Continuous bone remodeling occurs in the bones throughout the organism’s life cycle. Osteoblasts, osteoclasts, and osteocytes work together to complete the dynamic bone remodeling of bones (Figure 2) (Naik and Wala, 2013; Behzadi et al., 2017). Bone remodeling involves the Interplay of the time and space of osteoblast, which leads to bone formation, and osteoclast, which leads to bone resorption (Naik and Wala, 2013).

Osteoblasts are clusters of bone marrow mesenchymal stem cells covering the bone’s surface. They are metabolically active and can synthesize and secret collagen and non-collagen bone matrix proteins deposited between bone cells and the surface. These uncalcified deposits are called osteoid, and the osteoid mineralization cycle is 10 days. BMSCs can differentiate into osteoblasts. The process involves the expression of Runx2 and Osterix transcription factors based on external stimuli such as Parathyroid hormone (PTH), Prostaglandin E 2 (PGE2), and Insulin-like Growth Factor (IGF) (Tsukasaki and Takayanagi, 2019). Moreover, BMP-2 and Wnt signal pathways are responsible for osteoblast or BMSCs differentiation.

Osteocytes connect through a small tube connected to the bone surface and form a network, the dense signal communication path in the bones. Osteocytes are derived from bone osteoblasts, then wrapped in the bone matrix. However, Osteocytes begin to express some specific genes, but osteoblasts do not express these genes. Sclerostin is a product of osteocytes, which can bind to low-density lipoprotein receptor-related protein (LRP) and inhibit the Wnt signal pathway to reduce bone formation (Poole et al., 2005). Function Sclerostin (SOST) gene encoding sclerostin mutations results in an increased bone mass loss in humans, called sclerosis.

Osteoclasts originate from HSCs. HSCs first develop into monocytes. Then monocytes develop into mature osteoclasts under the stimulation of related factors. Osteoclast production requires macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κ B ligand (RANKL) as induction signals. Osteogenic precursor cells, stromal cells, and synovial endothelial cells express M-CSF and RANKL to induce osteoclastogenesis. Along with BMMs, they differentiate and form mature osteoclasts. At this time, osteoclasts also begin to express specific genes and fuse. Moreover, RANKL is expressed on preosteoblasts and activated T cells (Wada et al., 2006; McInnes and Schett, 2007). RANKL combines its receptor RANK with pro-osteoclast cells, which is grave for the differentiation of osteoclasts and their bone resorption capacity. The interaction between RANKL and RANK is regulated by the RANKL competitive receptor OPG, which inhibits osteoclast production in vitro and in vivo. In addition to the RANKL and RANK affecting each other, other key pro-osteoclast signaling pathways depend on trigger receptors (TREM) expressed on bone marrow cells. The OSCAR and the tyrosine kinase DAP12 interact with triggering receptors expressed on myeloid cells (TREM), which strongly promotes osteoclastogenesis (Barrow et al., 2011).

The immune system is essential for organisms to defend against foreign objects. In addition, the invasion of pathogens can also stimulate the evolution of the immune system. The body’s adaptability and innate immune response participate in this process. As mentioned above, both immune and bone cells are present in bone. Meanwhile, the two systems influence each other (Lee et al., 2019) (Figure 3A). Bone cells and their surrounding environment secrete chemokines [Macrophage chemoattractant protein-1 (MCP-1), Stromal cell-derived factor 1 (SDF-1), etc.] that attract the arrival of immune cells, which subsequently secrete cytokines (RANKL, IL-1, IL-6, IL-10, TNF-α, etc.) that affect the development of bone cells. Thus, basic and clinical researchers explore the interaction between immune cells and their factors with bone cells (Naik and Wala, 2013). Although immune cells are various, they originate from a common ancestor-HSCs. HSCs are finally differentiated into T cells, B cells, macrophages, NK cells, and neutrophils through pluripotent stem cells, myeloid stem cells, and lymphoid stem cells and enter different tissues or organs with the bloodstream to exert their physiological functions further.

