Abstract
Granulocytes, long considered short-lived effector cells, are increasingly recognized as key modulators of the foreign body response (FBR) to biomaterials and determinants of regenerative outcomes. This review summarizes current evidence on the roles of neutrophils, basophils, and eosinophils in biomaterial-associated inflammation and tissue remodeling. Particular focus is placed on protein adsorption, cytokine release, and downstream effects across diverse biomaterial classes, including bone substitutes, collagen scaffolds, titanium, magnesium, and synthetic polymers. Neutrophils dominate the acute phase through reactive oxygen species, proteases, and neutrophil extracellular traps, which can either support remodeling or drive fibrosis and implant failure. Basophils, though rare, release histamine and Th2 cytokines, enhancing angiogenesis but also contributing to fibrotic encapsulation. Eosinophils are recruited in material-dependent patterns, releasing cytotoxic granules and pro-regenerative mediators, thereby functioning as double-edged regulators of degradation, fibrosis, and vascularization. Overall, granulocytes act as critical, though often overlooked, determinants of biomaterial integration. Incorporating granulocyte biology into biomaterial design–through modulation of surface chemistry, protein adsorption, and degradation kinetics– offers a promising path to guide inflammatory cascades toward constructive remodeling, angiogenesis, and predictable clinical performance.
Introduction
Every biomaterial implanted into the human body elicits a specific cellular and tissue response, commonly referred to as the foreign body response to biomaterials (1, 2). This response includes injury, blood–material interactions, provisional matrix formation, and acute as well as chronic inflammation. These processes can be associated with granulation tissue formation, foreign body reactions characterized by multinucleated giant cells (MNGCs), and, in some cases, fibrosis and fibrous encapsulation (1, 2).
The first interaction after implantation is protein adsorption and the development of a blood-based provisional matrix on the material surface (3). This matrix formation is followed by acute and chronic inflammatory dynamics. During the acute phase, monocytes, macrophages, and polymorphonuclear leukocytes (PMNs, i.e., neutrophilic granulocytes) play central roles, not only through phagocytosis but also by releasing cytokines that orchestrate subsequent immune events (4). Even in the case of resorbable biomaterials such as bone substitutes or collagen matrices, acute inflammation often transitions into a chronic state, persisting in the form of granulation tissue until complete material degradation is achieved (5).
Material-induced chronic tissue reactions have traditionally been associated with adverse outcomes, such as fibrosis and fibrous encapsulation, which may impair implant integration and contribute to implant failure (6). However, more recent studies have demonstrated that moderate fibrosis does not necessarily preclude successful regeneration and may even support tissue remodeling under certain conditions (2). Importantly, macrophages and MNGCs exhibit both pro- and anti-inflammatory phenotypes, producing molecules such as vascular endothelial growth factor (VEGF) and heme oxygenase-1 (HO-1), which can promote angiogenesis and tissue regeneration (2, 6).
It is increasingly evident that the physicochemical properties of biomaterials modulate inflammatory outcomes, influencing not only macrophages and MNGCs but also other immune and stromal cell types, including lymphocytes, platelets, and granulocytes (1, 7). Despite this complexity, most research has focused on macrophage–biomaterial interactions, while the contributions of granulocytes and other immune cells remain underexplored (6).
A deeper understanding of the roles of all immune cell populations in biomaterial-associated tissue responses is essential for the design of next-generation biomaterials. Such materials could guide the inflammatory cascade toward constructive remodeling and support successful bone and soft tissue regeneration. This review therefore summarizes current knowledge on granulocyte subtypes, with a special focus on their involvement in biomaterial-induced inflammation, degradation processes, and regenerative outcomes.
Basic Knowledge About Granulocyte Subtypes
Neutrophilic granulocytes. Neutrophilic granulocytes, also known as polymorphonuclear leukocytes (PMNs), derive their name from the staining properties of their intracellular granules in hematoxylin and eosin (H&E) sections (2). Mature neutrophils, the most abundant granulocyte population (≈45-70% of circulating leukocytes), measure 12-15 μm in diameter and possess a segmented nucleus with up to five lobes (2).
