Neutrophils exhibit a phagocytic function, enabling them to directly engulf and eliminate bacterial particles and cellular debris. The neutrophil phagosome, a specialized organelle, is formed through the invagination of the plasma membrane, thereby encapsulating the phagocytosed material. The primary energy source for neutrophils is glycolysis (Toller-Kawahisa et al., 2023), with glucose-driven glycolysis specifically supplying the energy required for neutrophil phagocytosis (Borregaard and Herlin, 1982). Subsequently, intracellular lysosomes fuse with phagosomes to form phagolysosomes. Within these phagolysosomes, microorganisms are eradicated through a combination of oxidative and non-oxidative mechanisms. In the oxidative mechanism, neutrophils undergo a respiratory burst, producing substantial quantities of hydrogen peroxide (H₂O₂) (Iyer et al., 1961). Myeloperoxidase (MPO) then utilizes H₂O₂ to oxidize chloride ions, generating hypochlorous acid (HOCl), which subsequently damages the bacterial cell membrane and cell wall (Pattison et al., 2012). In the non-oxidative mechanism, neutrophils eliminate microorganisms within the phagolysosome through the release of granule proteins, including MPO, lysozyme, and defensins (Aratani, 2018).

NETs are structures formed by activated neutrophils that capture and neutralize extracellular pathogens through the release of extracellular trapping components. These components include nuclear materials such as DNA and histones, as well as intracellular granule proteins like neutrophil elastase (NE) and MPO, along with antimicrobial peptides (Wang H. et al., 2024). NETs consist of a DNA backbone intertwined with various proteins, creating a network structure that entraps and restricts the mobility of pathogens. Following entrapment, antibacterial proteins such as MPO and elastase within the NETs can degrade cell walls or cell membranes of the captured pathogens. NETs are categorized into NADPH oxidase (NOX)-dependent and NOX-independent types based on their formation mechanisms. NOX-dependent NETs primarily depend on the activation of NOX to enhance the production of superoxide and reactive oxygen species (ROS). These active substances can induce the degranulation of neutrophil granule proteins, such as MPO and NE, which subsequently cause cytoskeletal rearrangement and nuclear membrane rupture, ultimately resulting in the release of NETs (Feitz et al., 2021). Factors such as lipopolysaccharide (LPS), IL-6, IL-8, TNF-α, various pathogens, and chemicals have been shown to trigger NOX-dependent NETs (Fousert et al., 2020). In contrast, during the formation of NOX-independent NETs, NETs are predominantly released through nuclear membrane blistering and vesicle transport mechanisms (Kaplan and Radic, 2012). Certain bacteria are capable of inducing neutrophils to undergo NOX-dependent NETs. In contrast, Candida albicans can stimulate neutrophils to inhibit fungal dissemination through the formation of Dectin-2-mediated, NOX-independent NETs. Additionally, LPS from Gram-negative intracellular bacteria activates a caspase-11-dependent pathway that cleaves the gasdermin D protein, compromising plasma membrane integrity and facilitating the release of NETs (Liang et al., 2021).

Neutrophils encompass a diverse array of granules, which are categorized into primary granules, specific granules, tertiary granules, and secretory vesicles based on their distinct characteristics and constituent substances. Primary granules, in particular, are enriched with the most toxic mediators within the cells, including key components such as MPO, NE, cathepsin G, and defensins. Specific granules contain elements like lactoferrin and lysosomes. Tertiary granules primarily serve as storage sites for metalloproteinases, including gelatinase and leukolysin (Teng et al., 2017). The release of proteases and peptidases into phagolysosomes or through exocytosis to exert antibacterial effects is termed the degranulation process, which is crucial for the non-oxidative sterilization function of neutrophils. NE can directly disrupt the membrane structure of Gram-negative bacteria, such as Escherichia coli, leading to bacterial death (Teng et al., 2017). Additionally, lactoferrin not only binds iron, thereby reducing bacterial iron absorption and inhibiting bacterial growth, but also binds to the lipopolysaccharide of the bacterial cell wall, resulting in bacterial oxidation and cleavage (Telang, 2018).

