Tom Meseberg
Susanne Kurz- Bio- and Nanotechnology Department, Fraunhofer Institute for Ceramic Technologies and Systems (FHG), Dresden, Germany
The foreign body reaction (FBR), characterized by chronic inflammation and fibrotic capsule formation around implanted medical devices, remains a major cause in device-related complications. Current preclinical risk assessment relies on in vivo testing according to ISO 10993-6:2024, which are limited by species differences, incomplete mechanistic insight, and ethical concerns. Additionally, ISO/TS 10993-20:2006 outlines immunotoxicity knowledge regarding implant-induced effects such as FBR and specifies a collection of in vitro assays. The perspective presented here, aims to explore the applicability of the Adverse Outcome Pathway (AOP) framework to FBR in order to integrate evidence and methods into a structured mechanistic context and facilitate the application of in vitro tests in preclinical risk assessment of FBR. A targeted literature review was conducted to identify and organize biological mechanisms into a putative AOP, map available new approach methodologies, and highlight critical knowledge gaps and uncertainties. This initial framework may guide early screening for low-FBR materials and support mechanistically anchored, non-animal biocompatibility assessment strategies for medical devices.
Foreign body reaction to medical devices
The foreign body reaction (FBR), characterized by chronic inflammation and fibrotic capsule formation around implants, remains a major cause of device-related complications. While all materials induce a fibrotic host response after implantation (Anderson et al., 2008; Carnicer-Lombarte et al., 2021), the causes of excessive capsule formation and the impact of material modifications remain debated.
Mechanistically, the FBR begins with protein adhesion to the biomaterial surface, shaping cellular interactions. Monocyte-derived macrophages, with other immune cells, are activated and coordinate acute inflammation, tissue clearance, and early wound healing. When clearance of nondegradable foreign material is frustrated, adherent macrophages fuse into foreign body giant cells (FBGCs), sustaining the inflammatory milieu. Persistent macrophages at the implant site and elevated growth factor signaling promote myofibroblast activation, collagen deposition, and ultimately fibrotic encapsulation (Anderson et al., 2008; Chandorkar et al., 2019).
Across device classes, encapsulation has distinct adverse effects: Greater capsule thickness increases the likelihood and severity of capsular contracture in breast implants, distorting surrounding tissues, impairing implant mechanics, and causing pain (Bachour et al., 2018; Headon et al., 2015; Kim et al., 2022; Larsen et al., 2024). In neural and cochlear implants, “shielding” means that the capsule insulates electrodes from tissue and raises impedance, compromising signal quality and stability (Lotti et al., 2017; Hu et al., 2024; Foggia et al., 2019; Simoni et al., 2020). For implanted biosensors (e.g., glucose monitors), capsules impair diffusion, limiting analyte quantification and long-term reliability (McClatchey et al., 2019; Novak and Reichert, 2015). These results show that implants classified as biocompatible can be affected by FBR.
This raises the question: What does biocompatibility mean immunologically? Widely used medical-device biomaterials today are immunologically bioinert or biotolerable (Rostam et al., 2015; Ratner, 2016). However, because immunogenic response and subsequent tissue integration depend on clinical context, certain applications require a shift from passively bioinert to immunomodulating biomaterials that actively guide physiological wound healing and remodeling (Williams, 2008). Thus, evaluating fibrotic capsule formation as an adverse FBR outcome is important for functionality and safety testing of certain implantable devices in biocompatibility assessment.
Prediction of foreign body reaction in biological risk assessment
In vivo testing according to ISO (2016) is the gold standard for preclinical risk assessment of medical devices and predicting material-induced FBR. Fibrotic capsule formation and post-implantation inflammation are assessed by immune cell counts (macrophages, multinucleated cells) and capsule thickness in histology. While clinically relevant, these models are limited by species differences, mechanistic understanding, and ethical considerations.
ISO (2006) outlines immunotoxicity knowledge on implant-induced effects such as FBR. It identifies implantation-site histopathology per ISO (2016) as the most direct method to assess FBR and chronic inflammation. According to ISO (2006), in vitro assays lack intact immune-system complexity yet remain valuable for mechanistic studies. Hence, the tests and indicators listed (e.g., phagocytosis, antigen presentation, cytokine release, MHC phenotyping) remain an unstructured collection with limited predictivity.