Neutrophils originate from common myeloid precursor cells (CMPs), which also give rise to eosinophils, basophils, and monocytes. Under stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF) and other growth factors, CMPs differentiate through multiple stages (myeloblast, promyelocyte, myelocyte, metamyelocyte, and band cell) into mature neutrophils (8). This maturation process in the bone marrow takes about 7–8 days, followed by a storage phase of up to 5 days. In steady state, circulating neutrophils have a short half-life of approximately 6–8 hours; during infection or inflammation, they rapidly migrate into affected tissues, where they survive for 1-2 days (9). In the absence of inflammatory signals, neutrophils undergo apoptosis, a process that prevents collateral tissue damage through uncontrolled release of granule enzymes (10).
As essential effectors of the innate immune system, neutrophils constitute the first line of defense against pathogens and are hallmarks of acute inflammation. They are recruited in response to bacterial and fungal infections, sterile tissue injury, and foreign body implantation (11, 12). Besides classical phagocytosis, neutrophils contribute to antimicrobial defense by production of reactive oxygen species (ROS) during the “respiratory burst”, release of cytotoxic granule contents into the extracellular space (degranulation), and formation of neutrophil extracellular traps (NETs), a process termed NETosis (13). During the respiratory burst, NADPH oxidase reduces oxygen to superoxide, which is converted to hydrogen peroxide and peroxynitrite. Myeloperoxidase (MPO) subsequently generates hypochlorous acid, a potent antimicrobial agent (14).
Neutrophils contain four types of granules–primary (azurophilic), secondary (specific), tertiary (gelatinase), and secretory vesicles–that are produced sequentially during maturation. These granules contain proteases (e.g., elastase, cathepsin G, proteinase 3), antimicrobial peptides (e.g., defensins, LL-37), enzymes (e.g., lysozyme, MPO), and metal-chelating proteins (e.g., lactoferrin, calprotectin), which together provide a broad antimicrobial arsenal (15).
Neutrophil recruitment involves a multistep extravasation cascade. Pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) induce expression of P- and E-selectins, ICAM-1, and VCAM-1 on endothelial cells (16). Neutrophils tether and roll along the endothelium through selectin–ligand interactions (e.g., PSGL-1 and L-selectin), followed by firm adhesion via β2 integrins (LFA-1, Mac-1) binding to ICAM-1 (17). Subsequent diapedesis allows migration across the endothelium and through the extracellular matrix (ECM), a process facilitated by neutrophil-derived proteases and collagenases (18).
Once at the inflammatory site, neutrophils recognize opsonized antigens via Fc and complement receptors or detect pathogen-associated molecular patterns (PAMPs) through toll-like receptors (TLRs). For example, TLR4 senses lipopolysaccharide (LPS), TLR2 detects bacterial lipoproteins, TLR5 recognizes flagellin, and TLR9 binds unmethylated CpG DNA (19). After phagocytosis, pathogens are destroyed in phagolysosomes through fusion with neutrophil granules, ROS, and antimicrobial peptides (20).
NETs are extracellular web-like structures composed primarily of neutrophil DNA decorated with histones and granule proteins. They immobilize and neutralize bacteria, fungi, and viruses, but can also contribute to tissue injury and chronic inflammation if dysregulated (21). NETs have recently been implicated in sterile inflammatory processes such as autoimmune diseases, cancer, and foreign body responses to biomaterials (22).
Basophilic granulocytes. Basophilic granulocytes (basophils) represent the rarest population of circulating granulocytes, accounting for less than 1% of peripheral blood leukocytes (23). They are morphologically characterized by a diameter of 10-12 μm, a bilobed nucleus that is often obscured by numerous large basophilic cytoplasmic granules, and distinct staining properties with hematoxylin and eosin (H&E) as well as toluidine blue (24).
Basophils, like eosinophils and neutrophils, originate from common myeloid progenitor (CMP) cells within the bone marrow. Their differentiation is driven by interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and thymic stromal lymphopoietin (TSLP) (25). Basophil maturation requires approximately 7 days, after which mature cells are released into the peripheral blood, where they circulate for 1-2 days before migrating into tissues (26, 27). Unlike tissue-resident mast cells, which derive from different precursors, basophils are fully mature when they leave the bone marrow (28).