ROS are predominantly generated as byproducts within the electron transport chain of mitochondria, particularly during the oxidative phosphorylation processes at complex I and complex III (Zhao et al., 2019). In the endoplasmic reticulum, the presence of misfolded proteins or the accumulation of unfolded proteins can disrupt the redox balance and alter Ca²⁺ levels, subsequently inducing ROS production (Ong and Logue, 2023). Ionizing radiation has the capacity to generate ROS, which subsequently target biological macromolecules such as DNA and proteins, leading to cellular damage (Yang et al., 2021) (Figure 3A). Typically, these ROS are intracellularly converted to hydrogen peroxide (H₂O₂) by superoxide dismutase and ultimately rendered harmless as H₂O by catalase (Alfonso-Prieto et al., 2009). However, in neutrophils, the majority of ROS are actively produced through the activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. ROS exhibit significant oxidative potential, capable of inflicting damage on bacterial cell membranes, proteins, and nucleic acids, thereby leading to bacterial death or inactivity (Vatansever et al., 2013).

ROS not only directly eliminates bacteria but also modulates various biological functions of neutrophils, thereby influencing inflammatory processes (Lennicke and Cochemé, 2021). Phagolysosomes, organelles characterized by their oxidative and lytic properties, rely on ROS generated by NADPH oxidase for bacterial eradication (Figure 3B). Furthermore, neutrophil apoptosis plays a crucial role in maintaining homeostasis in vivo and facilitates the resolution of inflammation (Karmakar et al., 2021). Excessive production of ROS can result in mitochondrial damage and alterations in mitochondrial membrane potential, subsequently facilitating the release of cytochrome C. This release interacts with apoptotic protease-activating factor 1 to form apoptotic bodies, which then activate cysteine proteases, including caspase-9, thereby initiating the apoptotic pathway (Geering and Simon, 2011). ROS have been demonstrated to activate c-Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK), further promoting apoptosis (Zhang et al., 2015). Furthermore, the ROS-mediated PERK-eIF2α-ATF4 pathway is crucial in modulating CHOP-DR5 signaling and subsequent cell apoptosis (Liu and Zhang, 2020) (Figure 3C). Additionally, neutrophil oxidative respiratory bursts are implicated in the formation of NETs. The excessive ROS produced during neutrophil activation leads to significant DNA damage, which subsequently triggers NETs through the DNA repair pathway (Azzouz et al., 2021) (Figure 3D).

The initial phase of inflammation is characterized by vasodilation, enhanced blood flow, and increased vascular permeability. The release of histamine and leukotrienes from mast cells induces vasodilation and tissue fluid exudation. Concurrently, neutrophils release inflammatory mediators, including IL-1, IL-6, and TNF-α, which further promote vasodilation (Anzai et al., 2015) and facilitate the extravasation of leukocytes and plasma to the site of injury or infection (Figure 4B). Furthermore, neutrophils generate LTB4 and chemokines, which facilitate the recruitment of additional neutrophils to the site of inflammation (Ng et al., 2011). Upon arrival at the inflammatory site, neutrophils further recruit monocytes by secreting LL-37, cathepsin G, human neutrophil peptides 1-3 (HNP1-3), and protease 3 (PR3), thereby amplifying the inflammatory response (Soehnlein et al., 2008; McDonald et al., 2010).

