Xianrui Yang
Masashi Nagao
Chen-He Zhou- 1Department of Orthodontics, University of Florida College of Dentistry, Gainesville, FL, United States
- 2Department of Orthopaedics, Juntendo University School of Medicine, Tokyo, Japan
- 3Medical Technology Innovation Center, Juntendo University, Tokyo, Japan
- 4Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Editorial on the Research Topic
Biomaterials and biological regulation for bone tissue remodeling and regeneration
Bone tissue consists of an organic matrix, primarily collagen type I, and an inorganic mineral phase, mainly hydroxyapatite, which together provide bone strength, flexibility, and function (Šromová et al., 2023). Numerous cells are involved in the maintenance and dynamics of bone tissue. For instance, osteocytes embedded in the bone matrix function as mechanosensors and regulators, coordinating the activity of other cells in response to mechanical and biochemical signals (Delgado-Calle and Bellido, 2022). Mesenchymal stem cells (MSCs), located in the bone marrow and periosteum, are multipotent cells that can differentiate into osteoblasts and chondrocytes (Sheng, 2015). In addition to MSCs, osteogenic precursor cells within the periosteum also play a significant role in bone formation (Donsante et al., 2021). Furthermore, skeletal stem cells (SSCs) have been identified as a distinct population within bone tissue that possesses the ability to self-renew and generate various cell types, including osteoblasts, chondrocytes, and stromal cells (Yuan et al., 2022).
The bone remodeling process is continually active throughout life by the coordinated activities of osteoclasts and osteoblasts, which are essential for maintaining bone homeostasis and adapting to mechanical stresses (Bolamperti et al., 2022). For instance, during orthodontic tooth movement, alveolar bone remodeling occurs due to the actions of osteoblasts on the tension side and osteoclasts on the compression side. The process by which cells respond to mechanical forces is known as mechanotransduction, induced by mechanosensors such as those on osteocytes that detect mechanical loads and translate them into biochemical signals (Li et al., 2021). The bone regeneration process is reparative and occurs in response to injury and involves inflammation, soft callus formation, hard callus formation, and bone formation (Duda et al., 2023). The initial inflammatory phase activates immune cells, such as macrophages, and releases cytokines to recruit MSCs to the injury site (Duda et al., 2023). The subsequent phases involve the differentiation of MSCs into osteoblasts and chondrocytes to form new bone and synthesize a new bone matrix (Donsante et al., 2021). The regulation of biological signaling and the use of biomaterials play crucial roles in these processes.
Some essential biological mediators, including morphogenetic proteins (BMPs), transforming growth factor-beta (TGF-β), insulin-like growth factors (IGFs), vascular endothelial growth factors (VEGFs), receptor activator of nuclear factor kappa-B ligand (RANKL), and osteoprotegerin (OPG), are extensively studied in the process of bone turnover (Bartold and Ivanovski, 2025). Osteoblasts and stromal cells produce RANKL, which binds to the RANK receptor on osteoclast precursors, promoting their differentiation into mature osteoclasts (Udagawa et al., 2021). The decoy receptor OPG, secreted by osteoblasts, competes with RANKL to prevent excessive osteoclast activation, thereby maintaining bone dynamics (Udagawa et al., 2021). Additionally, systemic regulators like parathyroid hormone (PTH) and vitamin D influence calcium homeostasis and bone metabolism, stimulating osteoblast activity through RANKL (Russell, 2024). PTH has a dual role in these processes: It promotes bone formation with intermittent administration while leading to bone resorption with chronic elevation (Liu et al., 2024). Furthermore, inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins IL-6 and IL-1β play dual roles as well, initially promoting inflammation and bone resorption but later facilitating repair by recruiting progenitor cells (Yao et al., 2024).
Mechanosensors on the cell surface can convert mechanical stimuli into biochemical signals to regulate cellular responses to induce bone remodeling. For instance, piezo channels, especially piezo1 and piezo2, are found in osteoblasts, osteocytes, and mesenchymal stem cells (Xu et al., 2021). The activation of piezo1 by mechanical stress causes calcium influx, triggering downstream signaling pathways such as Wnt/β-catenin and Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), along with the release of signaling molecules like prostaglandins and nitric oxide, which influence the activity of osteoblasts and osteoclasts (Huang et al., 2023). Research also indicates that in osteocytes, piezo channels regulate mechanotransduction by modulating sclerostin expression, thus affecting bone resorption through osteoclast regulation (Huang et al., 2023). Furthermore, piezo1-mediated signaling affects MSC differentiation toward osteogenic lineages while inhibiting adipogenesis to enhance bone regeneration (Huang et al., 2023).
Various biomaterials have been developed and applied to enhance bone formation. Bioactive ceramics, such as hydroxyapatite (HA) and tricalcium phosphate (TCP), mimic the mineral composition of bone, improving osteointegration and stability (Juhasz and Best, 2012). Polymeric biomaterials, including natural types like collagen, chitosan, and alginate, as well as synthetic types like polycaprolactone (PCL), polylactic acid (PLA), and polyglycolic acid (PGA), provide tunable mechanical properties, biocompatibility, and degradation rates, making them suitable for a range of orthopedic applications (Asti and Gioglio, 2014). Composite biomaterials combine ceramics and polymers, further optimizing bioactivity and mechanical integrity (Vahidi et al., 2024). Moreover, scaffolds can be functionalized with growth factors, drugs, or peptides to enhance their regenerative capabilities. For instance, BMP2-loaded scaffolds have been widely utilized in clinical settings to promote bone formation in critical-sized bone defects (Chen et al., 2021).