Basophils are effector cells of the innate immune system with specialized roles in allergic inflammation, parasitic infections, and immune regulation. They express the high-affinity IgE receptor (FcεRI) on their surface, enabling rapid degranulation upon IgE-mediated crosslinking with allergens (29). Basophil granules contain histamine, heparin, and proteoglycans, which contribute to vasodilation, increased vascular permeability, and recruitment of other immune cells (30). In addition to classical degranulation, basophils release cytokines such as interleukin-4 (IL-4) and interleukin-13 (IL-13), thereby promoting T helper type 2 (Th2) immune responses (31). This positions basophils as important orchestrators of allergic diseases such as asthma, atopic dermatitis, and food allergy (32).
Although traditionally studied in the context of allergy, basophils also play a role in host defense against helminths and ectoparasites, where their secretion of IL-4 and histamine supports eosinophil recruitment and parasite clearance (33). More recently, basophils have been implicated in autoimmune and fibrotic diseases, as well as in modulating tumor immunity (34).
Eosinophilic granulocytes. Eosinophilic granulocytes (eosinophils) represent 1-5% of circulating leukocytes under physiological conditions and are readily identified by their bilobed nucleus and large cytoplasmic granules with strong eosinophilic staining properties (35). Their size ranges between 12-17 μm, making them slightly larger than neutrophils and basophils. Eosinophils derive from common myeloid progenitors (CMPs) in the bone marrow. Their differentiation is primarily regulated by interleukin-5 (IL-5), supported by IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (36). After maturation, which takes approximately one week, eosinophils circulate for 8-12 hours before migrating into tissues, where they can persist for several days depending on the local inflammatory milieu (37).
Traditionally, eosinophils are recognized for their role in host defense against helminths and other multicellular parasites. They exert their effector function through degranulation, releasing toxic cationic proteins such as major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN) (38). In addition, eosinophils contribute to the regulation of immune responses by secreting cytokines (e.g., IL-4, IL-5, IL-13, and TGF-β) and chemokines, thereby promoting type 2 immune responses and tissue remodeling (39).
Eosinophils are central players in allergic diseases such as asthma, rhinitis, and atopic dermatitis, where their accumulation in tissues is linked to chronic inflammation and fibrosis (40). Beyond allergy, eosinophils are increasingly recognized as modulators of autoimmunity, cancer, and tissue regeneration. Their ability to influence fibroblast activity and extracellular matrix remodeling suggests both protective and pathogenic roles depending on the context (37).
Protein Layer at the Biomaterial-tissue-interface and its Consequences for the Regeneration Success
Immediately upon implantation, the bare surface of a biomaterial is rapidly cloaked in a layer of adsorbed proteins derived from blood and interstitial fluids. This proteinaceous interface –not the clean biomaterial surface itself– becomes the first “language” through which immune cells, including granulocytes, “read” and respond to the implant. The nature, conformation, dynamics, and composition of this protein layer thus critically influence downstream inflammation, cell adhesion, and foreign body responses.
The initial adsorption process is highly dynamic. Low-molecular-weight, highly mobile proteins (e.g., albumin) adsorb first, but over time they may be displaced by higher-affinity proteins such as fibrinogen, fibronectin, complement components, and immunoglobulins – the so-called Vroman effect (41, 42). Moreover, upon adsorption, proteins often undergo conformational rearrangements, unfolding or partial denaturation, which can expose cryptic binding domains or epitopes that were not accessible in the native soluble form (43, 44). These conformational changes are strongly modulated by the physicochemical properties of the material surface-hydrophobicity, charge, wettability, topography, and stiffness all play roles in determining which proteins bind, how densely they pack, and how they reconfigure (43, 44).
