PITTSBURGH — Imagine a broken bone simply mending itself. It may sound like something out of a comic book, but young infants and newborn mice actually have the ability to naturally heal damage to the bones that form the top of the skull. Now, a new approach developed by University of Pittsburgh researchers can promote bone regeneration in adult mice without implantation of bone tissue or biomaterials.
The new technique utilizes a device that is quite similar to an orthodontic wire typically used to realign teeth to carefully stretch the skull along its sutures, activating skeletal stem cells found within these wiggly seams. In adult mice, the new approach repaired damage to the skull that normally would not have healed on its own.
“Our approach is inspired by babies because they have an amazing ability to regenerate bone defects in the calvarial bones that make up the top of the skull,” says senior author Giuseppe Intini, D.D.S., Ph.D., associate professor of periodontics and preventive dentistry at the Pitt School of Dental Medicine, member of the McGowan Institute for Regenerative Medicine, and an investigator at UPMC Hillman Cancer Center, in a media release. “By harnessing the body’s own healing capacity with autotherapies, we can stimulate bone to heal itself. We hope to build on this research in the future to develop novel therapies for people.”
Why are bones different in babies?
Common causes of damage to the human skull include head trauma, congenital defects, and surgery to treat cancer or other diseases. After roughly the age of two, such injuries don’t heal on their own.
“In babies, the calvarial bones are not completely fused, so the sutures where stem cells reside are still open,” Prof. Intini explains. “We wondered whether the unfused sutures had something to do with the bone regenerative capacity observed in babies and hypothesized that we could reverse engineer this in adults by mechanically opening the sutures to activate the stem cell niche and boost stem cell numbers.”
Mice have very similar skull development to humans. So, researchers used a “bone distraction device” to delicately apply a controlled pulling force to the calvarial bones, just strong enough to slightly widen the sutures yet not cause a fracture. Then, using a single-cell RNA sequencing and live-imaging microscopy, study authors uncovered that the number of stem cells in the expanded sutures of these animals had quadrupled. Consequently, rodents treated with the device regenerated bone to heal a large defect in the skull.
“If you can effectively activate the stem cell niche, you can increase the number of stem cells and sustain regeneration of bone defects,” Prof. Intini reports. “Remarkably, we showed that the defect can heal even if it’s away from the suture.”
The technique still faces challenges healing adults
While the new approach was effective in healing skeletally mature two-month-old mice, an age that roughly translates to young adulthood in humans, it did not appear to produce the same results in 10-month-old, or middle-aged, rodents.
“In older mice, the quantity of stem cells in calvarial sutures is very low, so expanding this niche is not as effective in boosting healing capacity,” Prof. Intini adds. “Overcoming this challenge is a focus of research to come.”
Today, current treatments for a damaged skull usually include bone grafts or implantation of biomaterials that act as scaffolds for bone regeneration. However, such approaches aren’t always effective and come with risks, study authors say.
Study authors are now looking into how their findings could inform novel therapies in people – not just when it comes to healing skull injuries but also fractures in long bones like the femur. Bone distraction devices are already in use to treat certain conditions such as a craniosynostosis, a birth defect in which the calvarial bones fuse too early. Thus, expanding on this technique to better promote bone regeneration could be a future focus of clinical trials. The research team is also analyzing non-mechanical approaches to activate skeletal stem cells such as medications.
The study is published in Proceedings of the National Academy of Sciences.