Bone regeneration and repair face formidable challenges under diabetic conditions, primarily due to the disruption of macrophage polarization induced by diabetes and the inflammatory imbalance within the bone microenvironment. We have developed a novel dynamic hydrogel system (AG-CD@LINA), constructed through the coordination crosslinking of thiolated gelatin (SH-Gelatin) and gold ions (Au3+), followed by grafting with cyclodextrin to load the ligand linagliptin. This hydrogel effectively inhibits the formation of M1 macrophages and the expression of pro-inflammatory cytokines by gradually releasing linagliptin. Simultaneously, it promotes the formation of M2 macrophages and the expression of anti-inflammatory cytokines, thus improving the inflammatory microenvironment of diabetic bone defects. Consequently, it facilitates the migration of mesenchymal stem cells and angiogenic cells, augments osteogenic activity, and promotes vascularization, collectively accelerating the regeneration of diabetic bone tissue. Mechanistically, polarization occurs through the TLR3-NF-κB signaling pathway. In vivo experiments demonstrate that the in-situ injection of the hydrogel enhances the regeneration of bone tissue and the restoration of bone structure in diabetic bone defects, effectively modulating local inflammation and promoting vascular formation. This study suggests that functionalized dynamic hydrogels can improve the inflammatory microenvironment by regulating in situ macrophage polarization, thereby facilitating the reconstruction of bone microstructure. This approach represents a promising novel therapeutic strategy for diabetic bone defects.

Unresolved inflammation and tissue destruction are supposed to underlie the failure of dental pulp repair. As crucial regulators of the injury response, dental pulp stem cells (DPSCs) play a key role in pulp tissue repair and regeneration. M2 macrophages have been demonstrated to induce osteogenic/odontogenic differentiation of DPSCs. Ginsenoside Rb1 (GRb1) is the major component of ginseng and manifested an anti-inflammatory role by promoting M1 macrophage polarised into M2 macrophage in inflammatory disease. However, whether GRb1 facilitates odontogenic differentiation of DPSCs via promoting M2 macrophage polarisation under inflammatory conditions has yet to be established.

Human monocyte leukemic cells (THP-1) differentiated macrophages were induced into M1 subsets and then treated with GRb1. After that, the conditioned medium was added to DPSCs. The cell co-cultured system was then subjected to odontogenic differentiation in osteogenic media. Effects of GRb1 on human dental pulp stem cells' (hDPSCs') osteogenic/odontogenic differentiation under inflammatory conditions were assessed by alkaline phosphatase (ALP) staining, Alizarin Red S (ARS) staining, and quantitative polymerase chain reaction testing.

Results demonstrated that GRb1 could facilitate the polarisation of macrophages from the M1 subtype to the M2 subtype. Conditioned medium from GRb1 + M1 macrophages, in comparison with M1 macrophages, may markedly increase the gene expression of ALP, DSPP, and DMP1. Moreover, ALP and ARS staining uncovered that the osteogenic/odontogenic differentiation ability of hDPSCs was strengthened in the M1 + GRb1 co-culture group.

GRb1 plays a crucial role in the inflammatory response and reparative dentine formation after dental pulp injury. Findings show that GRb1 modulates the interaction between macrophages and DPSCs during inflammation. The current study discusses modifications of deep caries therapy.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder primarily characterized by persistent synovial inflammation and progressive bone erosion. The pathogenesis of RA involves a complex cascade of cellular and molecular events, including sustained hyperactivation of macrophages, excessive recruitment and activation of neutrophils, pathological proliferation and invasion of fibroblast-like synoviocytes (FLS), and dysregulated differentiation and function of osteoclasts (OCs). The inflammatory factors secreted by these dysregulated cells significantly disrupt the joint microenvironment through multiple pathological mechanisms, primarily by promoting synovial inflammation, cartilage matrix degradation, osteoclast-mediated bone erosion, and pathological angiogenesis. Therapeutic strategies targeting the induction of apoptosis in these malignant cells have demonstrated considerable potential in preclinical studies, offering a promising approach to enhance treatment outcomes by simultaneously reducing inflammatory cytokine production and inhibiting pathogenic cell proliferation. However, conventional therapeutic drugs are limited in clinical applications because of their high toxicity and side effects. Inflammation induces morphological and functional changes in cells within the rheumatoid arthritis microenvironment (RAM), particularly the overexpression of specific receptors on cell membranes. This phenomenon has driven the development of ligand-modified targeted nanodelivery systems (NDSs), which can specifically target and induce apoptosis in specific cell types, thereby enhancing therapeutic efficacy. This paper comprehensively reviews the research progress of targeted NDSs based on apoptosis strategies for RA therapy, with a detailed discussion of their advantages in inducing apoptosis in various disease-associated cells. Furthermore, the potential of combining apoptosis of multiple cell types for RA treatment is explored. This review is expected to improve insights into the apoptosis of malignant cells to enhance RA therapy. STATEMENT OF SIGNIFICANCE: This review highlights recent advances in nanodelivery systems (NDSs) based on apoptotic strategies for enhanced rheumatoid arthritis (RA) therapy. Unlike conventional NDSs, these optimized systems specifically induce apoptosis in malignant cells within the RA microenvironment by integrating multiple therapeutic strategies. By summarizing the latest research, our work demonstrates the potential of these NDSs to suppress inflammatory responses and prevent bone destruction through targeted elimination of malignant cells, offering a novel direction for RA treatment. This review is significant as it provides a comprehensive overview for researchers and clinicians, facilitating the development of more effective therapeutic approaches for RA and other chronic inflammatory diseases.