Integrating these principles and methods into a structured mechanistic framework enables broader use of in vitro data for FBR risk assessment. The Adverse Outcome Pathway (AOP) concept, developed in chemical toxicology, is a systematic, data-driven method linking key events to an adverse outcome. For skin sensitization, ISO (2021) Annex C describes a defined approach combining assays along an AOP with four key events. Comprehensive validation studies on applicability to medical devices are promising but ongoing (Svobodová et al., 2021).
This perspective explores AOP applicability to FBR to support mechanistic, human-relevant testing strategies. Applying the AOP framework to material-induced reactions is novel and underexplored, offering potential to advance material and nanomaterial risk assessment. A comprehensive search of FBR literature was conducted using PubMed and Scopus. Information was analyzed to identify and organize biological mechanisms into key events. Evidence correlating each key event with fibrotic capsule formation was extracted from selected in vivo studies. New approach methodologies relevant to each key event were identified when available. This putative AOP (Figure 1) organizes FBR data, highlighting well-characterized mechanisms and knowledge gaps.
Figure 1. Novel putative adverse outcome pathway (AOP) for mechanism-driven testing of FBR outcome. Created with Biorender.
Molecular initiating event: protein denaturation at the implant surface
After implantation and tissue injury, plasma and extracellular matrix (ECM) proteins adsorb to the implant surface. Biomaterial properties (wettability, topography, hydrophilicity, surface charge) determine adsorption and denaturation extent (Lehká et al., 2023). Denatured ECM proteins expose adhesive motifs, such as RGD, that promote cell adhesion (Swartzlander et al., 2015). Damage-associated molecular patterns (DAMPs) and ECM proteins (e.g., fibrinogen, periostin) regulate immune-cell responses (Franz et al., 2011; Blackman et al., 2024).
A prominent example is denatured fibrinogen, which exposes two neo-epitopes and activates phagocyte pro-inflammatory state via Mac-1 (Hu et al., 2001). Fibrinogen-deficient C57BL/6J mice showed reduced fibrous capsule formation after intraperitoneal or subcutaneous polytetrafluoroethylene implantation (Balabiyev et al., 2021). Similarly, periostin-knockout mice with subcutaneous silicone implants have decreased capsule thickness (Bae et al., 2018). Activation of Toll-like receptors by DAMPs has comparable downstream effects in FBR, as TLR2/TLR4-knockout mice develop thinner capsules after polyethylene glycol hydrogel implantation (Thompson et al., 2025).
Opsonin-mediated recognition (IgG, C3b) likely induces innate immune responses (Anderson et al., 1996), although hypogammaglobulinemic mice showed unaffected neutrophil and monocyte recruitment (Kyriakides et al., 2022).
Lehka et al. introduced an in vitro model to evaluate protein adsorption and cell adhesion on biomaterials (Lehká et al., 2023). They reported that adsorbed protein quantity did not determine long-term cell adhesion leading to FBR, whereas dissolution rate was critical. Although data gaps remain and links between protein adsorption and FBR outcomes are debated, growing evidence indicates protein denaturation is crucial. Conversely, plasma treatment enabling covalent attachment of native host proteins reduced capsule formation after subcutaneous implantation of polyurethane in mice (Kondyurina and Kondyurin, 2023).
Key event 1: immune cell recruitment and adhesion
The interaction of host immune cells with biomaterials, particularly macrophages, is the first key event. Macrophage adhesion and spreading at the material–tissue interface initiate activation. Their activity with effector cells such as fibroblasts is required for capsular fibrosis (Robotti et al., 2018; Brown et al., 2012).
Macrophage depletion with clodronate liposomes reduced capsule formation after subcutaneous polycaprolactone implantation in C57BL/6 mice (Dondossola et al., 2016) and decreased capsule thickness in another study (Mooney et al., 2010). In Rag2/γ KO mice, macrophage depletion eliminated implant-induced fibrosis after alginate implantation (Doloff et al., 2017). Other immune cells appear less critical for FBR in knockout models. T cells (Rodriguez et al., 2009; Doloff et al., 2017), natural killer cells (Yang et al., 2014), and mast cells (Yang et al., 2014; Avula et al., 2014) showed limited or no essential roles. A data gap remains for B cells, as knockout (IghMnull) mice showed only partial reduction in fibrosis (Doloff et al., 2017).
