Researchers develop novel method to aid fracture recovery

Researchers from Michigan Medicine have developed a novel method to aid the repair of difficult-to-heal fractures.

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In most cases bones that are fractured heal with time when cast in a plaster and set in place. However, for others the healing process requires stabilization using plates, screws and pins, in addition to the cast.

In some patients, however, even these measures do not work and healing of the fractures is impaired.

Bone morphogenetic proteins (BMPs) were discovered a decade ago as an alternative therapy to aid fracture recovery. However, the side effects of these proteins; excessive or altered direction of growth during repair, mean they are rarely used.

Researchers at Michigan Medicine, in collaboration with other institutes, have released a new study showing that a protein called Jagged-1 can improve the recovery process for bone fractures that do not heal fully.

Novel therapies have gone underdeveloped because of this assumption that bones heal without problem. The reality is there's a huge number of fractures that occur each year that don't heal very well."

Kurt Hankenson, Lead Author and Professor of Orthopedic Surgery at Michigan Medicine.

Jagged-1 is an osteoinducing protein; protein that stimulates the production of bone. It activates a signaling pathway called Notch, which is involved in bone healing. Importantly, Notch signaling is only activated at the site of injury.

Hankenson explained that the trick was to deliver this protein to the site of action. The study, which was published in the journal NPJ Regenerative Medicine, involved the use of a wet collagen sponge to deliver the Jagged-1 protein to femoral bone and skull injuries in laboratory rodents.

One group of animals received BMPs as a treatment, whereas the others received Jagged-1. Results showed improvement in both groups, however, those with BMP showed hypertrophy (bone growth) that was misdirected and caused further disruption to the bone structure. Importantly, these outgrowths were not observed in the Jagged-1 group.

The researchers hope that this new method could eventually be used to treat humans with delayed bone healing.

The reason behind delayed healing or non-healing bones is still unknown. There could be a metabolic reason such as diabetes or aging, or a condition such as osteoporosis. Multiple fractures caused by severe trauma are also less likely to heal correctly.

We've hypothesized for many years that by binding the Jagged-1 to a biomaterial and delivering it to a bone injury site, we could enhance healing."

Kurt Hankenson, Lead Author and Professor of Orthopedic Surgery at Michigan Medicine

He added that this method is unique as the Notch protein only binds at the target site. This made it vital that Jagged-1 was able to not only reach the site of injury, but also remain in place and function in bone recovery.

The problem with BMPs is that they can move away from the site of action, triggering bone growth in other areas that is unproductive and unnecessary.

Whilst the body makes its own Jagged-1, the team used a synthetic version created in the laboratory for their experiments. Hankenson said that delayed healing is not due to a deficiency of this protein but that delivering additional synthetic forms of the protein to the site promotes healing and recovery.

The team will now carry out more in-depth research to see if the treatment could be applied to humans.