A material based on a natural product of bones and citrus fruits known as citrate provides the extra energy that stem cells need to form new bone tissue, report bioengineers at Penn State University. The new understanding of the mechanism that allows citrate to aid in bone regeneration will help the researchers develop slow-release, biodegradable citrate-releasing scaffolds to act as bone-growth templates to speed up healing in a variety of procedures.
“In our lab, we have been working with citrate for over a decade,” said Jian Yang, PhD, professor of biomedical engineering. “We knew that in the human body, 90% of organic citrate is located in skeletal tissue. But no one had really tried to use citrate as a building block to make bone biomaterials. Our new paper tries to understand how citrate helps in bone healing and uses the understanding to guide the design of new biomimetic materials for better bone repair.”
Though many bone regeneration procedures use them, autografts aren’t sustainable, especially for large wounds or bone tissue removed during cancer treatment. Yet current synthetic materials cause significant inflammation. Also, bone healing is slow and poor. The body encapsulates the implant with fibrotic tissues that prevent integration with surrounding bone. But Penn State’s material prevents encapsulation and minimizes chronic inflammation.
Doctoral student Chuying Ma found that the stem cell membrane has a transporter that is used to transport citrate into the cell to elevate the cellular energy level. When the bone stem cells differentiate to make new bone cells, they require more energy as support for active bone formation. The timing and dosage of citrate supply to stem cells are also critical. Yang and Ma called the citrate effect on stem cell differentiation “metabonegenic regulation.”
The team also identified a second factor involved in energy production, an amino acid called phosphoserine. With their new understanding of the mechanism for bone regrowth, they developed a biomaterial incorporating both citrate and phosphoserine and tested it on rat models.
“Using our new material, we see the early deposition of new bone at one month. This is much earlier than the biomaterials widely used in FDA-approved devices. In this study we tested two models, the femoral condyle bone and the cranial bone defects. In both animal models, we see the new biomaterial is better than the commercial materials in inducing early bone formation and also promoting bone maturation,” said Ma.
“To me, this is an important finding. Citrate is now recognized as a central linker between stem cell metabolism and differentiation. We are uncovering the mechanism whereby citrate influences stem cell activity, not only in bone, but by implication extending to other types of cells and tissues,” said Yang.
“For instance, there is a high concentration of citrate in the cerebrospinal fluid surrounding the brain. People can now use this understanding to start looking at citrate as a metabolism regulator to further regulate stem cells for other types of tissues and organs throughout the body,” Yang said.
“Although we have not tested our materials in the oral surgery setting, we do think our technique has great potential in related applications, such as filling of the extraction site, bone augmentation, and mandibular reconstruction,” said Ma.
“The materials may be also applied to soft tissue regeneration such as periodontal regeneration in oral surgery,” Yang added.
The study, “Citrate-based Materials Fuel Human Stem Cells by Metabonegenic Regulation,” was published by the Proceedings of the National Academy of Sciences.