Evidence indicates that integrin-mediated macrophage adhesion affects recruitment and activation. In a rat cage implant system, zwitterionic and anionic polyurethane chemistries reduced nonspecific adhesion, decreased inflammatory events, and promoted immune-cell apoptosis (Khandwekar and Rho, 2012). CD11b knockout and inhibition of RGD-binding integrins reduced capsule thickness around subcutaneous polyethylene terephthalate implants by 30%–45% (Eslami-Kaliji et al., 2023). In MyD88-deficient mice, reduced inflammatory-cell recruitment, mostly macrophages, correlated with a substantial decrease in capsule formation (Amer et al., 2019).
Evidence suggests a “sweet spot” for adhesion to the biomaterial surface. Sustained viable attachment maintains chronic responsiveness to the foreign body (Jannasch et al., 2017a). Too much adhesion may overactivate myofibroblasts, whereas too little adhesion may elicit strong inflammation; both outcomes are detrimental to implant integration (Noscovikova et al., 2021a).
In vitro approaches include cell adherence assays on defined surface chemistries with May–Grünwald/Giemsa staining (Chang et al., 2008; Jones et al., 2007; Al-Khoury et al., 2019). Additional assays quantify adhesion across materials using CD54 and beta-actin staining to assess activation-associated adhesion and cytoskeletal organization (Jannasch et al., 2017b).
Key event 2: macrophage activation and acute inflammation
Macrophage activation is required for FBR-associated fibrosis. However, the host macrophage response is essential for constructive tissue remodeling following implantation (Brown and Badylak, 2013). In physiological wound healing, macrophages shift from M1 to M2a-like during days four to seven post-injury (Witherel et al., 2019). Eliminating M1 signaling or prematurely promoting M2a is linked to excessive ECM deposition and pathological fibrosis, underscoring that polarization timing and dynamics are critical (Saleh et al., 2022). An optimal implant elicits a mild initial M1 response followed by early restricted M2 dominance (Klopfleisch, 2016).
After abdominal implantation of mesh materials in Sprague–Dawley rats, the day-14 M2:M1 ratio correlated with day-35 histological FBR scores (Brown et al., 2012; Wolf et al., 2014). In BALB/c mice, polymers that modulate macrophage polarization showed a balanced M1:M2 ratio which was associated with reduced capsule thickness compared with M1 or M2 predominance (Rostam et al., 2020). Modified polyurethane-coated implants reduced capsule thickness in Sprague–Dawley rats, correlated with increased M2:M1 ratio (CD86 vs. CD163) at 4 weeks (Huang et al., 2018). The macrophage M1:M2 ratio (CCR7+ vs. Arg-1+) correlated with capsule thickness after subcutaneous implantation of functionalized hernia mesh in Sprague–Dawley rats (Yang et al., 2025). Consistent with fibrous encapsulation as a wound-healing response that fails to resolve, the M2:M1 ratio is indicative in other chronic conditions, including spinal cord injury, chronic wounds, and inflammatory renal disease (Yu et al., 2016).
Data gaps remain. Macrophages at implant interfaces can display features of both M1 and M2, suggesting hybrid states that complicate simple dichotomy (Moore et al., 2015; Witherel et al., 2019).
In vitro approaches include macrophage cytokine secretion profiling on defined surface chemistries at set time points (Chang et al., 2008; Brodbeck et al., 2002; Huang et al., 2018; Jannasch et al., 2017a; Zhou et al., 2016; Al-Khoury et al., 2019). Polarization ratios are determined by dividing mean M1 by M2 cytokine percentages across biomaterials (Grotenhuis et al., 2013).
Key event 3: foreign body giant cell formation and chronic inflammation
A hallmark of the foreign body response is macrophage fusion into foreign body giant cells (FBGCs), defined as cells with three or more nuclei (Anderson et al., 2008; Saleh and Bryant, 2017; Witherel et al., 2018). FBGC formation occurs after implantation of diverse biomaterials and is reported in many case studies in rodents and humans (Larsen et al., 2024; Clauzel et al., 2024; Simoni et al., 2020; Doddridge et al., 2024; Álvarez-Ortega et al., 2021; Fatkhudinov et al., 2019). These cells can persist at the implant surface for the device lifetime, and their long-term presence reflects low-grade chronic inflammation (McNally et al., 2008; Álvarez-Ortega et al., 2021).