The immune system comprises a diverse array of immune cells that collaborate to achieve precise mutual regulation through a complex signaling network (Lokwani et al., 2024). As pivotal effector cells within the innate immune system, neutrophils not only directly engage in pathogen clearance but also modulate the function and activity of other immune cells by releasing cytokines, thereby further orchestrating the adaptive immune response (Herrero-Cervera et al., 2022; Scapini and Cassatella, 2014). Neutrophils, lymphocytes, macrophages, dendritic cells (DCs), and other immune cells dynamically interact during the immune response to collectively maintain immune equilibrium and homeostasis (Figure 4C). B cell helper neutrophils localize to the peri-follicular regions of the human spleen under homeostatic conditions, where they express B-cell activating factor. These neutrophils actively contribute to the survival, maturation, and differentiation of B cells, thereby facilitating the development of humoral immunity (Costa et al., 2019; Puga et al., 2011). Neutrophil-derived cathelicidin facilitates the differentiation of T cells towards the Th17 phenotype and enhances their survival (Minns et al., 2021). Soluble mediators secreted by memory T cells, along with direct cell-cell interactions between neutrophils and T cells, collectively promote the acquisition of antigen-presenting capabilities by neutrophils, thereby augmenting their role in adaptive immunity (Lin and Loré, 2017). Furthermore, neutrophils facilitate the recruitment of DCs through the secretion of chemokines such as CCL3, CCL4, CCL5, and CCL20, while the release of NETs stimulates plasmacytoid DCs to secrete inflammatory cytokines (Schuster et al., 2013). The activation of neutrophils to release their granular contents can modulate DC activity and consequently influence T cell function (Hafkamp et al., 2021). Additionally, the secretion of lactoferrin by neutrophils enhances the T cell stimulatory capacity of DCs (de la Rosa et al., 2008). Neutrophils collaborate with macrophages to augment their antibacterial activity (Ladero-Auñon et al., 2021). Macrophages facilitate the recruitment of neutrophils to inflamed sites through the secretion of chemoattractants such as CXCL1 and CXCL2, and they release granulocyte-macrophage colony-stimulating factors (GM-CSF, G-CSF) and TNFα to inhibit apoptosis (Prame Kumar et al., 2018). Simultaneously, neutrophils are capable of releasing LL-37, HNP1-3, and PR3, which serve to attract monocytes and subsequently amplify the inflammatory response. In response to pathogenic challenges, neutrophil-released NETs promote the polarization of macrophages towards the pro-inflammatory M1 phenotype (Tan et al., 2024). Conversely, following neutrophil apoptosis, the resultant apoptotic bodies facilitate the polarization of macrophages towards the anti-inflammatory M2 phenotype (Kraynak et al., 2020; Kraynak et al., 2022).

Neutrophils are capable of releasing a diverse array of inflammatory mediators, including proteases, ROS, cytokines, and chemokines. While these mediators play a crucial role in the body’s defense against pathogenic invasion, their excessive release can result in detrimental effects, such as the disruption of tissue architecture and increased vascular permeability (Saffarzadeh et al., 2012). This hyperactivity can further recruit additional immune cells, thereby exacerbating the inflammatory response. Specifically, neutrophil-derived proteases have the potential to degrade the extracellular matrix and compromise cellular structures, culminating in tissue damage (Cartwright et al., 2024). Furthermore, ROS produced by neutrophils can inflict damage on lipids, proteins, and DNA of normal cells, leading to cellular dysfunction and death (Lennicke and Cochemé, 2021; Ma et al., 2024). While NETs are capable of capturing and eliminating pathogens, they also play a role in the pathogenesis of various diseases (Chamardani and Amiritavassoli, 2022; He et al., 2023; Katsoulis et al., 2024; Leffler et al., 2012). Owing to their unique network structure, NETs provide an effective scaffold for thrombosis (Fuchs et al., 2010). The resultant thrombi can exacerbate tissue damage (Le et al., 2022; Thakur et al., 2023; Mereweather et al., 2023) (Figure 4D).