Among the key proteins involved, fibrinogen is particularly important. Fibrinogen adsorbs readily to many biomaterial surfaces and, when structurally altered, can mediate strong interactions with β2 integrins (e.g., Mac-1, LFA-1) on neutrophils. These interactions drive neutrophil adhesion, activation, reactive oxygen species (ROS) generation, degranulation, and even NETosis (neutrophil extracellular trap formation) (45, 46). In particular, denaturation of fibrinogen on a surface may expose otherwise hidden binding sites that promote integrin clustering and signaling, thus amplifying neutrophil activation beyond what native fibrinogen would evoke (45, 46).
Immunoglobulins, particularly IgG, also adsorb to biomaterial surfaces and can be conformationally rearranged. Adsorbed IgG often presents its Fc domain outward, enabling recognition by Fc gamma receptors (FcγR) on neutrophils and eosinophils. This can lead to opsonization, phagocytic attempts even on the biomaterial, and enhanced degranulation, further fueling local inflammation (44). Complement proteins, notably C3 and its activation fragments (C3b, iC3b), may bind directly or via other proteins. Adsorbed complement fragments present binding sites for complement receptors (CR1, CR3) on granulocytes and modulate cell recruitment, activation, and cytokine secretion (such as IL-8), thereby shaping the inflammatory milieu (47).
Interestingly, albumin–often one of the earliest proteins to coat an implant – can play an ambivalent role. In its native conformation, albumin tends to resist cell adhesion and may act as a “passivating” layer; however, if it denatures upon adsorption, it can reveal adhesive domains that support granulocyte binding and activation. Thus, the conformation and stability of albumin on the surface become critical determinants of whether it is inert or bioactive (43). Additionally, the deposited protein network often evolves into a provisional extracellular matrix containing fibrin, vitronectin, fibronectin, and other adhesive proteins. These further stabilize the protein layer and provide additional integrin-binding domains (e.g., αMβ2, αVβ3), facilitating more sustained granulocyte adhesion, migration, and activation in the periprosthetic environment (48).
For granulocytes–especially neutrophils–these protein–surface interfaces constitute both adhesion anchors and activation triggers. Neutrophils in contact with surfaces bearing denatured fibrinogen or adsorbed complement/IgG are more likely to spread, generate ROS, degranulate proteases, and release NETs. Such aggressive responses risk collateral damage to surrounding tissue and can promote chronic inflammation and fibrous encapsulation. Eosinophils and basophils, while less often studied, may similarly sense altered protein epitopes via complement or Fc-based interactions, potentially contributing to allergic-type responses, fibrosis, or modulation of the local immune milieu.
In summary, the conformation, composition, and dynamics of the protein layer on a biomaterial surface determine how granulocytes perceive and respond to the implant. Designing material surfaces that favor “benign” protein adsorption –minimizing conformational changes that expose pro-adhesive or pro-inflammatory epitopes–is a promising strategy to steer granulocyte behavior and improve biocompatibility and implant integration.
Interactions of Granulocytes With Biomaterials
Neutrophil interactions with biomaterials. Neutrophils represent the first line of immune defense at the site of biomaterial implantation, and their interactions strongly shape the early inflammatory phase, the transition to resolution, and the long-term fate of an implant (Table I). While the fundamental effector mechanisms of neutrophils –adhesion, oxidative burst, degranulation, and NET formation–are conserved, the magnitude and consequences of these responses vary considerably depending on the biomaterial type.
Neutrophil interactions with different biomaterial types.
Bone substitute materials such as hydroxyapatite, tricalcium phosphate, and biphasic calcium phosphates are rapidly infiltrated by neutrophils. Their proteases and ROS contribute to particle fragmentation and degradation (49). This can be advantageous for remodeling if balanced but may impair osteoconduction when neutrophil activation is excessive. Uncontrolled NET release at the bone substitute interface has been shown to hinder osteogenesis and delay osseointegration (50).
Collagen-based scaffolds and membranes are highly degradable and elicit pronounced neutrophil infiltration. Neutrophil elastase, collagenases, and MMPs accelerate scaffold resorption (6). While this supports matrix turnover and host tissue replacement, premature breakdown may compromise barrier membranes in guided bone regeneration. Crosslinking and surface modifications have been developed to mitigate rapid neutrophil-mediated degradation and extend material functionality (51, 52).