Two main hypotheses explain macrophage fusion. First, the lack of FBGCs undergoing apoptosis suggests fusion is an escape mechanism (Brodbeck et al., 2001; Christenson et al., 2005). Thereby, FBGCs may act as a cellular shield integrating into the fibrotic capsule (Trout and Holian, 2020). Second, frustrated phagocytosis of large non-internalizable objects can trigger fusion (Zhao et al., 1991; Kyriakides et al., 2004). However, whether FBGC phagocytic activity exceeds that of mononuclear macrophages remains unclear (Milde et al., 2015).
Sustained FBGC presence at the biomaterial interface correlates with progressive capsule formation. After silicone pad implantation in rats, capsule thickness correlated with FBGC accumulation after four and 12 weeks (Majd et al., 2015; Işıktekin et al., 2025). Similar correlations occurred two and 4 weeks after subcutaneous implantation of nanopatterned metallic glasses in C57BL/6 mice (Shayan et al., 2018). In C57BL/6 mice with drug-releasing spheres, capsule thickness at 4 weeks correlated with FBGC accumulation at 1 week (Morris et al., 2017).
Several in vitro models analyze FBGC formation. A standard metric is the fusion index, the number of nuclei within multinucleated giant cells divided by total nuclei per field, applied to PBMC-derived FBGCs across surface chemistries (Chang et al., 2008; Jones et al., 2007; Brodbeck et al., 2002). Additionally, THP-1–derived FBGCs were assessed by May–Grünwald/Giemsa staining to quantify the area percentage of FBGCs (Al-Khoury et al., 2019; Zhou et al., 2015). Murine FBGCs from RAW 264.7 and primary cells were analyzed by F4/80 staining to determine FBGC percentage per field (Majd et al., 2015; Morris et al., 2017). ELISA-based quantification of FBGCs on biomaterial surfaces is under investigation in our lab.
Key event 4: fibroblast recruitment and myofibroblast differentiation
Macrophage–fibroblast crosstalk via TGF-β1, PDGF, IL-6, and IL-13 promotes chemotaxis and myofibroblast differentiation (Pakshir and Hinz, 2018; Holt et al., 2010; Witherel et al., 2019; Noskovicova et al., 2021a). Precise signaling mechanisms remain incompletely defined. Myofibroblasts are a pathophysiologically relevant activation state marked by excessive collagen production, contraction, and crosslinking (Noskovicova et al., 2021a). Their accumulation drives ECM contracture and may necessitate repeat surgeries for soft-tissue implants (Baker et al., 1981; Coleman et al., 1993).
Alpha-smooth muscle actin (α-SMA) is standard marker of myofibroblast differentiation (Hinz et al., 2001) and linked to fibrotic capsule formation. After silicone implantation in Sprague–Dawley rats, capsule histology showed increased α-SMA–positive cell densities than controls (Liu et al., 2022). In Sprague–Dawley rats, α-SMA–positive myofibroblast counts at the tissue interface correlated with capsule thickness after subcutaneous implantation of functionalized hernia meshes (Yang et al., 2025). In Wistar rats with functionalized or micropatterned silicone pads, capsule thickness correlated with α-SMA–positive myofibroblast abundance (Majd et al., 2015). In C57BL/6 mice implanted with silicones of varying stiffness, capsule thickness correlated with α-SMA–positive myofibroblast density (Noskovicova et al., 2021b).
Feedback in fibroblast–macrophage crosstalk remains a data gap. Fibroblast-secreted mediators enhance FBGC formation, and direct contact enables macrophage fusion on non-permissive substrates (Stewart et al., 2024). Additionally, biomaterial integrin interaction can activate myofibroblast differentiation, independent of paracrine signals (Noskovicova et al., 2021b).
In vitro assays include immunofluorescence of fibronectin ED-A and α-SMA in primary human dermal fibroblasts to assess myofibroblast differentiation (Majd et al., 2015; Zhou et al., 2016). A fibroblast outgrowth assay measures outgrowth distance of primary human dermal fibroblasts in coculture with THP-1–derived macrophages on different surface chemistries (Zhou et al., 2016). A fibroblast migration assay quantifies velocity, directness, and forward migration index from live-cell imaging in macrophage–substrate–conditioned medium (Jannasch et al., 2017b).