Nanomaterial-mediated macrophage immune response plays a crucial role in bone regeneration microenvironment. Mesoporous silica nanoparticles are widely used as nano-drug carriers, imaging agents, and bioactivity regulators for potential tissue regeneration. It is known that surface topography features of nanomaterials play an important regulatory role in the immune response. In this study, it was found that the pollen-like surface morphology of mesoporous silica nanoparticles (PMSNs) inhibited the expression of pro-inflammatory markers at gene and protein levels in macrophages (RAW 264.7 cells) compared to the smooth surface morphology of mesoporous silica nanoparticles (MSNs). Scanning electron microscopy images showed distinct macrophage membrane surface binding patterns of MSNs and PMSNs. MSNs were more evenly dispersed across the macrophage cell membrane, while PMSNs were aggregated on the membrane and prevented the M1 polarization of macrophages. PMSNs-induced macrophage anti-inflammatory responses were associated with up-regulation of the cell surface receptor CD28 and inhibition of ERK phosphorylation. TEM images showed that macrophages phagocytosed both MSNs and PMSNs while inhibiting nanoparticle phagocytosis did not affect the expression of anti-inflammatory genes and proteins. Moreover, PMSNs-induced conditioned medium from macrophages promoted osteogenic differentiation of mouse bone marrow-derived stromal cells (mBMSCs), evidenced by increased mineralization and osteogenic marker BMP2 expression via Alizarin Red S and LSCM assays compared to MSNs-induced conditioned medium. Moreover, a lipopolysaccharide (LPS)-induced osteolysis model in mouse cranial bone further demonstrated that PMSNs prevent bone resorption by mitigating LPS-induced inflammation. Our results revealed that PMSNs-mediated macrophage immunomodulation promotes bone regeneration via surface topology-related physical contact cues. STATEMENT OF SIGNIFICANCE: Nanomaterials have been widely used in bone regeneration. The immune response of macrophages induced by nanomaterials, plays a crucial role in bone regeneration. However, most nanomaterial immunomodulatory research focus on macrophage internalization or phagocytosis. The early contact between the cell membrane and nanomaterials is often easily overlooked. To clarify how early contact between nanomaterial-cell membrane regulates macrophage immune response. We developed MSN particles with special pollen-like surface morphology and studied the impact of nanoparticle morphology on the early contact between materials and macrophage cell membranes, as well as the subsequent impact on macrophage immune response and bone regeneration and related regulatory mechanisms. The results can provide new guidance for the design and development of osteoimmunomodulatory nanomaterials.

Osteoarthritis (OA) is a debilitating disease that predominantly impacts the hip, hand, and knee joints. Its pathology is defined by the progressive degradation of articular cartilage, formation of bone spurs, and synovial inflammation, resulting in pain, joint function limitations, and substantial societal and familial burdens. Current treatment strategies primarily target pain alleviation, yet improved interventions addressing the underlying disease pathology are scarce. Recently, exosomes have emerged as a subject of growing interest in OA therapy. Numerous studies have investigated exosomes to offer promising therapeutic approaches for OA through diverse in vivo and in vitro models, elucidating the mechanisms by which exosomes from various cell sources modulate the cartilage microenvironment and promote cartilage repair. Preclinical investigations have demonstrated the regulatory effects of exosomes originating from human cells, including mesenchymal stem cells (MSC), synovial fibroblasts, chondrocytes, macrophages, and exosomes derived from Chinese herbal medicines, on the modulation of the cartilage microenvironment and cartilage repair through diverse signaling pathways. Additionally, therapeutic mechanisms encompass cartilage inflammation, degradation of the cartilage matrix, proliferation and migration of chondrocytes, autophagy, apoptosis, and mitigation of oxidative stress. An increasing number of exosome carrier scaffolds are under development. Our review adopts a multidimensional approach to enhance comprehension of the pivotal therapeutic functions exerted by exosomes sourced from diverse cell types in OA. Ultimately, our aim is to pinpoint therapeutic targets capable of regulating the cartilage microenvironment and facilitating cartilage repair in OA.

Osteoporosis (OP) is a systemic skeletal disease characterized by low bone mineral density and deterioration of bone architecture, resulting in bone strength reduction and increased fracture susceptibility. Estrogen deficiency in post-menopausal women is possibly responsible for the instability between bone formation and resorption, which is managed by specific osteoclastogenic cytokines that may be leading to resorption. This study aims to estimation of the concentrations of interleukins -8, -17, -22, beside to certain parameters in blood serum and explained their roles in the development of osteoporosis pathogenicity in postmenopausal women.

A case-control study included 108 Iraqi postmenopausal women participants their ages ranged between 45 and 70 years. All participants subjected to the DEXA scan, 58 samples were osteoporotic patients, whereas 50 were healthy controls. Blood samples collected from all participants in order to assess the levels of interleukins -8, -17, -22, CBC, CRP, RF, and ACPA.

The concentrations of IL-8, -17, -22, ESR, PLT, CRP, RF and ACPA exhibited a positive correlation with OP development. Conversely, WBC and HGB concentrations showed a negative association with osteoporosis.

A remarkable relationship was obtained between the values of IL-8, 17, -22, CRP, RF, ACPA, ESR, PLT and osteoporosis but in contrary with WBCs and HGB. IL-8, -17, and - 22 can be linked to specific inflammatory diseases associated with the postmenopausal period, may act as one of the main biomarkers for osteoporosis due to their ability to stimulate osteoclastogenesis and bone resorption, and may be considered potential prognostic factors for osteoporosis.

Osteoclasts (OCs) are important therapeutic targets in the treatment of osteoporosis. The aim of this study was to explore a novel therapeutic approach for osteoporosis using Arcyriaflavin A (ArcyA), a natural compound derived from the marine invertebrate Eudistoma sp. We systematically evaluated the effects of ArcyA on OC differentiation and function in mouse models using molecular biology assays, cellular function analyses and in vivo animal experiments. We also evaluated the efficacy of ArcyA in human cells. The TRAP staining results provide the first clear evidence of the drug's inhibitory effect, whereby the administration of ArcyA led to a significant reduction in TRAP-positive cells compared to the control group at concentrations that were non-toxic to bone marrow macrophages. Meanwhile, a significant reduction in the number of multinucleated giant cells with more than ten nuclei was observed. Furthermore, similar TRAP staining results were reproduced in human OCs, suggesting that ArcyA has the same effect on OCs derived from human PBMCs. At the molecular level, ArcyA treatment resulted in the downregulation of genes relevant to OC differentiation (NFATc1, cFos and TNFrsf11α), fusion and survival (DCstamp and ATP6v0d2) and resorption function (CTSK, MMP9, integrin β3 and ACP5). A western blot analysis of the corresponding proteins (NFATc1, cFos, CTSK and integrin β3) further confirmed the PCR results. Furthermore, ArcyA-treated OCs produced significantly fewer resorption pits, indicating suppressed bone resorption activity. Consistent with this, in vivo experiments using an ovariectomy (OVX)-induced osteoporosis mouse model showed that ArcyA treatment significantly alleviated bone loss. Mice in the treatment groups had higher BV/TV values, and this therapeutic effect was enhanced in a dose-dependent manner. In addition, our research also showed that IκB could be a potential target for the inhibitory effect of ArcyA. In conclusion, these findings suggest that ArcyA has significant therapeutic potential for the treatment of osteoporosis by inhibiting osteoclastogenesis and bone resorption. Further studies are warranted to explore its clinical applications.