Titanium implants represent the gold standard in dental and orthopedic applications due to their excellent mechanical stability and biocompatibility (52). Neutrophils are among the first cells adhering to the titanium oxide surface. Surface roughness and chemical modifications strongly influence neutrophil adhesion and activation. Smooth, passivated surfaces tend to reduce ROS generation and NET formation, whereas rough or contaminated surfaces can exacerbate neutrophil-driven inflammation, impairing osseointegration (51). Recent studies suggest that controlled neutrophil responses on titanium may even promote angiogenesis and osteoprogenitor recruitment, emphasizing their dual role (4).
Magnesium-based implants are increasingly investigated as biodegradable metals. Magnesium degradation releases Mg2+ ions and elevates local alkalinity, both of which strongly activate neutrophils. This leads to ROS release, NET formation, and a prolonged inflammatory response (53). While these effects can accelerate corrosion and compromise implant stability, moderate Mg2+ release may also support bone regeneration and angiogenesis by stimulating early immune responses (54). Controlling degradation kinetics is therefore critical to balance neutrophil-mediated benefits and adverse effects.
Other biomaterials such as synthetic polymers (e.g., PLGA, PEG-based scaffolds) and composite hydrogels elicit neutrophil responses that are highly dependent on surface chemistry and degradation by-products. Acidic degradation products from polyesters, for example, may prolong neutrophil survival and sustain inflammation, while hydrophilic, zwitterionic coatings reduce neutrophil adhesion and activation (55).
Taken together, neutrophil–biomaterial interactions are highly context dependent. For all biomaterial classes, neutrophils act as double-edged regulators: they can orchestrate regeneration by recruiting macrophages, stimulating angiogenesis, and clearing debris, but they may also drive chronic inflammation, fibrotic encapsulation, or implant degradation (Figure 1). Future biomaterial design strategies therefore focus on tailoring surface chemistry, degradation kinetics, and bioactive coatings to steer neutrophil responses toward pro-regenerative phenotypes.
Neutrophil responses to different biomaterial types. Heatmap illustrating the qualitative intensity of neutrophil-mediated reactions in response to various classes of biomaterials, including bone substitutes, collagen scaffolds, titanium, magnesium, and synthetic polymers. Key neutrophil activities such as reactive oxygen species (ROS) production, neutrophil extracellular trap (NET) formation, protease release and degradation activity, fibrosis induction, and regeneration support are displayed. Response intensities were categorized on a semi-quantitative scale (low, moderate, strong, variable, conditional, supportive, or risk) and mapped to a color gradient (0 = low, 3 = strong/risk). The visualization highlights the material-dependent dual role of neutrophils as both drivers of inflammatory damage (e.g., ROS, fibrosis) and facilitators of constructive remodeling (e.g., regeneration, angiogenesis).
Basophil interactions with biomaterials. Basophils are the least abundant granulocyte subset in peripheral blood, accounting for less than 1% of circulating leukocytes. Despite their low frequency, they play a disproportionately important role in type I hypersensitivity reactions, allergy, and chronic inflammation. In the context of biomaterial implantation, basophils have traditionally received little attention compared to neutrophils and macrophages; however, increasing evidence suggests that they can significantly modulate local immune responses and long-term integration outcomes (Table II) (25).
Basophil interactions with different biomaterial types.
Upon implantation, basophils are recruited to biomaterial surfaces by chemokines such as CCL2 and CCL11 and can be activated through FcεRI-mediated crosslinking by IgE bound to adsorbed proteins. Once activated, basophils rapidly release histamine, leukotrienes, and heparin from their granules, as well as cytokines including IL-4 and IL-13 (56). These mediators shape the local immune microenvironment by promoting Th2 polarization, enhancing vascular permeability, and recruiting eosinophils. In the context of collagen-based biomaterials and natural scaffolds, this may accelerate angiogenesis and early vascular infiltration but can also favor fibrotic encapsulation if the response persists (57).