The balance of HSCs in the bone is inseparable from the role of cytokines like Stem cell factor and chemokine C-X-C ligand12 (CXCL12). Since CXCL12 is produced in the body by abundant reticulocytes and leptin receptor-positive osteoblasts or osteoprogenitor cells instead of mature osteocytes, it is an essential source of these niche factors regulated by HSCs (Zhou et al., 2014). Immune cells originate from the bone. Osteoblasts modulate the differentiation of immune cells beyond doubt. For example, it has been reported that consuming osteoblasts’ CXCL12 reduces the number of B lymphoid progenitor cells in the bone marrow. Moreover, osteoblasts express Notch ligand delta-like 4, which helps support the growth of T cell progenitor cells (Yu et al., 2015). Under certain conditions, osteoblasts may also have different roles in the process of hematopoiesis. For example, bone cell-derived Dickkopf-1 (DKK1) directly promotes hematopoietic reconstitution after bone marrow suppression by inhibiting HSCs senescence and indirectly promotes hematopoietic reconstitution by inducing the secretion of bone epidermal growth factor. It is reported that bone marrow endothelial cells (Himburg et al., 2017) and osteoblasts can regulate red blood cell production. Activated osteoblasts can weaken the development of leukemia (Krevvata et al., 2014). Activated CD4⁺ T cells reduce the bone formation of osteoblasts and lead to imperfect B-cell lymphocyte production, which proves an interaction between bone and immune cells (Shono et al., 2010).

The osteoclast bone resorption produces the bone marrow cavity where the secretion of osteoblasts, bone cells, and other cells are attached. Due to the abnormal balance of osteoclastic and osteogenic differentiation in osteosclerotic animals, there is insufficient space in the bone marrow to support the differentiation of hematopoietic cells, ultimately leading to abnormal extramedullary hematopoiesis in the spleen and liver. This abnormal process is detrimental to the formation of immune cell differentiation and function (Okamoto et al., 2017). Patients with bone sclerosis may appear with anemia and infections due to abnormal hematopoietic function (Sreehari et al., 2011). Therefore, the cavity microenvironment formed by osteoclast resorption is necessary for normal functional hematopoiesis. Moreover, osteoclasts play a certain role in the mobilization of HSCs.

With the development of biomaterials, their status in medical care is getting higher and higher. At the same time, many new disciplines have been produced, and huge development and applications have been achieved, such as medical implants, drug delivery, tissue engineering, and immunotherapy (Vishwakarma et al., 2016; Roseti et al., 2017). Biomaterials include a series of compounds with very different functions and structural characteristics, from macromolecules taken from nature to completely synthetic nanoparticles. Biomaterials should be mechanically resilient, Biocompatibility, or capable of degradation in the time required for bone cell colonization and mineralization. Biocompatibility is the primary target of choice for bone implant materials. Moreover, bone is a load-bearing organ with certain mechanical strength, and biomaterials with the same Young’s modulus as bone are highly sought after. For repairable bone injuries, biomaterials are generally selected to be biodegradable at a rate comparable to the bone healing cycle (Borchers and Pieler, 2010; Gorejová et al., 2018; Zhu et al., 2022).

There are many classification methods for biomaterials, which are classified into natural polymers and synthetic polymers according to polymers. The most commonly used tissue regeneration materials, especially orthopedics materials, like synthetic polymers, ceramics, and natural polymers (Mariani et al., 2019). Ceramic materials (glass, alumina, zirconia, calcium phosphate) are mainly used in orthopedics, dental implants, and bone filling. They have the characteristics of low elasticity, high-temperature resistance/hardness, and high brittleness. The chemical structure and physical properties similar to natural bone tissue show good biocompatibility (Mariani et al., 2019). Synthetic polymers as promising biomaterials for bone tissue engineering research and use. Moreover, natural polymers similar to natural ECM make them great biocompatible. They combine synthetic and natural polymers’ advantages, including immunological properties. The morphology and physical properties of the materials have different effects on cell behavior (Table 1). With the development of material technology, biodegradable biomaterials are particularly popular in bone tissue engineering.