Key event 5: extracellular matrix deposition
Fibrosis, including capsule formation, occurs when myofibroblast-mediated collagen synthesis exceeds degradation, causing collagen accumulation (Wynn, 2008). Capsule collagen abundance correlates with thickness. Histochemical collagen density correlated with capsule thickness after micropatterned silicone implantation in Wistar rats (Majd et al., 2015). Similarly, collagen density correlated with thickness after implanting silicones of varying stiffness, in C57BL/6 mice (Noskovicova et al., 2021b).
Intervention studies in Sprague–Dawley rats support causality of collagen synthesis in capsule formation. Subcutaneous implantation of COL1A1 siRNA scaffolds downregulated collagen I (COL1A1) and significantly reduced capsule thickness at 2 and 4 weeks versus plain nanofibers (Rujitanaroj et al., 2013). Silicone implants coated with phosphorylcholine or collagen I synthesis inhibitor halofuginone lowered collagen I and III levels and reduced capsule thickness after 3 months versus uncoated controls (Zeplin et al., 2010a; Zeplin et al., 2010b). Silicone coated with TGF-β inhibitor Tranilast similarly decreased collagen density and capsule thickness from 1 to 12 weeks (Park et al., 2015).
In vitro models enable ECM deposition analysis. A co-culture wound model of primary fibroblasts and macrophages embedded in matrix proteins (collagen, fibrin) and exposed to biomaterials enables quantifying collagen I (Western blot) and collagen I/III (histochemical staining) (Jannasch et al., 2019). Sircol and Fastin assays quantify collagen and elastin in rat dermal fibroblast–alveolar macrophage co-cultures in agarose gels contacting polyamide with modified chemistries (Damanik et al., 2014).
Adverse outcome: fibrotic capsule formation
After preceding key events, a collagenous, largely avascular capsule envelops the biomaterial within 2–4 weeks after implantation (Kyriakides et al., 2004; Anderson et al., 2008). At this stage, the local response stabilizes, and inflammation subsides. However, this fibrotic capsule can isolate the device from surrounding tissue, impair performance, and ultimately render the implant nonfunctional (Sudarsanam et al., 2024).
Although capsule thickness is the benchmark in cited literature, the threshold of capsule formation with observed adverse effect on medical device or patient is decisive for regulation. While the causality is shown, quantitative correlation of capsule formation to clinical adverse outcomes goes beyond this work’s scope.
Discussion
This perspective initially applies the AOP framework to the FBR. The macrophage-centered AOP maps material–host interactions into key events culminating in fibrotic encapsulation. This structure may guide early screening of biomaterials for low-FBR potential, promote methodology development anchored to key events, and provide assay templates to improve standardization across studies. This aligns with efforts to build AOPs for materials and nanomaterials (Halappanavar et al., 2020; Beasley et al., 2022).
Uncertainties remain and require targeted research. Key event relationships remain unresolved, particularly the transition from macrophage activation to FBGC formation and macrophage–fibroblast crosstalk mechanisms (Witherel et al., 2019). Lymphocyte impact is not addressed due to conflicting data: some studies report macrophage modulation and B-cell chemotaxis (Chang et al., 2009; Doloff et al., 2017), while others indicate minimal involvement (Kyriakides et al., 2022; Rodriguez et al., 2009).
Several studies implicate cytokines, growth factors, and chemokines in capsule formation, yet their spatial and temporal distribution remain incompletely defined (Higgins et al., 2009). Progress from transcriptomics (Liang et al., 2024; Liu et al., 2022; Larsen et al., 2025), proteomics (Schoberleitner et al., 2023), and cell painting (Klinge et al., 2020) is encouraging, but more studies are needed for robust data. Large-scale screenings of biomaterial libraries to uncover quantitative structure–function relationships remain lacking, although initial profiling of polymer libraries is promising (Rostam et al., 2020).
Factors beyond host–material interactions influence FBR and are outside this AOP. Examples include patient-specific variables such as age and radiation, which affect capsular contracture in breast implants (Bachour et al., 2018). Biofilm impact in clinical context is highly controversial (Poppler et al., 2015). Implantation method and site affect FBR. Subcutaneous or peritoneal sites often achieve better outcomes than fat or muscle compartments (Kalashnikov et al., 2025).