On bone substitutes and metallic implants such as titanium, direct basophil adhesion appears limited; instead, their effects are mediated through cytokine and histamine release, which can amplify mast cell and eosinophil activity. This creates a pro-fibrotic and pro-angiogenic environment that may influence peri-implant tissue remodeling (58). In magnesium-based implants, basophil-derived mediators may synergize with ion-induced immune activation, potentially enhancing allergic-type inflammation (27).
Although data remain scarce, emerging work suggests that basophils contribute to the chronic phases of the foreign body response by sustaining Th2-biased inflammation and fibrosis. At the same time, their release of angiogenic factors such as VEGF and histamine may support early vascularization of biomaterials (48). Therefore, basophils appear to act as double-edged regulators-potentially promoting both constructive angiogenesis and detrimental fibrosis (Figure 2). Modulating basophil recruitment and activation, for example by tuning protein adsorption or incorporating anti-IgE/anti-histamine functionalities into biomaterial coatings, may represent novel strategies to improve biocompatibility (59).
Basophil responses to different biomaterial types. Heatmap summarizing the qualitative intensity of basophil-mediated responses in relation to distinct biomaterial classes, including bone substitutes, collagen scaffolds, titanium, magnesium, and synthetic polymers. Key parameters include histamine release, IL-4/IL-13 secretion, direct adhesion, angiogenesis support, and fibrosis risk. Responses were categorized on a semi-quantitative scale (low, moderate, strong, variable, possible, or risk) and visualized through a color gradient (0 = low, 3 = strong/risk). The figure illustrates the limited but distinct contribution of basophils to material-induced immune modulation, highlighting their role in type 2 inflammation, vascular responses, and fibrotic tissue outcomes.
Eosinophil interactions with biomaterials. Eosinophils are granulocytes primarily associated with type II immune responses, allergy, and defense against helminthic parasites. They account for 1-4% of circulating leukocytes under homeostatic conditions but can be strongly recruited to sites of chronic inflammation and foreign body reactions. In the context of biomaterial implantation, eosinophils have been less extensively studied than neutrophils or macrophages; however, accumulating evidence indicates that they play significant roles in modulating tissue remodeling, fibrosis, and angiogenesis (Table III) (60, 61).
Eosinophil interactions with different biomaterial types.
Following implantation, eosinophils are attracted to biomaterial surfaces via chemokines such as eotaxins (CCL11, CCL24, CCL26) and can persist within the inflammatory infiltrate for extended periods (62). Upon activation, eosinophils release cytotoxic granule proteins including major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN). These mediators can damage local cells and extracellular matrix components, thereby contributing to chronic inflammation or fibrotic encapsulation. In collagen-based scaffolds, eosinophil-derived proteases and MBP may accelerate degradation and stimulate fibroblast activity, favoring fibrotic tissue development (63).
Histological studies by Barbeck and collaborators have demonstrated that eosinophils are indeed part of the early infiltrate around implanted biomaterials. In a mouse model comparing magnesium-based volume-stable barrier membranes with collagen membranes, infiltrates rich in eosinophilic granulocytes were observed as early as day 10, and single eosinophils persisted up to day 30 (64). Similarly, comparative analyses of collagen membranes and bone substitutes indicated that faster degrading materials or those with strong immunogenicity induced a more pronounced eosinophil presence, while slowly resorbing biomaterials showed reduced eosinophil recruitment and were instead dominated by macrophage-driven remodeling (65). Furthermore, in studies on fish collagen membranes, eosinophil infiltration was found to be lower compared to pericardial collagen, pointing to differences in immunogenicity depending on material source and processing (66). These findings highlight that eosinophil recruitment is not incidental but rather a material-dependent phenomenon tied to degradation dynamics and protein recognition.
At bone substitute surfaces, eosinophils may contribute indirectly to bone remodeling by releasing cytokines such as TGF-β and IL-4, which promote fibroblast proliferation and extracellular matrix deposition (67). In titanium and magnesium implants, eosinophil infiltration has been linked to peri-implant fibrosis and foreign body giant cell formation, suggesting a role in long-term implant encapsulation (64).