This study aimed to investigate the role and mechanism of the Akt2 pathway in different stages of anterior disc displacement (ADD)-induced temporomandibular joint osteoarthritis (TMJOA).

A rat model for TMJOA that simulates anterior disc displacement was established. For inhibit Akt2 expression in subchondral bone, rats were intravenously injected with adeno-associated virus carrying Akt2 shRNA at a titer of 1 × 1012 transducing units/mL 10 days before the ADD or sham operations. The rats were euthanized and evaluated 1 or 8 weeks after surgery, as these time points represented the early or advanced stage of ADD. Immunostaining was performed to examine the expression and location of phosphorylated Akt2 in different stages of ADD. Microcomputed tomography, hematoxylin and eosin staining, toluidine blue staining, Western blotting, immunohistochemical and immunofluorescence staining were used to elucidate the pathological changes and potential mechanisms underlying ADD-induced TMJOA.

In the rat model of ADD-induced TMJOA, rapid condylar bone loss occurred with increased phosphorylation of Akt2 in subchondral bone macrophages within 1 week post-surgery. At 8 weeks after surgery, abnormal remodeling of subchondral bone and degenerative changes in cartilage were observed. Inhibiting Akt2 reduced condylar bone resorption following ADD surgery while improving condylar bone morphology at 8 weeks post-surgery. Additionally, inhibition of Akt2 alleviated cartilage degeneration characterized by a decreased number of apoptotic chondrocytes, reduced expression of matrix metalloproteinases, and increased collagen type II expression in cartilage tissue.

The Akt2 pathway is activated mainly in subchondral bone macrophages during the early stage of ADD and plays an important role in regulating subchondral bone remodeling. Inhibition of Akt2 could serve as a prophylactic treatment to slow the progression of ADD-induced TMJOA.

Addressing bone tissue defects is a critical challenge in clinical practice, necessitating the development of biomaterials that can orchestrate both immune modulation and tissue regeneration. This study introduces and assesses the immunomodulatory effects and bone repair capabilities of a novel 3D-printed scaffold composed of gelatin methacryloyl (GelMA), nanohydroxyapatite, and melanin nanoparticles (GHM). The GHM scaffolds, characterized by their optimal porosity, viscosity, and mechanical strength, have been shown to effectively direct macrophage polarization from the initial M0 state to the anti-inflammatory M2 phenotype. Concurrently, osteogenic precursor cell lines MC3T3 are stimulated to differentiate into osteoblasts under the influence of macrophage-conditioned medium. In vivo studies using normal mice cranial defect models and macrophage-depleted cranial defect models have demonstrated that GHM scaffolds can attract macrophages to the implantation site, promote their M2 polarization, and consequently, significantly enhance bone formation and effectively treat cranial defects in mice. RNA-sequencing analysis has revealed elevated expression of the Leukemia inhibitory factor (Lif) gene in macrophages treated with GHM, implicating its role in regulating macrophage polarization. These findings underscore the potential of GHM scaffolds as an immunomodulatory biomaterial for bone tissue engineering applications.

The skeleton is an important organ in the human body. Bone defects caused by trauma, inflammation, tumors, and other reasons can impact the quality of life of patients. Although the skeleton has a certain ability to repair itself, the current most effective method is still autologous bone transplantation due to factors such as blood supply and defect size. Modern medicine is attempting to overcome these limitations through cell therapy, with mesenchymal stem cells (MSCs) playing a crucial role. MSCs can be extracted from different tissues, and their differentiation potential varies depending on the source. Various cells and cell secretions can influence this process. This article, based on previous research, reviews the effects of macrophages, endothelial cells (ECs), nerve cells, periodontal cells, and even some bacteria on MSC osteogenic differentiation, aiming to provide a reference for multicell coculture strategies related to osteogenesis.

As a GLP-1 receptor agonist widely used in treating type 2 diabetes, liraglutide shows potential applications in bone tissue engineering. This study investigated liraglutide's direct effects on rat bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation and its regulatory mechanism through macrophage polarization. Results showed that liraglutide significantly enhanced BMSC migration and osteogenic differentiation. Additionally, liraglutide markedly inhibited M1 macrophage polarization induced by LPS and IFN-γ, reducing inflammatory factors CXCL9 and TNF-α secretion, possibly by partially reversing M1 macrophage regulatory signals (AMPK and NF-κB pathways). Compared to M1 macrophage-conditioned medium (M1-CM), conditioned medium from liraglutide-treated macrophages showed stronger promotion of BMSC osteogenic differentiation, though this effect was reversed by CXCL9 addition. The study demonstrates that liraglutide enhances BMSC osteogenic capacity both directly and by inhibiting M1 macrophage polarization and CXCL9 secretion, offering a new therapeutic option for severe bone defects with inflammatory responses.

With the ongoing development of osteoimmunology, increasing evidence indicates that the local immune microenvironment plays a critical role in various stages of bone formation. Consequently, modulating the immune inflammatory response triggered by biomaterials to foster a more favorable immune microenvironment for bone regeneration has emerged as a novel strategy in bone tissue engineering. This review first examines the roles of various immune cells in bone tissue injury and repair. Then, the contributions of different biomaterials, including metals, bioceramics, and polymers, in promoting osteogenesis through immune regulation, as well as their future development directions, are discussed. Finally, various design strategies, such as modifying the physicochemical properties of biomaterials and integrating bioactive substances, to optimize material design and create an immune environment conducive to bone formation, are explored. In summary, this review comprehensively covers strategies and approaches for promoting bone tissue regeneration through immune modulation. It offers a thorough understanding of current research trends in biomaterial-based immune regulation, serving as a theoretical reference for the further development and clinical application of biomaterials in bone tissue engineering.