The regression of neutrophils from the site of inflammation is primarily mediated through macrophage endocytosis or their return to vascular circulation via reverse migration (de Oliveira et al., 2016; Greenlee-Wacker, 2016). Upon neutrophil apoptosis, low concentrations of nucleotides such as ATP and UTP, which can be released by the cells, act as “Find-me” signals. These nucleotides bind to P2Y2 purinergic receptors on macrophages, facilitating their recognition and subsequent phagocytosis by macrophages (Leist et al., 1997; Elliott et al., 2009). Following apoptosis, the formation of granular shedding or autophagosomes leads to the creation of apoptotic bodies. These apoptotic bodies are primarily composed of extracellular vesicles containing cytoplasm, organelles, and nuclear debris. Subsequently, macrophages phagocytose these apoptotic bodies, a process that promotes macrophage polarization towards the M2 phenotype (Liu et al., 2024). This polarization promotes the production of anti-inflammatory cytokines such as IL-10 and TGFβ, while simultaneously reducing the levels of pro-inflammatory cytokines including TNFα, IL-1β, IL-8 and IL-12 (Fadok et al., 1998; Xu et al., 2025) (Figure 4E). Engineered neutrophil apoptotic bodies mitigate myocardial infarction by facilitating macrophage endocytosis and promoting the resolution of inflammation (Bao et al., 2022). In the absence of rapid clearance, apoptotic neutrophils have the potential to form Gasdermin E pores, activate Peptidylarginine deiminase 4, and induce the release of NETs from apoptotic cells (Zhu et al., 2023).

Neutrophil apoptosis constitutes a fundamental physiological mechanism that facilitates the resolution of inflammation and promotes tissue repair (Karmakar et al., 2021). Nonetheless, the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) (Yamasawa et al., 2004), Type-1 interferons (Aga et al., 2018), IL-8 (Porter et al., 2017), bacterial components (Miralda et al., 2022), hypoxic conditions (Porter et al., 2017; Dölling et al., 2022), and various other pro-inflammatory mediators can extend neutrophil lifespan, thereby contributing to a sustained inflammatory response. For instance, both Anaplasma phagocytophilum and Chlamydia pneumoniae have been shown to enhance the phosphorylation of p38 MAPK, activate the PI3K/Akt signaling pathway, and sustain the expression of the anti-apoptotic protein Mcl-1, thereby leading to delayed neutrophil apoptosis (Sarkar et al., 2012; Sarkar et al., 2015). Conversely, hypoxia-inducible factors HIF-1α and HIF-2α can extend the lifespan of neutrophils in vivo under hypoxic conditions (Thompso et al., 2014; Walmsley et al., 2005). The inhibition of neutrophil apoptosis consequently promotes the inflammatory response (Wang et al., 2021). The sustained presence and activation of neutrophils in chronic inflammation can perpetuate the inflammatory response, disrupt the equilibrium of tissue repair and regeneration processes, and ultimately result in tissue fibrosis and the onset of other chronic diseases.

Bone scaffolds serve as carriers capable of incorporating various components, including pharmaceuticals, cytokines, genetic material, and cells, which can be subsequently released at the site of bone defects to fulfill diverse functional roles (Hu et al., 2024) (Figure 6A). The phenotypic switching of neutrophils is regulated by signaling pathways involving TGF-β and IFN-β. Specifically, TGF-β can mediate the conversion of N1 neutrophils to the N2 phenotype (Bu et al., 2022). Exposure of neutrophils to transforming TGF-β or G-CSF results in their polarization towards the N2 phenotype. Conversely, IFN-β has been identified as a pivotal factor in the polarization of neutrophils towards the N1 phenotype in both cancer patients and tumor-bearing mice (Andzinski et al., 2016). N1 neutrophils are capable of upregulating pro-inflammatory mediators such as TNFα, IL-1β, Ccrl2, and Cxcr5. In contrast, N2 neutrophils upregulate anti-inflammatory mediators including IL-4, IL-10, and Cxcr2 (Figure 6B). In a related study, Shi et al. (Shi et al., 2024) developed a genetically engineered composite scaffold by incorporating a hyaluronic acid methacryloyl hydrogel, loaded with a TGF-β1 adenovirus, into a mesoporous bioactive glass scaffold (MBG). Among these, TGF-β1 has been shown to regulate the polarization of neutrophils towards the N2 phenotype and macrophages towards the M2 phenotype through a “relay” mechanism, thereby exerting a reparative effect. Xu et al. (2023) utilized the electrospinning technique to prepare PCL/LAP composites, employing polycaprolactone (PCL) and laponite (LAP) as the constituent materials. The supernatant derived from the co-culture of periodontal ligament cells and a nanofiber membrane has been shown to downregulate the expression of classical pro-inflammatory genes while upregulating the expression of anti-inflammatory and pro-remodeling genes in neutrophils. This suggests a potential role in inducing the polarization of neutrophils towards an anti-inflammatory and pro-remodeling N2 phenotype.