Interestingly, eosinophils also secrete pro-angiogenic factors such as VEGF and can modulate macrophage polarization toward M2-like phenotypes, thereby supporting wound healing and vascularization under certain conditions (37). This dual activity reflects their double-edged role: promoting vascular ingrowth and resolution on one side, while driving fibrosis and impaired integration on the other (Figure 3). Recent data even show that eosinophils are indispensable for certain biomaterial-mediated regenerative effects, as knockout models failed to demonstrate repair benefits otherwise observed with acellular matrix implants (68, 69).
Eosinophil responses to different biomaterial types. Heatmap depicting eosinophil-related reactions to biomaterial implantation, with focus on bone substitutes, collagen scaffolds, titanium, magnesium, and polymers. Key functions considered are granule protein release (MBP, ECP), cytokine secretion (IL-4, TGF-β), fibroblast stimulation, angiogenesis support, and fibrosis risk. Responses were classified on a semi-quantitative scale (possible, moderate, strong, risk, variable) and represented in a graded color scheme (0 = low, 3 = strong/risk). The visualization emphasizes the dual role of eosinophils as mediators of pro-regenerative processes (e.g., angiogenesis and fibroblast activity) and drivers of chronic inflammation and fibrosis in a material-dependent manner.
Because eosinophils are closely tied to Th2-dominated immune responses, biomaterials that strongly adsorb IgE or activate basophils and mast cells are particularly likely to recruit eosinophils. Strategies to mitigate eosinophil-driven fibrosis include surface modifications to reduce IgE adsorption, incorporation of anti-inflammatory coatings, and modulation of chemokine release (48).
Role of Blood Concentrates in Regenerative Medicine With a Focus on Granulocytes
Autologous blood concentrates such as platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) have gained widespread clinical application in regenerative medicine, oral surgery, and orthopedics due to their capacity to deliver growth factors, cytokines, and cellular components in a controlled manner. While most studies have traditionally emphasized the role of platelets in releasing growth factors such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor-β (TGF-β) (48, 70), it has become increasingly evident that leukocyte fractions, particularly granulocytes, contribute significantly to the biological activity of blood concentrates.
Neutrophils are the most abundant granulocytes in PRP/PRF preparations and are rapidly recruited to sites of implantation (71). Their release of reactive oxygen species, proteolytic enzymes, and neutrophil extracellular traps (NETs) contributes to initial antimicrobial defense and matrix remodeling (72). While excessive activation may promote tissue degradation and fibrosis, controlled neutrophil activity supports debridement of damaged tissue and paves the way for angiogenesis and regeneration (73, 74).
Eosinophils, though present at lower frequencies, may contribute through secretion of interleukin-4 (IL-4) and IL-13, which polarize macrophages toward a pro-regenerative M2 phenotype, and by releasing angiogenic mediators (65). Basophils, albeit rare, can release histamine and type-2 cytokines, modulating vascular permeability and early immune cell recruitment (73). Together, these granulocyte subsets provide a transient but influential immunomodulatory effect that complements the growth factor activity of platelets (75).
Recent clinical and preclinical studies suggest that blood concentrates with a balanced leukocyte and granulocyte fraction may accelerate wound healing, reduce infection risk, and improve integration of biomaterials by shaping the early inflammatory phase toward a regenerative outcome (76). However, the optimal composition remains debated, as excessive granulocyte content can drive prolonged inflammation and fibrotic responses (77, 78). Future approaches will likely focus on tailoring leukocyte inclusion in blood concentrate protocols to maximize regenerative potential while minimizing adverse immune activation (79, 80).
Conclusion
Granulocytes, though historically overshadowed by macrophages in biomaterial research, emerge as pivotal regulators of the foreign body response and subsequent tissue regeneration (Figure 4). Neutrophils dominate the acute phase after implantation, shaping the inflammatory milieu through reactive oxygen species, proteases, and neutrophil extracellular traps, with context-dependent outcomes that can either support remodeling or drive fibrosis and implant failure. Basophils, despite their low abundance, influence local immune polarization via histamine and Th2 cytokines, contributing to both angiogenesis and fibrotic encapsulation. Eosinophils, recruited in material-dependent patterns, add further complexity by releasing cytotoxic granules and pro-regenerative mediators, thereby acting as double-edged players in matrix degradation, fibrosis, and vascularization.