Emerging technologies such as 3D bioprinting and gene editing are increasingly being utilized to create patient-specific solutions, allowing precise control over scaffold architecture and bioactive properties for bone regeneration (Lee et al., 2024). Nanomaterials, including nanohydroxyapatite and graphene-based substances, provide superior bioactivity and mechanical strength by mimicking the nanoscale structure of the bone matrix while also serving as carriers for growth factors, genes, and drugs (Chinnaiyan et al., 2024). Additionally, bioactive coatings that incorporate antimicrobial agents, peptides, or stem cell-derived exosomes further enhance the regenerative potential of biomaterial implants (Agnihotri et al., 2024). Furthermore, DNA hydrogels represent innovative emerging biomaterials and show significant promise as bone-promoting scaffolds, as demonstrated by researchers in mouse calvarial regeneration (Athanasiadou et al., 2023).
Although extensive research has been conducted to improve bone regeneration and remodeling, challenges persist in translating laboratory findings into clinical therapies for patients. To ensure successful outcomes, several factors, including biomaterial degradation rates, immune compatibility, and cost-effectiveness, need to be addressed. Moreover, the field is shifting towards personalized medicine approaches, where patient-specific factors inform the selection of biomaterials, stem cells, and therapeutic strategies. Advanced bioprinting and tissue engineering techniques have the potential to create custom scaffolds with precise architectural and biological properties. With the advancement of microfluidic devices, organ-on-a-chip models have also been utilized in the bone field, such as a bone-on-a-chip platform that simulates the dynamic biological processes of bone remodeling and mineralization (Mansoorifar et al., 2021), which could provide a personalized testing platform for treating patients with bone diseases.
The six papers collected for our special issues are all discussing about novel biomaterials for bone tissue regeneration (Kitahara et al.; Lei et al.; Wang et al.; El-Nablaway et al.; El-Nablaway et al.; Indurkar et al.). Lei et al. built rabbit critical-size bone defects and tested porous calcium-phosphate (CaP) ceramics for bone regeneration, and they found that CaP ceramics can improve bone-forming ability with adequate time (Lei et al.). Wang et al. established SD-rat calvarial critical-sized defects and tested the effect of α-calcium sulfate hemihydrate/treated detin matrix composite, and they suggest that the composite cement has promising potential to be an alternative for bone regeneration (Wang et al.). Kitahara et al. created a novel rat femoral nonunion model and tested rhBMP-2-loaded hydroxyapatite/betatricalcium phosphate microsphere/hydrogel composite and indicated it significantly improved bone union rates and new bone formation (Kitahara et al.). El-Nablaway et al. reviewed the locally applied repurposed pharmaceuticals for periodontal tissue regeneration with their success and drawbacks to help explore the effectiveness and efficiency, economical, and state topical pharmaceutical preparations (El-Nablaway et al.). They also reviewed the cutting-edge bioactive polymeric hydrogels for periodontal regeneration to help establish prospective clinical applications (El-Nablaway et al.). Indurkar et al. use gelatin methacrylate and citrate-containing amorphous calcium phosphate to develop nanocomposite hydrogel (Indurkar et al.). All these studies provide novel information in the field of bone regeneration and help advance its application for clinical treatment in the future.
Author contributions
XY: Writing – original draft, Writing – review and editing. MN: Writing – review and editing. C-HZ: Writing – review and editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. The authors want to acknowledge the support from the American Association of Orthodontists Foundation.
Acknowledgments
We appreciate all the contributors who shared their research with us and all the reviewers who made efforts to provide their constructive comments.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Agnihotri, T. G., Gomte, S. S., Peddinti, V., Rout, B., and Jain, A. (2024). Biomimetic coatings for drug delivery. InSmart Biomim. Coatings 1, 173–209. doi:10.1016/b978-0-443-21738-8.00008-4
Asti, A., and Gioglio, L. (2014). Natural and synthetic biodegradable polymers: different scaffolds for cell expansion and tissue formation. Int. J. Artif. Organs 37 (3), 187–205. doi:10.5301/ijao.5000307
Athanasiadou, D., Meshry, N., Monteiro, N. G., Ervolino-Silva, A. C., Chan, R. L., McCulloch, C. A., et al. (2023). DNA hydrogels for bone regeneration. Proc. Natl. Acad. Sci. 120 (17), e2220565120. doi:10.1073/pnas.2220565120
Bartold, M., and Ivanovski, S. (2025). Biological processes and factors involved in soft and hard tissue healing. Periodontol. 2000 97, 16–42. doi:10.1111/prd.12546
Bolamperti, S., Villa, I., and Rubinacci, A. (2022). Bone remodeling: an operational process ensuring survival and bone mechanical competence. Bone Res. 10 (1), 48. doi:10.1038/s41413-022-00219-8
Chen, X., Tan, B., Bao, Z., Wang, S., Tang, R., Wang, Z., et al. (2021). Enhanced bone regeneration via spatiotemporal and controlled delivery of a genetically engineered BMP-2 in a composite Hydrogel. Biomaterials 277, 121117. doi:10.1016/j.biomaterials.2021.121117
Chinnaiyan, S. K., Arthanari, S., and Subramanian, M. (2024). “Nanoparticles in tissue engineering application and regenerative medicine,” in Introduction to functional nanomaterials, 93–119.