The most common natural biomaterial polymers are collagen, chitosan, fibrin, and silk fibroin, which have good histocompatibility and low immunogenicity due to their close similarity to animal tissue components. Decomposition products are also the best raw materials for the body’s biosynthesis, so they are prevalent in tissue engineering. However, these single materials have poor mechanical strength and rapid degradation, and their application in bone tissue is limited. Therefore, these materials are often combined with bioceramics and synthetic polymers.

Synthetic biomaterial polymers such as poly(ε-caprolactone) (PCL), polylactic acid, PGA, copolymer PLGA, poly(3-hydroxybutyrate) PHB, biodegradable ceramics, bioactive glasses, and biodegradable metal materials, which are biocompatible and have a controllable rate of degradation, and their degradation products have no toxic effects on tissues in vivo. Moreover, manual control of design and synthesis parameters can produce polymers with better mechanical properties.

Preparing the materials mentioned above into biodegradable composite materials is the focus of current research. These composites possess excellent biocompatibility, osteoconductivity, mechanical strength, and osteogenic properties. Meanwhile, these composite materials have become the most promising materials in bone defect repair with the help of new preparation technologies that have emerged in recent years. A systematic understanding of the specific processes of materials in bone regeneration in the emergency immune response is the practical basis for designing composite materials for immune cell regulation (Xie et al., 2020) (Figure 4).

The implant is placed a second later, and blood from the damaged blood vessel surrounds the biomaterial and begins interacting with the graft. And then, Plasma contents of the body, including proteins (fibrinogen, albumin, vitronectin, fibronectin, gamma globulin), attach to the implant surface quickly and autonomously (Wilson et al., 2005). These are affected by the process, quantity, composition, and conformational changes of adsorbed molecules of biological materials.

The clot formed by blood exudate defines the temporary matrix surrounding the biological material (Ekdahl et al., 2011) and is cleaved into fibrin by thrombin. Moreover, the complement protein is activated when it comes into contact with biological materials to support platelet adhesion and activation. The recruitment and adhesion of sufficient immune cells are seduced by abundant pro-inflammatory cytokines, chemokines, and growth factors (Anderson et al., 2008), and with the formation of the temporary matrix, acute and chronic inflammation also follows.

The chemokine produced by the host cell or damaged tissue induces activated neutrophils to be recruited from the peripheral blood and adhere to the implantation site (via β2 integrin). It also attempts to produce engulfing proteolytic enzymes and ROS to destroy/degrade biological materials (Grandjean-Laquerriere et al., 2007).

After neutrophils are activated, they will synthesize a large number of immunomodulatory signals (Mariani et al., 2019): CXCL8 (the most significant chemokine, the main target of which is the neutrophil itself), CCL2 (C Chemokine ligands2), and CCL4. CCL2 and CCL4 are both effective chemotactic and activating factors for immune cells (Yamashiro et al., 2001). The gradual increase of these chemokines promotes the infiltration of monocytes and inhibits the infiltration of neutrophils. The lack of this signal cannot further activate neutrophils, enter the apoptotic pathway, and then be cleared from the site by phagocytes (Anderson et al., 2008). At the same time, circulating monocytes respond to chemotactic agents and bind to the fibrinogen in the temporary matrix of biological materials, thereby being activated (Shen et al., 2004) and differentiated into classical activation or “M1” macrophages (Mariani et al., 2019). The classification of these cells is based on the secretion of IL-1β, IL-6, TNF-α, chemokines (Jones et al., 2007; Mesure et al., 2010), and enzymes.