Granulocyte responses to biomaterials and interactions with other immune cells. Flowchart depicting the cellular cascade following biomaterial implantation. Protein adsorption and conformational changes (fibrinogen, IgE/IgG, complement C3b/iC3b) trigger differential granulocyte recruitment. Neutrophils produce ROS, release proteases (MPO, elastase), and form NETs, with moderate activation supporting remodeling and excessive activation impairing integration. Basophils release histamine and IL-4/IL-13 via FcεRI activation, driving Th2 polarization and vascular permeability. Eosinophils secrete cytotoxic granule proteins (MBP, ECP, EPO), cytokines (IL-4, IL-13, TGF-β), and VEGF, promoting ECM degradation, fibroblast stimulation, and angiogenesis. All pathways converge on macrophage polarization: M1 activation leads to chronic inflammation and fibrotic encapsulation with MNGC formation; M2 activation supports angiogenesis and tissue integration. Color coding: blue: initial events; red tones: granulocytes; green: macrophages/regeneration; light red: adverse outcomes; light green: successful integration. C3b/iC3b, Complement component 3b/inactivated 3b; ECP, eosinophil cationic protein; ECM, extracellular matrix; EPO, eosinophil peroxidase; FcεRI, Fc epsilon receptor I; IgE/IgG, immunoglobulin E/G; IL, interleukin; M1/M2, classically/alternatively activated macrophage; MBP, major basic protein; MNGC, multinucleated giant cell; MPO, myeloperoxidase; NETs, neutrophil extracellular traps; ROS, reactive oxygen species; TGF-β, transforming growth factor-beta; Th2, T helper type 2; VEGF, vascular endothelial growth factor. The software Draw.io was used for the flowchart generation.
Importantly, the adsorption and conformational rearrangement of proteins at the biomaterial surface serve as the initial ‘language’ guiding granulocyte activation. The resulting granulocyte-driven responses differ substantially across biomaterial classes such as bone substitutes, collagen scaffolds, titanium, magnesium, and synthetic polymers. These insights highlight that granulocytes are not merely transient bystanders of early inflammation, but integral determinants of long-term implant integration and regenerative success.
Future biomaterial design must therefore integrate granulocyte biology into immunomodulatory strategies. By tailoring surface chemistry, protein adsorption, and degradation kinetics, it will be possible to steer granulocyte responses away from chronic inflammation and fibrosis and toward constructive remodeling and regeneration. This broader immune-centered perspective offers a pathway toward the development of next-generation biomaterials with improved predictability and clinical performance.
Acknowledgements
The Authors gratefully acknowledge the funding by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) for the research unit 5250 “Mechanism-based characterization and modeling of permanent and bioresorbable implants with tailored functionality based on innovative in-vivo, in-vitro and in-silico methods” (project no. 449916462).
Footnotes
Authors’ Contributions
Conceptualization: M.B. and O.J.; resources: M.B. and O.J.; data curation: M.B. and O.J.; writing – original draft preparation: M.B. and O.J.; writing – review and editing: M.B. and O.J.; visualization: M.B. and O.J.; funding acquisition: M.B. and O.J. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
All the Authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Artificial Intelligence (AI) Disclosure
During the preparation of this manuscript, a large language model (Microsoft Copilot) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning–based image enhancement tools.
- Received September 30, 2025.
- Revision received October 26, 2025.
- Accepted October 29, 2025.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
References
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- Abstract
- Introduction
- Basic Knowledge About Granulocyte Subtypes
- Protein Layer at the Biomaterial-tissue-interface and its Consequences for the Regeneration Success
- Interactions of Granulocytes With Biomaterials
- Role of Blood Concentrates in Regenerative Medicine With a Focus on Granulocytes
- Conclusion
- Acknowledgements
- Footnotes
- References
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