Ulcerative colitis (UC) involves persistent inflammation in the colon and rectum, with excessive reactive oxygen species (ROS) accumulation. This ROS buildup damages colonic epithelial cells and disrupts intestinal flora, worsening disease progression. Current antioxidant therapies are limited due to their instability in the gut and lack of targeting, hindering precise intervention at the lesion site. This study prepares an L-Arginine-modified selenium nanozyme (Se-CA) for the targeted oral treatment of UC. Se-CA specifically targets M1-type macrophages at sites of inflammation by binding to cationic amino acid transporter protein 2 on the surface of M1-type macrophages. In vitro studies show that Se-CA scavenges reactive ROS and reactive nitrogen species (RNS) in artificial gastric acid and intestinal fluids, and inhibits iron death in intestinal epithelial cells. In mice model of ulcerative colitis, oral administration of Se-CA is effective in the treatment of colitis through its anti-inflammatory and antioxidant properties, inhibition of iron death and regulation of intestinal flora. In conclusion, this work provides new insights into the targeted oral treatment of UC.

Advancements in tissue regeneration, particularly bone regeneration is key area of research due to potential of novel therapeutic approaches. Efforts to reduce reliance on autologous and allogeneic bone grafts have led to the development of biomaterials that promote synchronized and controlled bone healing. However, the use of growth factors is limited by their short half-life, slow tissue penetration, large molecular size and potential toxicity. These factors suggest that traditional delivery methods may be inadequate hence, to address these challenges, new strategies are being explored. These novel approaches include the use of bioactive substances within advanced delivery systems that enable precise spatiotemporal control. Dual-release composite scaffolds offer a promising solution by reducing the need for multiple surgical interventions and simplifying the treatment process. These scaffolds allow for sustained and controlled drug release, enhancing bone repair while minimizing the drawbacks of conventional methods. This review explores various dual-drug release systems, discussing their modes of action, types of drugs used and release mechanisms to improve bone regeneration.

Moringa oleifera (MO) is renowned for its remarkable medicinal uses, supported by claims across various cultures and growing scientific evidence. Preclinical experimental evidence indicated that MO may effectively reduce bone loss and promote bone remodelling through its effects on osteoclasts and osteoblasts. In vivo studies demonstrated that MO enhances critical aspects of bone health, such as bone volume, trabecular thickness and overall bone density. Furthermore, MO positively influenced bone biomarkers including alkaline phosphatase and procollagen type 1 N-terminal propeptide, reflecting improved bone formation. Additionally, in vitro and ex vivo studies revealed that MO boosted bone regeneration, stimulated osteoblast activity and reduced inflammation. In terms of mechanisms, MO may modulate signalling pathways related to bone metabolism, such as BMP2, PI3K/Akt/FOXO1, p38α/MAPK14 and RANKL/RANK//OPG pathways. This evidence provides a strong foundation for future clinical research and potential therapeutic applications in managing and preventing bone loss conditions.

Tooth loss is a prevalent problem faced by individuals of all ages across the globe. Various biomaterials, such as metals, bioceramics, polymers, composites of ceramics and polymers, etc., have been used for the manufacturing of dental implants. The success of a dental implant primarily depends on its osseointegration rate. The current surface modification techniques fail to imbibe the basics of tooth development, which can impart better mineralization and osseointegration. This can be improved by developing an understanding of the developmental pathways of dental tissue. Stimulating the correct signaling pathways through inductive material systems can bring about a paradigm shift in dental implant materials. The current review focuses on the developmental pathway and mineralization process that happen during tooth formation and how surface modifications can help in biomimetic mineralization, thereby enhancing osseointegration. We further describe the effect of dental implant surface modifications on mineralization, osteoinduction, and osseointegration; both in vitro and in vivo. The review will help us to understand the natural process of teeth development and mineralization and how the surface properties of dental implants can be further improved to mimic teeth development, in turn increasing osseointegration.

The controlled release of drugs remains a huge challenge in the field of tissue engineering. Current research focuses on the construction of drug carriers by using various advanced technologies. However, the pore-like structure that exists within our human body is ignored. Herein, a dental particle loaded with FTY720 by using dentin tubules (Dent-FTY720) was successfully prepared, which could achieve long-term sustained release of drugs. Meanwhile, Dent-FTY720 significantly promoted bone defect repair because of the similarity in composition to bone including hydroxyapatite and collagen. Furthermore, the loaded drugs exhibited both anti-immune and anti-inflammatory properties. This research introduces a novel concept in drug loading, highlighting the potential of dentin tubules as a drug delivery system.

Osteoporosis presents a marked global public health challenge, characterized by deficient osteogenesis and a deteriorating immune microenvironment. Conventional clinical interventions primarily target osteoclast-mediated bone damage, yet lack a comprehensive therapeutic approach that balances bone formation and resorption. Herein, we introduce a bone-targeted nanocomposite, A-Z@Pd(H), designed to address these challenges by integrating diverse functional components. The nanocomposite incorporates internal hydrogen-carrying nanozymes, which effectively scavenge multiple reactive oxygen species (ROS) and synergistically engage the autophagy-lysosome pathway to accelerate endogenous ROS degradation in macrophages. This mechanism disrupts the vicious cycle of autophagic dysfunction-ROS accumulation-macrophage inflammation. In addition, external metal-organic frameworks release zinc ions (Zn2+) in response to the acidic osteoporotic environment, thereby promoting osteogenesis. In a murine model of osteoporosis, intravenous administration of A-Z@Pd(H) leads to preferential accumulation in the femur, thereby remodeling the osteoporotic microenvironment through immune regulation, osteogenesis promotion, and osteoclast inhibition. These findings suggest that this system composed of hydrogen therapy and ion therapy may be a promising candidate for bone-targeted comprehensive therapy in osteoporosis.

Macrophages play an important role in the symptoms and structural progression of periodontitis, and are receiving increasing attention. In recent years, research has shown significant progress in macrophage associated periodontitis. However, there is still lack of comprehensive and methodical bibliometric analysis in this domain. Therefore, this research aims to describe the state of the research and current research hotspots of macrophage associated periodontitis from the perspective of bibliometrics.

This study collected and screened a total of 1424 articles on macrophage associated periodontitis retrieved between 2004 and 2023 from Web of Science Core Collection database. Use Citespace (6.1. R6), Bibliometrix-R (4.1.3), VOSviewer (1.6.19), and Graphpad Prism8 software to analyze and plot countries/regions, institutions, journals, authors, literature, and keywords to explore the research hotspots and development trends of macrophage associated periodontitis.