Macrophages induce invasion of inflammatory cells via CCL2, CCL4, and CXCL8 (Jones et al., 2007), and before experiencing the “frustrated” phagocytosis (because the biological material is too large), they try to decompose the biological materials by producing ROS and releasing degrading enzymes (Mariani et al., 2019). This pathway eventually leads to increased cytokine release (Underhill and Goodridge, 2012). Like the wound healing stage (Mariani et al., 2019), the adherent macrophages may eventually transfer to the “M2” phenotype (Mariani et al., 2019), which secrete IL-10 and so on (various anti-inflammatory cytokines). These cytokines can reduce their degradation ability, complete body activity reproduction, induce fibroblast movement and proliferation, and then achieve bone regeneration. Conversion between M1 and M2 and the mechanism of blocked phagocytosis leads to the fusion of macrophage membranes and the formation of foreign body giant cells (FBGCs), a sign of chronic inflammation on the coverage of biological materials. FBGCs formation is usually a landmark part of Foreign body reaction (FBR) induced by biological materials. It promotes the formation of FBR by activating mast cells, basophils, and Th cells. These cells can produce IL-4 and IL-13, enhancing the fusion of macrophages on biological materials (Brodbeck et al., 2005).

In the chronic inflammatory stage, some cytokines are secreted by Th cells. Their rich cytokines produce a wide range of regulation of pro-inflammatory or anti-inflammatory sequels (Mariani et al., 2019). The interactions between M1 and M2 macrophages and the changes of Th1 to Th2 cells express cell factors, indicating that T cells play a vital role in promoting the resolution and regeneration of inflammation.

The synergy of immune cells induces the production of pro-fibrotic factors, such as Platelet-derived growth factor (PDGF) (Shen et al., 2006), vascular endothelial growth factor (VEGF) (Chen et al., 2010), and TGF-β (Garg et al., 2009), which can recruit some fibroblasts. Experimental repair of damaged tissue, activated type I and type III collagen. Fibroblasts are responsible for accumulating new substrate, which is the process of fibrosis reaction.

Regarding the mechanism of promoting regeneration, M2 macrophages with anti-inflammatory/anti-fibrotic phenotypes promote regeneration through mutual interference with regulatory T cell subsets (Tregs) that play a vital part in the immune system. These cells regulate the tilt of the local immune response to inflammation, which further promotes the cascade of tissue regeneration and repair. Moreover, maintain anti-inflammatory and anti-fibrotic phenotypes by secreting IL-10. In addition, Tregs can enhance the ability to heal by inducing type 2 responses. After the reduction of T cells, the level of resident Tregs is still elevated, which may be because they lack epidermal growth factor receptor (EGFR) (Zaiss et al., 2013; Arpaia et al., 2015), whose expression can promote the cell factors secreting by mast cells to keep the Tregs in the damaged spot (Zaiss et al., 2013). Once Treg cells appear, they will proliferate and upregulate the secretion of bimodules, which is necessary for cell regeneration and may produce cell proliferation or induce cell differentiation. Treg cells may also enhance the regeneration ability of endogenous stem cells and progenitor cells through growth factors secret.

Although neutrophils do not make up much in the bone marrow, they are the first cells to be mobilized in inflammatory and traumatic fractures. Neutrophils, pioneer cells of the inflammatory response, play a dual role in bone regeneration and repair. On the one hand, neutrophils eliminate cell debris, infectious substances, and phagocytic material scaffolds at the injury site by secreting proteases (e.g., matrix metalloproteinases, collagenases) and provide sites for subsequent bone regeneration. Cytokines such as IL-17 and TNF-α synthesized by neutrophils activate osteoclast through the RANKL-RANK signaling pathway (Chang et al., 2013). On the other hand, neutrophils stimulate angiogenesis (Christoffersson et al., 2012) and bone regeneration through direct or indirect action. Neutrophils in liver injury achieve angiogenesis and maturation by secreting MMP-9 to promote the expression of VEGF (Christoffersson et al., 2012). In the early stage of inflammation, neutrophils alleviate acute inflammation and reduce the secretion of inflammatory cytokines, thereby reducing the activation of osteoclast precursor cells and promoting bone repair (Bastian et al., 2018). The application of biologically active neutrophil membrane materials is enthusiastically sought after by scientific researchers. After implantation, the membrane material simulates the post-inflammatory process, and the apoptosis of neutrophils induces the entrapment of macrophages, which further promotes the polarization of macrophages to M2 to play an anti-inflammatory role and promotes bone regeneration. During this process, TGF-β and IL-10 secreted by macrophages promote anti-inflammatory and bone regeneration repair. IL-8-induced polarization of neutrophils contributes to endochondral ossification (Cai et al., 2021). These will provide strong support for designing materials to regulate neutrophil behavior.

