Original source: Materials Today
A material based on citrate, a natural product found in bones and citrus fruit, can provide the extra energy that stem cells need to form new bone tissue, according to a team of Penn State bioengineers.
Their new understanding of the mechanism that allows citrate to aid bone regeneration will help the bioengineers to develop slow-release, biodegradable, citrate-releasing scaffolds to act as bone-growth templates to speed up healing in the body. The team report their work in a paper in the Proceedings of the National Academy of Sciences.
“In our lab, we have been working with citrate for over a decade,” said Jian Yang, professor of biomedical engineering at Penn State. “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 biomaterials for better bone repair.”
Autografting – taking bone from another part of a patient’s body and grafting it to a damaged area – is the main method used for bone regeneration in a hospital setting. This is not always a suitable method, however, especially in the case of large wounds or when bone tissue is removed during cancer treatment.
Synthetic biomaterials would be a welcome replacement and many labs are working on developing them. But current synthetic materials can cause significant inflammation, and the bone healing rate is often slow and the healing quality can be poor. This is because the body tends to encapsulate the implant with fibrotic tissues that keep it from integrating with surrounding bone. With Yang’s material, the researchers do not see encapsulation, and chronic inflammation is minimal.
Chuying Ma, a doctoral student in Yang’s lab, is lead author on the paper. Ma was given the problem of elucidating the poorly understood mechanism underlying the body’s use of citrate to regenerate bone. She found that the outer membrane of bone stem cells contains 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 to stem cells are also critical. In the paper, Yang and Ma used the term ‘metabonegenic regulation’ to describe the newly identified citrate effect on stem cell differentiation.
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 biodegradable polymer that incorporated 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,” Ma said. “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 cranial bone defects.” In both animal models, they found that the new biomaterial was better than commercial materials at inducing early bone formation and also promoting bone maturation.
“To me, this is an important finding,” said Yang, who is a faculty member in Penn State’s Materials Research Institute and the Huck Institutes of the Life Sciences. “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. 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.”