Despite uncertainties, novel biomaterials are entering clinical development. To implement them in medical devices, biocompatibility testing must be sensitive to immunomodulation and FBR. As Anderson emphasized, ISO 10993 is a living document, and biocompatibility assessment is evolving with biomaterial features (Anderson, 2016). Therefore, advanced medical devices require appropriate FBR screening of immunomodulating biomaterials to ensure biological safety.
Investigators in biomaterials toxicology are encouraged to address data gaps identified here and build evidence needed for OECD-level acceptance of an AOP for FBR. Integrating spatial omics and imaging is crucial to fully understand and map cellular signals around implants. Coupling in vitro and in vivo data with clinical outcomes of biomaterials forms an integrated approach and can establish quantitative key event relationships. Curated datasets will accelerate AOP refinement and comparability across studies.
Reaching these goals will enable a defined approach for FBR assessment in regulatory toxicology anchored to an AOP. Thereby, we may predict how material properties influence encapsulation and engineer devices toward a favorable, low-FBR outcome. This will render biocompatibility assessment more mechanistic and human-relevant, supporting safe translation of next-generation biomaterials.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.
Author contributions
TM: Writing – original draft, Visualization, Investigation, Writing – review and editing. SK: Writing – review and editing, Supervision. JS: Supervision, Writing – review and editing, Funding acquisition.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This project has received funding from the European Union’s Horizon Europe Framework Program under grant agreement number 101058554 NOVA. This work was co-funded by the Swiss State Secretariat for Education, Research and Innovation (SERI) and the United Kingdom Research and Innovation (UKRI) under the United Kingdom government’s Horizon Europe funding guarantee grant number 10042534 and grant number 10055606.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was used in the creation of this manuscript. FhGenie (model: Open AI GPT, version: GPT-5, source: FhGenie platform) was used solely to shorten and edit the manuscript text. FhGenie is not listed as an author. All AI-edited content was checked for factual accuracy and plagiarism. The final prompts are provided in the Supplementary Material.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/ftox.2026.1735871/full#supplementary-material
References
Al-Khoury, H., Espinosa-Cano, E., Aguilar, M. R., Román, J. S., Syrowatka, F., Schmidt, G., et al. (2019). Anti-inflammatory surface coatings based on polyelectrolyte multilayers of heparin and polycationic nanoparticles of naproxen-bearing polymeric drugs. Biomacromolecules 20, 4015–4025. doi:10.1021/acs.biomac.9b01098
Álvarez-Ortega, O., Ruiz-Ramírez, L. R., Garibay-Alvarado, J. A., Donohue-Cornejo, A., Espinosa-Cristóbal, L. F., Cuevas-González, J. C., et al. (2021). Preliminary biocompatibility tests of Poly-ε-Caprolactone/Silver nanofibers in wistar rats. Polym. (Basel) 13. doi:10.3390/polym13071135
Amer, L. D., Saleh, L. S., Walker, C., Thomas, S., Janssen, W. J., Alper, S., et al. (2019). Inflammation via myeloid differentiation primary response gene 88 signaling mediates the fibrotic response to implantable synthetic poly(ethylene glycol) hydrogels. Acta Biomater. 100, 105–117. doi:10.1016/j.actbio.2019.09.043
Anderson, J. M. (2016). Future challenges in the in vitro and in vivo evaluation of biomaterial biocompatibility. Regen. Biomater. 3, 73–77. doi:10.1093/rb/rbw001
Anderson, J. M., Cook, G., Costerton, B., Hanson, S. R., Hensten-Pettersen, A., Jacobsen, N., et al. (1996). “Host reactions to biomaterials and their evaluation,” in Biomaterials science (Elsevier), 293–X.
