Study Shifts Understanding of How Bone Fractures Heal
It may be time to rewrite the textbook description of bone fracture healing.
Investigators from Vanderbilt University have discovered that fibrin is not needed to facilitate fracture healing. Instead, the breakdown of fibrin is essential for fracture repair.
Their findings, reported in the August issue of the Journal of Clinical Investigation, shift understanding of how fractures heal and have implications for efforts to promote fracture repair.
“Many of the current pharmaceutical protocols are based on using fibrin to promote fracture healing,” said Jonathan Schoenecker, MD, PhD, assistant professor of orthopaedic surgery and rehabilitation at Vanderbilt.
“In certain instances it may help, but we’ve shown for sure that you don’t need it. Bone biology does not require fibrin to heal a fracture.”
Fibrin is involved in blood clotting; it forms a mesh-like net that traps platelets to form a clot. When bones break, so do blood vessels, and clots form to stop the bleeding.
“Most people don’t realize that bone is the most vascular organ in our bodies,” Dr. Schoenecker said. “When you have a fracture, you have a huge disruption of that vascularity.”
Because fibrin is the main protein at the site of a fracture, it was thought to promote repair by providing a scaffold for the initial phase of new bone formation. Dr. Schoenecker and colleagues found, however, that fracture repair was normal in mice that were missing the fibrin precursor fibrinogen.
The investigators had previously reported the importance of vascular reconnection for bone fracture healing. Using imaging techniques they developed to simultaneously study angiogenesis and bone formation after fracture, they found that blood vessels grow first at the ends of the fracture, extend, and reconnect. Then new bone forms.
“Therefore, any condition associated with vascular disease and thrombosis will impair fracture healing,” Dr. Schoenecker said.
It follows that if fibrin is not efficiently removed, it can impede fracture healing, he said. In the new studies, the team demonstrated that mice missing the factor that clears fibrin had impaired vascularization and bone union. Genetic manipulations to deplete fibrinogen in these mice restored normal fracture repair.
The findings from this study may explain why obesity, diabetes, smoking, and advanced age impair fracture repair: All are associated with impaired fibrin clearance, Dr. Schoenecker said.
They may also explain why children heal so quickly: Their fibrinogen levels are about half those in adults.
“If we could lower fibrinogen levels – or increase the activity of enzymes that get rid of fibrin – we could make adult patients more like kids and improve healing,” Dr. Schoenecker said.
In the current studies, the investigators also found that mice unable to clear fibrin developed heterotopic ossification, which can complicate healing after trauma and orthopaedic surgery.
“It was totally unexpected that fibrin clearance is essential to prevent heterotopic ossification,” Dr. Schoenecker said.
Dr. Schoenecker and his team are working toward developing orthobiologics that will reduce fibrin levels or enhance fibrin clearance and improve fracture healing. They are also working to improve the mechanical devices – such as rods and plates – used in orthopaedic surgeries so that those devices don’t disrupt the ability of blood vessels to grow and reconnect.
“The link between coagulation and orthopaedics has been observed for more than a century, as [large] injuries of an incredibly vascular structure inevitably require a clot [so that the patient does] not to bleed to death,” Dr. Schoenecker said.
“But the understanding that the resolution of this clot has such an impact on the way a bone heals is completely new.”
He pointed out that some of the medications developed to prevent clotting may find new purposes in enhancing tissue repair and regeneration.
Yuasa M, Mignemi NA, Nyman JS, et al. Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification.J Clin Invest. 2015 Aug 3;125(8):3117-31. doi: 10.1172/JCI80313. Epub 2015 Jul 27.