The application of macrophage polarization in the regeneration of bone defect sites is favored. The changes in macrophage behavior promote vascular and bone regeneration (Loi et al., 2016; ElHawary et al., 2021). Angiogenesis provides various nutrients and cells for bone repair. Therefore, coupling blood vessels and bone regeneration is another entry point for material design in fracture repair. The modified application of various bioactive molecules combined with biomaterials promotes vascular or bone regeneration by regulating macrophage polarization (Loi et al., 2016; Wang et al., 2022). Calcium silicate combined with β-tricalcium silicate stimulates the polarization of macrophages to M1/M2 by releasing IFN-γ and Si to secrete further vascular growth factors (VEGF, CXCL-12, PDGF-BB) to promote angiogenesis (Loi et al., 2016). Mesoporous silica (MNS)-loaded BMP bioactive molecules were incorporated into 3D printed scaffolds made of modified GelMA to release bioactive molecules and promote macrophage M2 polarization, BMP active molecules, and M2-secreted anti-inflammatory cells factors to promote the repair of diabetic bone defects. The release of BMP-2 and zinc particles regulates the increased proportion of M2 macrophages on the screw-coated surface to promote bone regeneration (Wang et al., 2022) (Figures 5B–D). Although macrophage polarization occurs in both angiogenesis and bone regeneration, there is a particular deviation in the macrophage’s temporal and spatial control time. It is urgent to develop new biomaterials to simultaneously realize the classification of the fate of macrophages in angiogenesis and bone regeneration.

T cells play an indirect role in bone regeneration and repair, and factors secreted by various T cell subtypes indirectly regulate the process of bone regeneration. Like macrophages, T cells can be roughly divided into pro-inflammatory cell subtypes (Th1, Th17) and anti-inflammatory cell subtypes (Th2, Treg). Th1 cells can inhibit the expression of RUNX2 in BMSCs by secreting the IFN-γ factor to reduce bone repair ability (Liu et al., 2011). In addition, IFN-γ secreted by Th1 cells is associated with the polarization of M1 macrophages, and sustained M1 polarization leads to sustained inflammatory activation that prevents bone repair from occurring (Spiller et al., 2015). Th17 acts as the ability to secrete pro-inflammatory cytokine IL-17, but its role can promote bone regeneration and repair. IL-17A combined with BMP-2 can significantly enhance the osteogenic ability of BMSCs (Moon et al., 2016). Th2 and Treg cells promote bone homeostasis towards osteogenesis and bone regeneration by inducing the formation of M2 macrophages (Chen et al., 2012) and inhibiting osteoclast differentiation (Lu et al., 2017). And the surface of PEEK implants promotes bone regeneration by regulating T cell differentiation via lickable mussel-inspired azide-DOPA4 and BMP2p coupling (Zhao et al., 2021c) (Figure 6). Although there are few studies on T cells in bone regeneration biomaterials, the regulation of macrophages and osteoclasts by T cells will be a practical starting point for biomaterials to regulate the immune microenvironment to achieve bone regeneration and bone disease treatment. This will provide new therapeutic strategies for clinical bone defect regeneration and disease treatment.