After analysis, the amount of macrophage associated periodontitis publications has been rising consistently over time, with China having the most publications (29.32%). 3 countries accounted for 65.57% of the total publications: the United States, China, and Japan, occupying a dominant position in this research field. China publications have the fastest growth rate and played a driving role. The most productive institution is the Sichuan University in China. Journal of Periodontal Research is highly popular in the field of macrophage associated periodontitis, with the highest number of publications. Grenier, Daniel is the most prolific author. Inflammation and Bone Loss in Periodontal Disease are the most cited literature. "Biological pathogenic factors," "immune regulation," "mechanism research," "susceptibility factor research," "pathological processes and molecular correlation," "pathological characteristics," "inflammatory response" are the main keyword groups in this field.

This study systematically analyzes and describes the development process, direction, and hotspots of macrophage associated periodontitis using bibliometric methods, providing a reference for future researchers who continue to study macrophage associated periodontitis.

Osteoporosis is a metabolic bone disease that seriously jeopardizes the health of middle-aged and elderly people. Mesenchymal stem cell-based transplantation for osteoporosis is a promising new therapeutic strategy. Induced mesenchymal stem cells (iMSCs) are a new option for stem cell transplantation therapy. Acquired mouse skin fibroblasts were transduced and reprogrammed into induced pluripotent cells and further induced to differentiate into iMSCs. The iMSCs were tested for pluripotency markers, trilineage differentiation ability, cell surface molecular marker tests, and gene expression patterns. The iMSCs were injected into the tail vein of mice by tail vein injection, and the distribution of cells in various organs was observed. The effect of iMSCs on the bone mass of mice was detected after injection into the mouse osteoporosis model. The effects of iMSCs infusion on metabolites in femoral tissue and peripheral blood plasma were detected based on LC-MS untargeted metabolomics. iMSCs have similar morphology, immunophenotype, in vitro differentiation potential, and gene expression patterns as mesenchymal stem cells. The iMSCs were heavily distributed in the lungs after infusion and gradually decreased over time. The iMSCs in the femoral bone marrow cavity gradually increased with time. iMSCs infusion significantly avoided bone loss due to oophorectomy. The results of untargeted metabolomics suggest that amino acid and lipid metabolic pathways are key factors involved in iMSCs bone protection and prevention of osteoporosis formation. iMSCs obtained by reprogramming-induced differentiation had cellular properties similar to those of bone marrow mesenchymal stem cells. The iMSCs could promote the remodelling of bone structure in ovariectomy-induced osteoporotic mice and affect the changes of several key metabolites in bone and peripheral blood. Some of these metabolites can serve as potential biomarkers and therapeutic targets for iMSCs intervention in osteoporosis. Investigating the effects of iMSCs on osteoporosis and the influence of metabolic pathways will provide new ideas and methods for the clinical treatment of osteoporosis.

Bone defects can arise from trauma or pathological factors, resulting in compromised bone integrity and the loss or absence of bone tissue. As we are all aware, repairing bone defects is a core problem in bone tissue engineering. While minor bone defects can self-repair if the periosteum remains intact and normal osteogenesis occurs, significant defects or conditions such as congenital osteogenesis imperfecta present substantial challenges to self-healing. As research on mesenchymal stem cell (MSC) advances, new fields of application have emerged; however, their application in orthopedics remains one of the most established and clinically valuable directions. This review aims to provide a comprehensive overview of the research progress regarding MSCs in the treatment of diverse bone defects. MSCs, as multipotent stem cells, offer significant advantages due to their immunomodulatory properties and ability to undergo osteogenic differentiation. The review will encompass the characteristics of MSCs within the osteogenic microenvironment and summarize the research progress of MSCs in different types of bone defects, ranging from their fundamental characteristics and animal studies to clinical applications.

Osteoporosis (OP), the most prevalent bone degenerative disease, has become a significant public health challenge globally. Current therapies primarily target inhibiting osteoclast activity or stimulating osteoblast activation, but their effectiveness remains suboptimal. This paper introduced a "three birds, one stone" therapeutic approach for osteoporosis, employing upconversion nanoparticles (UCNPs) to create a dual-gas storage nanoplatform (UZPA-CP) targeting bone tissues, capable of concurrently generating carbon monoxide (CO) and hydrogen sulfide (H2S). Through the precise modulation of 808 nm near-infrared (NIR) light, the platform could effectively control the release of CO and H2S in the OP microenvironment, and realize the effective combination of promoting osteogenesis, inhibiting osteoclast activity, and improving the immune microenvironment to achieve the therapeutic effect of OP. High-throughput sequencing results further confirmed the remarkable effectiveness of the nanoplatform in inhibiting apoptosis, modulating inflammatory response, inhibiting osteoclast differentiation and regulating multiple immune signaling pathways. The gas storage nanoplatform not only optimized the OP microenvironment with the assistance of NIR, but also restored the balance between osteoblasts and osteoclasts. This comprehensive therapeutic strategy focused on improving the bone microenvironment, promoting osteogenesis and inhibiting osteoclast activity provides an ideal new solution for the treatment of metabolic bone diseases.

The Hippo signalling pathway is a conserved kinase cascade that orchestrates diverse cellular processes, such as proliferation, apoptosis, lineage commitment and stemness. With the onset of society ages, research on skeletal aging-mechanics-bone homeostasis has exploded. In recent years, aging and mechanical force in the skeletal system have gained groundbreaking research progress. Under the regulation of mechanics and aging, the Hippo signalling pathway has a crucial role in the development and homeostasis of bone. We synthesize the current knowledge on the role of the Hippo signalling pathway, particularly its downstream effectors yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), in bone homeostasis. We discuss the regulation of the lineage specification and function of different skeletal cell types by the Hippo signalling pathway. The interactions of the Hippo signalling pathway with other pathways, such as Wnt, transforming growth factor beta and nuclear factor kappa-B, are also mentioned because of their importance for modulating bone homeostasis. Furthermore, YAP/TAZ have been extensively studied as mechanotransducers. Due to space limitations, we focus on reviewing how mechanical forces and aging influence cell fate, communications and homeostasis through a dysregulated Hippo signalling pathway.