Delgado-Calle, J., and Bellido, T. (2022). The osteocyte as a signaling cell. Physiol. Rev. 102 (1), 379–410. doi:10.1152/physrev.00043.2020
Donsante, S., Palmisano, B., Serafini, M., Robey, P. G., Corsi, A., and Riminucci, M. (2021). From stem cells to bone-forming cells. Int. J. Mol. Sci. 22 (8), 3989. doi:10.3390/ijms22083989
Duda, G. N., Geissler, S., Checa, S., Tsitsilonis, S., Petersen, A., and Schmidt-Bleek, K. (2023). The decisive early phase of bone regeneration. Nat. Rev. Rheumatol. 19 (2), 78–95. doi:10.1038/s41584-022-00887-0
Huang, Z., Huang, Y., Ning, X., Li, H., Li, Q., and Wu, J. (2023). The functional effects of Piezo channels in mesenchymal stem cells. Stem Cell Res. and Ther. 14 (1), 222. doi:10.1186/s13287-023-03452-y
Juhasz, J. A., and Best, S. M. (2012). Bioactive ceramics: processing, structures and properties. J. Mater. Sci. 47, 610–624. doi:10.1007/s10853-011-6063-x
Lee, S. J., Jeong, W., and Atala, A. (2024). 3D bioprinting for engineered tissue constructs and patient-specific models: current progress and prospects in clinical applications. Adv. Mater. 36 (49), 2408032. doi:10.1002/adma.202408032
Li, Y., Zhan, Q., Bao, M., Yi, J., and Li, Y. (2021). Biomechanical and biological responses of periodontium in orthodontic tooth movement: up-date in a new decade. Int. J. oral Sci. 13 (1), 20. doi:10.1038/s41368-021-00125-5
Liu, H., Liu, L., and Rosen, C. J. (2024). PTH and the regulation of mesenchymal cells within the bone marrow niche. Cells 13 (5), 406. doi:10.3390/cells13050406
Mansoorifar, A., Gordon, R., Bergan, R. C., and Bertassoni, L. E. (2021). Bone-on-a-chip: microfluidic technologies and microphysiologic models of bone tissue. Adv. Funct. Mater. 31, 2006796. doi:10.1002/adfm.202006796
Russell, G. (2024). Introduction: bone metabolism and its regulation. InBone markers 1, 1–26. doi:10.1201/9781003579472-1
Sheng, G. (2015). The developmental basis of mesenchymal stem/stromal cells (MSCs). BMC Dev. Biol. 15, 44–48. doi:10.1186/s12861-015-0094-5
Šromová, V., Sobola, D., and Kaspar, P. (2023). A brief review of bone cell function and importance. Cells 12 (21), 2576. doi:10.3390/cells12212576
Udagawa, N., Koide, M., Nakamura, M., Nakamichi, Y., Yamashita, T., Uehara, S., et al. (2021). Osteoclast differentiation by RANKL and OPG signaling pathways. J. bone mineral metabolism 39, 19–26. doi:10.1007/s00774-020-01162-6
Vahidi, M., Rizkalla, A. S., and Mequanint, K. (2024). Extracellular matrix-surrogate advanced functional composite biomaterials for tissue repair and regeneration. Adv. Healthc. Mater. 13 (27), 2401218. doi:10.1002/adhm.202401218
Xu, X., Liu, S., Liu, H., Ru, K., Jia, Y., Wu, Z., et al. (2021). Piezo channels: awesome mechanosensitive structures in cellular mechanotransduction and their role in bone. Int. J. Mol. Sci. 22 (12), 6429. doi:10.3390/ijms22126429
Yao, Q., He, L., Bao, C., Yan, X., and Ao, J. (2024). The role of TNF-α in osteoporosis, bone repair and inflammatory bone diseases: a review. Tissue Cell 27, 102422. doi:10.1016/j.tice.2024.102422
Keywords: biomaterials, biological regulation, bone regeneration, bone remodeling, signaling/signaling pathways
Citation: Yang X, Nagao M and Zhou C-H (2025) Editorial: Biomaterials and biological regulation for bone tissue remodeling and regeneration. Front. Bioeng. Biotechnol. 13:1582215. doi: 10.3389/fbioe.2025.1582215
Received: 24 February 2025; Accepted: 27 March 2025;
Published: 02 April 2025.
Edited and reviewed by:
Candan Tamerler, University of Kansas, United StatesCopyright © 2025 Yang, Nagao and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xianrui Yang, eWFuZ3hpYW5ydWkwMDFAZ21haWwuY29t