Broken bones regrow quickly with help of biodegradable implant

UNIVERSITY PARK, Pa. — For most broken bones, bone cells regrow on their own while patients wear a cast or brace to keep the injury steady. But for complex or severe fractures, surgeons may intervene by placing grafts or scaffolds made of biocompatible materials, or by using metal fixation devices to ensure proper bone healing and alignment. Collaborating with orthopedic surgeons, a team led by biomedical engineering researchers at Penn State created CitraBoneQMg, an implantable biodegradable scaffold to support bone regrowth made by combining magnesium and glutamine with citric acid. They published research on their implant, for which they filed a U.S. patent application, in Science Advances.

“By integrating magnesium and glutamine — two small molecules found naturally in the body and in food — with citric acid, we found that the molecules work together to promote bone growth by encouraging increased intracellular energy metabolism,” said first author Hui Xu, a doctoral student in biomedical engineering, who is advised by co-corresponding author Su Yan, assistant research professor of biomedical engineering.

The researchers found that adding magnesium and glutamine to a traditional citric acid-only based implant, which was approved by the U.S. Food and Drug Administration and on the market, increased intracellular energy and helped regulate two energy pathways that are essential for bone growth, AMPK and mTORC1. The pathways act as control systems inside the cell, balancing fuel use so cells have the energy to make new bone.

“The molecules concurrently regulate the two energy pathways, which is different than what normally happens – usually they act as a seesaw, one speeding up while the other slows down,” Xu said. “The scaffold essentially powers up a bone cell: both nutrients act in a synergistic relationship with the citric acid to give stem cells more energy to grow and differentiate to bone cells, leading to better bone regrowth.”

To test CitraBoneQMg, the researchers implanted their experimental scaffold into a cranial defect of the skull of rats and compared its resulting bone growth to rats with a citric acid only-based scaffold implant and one with a traditional bone material implant.

They found that after 12 weeks, CitraBoneQMg had increased the bone growth surrounding the cranial injury by 56% as compared to the animals with the citric acid only-based scaffold and 185% compared to the animals with a traditional bone material implant.

“The three molecules work as a healing recipe for the bone, paving the way for a new way of thinking of bone repair,” Yan said. “Alongside rapid bone growth, we also saw nerve regeneration and antiinflammation properties at the site of the scaffold, two elements that are important to long-term healing of the bone.”

Releasing the molecules directly at the site of the injury via the scaffold helps transport a high concentration of nutrients directly to where they are most needed, the researchers explained, rather than relying on oral ingestion, where only a small percentage reaches the injury site.

Additionally, the researchers discovered that the polymer scaffold contains inherent photoluminescent and photoacoustic properties, which allows it to be easily imaged after it is implanted at the injury site.

“With photoacoustic properties, CitraBoneQMg has great potential for in vivo tracking, where it can be detected by ultrasound underneath deep tissue,” Xu said.

In addition to Xu and Yan, the Penn State-affiliated co-authors include Ethan Gerhard, Rohitraj Ray and Yuqi Wang, doctoral students in biomedical engineering; Sri-Rajasekhar Kothapalli, associate professor of biomedical engineering; and April D. Armstrong, the C. McCollister Evarts Professor and chair of the Department of Orthopaedics and Rehabilitation and chief of the Shoulder and Elbow Service, Penn State Health. For a full list of authors and their affiliations, as well as the funding agencies that supported this research, see Science Advances.