Seoul National University (SNU) College of Engineering announced that a research team led by Professor Nathaniel S. Hwang of the Department of Chemical and Biological Engineering has developed a new bioceramic fracture fixation material that promotes bone regeneration by precisely controlling the timing of magnesium ion (Mg²⁺) release to suppress inflammatory immune responses during osteoporotic fracture healing.
The research team discovered that magnesium ions do not always promote bone regeneration; rather, their effects on immune responses and bone healing vary depending on the timing and duration of release. Based on this finding, the team proposed a fracture fixation material that releases magnesium ions in accordance with the stages of healing, and demonstrated its bone regeneration efficacy through animal experiments.
Furthermore, the study suggests the possibility of advancing fracture treatment materials beyond simple mechanical fixation devices into therapeutic technologies that actively regulate immune responses according to healing stages. The newly developed material is expected to be applied to next-generation orthopedic medical devices and personalized bone regeneration therapies for patients with osteoporotic fractures.
The research was published on June 26 in the world-renowned journal Science Advances.
“Osteoporotic fractures,” which commonly occur in the elderly, arise when bones weakened by osteoporosis fracture easily under external impact. These fractures are not merely structural damage caused by reduced bone density. At the fracture site, inflammatory helper T cells* and macrophages* become excessively activated, promoting bone resorption, which can delay bone regeneration and increase the risk of refracture. Therefore, effective treatment of osteoporotic fractures requires not only physical stabilization of the bone but also precise regulation of the immune microenvironment at appropriate stages of healing.
* inflammatory helper T cells: A subtype of helper T cells that induce inflammatory responses; excessive activation at fracture sites can hinder bone regeneration.
* Macrophages: Immune cells that remove foreign substances and damaged cells while regulating inflammation; they play roles in both early inflammatory responses and later tissue repair at fracture sites.
Meanwhile, magnesium ions have attracted attention as promising materials in orthopedic biomaterials due to their ability to support bone formation, promote angiogenesis, and alleviate inflammatory responses. However, previous studies have suggested that magnesium does not always exert beneficial effects on bone regeneration. Excessive or prolonged exposure of immune cells at fracture sites to magnesium can instead reactivate inflammation and impair bone remodeling.
In particular, in osteoporotic fractures where inflammatory responses are prone to becoming excessive, it is critical to precisely understand how magnesium ion concentration and exposure duration affect fracture healing. However, it has not yet been clearly elucidated how magnesium ions regulate cells involved in fracture healing and bone regeneration—such as CD4+ T cells*, macrophages, and osteoclasts*—over time.
* CD4+ T cells: Representative helper T cells that coordinate immune responses and can differentiate into various subtypes such as Th1 or Th2 depending on surrounding signals.
* Osteoclasts: Cells responsible for breaking down and resorbing old bone tissue, playing a key role in bone remodeling.
To address this issue, Professor Hwang’s team demonstrated that the bone healing process is influenced by how much and how long magnesium ions regulate immune responses at the fracture site. Specifically, during the early stage immediately after fracture—when strong inflammatory responses occur—magnesium ions were found to suppress excessive inflammation by regulating calcium signaling within CD4+ T cells, thereby creating an environment conducive to tissue repair.
More precisely, magnesium ions inhibited signals that excessively activate immune cells during the early inflammatory phase, including TRPM7-mediated calcium signaling and NFATc1-based inflammatory pathways**. As a result, pro-inflammatory immune responses (Th1/M1) were reduced, while immune responses that promote tissue regeneration and recovery (Th2/M2) were enhanced.
* TRPM7-mediated calcium signaling: TRPM7 is a channel protein in the cell membrane that regulates the transport of divalent cations such as calcium and is involved in cellular signal transduction.
* NFATc1 pathway: NFATc1 is a protein that regulates gene expression within cells and plays roles in immune responses and osteoclast formation.
However, the study also revealed that simply maintaining high concentrations of magnesium ions for extended periods does not necessarily aid fracture healing. The researchers found that prolonged exposure to high magnesium levels can alter immune signaling in CD4+ T cells, leading to the reactivation of pro-inflammatory responses (Th1/M1). This finding highlights the importance of precisely controlling both the amount and duration of magnesium release according to the stage of fracture healing, rather than simply increasing magnesium content.
Based on this principle, the research team developed a bioceramic-coated intramedullary nail (IMN) that rapidly releases magnesium ions in the early stage of fracture healing and gradually decreases the release thereafter. When applied to an ovariectomized mouse model simulating osteoporotic fractures, the material suppressed excessive inflammation in the early phase and enhanced regenerative immune responses during the later bone formation stage.
As a result, immune balance was more stably maintained throughout the entire healing process, and bone regeneration was effectively promoted.
Through this study, the team demonstrated that fracture treatment materials can evolve beyond passive fixation devices into active therapeutic platforms that regulate immune responses in a stage-specific manner to facilitate healing.
This study is significant in that it presents a new standard for designing next-generation biomaterials for the treatment of osteoporotic fractures. In particular, the bioceramic fracture fixation material developed in this work—capable of simultaneously stabilizing fractures, regulating inflammation, and promoting bone regeneration—is expected to have high clinical applicability in an aging society where osteoporotic fractures are increasingly prevalent.
The proposed strategy of “temporal magnesium ion release” can be applied to a wide range of orthopedic medical devices, including fracture fixation pins, artificial bone materials, and bioceramic-coated implants. Furthermore, it is expected to contribute to the development of personalized therapeutic technologies that support bone regeneration based on a patient’s bone condition and inflammatory status.
Professor Nathaniel S. Hwang stated,
“This study is meaningful in that it demonstrates that the bone regeneration effects of magnesium ions are not determined solely by concentration, but also depend on the immune stimulation environment and timing during fracture healing. We expect this work to lead to the development of immunomodulatory orthopedic materials for improving recovery in patients with osteoporotic fractures.”
The first author of the paper, Jung Hun Kim, is currently a postdoctoral researcher in the Department of Chemical and Biological Engineering and the Institute of Engineering Research at Seoul National University. He is conducting research on biomaterial-based bone regeneration and osteoimmunomodulation technologies, and plans to continue developing immunomodulatory biomaterials and precision regenerative medicine platforms for osteoporotic fracture treatment.
This research was supported by the National Research Foundation of Korea (NRF) Post-Doc Growth-Oriented Collaborative Research Program funded by the Ministry of Education, the Korean Fund for Regenerative Medicine (KFRM), and the Korea Medical Device Development Fund (KMDF).
□ Introduction to the SNU College of Engineering
Seoul National University (SNU) founded in 1946 is the first national university in South Korea. The College of Engineering at SNU has worked tirelessly to achieve its goal of ‘fostering leaders for global industry and society.’ In 12 departments, 323 internationally recognized full-time professors lead the development of cutting-edge technology in South Korea and serving as a driving force for international development.
Science Advances
Experimental study
Animals
The authors declare that they have no competing interests.