The neutrophil oxidative respiratory burst is crucial for inflammation and antimicrobial activity, consuming large amounts of oxygen to produce superoxide radicals. Activated neutrophils experience increased oxygen consumption during an “oxygen burst” facilitated by NOX2, generating two superoxide radicals per NADPH molecule and two oxygen molecules (Figure 6C). Fractures often damage bone blood vessels, creating a hypoxic microenvironment around the fracture site. Hypoxic conditions can impair ROS synthesis in neutrophils, thereby diminishing their bactericidal capabilities (Beebout et al., 2022). Additionally, hypoxia can inhibit neutrophil apoptosis and extend the inflammatory phase in vivo (Rani Talla et al., 2016), which may result in delayed fracture healing (Claes et al., 2012). Consequently, early oxygen supplementation is crucial for both bacterial defense and tissue repair. Enhancing neutrophil antibacterial activity through oxygen delivery has emerged as a strategic approach in the design of effective antibacterial materials. Currently, materials that produce oxygen are utilized to construct oxygen supply platforms. These include the use of solid or liquid peroxides (e.g., CaO₂, H₂O₂) to generate oxygen, or the transportation and release of oxygen via carriers such as fluorinated compounds and erythrocyte membranes. Chu et al. (Chu et al., 2024) introduced an innovative approach by employing in-situ deposition of nano-CaO₂ on the surface of implants to provide localized oxygen support. This method demonstrated a peak oxygen release at 4 h, with sustained release lasting up to 24 h. The CaO₂/PA-Zn@TiNPs scaffolds were fabricated using a layer-by-layer deposition technique on the surface of TiO₂ nanopillars, which were pre-coated with a PA-Zn²⁺ coordination complex, followed by the in-situ deposition of nano CaO₂. These scaffolds demonstrated the capability to restore oxygen-dependent neutrophil bactericidal function and support neutrophil ROS production under hypoxic conditions. Additionally, they promoted neutrophil apoptosis, thereby mitigating the subsequent inflammatory response. Zhu et al. (2024) developed a nanomedicine, designated as Hb-Naf@RBCM NPs, by encapsulating red blood cell membrane (RBCM) with nanoparticles formed through the self-assembly of naftifen (Naf) and oxygenated hemoglobin (Hb). The Hb-Naf@RBCM NPs demonstrated the capability to stimulate neutrophils to release superoxide anions and enhance intracellular ROS production, thereby augmenting the neutrophils' response to Staphylococcus aureus, multidrug-resistant S. aureus, and methicillin-resistant S. aureus.

