Research at the Herman Ostrow School of Dentistry at the University of Southern California (USC) may lead to treatment for craniosynostosis, a defect caused by the premature fusion of the different bones that comprise the human skull.
One out of every 2,500 infants born in the United States will suffer from the defect, the researchers said. In a typically developing infant, these bones are separated by fibrous joints or “soft spots” that allow for the skull’s continuing expansion as the brain grows.
When an infant develops craniosynostosis, the brain continues to grow while the skull does not, causing anything from a misshapen skull in mild cases to development delays, hearing loss, blindness, and even death.
Until now, the standard treatment has been to break apart the skull, using plates and screws to separate the bones and hold them in place. It’s an incredibly invasive surgery that often has to be done more than once, the researchers said.
In their study, the researchers showed that mice with a mutation in the TWIST1 gene also suffer from neurological and cognitive aspects of craniosynostosis, just like in human beings. But no animal models have previously been established for some of the more devastating neurocognitive symptoms beyond those affecting the bones themselves.
Building on knowledge they had previously discovered, including the role of the Gli1+ stem cells in keeping sutures from prematurely fusing, the researchers added the Gli1+ stem cells to a biodegradable gel and placed the mixture in the sutures.
Six months later, new fibrous sutures had formed in the treated areas, according to skull imaging and tissue analysis. The discovery is the closest we’ve come to treating craniosynostosis without overly invasive and often multiple surgeries, the researchers said.
“I started my career as a clinician treating kids with congenital defects, and we always wanted to do something better for these patients,” said professor and study leader Yang Chai, PhD, DDS, associate dean of research at director of the Center for Craniofacial Molecular Biology.
“I think, with this stem cell-mediated suture regeneration approach, it truly gives us the hope that one day we can apply this as a biological solution for this biological problem,” Chai said.
“As someone who operates weekly on babies with craniosynostosis, this work could someday put me out of a job,” said Mark Urata, chief of the Division of Plastic Surgery and Reconstructive Surgery at the Keck School of Medicine at USC and a study contributor.
“Currently, these are operations that involve moving the bones of the forehead and skull while operating on top of the brain. To be able to avoid those risks would obviously be a tremendous paradigm shift for the field of craniofacial surgery,” said Urata, who also is chair of the Division of Oral and Maxillofacial Surgery at Ostrow and head of the Division of Plastic and Maxillofacial Surgery at the Children’s Hospital of Los Angeles.
The discovery could lead to much more than simply fixing an aesthetic condition, the researchers said. It also could be life-altering for those experiencing neurocognitive issues resulting from craniosynostosis as the researchers examined the link between the defect and the elevated intracranial pressure that arises from it, which can lead to learning deficiencies and neurocognitive behavioral issues.
“The connection between changes in the skull and the development of cognitive deficits had not been fully explored,” said Chai. “We wanted to know if restoring sutures could improve neurocognitive function in the mice.”
Before the intervention, the mice with craniosynostosis had increased pressure inside their skulls and performed poorly on social and spatial memory and motor learning tests. After treatment, these measures all returned to levels typical of healthy mice.
“We have always suspected that craniosynostosis might create pressure on the brain and that, in turn, could create developmental disadvantages for these children,” Urata said. “Side by side with our work to regenerate a functioning suture, this could be life changing for so many babies yet to be born.”
“I hope we will be able to use this approach to regenerate a biological suture, and then the infants’ skulls and brains will develop just like normal,” Chai said.
“They will basically be starting at the same point as everyone else instead of having any type of neurocognitive abnormalities that require extra help in their studies. So they will be able to play as children or advance in their careers as adults on equal footing,” Chai said.
Next, the researchers expect to scale up to larger animals before entering a Phase 1 clinical trial on human beings. The discovery also represents a collaborative group of clinicians and researchers from around the world, USC said.
“It was just really beyond what I could ever have asked for,” Chai said. “It was really just like all the stars aligned. I have no words to describe how grateful I am for all the collaboration.”
“Forging a bond between a world-class craniofacial research center (the Center for Craniofacial Molecular Biology) and a world-class craniofacial care center (Children’s Hospital of Los Angeles) cross schools (medicine and dentistry) and disciplines for the sake of improving care for children,” Urata said. “This is one of the truly special aspects of USC.”
The study, “Cranial Suture Regeneration Mitigates Skull and Neurocognitive Defects in Craniosynostosis,” was published by Cell.
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