Anderson, J. M., Rodriguez, A., and Chang, D. T. (2008). Foreign body reaction to biomaterials. Semin. Immunol. 20, 86–100. doi:10.1016/j.smim.2007.11.004
Avula, M. N., Rao, A. N., McGill, L. D., Grainger, D. W., and Solzbacher, F. (2014). Foreign body response to subcutaneous biomaterial implants in a mast cell-deficient kit(w-Sh) murine model. Acta Biomater. 10, 1856–1863. doi:10.1016/j.actbio.2013.12.056
Bachour, Y., Bargon, C. A., Blok, C. J. M. de, Ket, J. C. F., Ritt, M. J. P. F., and Niessen, F. B. (2018). Risk factors for developing capsular contracture in women after breast implant surgery: a systematic review of the literature. J. Plast. Reconstr. Aesthet. Surg. 71, e29–e48. doi:10.1016/j.bjps.2018.05.022
Bae, H.-S., Son, H.-Y., Lee, J. P., Chang, H., and Park, J.-U. (2018). The role of periostin in capsule formation on silicone implants. Biomed. Res. Int. 2018, 3167037. doi:10.1155/2018/3167037
Baker, J. L., Chandler, M. L., and LeVier, R. R. (1981). Occurrence and activity of myofibroblasts in human capsular tissue surrounding mammary implants. Plast. Reconstr. Surg. 68, 905–912. doi:10.1097/00006534-198112000-00010
Balabiyev, A., Podolnikova, N. P., Kilbourne, J. A., Baluch, D. P., Lowry, D., Zare, A., et al. (2021). Fibrin polymer on the surface of biomaterial implants drives the foreign body reaction. Biomaterials 277, 121087. doi:10.1016/j.biomaterials.2021.121087
Beasley, J.-M. T., Korn, D. R., Popov, K. I., Dumproff, R. L., Sessions, Z. L., Rath, M. K., et al. (2022). Integrated approach to elucidate metal-implant related adverse outcome pathways. Regul. Toxicol. Pharmacol. 136, 105277. doi:10.1016/j.yrtph.2022.105277
Blackman, S. A., Miles, D., Suresh, J., Calve, S., and Bryant, S. J. (2024). Cell- and serum-derived proteins act as DAMPs to activate RAW 264.7 macrophage-like cells on silicone implants. ACS Biomater. Sci. Eng. 10, 1418–1434. doi:10.1021/acsbiomaterials.3c01393
Brodbeck, W. G., Shive, M. S., Colton, E., Nakayama, Y., Matsuda, T., and Anderson, J. M. (2001). Influence of biomaterial surface chemistry on the apoptosis of adherent cells. J. Biomed. Mater Res. 55, 661–668. doi:10.1002/1097-4636(20010615)55:4<661:AID-JBM1061>3.0.CO;2-F
Brodbeck, W. G., Nakayama, Y., Matsuda, T., Colton, E., Ziats, N. P., and Anderson, J. M. (2002). Biomaterial surface chemistry dictates adherent monocyte/macrophage cytokine expression in vitro. Cytokine 18, 311–319. doi:10.1006/cyto.2002.1048
Brown, B. N., and Badylak, S. F. (2013). Expanded applications, shifting paradigms and an improved understanding of host-biomaterial interactions. Acta Biomater. 9, 4948–4955. doi:10.1016/j.actbio.2012.10.025
Brown, B. N., Londono, R., Tottey, S., Zhang, L., Kukla, K. A., Wolf, M. T., et al. (2012). Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials. Acta Biomater. 8, 978–987. doi:10.1016/j.actbio.2011.11.031
Brown, B. N., Ratner, B. D., Goodman, S. B., Amar, S., and Badylak, S. F. (2012). Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials 33, 3792–3802. doi:10.1016/j.biomaterials.2012.02.034
Carnicer-Lombarte, A., Chen, S.-T., Malliaras, G. G., and Barone, D. G. (2021). Foreign body reaction to implanted biomaterials and its impact in nerve neuroprosthetics. Front. Bioeng. Biotechnol. 9, 622524. doi:10.3389/fbioe.2021.622524
Chandorkar, Y., K, R., and Basu, B. (2019). The foreign body response demystified. ACS Biomater. Sci. Eng. 5, 19–44. doi:10.1021/acsbiomaterials.8b00252
Chang, D. T., Jones, J. A., Meyerson, H., Colton, E., Kwon, I. K., Matsuda, T., et al. (2008). Lymphocyte/macrophage interactions: biomaterial surface-dependent cytokine, chemokine, and matrix protein production. J. Biomed. Mater Res. A 87, 676–687. doi:10.1002/jbm.a.31630
