Editorial: Biomaterials and Biological Regulation for Bone Tissue Remodeling and Regeneration

Xianrui Yang ^1* Masashi Nagao ² Chen-he Zhou ³

• ¹ University of Florida, Gainesville, United States
• ² Department of Orthopedic Surgery, School of Medicine, Juntendo University, Bunkyō, Tōkyō, Japan
• ³ Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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 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 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 2023]. The initial inflammatory phase activates immune cells, such as macrophages, and releases cytokines to recruit MSCs to the injury site [Duda 2023]. The subsequent phases involve the differentiation of MSCs into osteoblasts and chondrocytes to form new bone and synthesize a new bone matrix [Donsante 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 2024]. Osteoblasts and stromal cells produce RANKL, which binds to the RANK receptor on osteoclast precursors, promoting their differentiation into mature osteoclasts [Udagawa 2021]. The decoy receptor OPG, secreted by osteoblasts, competes with RANKL to prevent excessive osteoclast activation, thereby maintaining bone dynamics [Udagawa 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 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 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 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 2023]. Research also indicates that in osteocytes, piezo channels regulate mechanotransduction by modulating sclerostin expression, thus affecting bone resorption through osteoclast regulation [Huang 2023]. Furthermore, piezo1-mediated signaling affects MSC differentiation toward osteogenic lineages while inhibiting adipogenesis to enhance bone regeneration [Huang 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 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 2014]. Composite biomaterials combine ceramics and polymers, further optimizing bioactivity and mechanical integrity [Vahidi 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 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 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 2024]. Additionally, bioactive coatings that incorporate antimicrobial agents, peptides, or stem cell-derived exosomes further enhance the regenerative potential of biomaterial implants [Agnihotri 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 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 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 2024 [Indurkar 2024]. All these studies provide novel information in the field of bone regeneration and help advance its application for clinical treatment in the future.