Bone defects are a prevalent category of skeletal tissue disorders in clinical practice, with a range of pathogenic factors and frequently suboptimal clinical treatment effects. In bone regeneration of bone defects, the bone regeneration microenvironment-composed of physiological, chemical, and physical components-is the core element that dynamically coordinates to promote bone regeneration. In recent years, medical biomaterials with bioactivity and functional tunability have been widely researched upon and applied in the fields of tissue replacement/regeneration, and remodelling of organ structure and function. The biomaterial treatment system based on the comprehensive regulation strategy of bone regeneration microenvironment is expected to solve the clinical problem of bone defect. Hydrogel microspheres (HMS) possess a highly specific surface area and porosity, an easily adjustable physical structure, and high encapsulation efficiency for drugs and stem cells. They can serve as highly efficient carriers for bioactive factors, gene agents, and stem cells, showing potential advantages in the comprehensive regulation of bone regeneration microenvironment to enhance bone regeneration. This review aims to clarify the components of the bone regeneration microenvironment, the application of HMS in bone regeneration, and the associated mechanisms. It also discusses various preparation materials and methods of HMS and their applications in bone tissue engineering. Furthermore, it elaborates on the relevant mechanisms by which HMS regulates the physiological, chemical, and physical microenvironment in bone regeneration to achieve bone regeneration. Finally, we discuss the future prospects of the HMS system application for comprehensive regulation of bone regeneration microenvironment, to provide novel perspectives for the research and application of HMS in the bone tissue engineering field.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a debilitating condition caused by long-term corticosteroid use, leading to impaired blood flow and bone cell death. The disruption of cellular processes and promotion of apoptosis by endoplasmic reticulum stress (ERS) is implicated in the pathogenesis of SONFH. We identified ERS-associated genes in SONFH and investigated their potential as therapeutic targets. We analysed the GSE123568 GEO dataset to identify differentially expressed genes (DEGs) related to ERS in SONFH. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, identified hub genes by protein-protein interaction (PPI) analyses, and evaluated their functions by gene set enrichment analysis (GSEA). We constructed mRNA-miRNA networks, identified potential therapeutics, and assessed immune cell infiltration. We performed cross-validation using the GEO dataset GSE74089, qRT-PCR on clinical samples from patients with SONFH and controls, and a receiver operating characteristic (ROC) curve analysis to assess the diagnostic performance of the hub genes. We identified 195 ERS-related genes in SONFH, which were primarily involved in oxidative stress, immune responses, and metabolic pathways. The PPI network suggested CXCL8, STAT3, IL1B, TLR4, PTGS2, TLR2, CASP1, CYBB, CAT, and HOMX1 to be key hub genes, which were shown by GSEA to be involved in biological pathways related to metabolism, immune modulation, and cellular integrity. We also identified 261 microRNAs (miRNAs) as well as drugs such as dibenziodolium and N-acetyl-L-cysteine that modulated inflammatory responses in SONFH. Twenty-two immune cell subtypes showed significant correlations, such as a positive correlation between activated mast cells and Tregs, and patients with SONFH had fewer dendritic cells than controls. The hub genes CYBB and TLR4 showed significant correlations with M1 macrophages and CD8 T cells, respectively. Cross-validation and qRT-PCR confirmed the upregulation of STAT3, IL1B, TLR2, and CASP1 in patients with SONFH, validating the bioinformatics findings. An ROC curve analysis confirmed the diagnostic potential of the hub genes. The top 10 hub genes show promise as ERS-related diagnostic biomarkers for SONFH. We discovered that 261 miRNAs, including hsa-miR-23, influence these genes and identified potential therapeutics such as dibenziodolium and simvastatin. Immune profiling indicated altered immune functions in SONFH, with significant correlations among immune cell types. Validation confirmed the upregulation of STAT3, IL1B, TLR2 and CASP1, which had diagnostic potential. The findings suggest potential diagnostic markers and therapeutic targets for SONFH.

To assess the efficacy of a novel 3D biomimetic hydrogel scaffold with immunomodulatory properties in promoting fracture healing. Immunomodulatory scaffolds were used in cell experiments, osteotomy mice treatment, and single-cell transcriptomic sequencing. In vitro, fluorescence tracing examined macrophage mitochondrial transfer and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Scaffold efficacy was assessed through alkaline phosphatase (ALP), Alizarin Red S (ARS) staining, and in vivo experiments. The scaffold demonstrated excellent biocompatibility and antioxidant-immune regulation. Single-cell sequencing revealed a shift in macrophage distribution towards the M2 phenotype. In vitro experiments showed that macrophage mitochondria promoted BMSCs' osteogenic differentiation. In vivo experiments confirmed accelerated fracture healing. The GAD/Ag-pIO scaffold enhances osteogenic differentiation and fracture healing through immunomodulation and promotion of macrophage mitochondrial transfer.

Ferroptosis is a type of programmed cell death driven by iron-dependent lipid peroxidation. The TNF-mediated biosynthesis of glutathione has been shown to protect synovial fibroblasts from ferroptosis in the hyperplastic synovium. Ferroptosis induction provides a novel therapeutic approach for rheumatoid arthritis (RA) by reducing the population of synovial fibroblasts. The beginning and maintenance of synovitis in RA are significantly influenced by macrophages, as they generate cytokines that promote inflammation and contribute to the destruction of cartilage and bone. However, the vulnerability of macrophages to ferroptosis in RA remains unclear. In this study, we found that M2 macrophages are more vulnerable to ferroptosis than M1 macrophages in the environment of the arthritis synovium with a high level of iron, leading to an imbalance in the M1/M2 ratio. During ferroptosis, HMGB1 released by M2 macrophages interacts with TLR4 on M1 macrophages, which in turn triggers the activation of STAT3 signaling in M1 macrophages and contributes to the inflammatory response. Knockdown of TLR4 decreased the level of cytokines induced by HMGB1 in M1 macrophages. The ferroptosis inhibitor liproxstatin-1 (Lip-1) started at the presymptomatic stage in collagen-induced arthritis (CIA) model mice, and GPX4 overexpression in M2 macrophages at the onset of collagen antibody-induced arthritis (CAIA) protected M2 macrophages from ferroptotic cell death and significantly prevented the development of joint inflammation and destruction. Thus, our study demonstrated that M2 macrophages are vulnerable to ferroptosis in the microenvironment of the hyperplastic synovium and revealed that the HMGB1/TLR4/STAT3 axis is critical for the ability of ferroptotic M2 macrophages to contribute to the exacerbation of synovial inflammation in RA. Our findings provide novel insight into the progression and treatment of RA.