Metal ions, including strontium, copper, zinc, silver, magnesium, and iron, are extensively utilized in the design of bone scaffolds due to their ability to regulate the functional balance of osteoblasts and osteoclasts, as well as to promote bone angiogenesis (Luo et al., 2023; Bosch-Rué et al., 2023; O'Neill et al., 2018; Tao et al., 2024; Qian et al., 2021a; Liu et al., 2023; Wang N. et al., 2025). Additionally, these metal ions can influence bacterial metabolic activity and exhibit bactericidal properties (Lemire et al., 2013; Qian et al., 2021b). Specifically, zinc and copper ions have been shown to interfere with bacterial metabolic processes and DNA replication (Wei et al., 2022). Gallium ions (Ga³⁺) interfere with bacterial iron metabolism due to their chemical similarity to iron ions (Fe³⁺), thereby exerting antibacterial and antibiofilm effects (Kaneko et al., 2007). Furthermore, metal nanoparticles, such as those composed of silver and copper, can directly damage bacterial cell walls. These nanoparticles induce the production of ROS, which attack bacterial cell membranes and proteins, ultimately leading to cell death. Additionally, metal ions are crucial components of the body’s immune system (Wang et al., 2020). Metal ions play a pivotal role in regulating various aspects of the immune response and are intricately linked to the pathogenesis and progression of numerous diseases. Specifically, ions such as calcium (Ca), zinc (Zn), manganese (Mn), and magnesium (Mg) are integral to immune signal transduction processes, functioning as second messengers to activate immune cells (Chaigne-Delalande and Lenardo, 2014; Subramanian Vignesh and Deepe, 2016; Krzywoszyńska et al., 2020). Additionally, iron (Fe) and copper (Cu) serve as essential cofactors in the active center of NADPH oxidase, which is critical for the generation of reactive oxygen species (Wu et al., 2020). Iron and zinc chelators have been shown to modulate NETs release (Kuźmicka et al., 2021). Furthermore, an excess of iron, whether due to congenital factors or a high-iron diet, has been found to reduce the release of extracellular traps and reactive oxygen species (Kuźmicka et al., 2022). The release of silver ions (Ag⁺) and zinc ions (Zn²⁺) has been observed to stimulate immune function, leading to an increased production of leukocytes and neutrophils, thereby enhancing antibacterial activity (Mao et al., 2017) (Figure 6D). Pure Zn augmented the bactericidal capacity of peri-implant neutrophils, as evidenced by (Peng et al., 2023). Additionally, Zn plays a pivotal role in mediating the formation of NETs (Hasan et al., 2012). Li et al. (2022) conducted a study where they synthesized Zn-doped FeOOH nanolayers via plasma electrolytic oxidation (PEO) on the surface of a Mg alloy and subsequently coated the alloy with these nanolayers. The incorporation of zinc into the PEO-Fe coating markedly augmented the formation of NETs by diminishing the expression of immune evasion factors and promoting the citrullination of histones and intracellular chromatin depolymerization in neutrophils at the infection site, thereby facilitating NETs formation.

Upon in vivo implantation, the scaffold, functioning as an integral component of the extracellular matrix, has the potential to replicate the characteristics of the physiological milieu, thereby influencing cellular behavior (Zhou et al., 2023). The scaffold’s topology, stiffness, and surface topography are critical factors that can modulate neutrophil activity and assume various functional roles. In a study by Won et al. (Won et al., 2020), a hierarchical scaffold incorporating microchannels was fabricated using camphene in a polycaprolactone solution through three-dimensional (3D) printing technology. The internal pore diameter of the scaffold is measured at 12.9 ± 7.69 μm, while the surface pore diameter is 21.1 ± 16.6 μm. Microchannels constitute approximately 28% of the scaffold’s volume. In comparison to 3D printed PCL scaffolds of identical chemical composition but lacking microchannels, the microchannel-incorporated scaffolds demonstrated a significant reduction in NETs, facilitated the resolution of inflammation, and ultimately promoted angiogenesis. Additionally, these scaffolds enhanced stem cell recruitment and chemotaxis, thereby fostering osteogenic differentiation in vivo. Allison et al. (Fetz et al., 2017) fabricated electrospun polydioxanone (PDO), type I collagen (COL), and PDO-COL hybrid scaffolds utilizing fibers of small (0.25–0.35 µm) and large (1–2 µm) diameters, observing that larger fiber diameters mitigated the formation of NETs on PDO templates. Furthermore, the pore size of the scaffold can influence the antibacterial efficacy of neutrophils. Mukhopadhyay et al. (2024) demonstrated using a microfluidic device that neutrophils exhibited a significantly enhanced bacterial clearance capability after traversing 5 μm pores compared to 200 μm pores. As neutrophils traverse the pores, their cell membranes experience mechanical stress, which activates the mechanosensor Piezo1. This activation leads to the upregulation of NADPH oxidase 4, thereby augmenting the antibacterial efficacy of polymorphonuclear leukocytes (Figure 7A).

