
Usually diagnosed at birth, NBPI is characterized by a loss of movement or weakness in the arm or hand due to damaged nerves around the shoulder. Most children with NBPI recover, but 20 to 30 percent sustain permanent disability.2
In those who do not recover, the weakness is complicated by contractures, or loss of joint flexibility, that persist even if the nerves are repaired.
Now, with the help of a 2013 Career Development Grant from the Orthopaedic Research and Education Foundation (OREF), pediatric orthopaedic surgeon Roger Cornwall, MD, is conducting a first-of-its-kind research study that may provide new hope for NBPI patients with such contractures.
A contracture is a contracture...or is it?
For the last 100 years orthopaedic surgeons have treated all contractures for all patients—from newborns to mature adults, regardless of the specific disease condition—with essentially the same surgical procedures. And it wasn’t until the 1970s that orthopaedic surgeons began to be trained to treat NBPI contractures at all. “Many among the generation of surgeons that are the most senior folks now were brought up assuming NBPI doesn’t need any treatment at all,” Dr. Cornwall explained.
In 2005, Dr. Cornwall modified a surgical technique to specifically relieve NBPI muscle contractures. His innovation showed great promise. Patients recovered more range of motion in their arms. Dr. Cornwall’s practice was thriving. His contribution to pediatric orthopaedics was being acknowledged.
But it was soon clear that this new technique was still merely palliative, leading to slight improvements in flexibility and muscle function, but no more. Further, Dr. Cornwall couldn’t establish any scientific logic for the results.
Effective, but why?
The surgical innovation that Dr. Cornwall developed involved cutting the paralyzed portion of a partially denervated subscapularis to relieve the contracture without weakening the muscle.
As Dr. Cornwall stated his dilemma: “It’s the working muscle that’s supposedly causing the contracture, so how does cutting the paralyzed part of that muscle relieve the contracture?”
Dr. Cornwall took a deep dive into the scientific literature and found a few studies that suggested muscle growth could be impeded after damage at birth, but nothing that looked at impaired muscle function. “I realized I needed to investigate this,” he said.
As hard as orthopaedic surgeons try, “we can’t fix this surgically,” Dr. Cornwall said. “There’s something much more global and biologically wrong with these muscles.”
What happens—or doesn’t—in satellite cells?
The OREF grant is giving Dr. Cornwall the opportunity to test his hypothesis that disturbances in muscle satellite cell behavior are responsible for NBPI contractures.
Dr. Cornwall explained that there is a population of stem cells in muscle tissue known as satellite cells because they reside on the periphery of muscle fiber. The satellite cells are plentiful and replicate freely. However, in muscles denervated by NBPI, satellite cells fail to receive—or fail to respond to—signals that command them to make muscle.
Dr. Cornwall’s study aims to identify ways to counteract these cellular signaling problems so that NBPI might be more effectively treated with secondary contractures prevented outright.
“If we can understand why the satellite cells aren’t doing what they’re supposed to be doing, then we can identify the signals that are missing or the signals that are actively suppressing them, and reverse those signals or add the missing signals to harness that population of satellite cells,” Dr. Cornwall said.
Using a mouse model he developed in earlier studies, Dr. Cornwall is performing a series of experiments with control and test subjects with paralyzed muscles to determine:
what accounts for the disproportionate number of dormant satellite cells in denervated muscles;
- how satellite cells behave following muscle paralysis;
- how that behavior might differ depending on the severity of paralysis;
what cellular processes trigger the manufacture of fat and fibrous tissue in place of muscle; and
- how those processes might be interrupted.
Innovative research with broader implications
Building on a series of firsts from Dr. Cornwall’s previous research, the OREF-supported study is the first to investigate the biological mechanisms that lead to NBPI contractures. This research is leading the way in looking at alterations in satellite cell proliferation and differentiation following paralysis at birth, and in correlating these abnormalities with muscle growth.
Further, the study will also investigate the relationship between the function of nerve fibers and postnatal muscle development. This will expand what is currently known about a number of childhood neuromuscular and musculoskeletal disorders, such as cerebral palsy.
OREF support indispensable
Basic science research like Dr. Cornwall’s study has game-changing potential, but needs sustained funding. The OREF Career Development Grant provides $75,000 per year for three years; it will yield preliminary data crucial to obtaining long-term grant support to fully answer questions that have already emerged—and as-yet hidden questions that will surface as the research continues.
“There’s a great deal of faith involved,” Dr. Cornwall said. “Faith that this research will amount to something. Actual findings that will help kids. And it’s a daunting prospect for a surgeon to compete against scientists for National Institutes of Health (NIH) dollars, especially as those dollars get thinner and thinner.”
That’s why, Dr. Cornwall said, OREF is key, free of bias inherent in direct industry funding and more robust than the smaller and sometimes narrowly focused grants available through specialty societies.
“OREF is certainly, by far, the biggest funding source for orthopaedic research that I know, and well-recognized as impartial. And OREF awards come with a certain degree of prestige that gives credibility to the research itself—and to my ability to perform it. That can be used to achieve NIH funding, which is the ultimate goal.”
Using preliminary data from his OREF-funded study, Dr. Cornwall submitted his first NIH R01 grant in June.
1 Foad, S.L., C.T. Mehlman, and J. Ying, The epidemiology of neonatal brachial plexus palsy in the United States. J Bone Joint Surg Am, 2008. 90(6): p. 1258-64.
2 Pondaag, W., et al., Natural history of obstetric brachial plexus palsy: a systematic review. Dev Med Child Neurol, 2004. 46(2): p. 138-44.