Periodontitis is a chronic infectious disease characterized by progressive inflammation and alveolar bone loss. Forkhead box O1 (FoxO1), an important regulator, plays a crucial role in maintaining bone homeostasis and regulating macrophage energy metabolism and osteogenic differentiation of mesenchymal stem cells (MSCs). In this study, FoxO1 was overexpressed into small extracellular vesicles (sEV) using engineering technology, and effects of FoxO1-overexpressed sEV on periodontal tissue regeneration as well as the underlying mechanisms were investigated.

Human periodontal ligament stem cell (hPDLSCs)-derived sEV (hPDLSCs-sEV) were isolated using ultracentrifugation. They were then characterized using transmission electron microscopy, Nanosight, and Western blotting analyses. hPDLSCs were treated with hPDLSCs-sEV in vitro after stimulation with lipopolysaccharide, and osteogenesis was evaluated. The effect of hPDLSCs-sEV on the polarization phenotype of THP-1 macrophages was also evaluated. In addition, we measured the reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) production, mitochondrial characteristics, and metabolism of hPDLSCs and THP-1 cells. Experimental periodontitis was established in vivo in mice. HPDLSCs-sEV or phosphate-buffered saline (PBS) were injected into periodontal tissues for four weeks, and the maxillae were collected and assessed by micro-computed tomography, histological staining, and small animal in vivo imaging.

In vitro, FoxO1-overexpressed sEV promoted osteogenic differentiation of hPDLSCs in the inflammatory environment and polarized THP-1 cells from the M1 phenotype to the M2 phenotype. Furthermore, FoxO1-overexpressed sEV regulated the ROS level, ATP production, mitochondrial characteristics, and metabolism of hPDLSCs and THP-1 cells in the inflammatory environment. In the in vivo analyses, FoxO1-overexpressed sEV effectively promoted bone formation and inhibited inflammation.

FoxO1-overexpressed sEV can regulate osteogenesis and immunomodulation. The ability of FoxO1-overexpressed sEV to regulate inflammation and osteogenesis can pave the way for the establishment of a therapeutic approach for periodontitis.

Osteonecrosis (ON) of the femoral head (ONFH) is a devastating bone disease affecting over 20 million people worldwide. ONFH is caused by a disruption of the blood supply, leading to necrotic cell death and increased inflammation. Macrophages are the key cells mediating the inflammatory responses in ON. It is unclear what the dynamic phenotypes of macrophages are and what mechanisms may affect macrophage polarization and, therefore, the healing process. In our preliminary study, we found that there is an invasion of macrophages into the repair tissue during ON healing. Interestingly, in both ONFH patients and a mouse ON model, fat was co-labeled within macrophages using immunofluorescence staining, indicating the phagocytosis of fat by macrophages. To study the effects of fat phagocytosis on the macrophage phenotype, we set up an in vitro macrophage and fat co-culture system. We found that fat phagocytosis significantly decreased M1 marker expression, such as IL1β and iNOS, in macrophages, whereas the expression of the M2 marker Arg1 was significantly increased with fat phagocytosis. To investigate whether the polarization change is indeed mediated by phagocytosis, we treated the cells with Latrunculin A (LA, which inhibits actin polymerization and phagocytosis). LA supplementation significantly reversed the polarization marker gene changes induced by fat phagocytosis. To provide an unbiased transcriptional gene analysis, we submitted the RNA for bulk RNA sequencing. Differential gene expression (DGE) analysis revealed that the top upregulated genes were related to anti-inflammatory responses, while proinflammatory genes were significantly downregulated. Additionally, using pathway enrichment and network analyses (Metascape), we confirmed that gene-enriched categories related to proinflammatory responses were significantly downregulated in macrophages with fat phagocytosis. Finally, we validated the similar macrophage phenotype changes in vivo. To summarize, we discovered that fat phagocytosis occurs in both ONFH patients and an ON mouse model, which inhibits proinflammatory responses with increased anabolic gene expression in macrophages. This fat-phagocytosis-induced macrophage phenotype is consistent with the in vivo changes shown in the ON mouse model. Our study reveals a novel phagocytosis-mediated macrophage polarization mechanism in ON, which fills in our knowledge gaps of macrophage functions and provides new concepts in macrophage immunomodulation as a promising treatment for ON.

Although calcium phosphate has been extensively utilized in orthopedic applications such as spine, limbs, dentistry, and maxillofacial surgery, the lack of osteoinductive properties often hinders its effectiveness in treating bone defects resulting from pathological micro-environment such as tumor surgery, osteoporosis, osteomyelitis, and diabetic. Therefore, a novel bone cement based on magnesium-doped bioactive glass was developed in this study. The moderate release of magnesium ions improved the mechanical properties by controlling the crystal size of hydroxyapatite. Through detailed discussion of element content and heat treatment temperature, it was found that 2Mg-BG-800 was suitable for the construction of bone cement. 2Mg-BG-BC exhibited favorable initial (15 min) and final (30 min) setting time, compressive strength (29.45 MPa), compressive modulus (1851.49 MPa), injectability, and shape-adaptability. Furthermore, Mg-BG-BC demonstrated the ability to enhance the osteogenic differentiation of BMSCs, and induce macrophage polarization towards the M2 phenotype, suggesting its potential for osteoporotic fracture regeneration.

Osteoclasts are pivotal in regulating bone metabolism, with immune cells significantly influencing both physiological and pathological processes by modulating osteoclast functions. This is particularly evident in conditions of inflammatory bone resorption, such as rheumatoid arthritis and periodontitis. This review summarizes and comprehensively analyzes the research progress on the regulation of osteoclast formation by immune cells, aiming to unveil the underlying mechanisms and pathways through which diseases, such as rheumatoid arthritis and periodontitis, impact bone metabolism.