Stiffness denotes the capacity of a material or structure to withstand deformation under the influence of external forces. The stiffness of the ECM is crucial in modulating cellular functions, including viability, communication, migration, and differentiation (Fletcher and Mullins, 2010). Cells can sense ECM stiffness through cell membrane surface receptors and respond accordingly. Additionally, the migration of neutrophils through vascular endothelial cells is influenced by the stiffness of the endothelial cell matrix (Stroka and Aranda-Espinoza, 2011). Neutrophils exhibit reduced migration rates on stiffer substrates but demonstrate enhanced adhesion to rigid surfaces, facilitating their ability to traverse longer distances (Oakes et al., 2009). Abaricia et al. (2021) observed that the formation of NETs was augmented in a stiffness-dependent manner on polydimethylsiloxane (PDMS) substrates with varying physiologically relevant stiffnesses (0.2–32 kPa). Furthermore, the expression of neutrophil chemoattractants and pro-inflammatory factors was elevated on stiffer matrices, a process regulated by integrin/FAK signaling pathways. In a similar vein, Erpenbeck et al. (2019) observed a significant increase in NETs on stiffer polyacrylamide gels following stimulation with LPS, a phenomenon that was attenuated by PI3K inhibition (Figure 7B). Conversely, Jiang et al. (2023) reported that neutrophils exhibited reduced production of ROS and anti-inflammatory cytokines in three-dimensional hydrogel culture systems with higher stiffness. Gelatin methacrylate hydrogels were synthesized with varying degrees of stiffness, revealing that the secretion of pro-inflammatory factors diminished as matrix stiffness increased. Furthermore, the stiffer matrices facilitated the transition of neutrophils to the N2 phenotype, a process regulated by the JAK1/STAT3 signaling pathway.

The interaction between scaffolds and cells is predominantly influenced by the surface topography, which plays a critical role in cell and tissue organization. Surface topography can be engineered on the scaffold through various techniques such as photolithography (Kurland et al., 2014), 3D printing (Liu et al., 2022; Kim et al., 2021), and deposition methods. Upon in vivo implantation, the scaffold’s surface topography interfaces with cells, thereby modulating cellular behavior and fate (Rabel et al., 2020; Wang et al., 2012). When cells adhere to various topographical features, they undergo deformation, leading to the activation of mechanoreceptors on the cell membrane. These signals are subsequently transmitted to the nucleus via signaling pathways, ultimately resulting in diverse biological responses (Könnig et al., 2018). Specifically, on smooth titanium (Ti) surfaces, neutrophils adopt a rounded morphology, whereas on rough Ti surfaces, they display a spread-out, flattened morphology (Campos et al., 2014). Modulating the surface topography of the scaffold can influence the cell phenotype, transitioning it from a pro-inflammatory to an anti-inflammatory state. The unique morphological structure of the surface, in response to the shear stress generated by cell membrane contact, can mediate calpain activity and cytoskeletal remodeling through the activation of Piezo1, thereby inducing the production of NETs (Baratchi et al., 2024) (Figure 7B). Neutrophils cultured on rough Ti surfaces exhibited a reduction in the production of pro-inflammatory cytokines and enzymes, as well as a decreased formation of NETs, in comparison to neutrophils on smooth Ti surfaces (Abaricia et al., 2020). This attenuation in NET formation is associated with an accelerated resolution of inflammation and enhanced bone formation on Ti implants (Morandini et al., 2023).