Periodontitis is a chronic inflammatory disease with the destruction of supporting periodontal tissue. This study evaluated the role of insulin-like growth factor 2 (IGF2) in periodontitis by inhibiting the polarization of M1 macrophages via the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. IGF2 was enriched in the gingival tissue of murine periodontitis model identified by RNA sequencing. IGF2 application alleviated the expression of pro-inflammatory factors and promoted osteogenesis and the expression of related genes and proteins in a dose-dependent manner in periodontitis. The result of micro-CT verified this finding. Both in vivo and in vitro results revealed that IGF2 decreased the polarization of M1 macrophages and pro-inflammatory factors by immunofluorescence staining, flow cytometry, western blotting and RT-PCR. IGF2 application promoted the osteogenic ability of periodontal ligament fibroblasts (PDLFs) indirectly via its inhibition of M1 polarization evaluated by alkaline phosphatase and alizarin red staining. Then, the cGAS/STING pathway was upregulated in periodontitis and macrophages challenged by LPS, the inhibition of which led to downregulation of M1 polarization. Furthermore, IGF2 could downregulate cGAS, STING and the phosphorylation of P65. Collectively, our study indicates IGF2 can regulate the polarization of M1 macrophages via the cGAS/STING pathway and highlights the promising future of IGF2 as a therapeutic treatment for periodontitis.

The repair of bone tissue damage is a complex process that is well-orchestrated in time and space, a focus and difficulty in orthopedic treatment. In recent years, the success of mesenchymal stem cells (MSCs)-mediated bone repair in clinical trials of large-area bone defects and bone necrosis has made it a candidate in bone tissue repair engineering and regenerative medicine. MSCs are closely related to macrophages. On one hand, MSCs regulate the immune regulatory function by influencing macrophages proliferation, infiltration, and phenotype polarization, while also affecting the osteoclasts differentiation of macrophages. On the other hand, macrophages activate MSCs and mediate the multilineage differentiation of MSCs by regulating the immune microenvironment. The cross-talk between MSCs and macrophages plays a crucial role in regulating the immune system and in promoting tissue regeneration. Making full use of the relationship between MSCs and macrophages will enhance the efficacy of MSCs therapy in bone tissue repair, and will also provide a reference for further application of MSCs in other diseases.

Aim: The purpose of the study was to determine the features of the expression of T-lymphocytes, B-lymphocytes, macrophages in the post-traumatic regenerate of the mandible rats under conditions of filling a bone defect with hydroxyapatite-containing osteotropic material and thymalin injecting the surrounding soft tissues.

Materials and Methods: An experiment was conducted on 48 mature rats of the WAG population weighing 160-180 grams. Four groups were formed. Group 1 included 12 rats with a simulated holey defect in the lower jaw. Group 2 included 12 rats with a simulated holey defect in the lower jaw followed by its closure with hydroxyapatite-containing osteotropic material (bone graft "Biomin GT"). Group 3 included 12 rats with a simulated holey defect in the lower jaw with injecting the surrounding soft tissues with thymalin. Group 4 included 12 rats with a simulated holey defect in the lower jaw followed by its closure with hydroxyapatite-containing osteotropic material (bone graft "Biomin GT") and injecting the surrounding soft tissues with thymalin. The material for the morphological study was a fragment of the lower jaw from the area of the simulated holey defect. An immunohistochemical study was aperformed using monoclonal antibodies to CD68, CD20, CD163, CD86, CD3.

Results: A comprehensive experimental and morphological study conducted by the authors revealed that thymalin injection of the soft tissues surrounding the bone defect of the lower jaw, filled with hydroxyapatite-containing osteotropic material "Biomin GT", stimulates local immune reactions in the post-traumatic regenerate, which is manifested, firstly, by an increase in the number T-lymphocytes on the 3rd day of the experiment and their increase up to the 28th day; secondly, by increasing the number of B-lymphocytes on the 14th day of the experiment with their further increase up to the 28th day; thirdly, by increasing the number of macrophages on the 3rd day of the experiment and their growth up to the 28th day; fourth, changes in macrophages phenotypes (decrease in the number of M1-macrophages and increase in the number of M2-macrophages).

Conclusions: Stimulation of local immune reactions in the post-traumatic regenerate can be one of the mechanisms that activate reparative osteogenesis in the lower jaw of rats under the conditions of filling bone defects with hydroxyapatite-containing osteotropic material "Biomin GT" and thymalin injecting the surrounding soft tissues.

The study aimed to study the differential gene expression and immune cell infiltration in patients with steroid-induced necrosis of the femoral head (SANFH), identify the key genes and immune cells of SANFH, and explore the relationship between immune cells and SANFH.

The high-throughput gene chip dataset GSE123568 was downloaded from the GEO database, and the differential gene expression was analyzed with the R language. The STRING database and Cytoscape software were used to analyze the protein interaction network and screen key genes, and enrichment analysis was carried out on key genes. The infiltration of immune cells in SANFH patients was analyzed and verified by immunohistochemistry.

EP300, TRAF6, STAT1, JAK1, CASP8, and JAK2 are key genes in the pathogenesis of SANFH, which mainly involve myeloid cell differentiation, cytokine-mediated signaling pathway, tumor necrosis factor-mediated signaling pathway, and cellular response to tumor necrosis factor through JAK-STAT, NOD-like receptor, toll-like receptor, and other signaling pathways, leading to the occurrence of diseases; immune infiltration and immunohistochemical results have shown the expression of memory B cells and activated dendritic cells as reduced in SANFH patients, while in the same SANFH samples, M1 macrophages have been positively correlated with monocytes, and neutrophils have been negatively correlated with monocytes expression.

EP300, TRAF6, STAT1, JAK1, CASP8, and JAK2 have exhibited significant differences in SANFH (spontaneous osteonecrosis of the femoral head). Memory B cells, activated dendritic cells, M1 macrophages, monocytes, and neutrophils have shown abnormal expression in SANFH.

While bone tissue is known for its inherent regenerative abilities, various pathological conditions and trauma can disrupt its meticulously regulated processes of bone formation and resorption. Bone tissue engineering aims to replicate the extracellular matrix of bone tissue as well as the sophisticated biochemical mechanisms crucial for effective regeneration. Traditionally, the field has relied on external agents like growth factors and pharmaceuticals to modulate these processes. Although efficacious in certain scenarios, this strategy is compromised by limitations such as safety issues and the transient nature of the compound release and half-life. Conversely, bioactive elements such as zinc (Zn), magnesium (Mg) and silicon (Si), have garnered increasing interest for their therapeutic benefits, superior stability, and reduced biotic risks. Moreover, these elements are often incorporated into biomaterials that function as multifaceted bioactive components, facilitating bone regeneration via release on-demand. By elucidating the mechanistic roles and therapeutic efficacy of the bioactive elements, this review aims to establish bioactive elements as a robust and clinically viable strategy for advanced bone regeneration.