Chang, D. T., Colton, E., and Anderson, J. M. (2009). Paracrine and juxtacrine lymphocyte enhancement of adherent macrophage and foreign body giant cell activation. J. Biomed. Mater Res. A 89, 490–498. doi:10.1002/jbm.a.31981
Christenson, E. M., Dadsetan, M., and Hiltner, A. (2005). Biostability and macrophage-mediated foreign body reaction of silicone-modified polyurethanes. J. Biomed. Mater Res. A 74, 141–155. doi:10.1002/jbm.a.30317
Clauzel, J., Colitti, N., Combeau, M., Labriji, W., Robert, L., Brilhault, A., et al. (2024). In vivo biocompatibility assessment of 3D printed bioresorbable polymers for brain tissue regeneration. A feasibility study. Regen. Ther. 26, 941–955. doi:10.1016/j.reth.2024.10.004
Coleman, D. J., Sharpe, D. T., Naylor, I. L., Chander, C. L., and Cross, S. E. (1993). The role of the contractile fibroblast in the capsules around tissue expanders and implants. Br. J. Plast. Surg. 46, 547–556. doi:10.1016/0007-1226(93)90104-j
Damanik, F. F. R., Rothuizen, T. C., van Blitterswijk, C., Rotmans, J. I., and Moroni, L. (2014). Towards an in vitro model mimicking the foreign body response: tailoring the surface properties of biomaterials to modulate extracellular matrix. Sci. Rep. 4, 6325. doi:10.1038/srep06325
Doddridge, J. R., Banner, K. A., Hunter, N. B., and Beckmann, N. M. (2024). Foreign body giant cell reaction due to durolane (hyaluronic acid derivative) injection - a case report. Skelet. Radiol. 54, 1359–1364. doi:10.1007/s00256-024-04824-y
Doloff, J. C., Veiseh, O., Vegas, A. J., Tam, H. H., Farah, S., Ma, M., et al. (2017). Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates. Nat. Mater 16, 671–680. doi:10.1038/nmat4866
Dondossola, E., Holzapfel, B. M., Alexander, S., Filippini, S., Hutmacher, D. W., and Friedl, P. (2016). Examination of the foreign body response to biomaterials by nonlinear intravital microscopy. Nat. Biomed. Eng. 1. doi:10.1038/s41551-016-0007
Eslami-Kaliji, F., Hedayat Nia, N., Lakey, J. R. T., Smink, A. M., and Mohammadi, M. (2023). Mechanisms of foreign body giant cell formation in response to implantable biomaterials. Polym. (Basel) 15, 1313. doi:10.3390/polym15051313
Fatkhudinov, T., Tsedik, L., Arutyunyan, I., Lokhonina, A., Makarov, A., Korshunov, A., et al. (2019). Evaluation of resorbable polydioxanone and polyglycolic acid meshes in a rat model of ventral hernia repair. J. Biomed. Mater Res. B Appl. Biomater. 107, 652–663. doi:10.1002/jbm.b.34158
Foggia, M. J., Quevedo, R. V., and Hansen, M. R. (2019). Intracochlear fibrosis and the foreign body response to cochlear implant biomaterials. Laryngoscope Investig. Otolaryngol. 4, 678–683. doi:10.1002/lio2.329
Franz, S., Rammelt, S., Scharnweber, D., and Simon, J. C. (2011). Immune responses to implants - a review of the implications for the design of immunomodulatory biomaterials. Biomaterials 32, 6692–6709. doi:10.1016/j.biomaterials.2011.05.078
Grotenhuis, N., Bayon, Y., Lange, J. F., van Osch, G. J. V. M., and Bastiaansen-Jenniskens, Y. M. (2013). A culture model to analyze the acute biomaterial-dependent reaction of human primary macrophages. Biochem. Biophys. Res. Commun. 433, 115–120. doi:10.1016/j.bbrc.2013.02.054
Halappanavar, S., van den Brule, S., Nymark, P., Gaté, L., Seidel, C., Valentino, S., et al. (2020). Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale. Part Fibre Toxicol. 17, 16. doi:10.1186/s12989-020-00344-4
Headon, H., Kasem, A., and Mokbel, K. (2015). Capsular contracture after breast augmentation: an update for clinical practice. Arch. Plast. Surg. 42, 532–543. doi:10.5999/aps.2015.42.5.532
Higgins, D. M., Basaraba, R. J., Hohnbaum, A. C., Lee, E. J., Grainger, D. W., and Gonzalez-Juarrero, M. (2009). Localized immunosuppressive environment in the foreign body response to implanted biomaterials. Am. Journal Pathology 175, 161–170. doi:10.2353/ajpath.2009.080962
Hinz, B., Celetta, G., Tomasek, J. J., Gabbiani, G., and Chaponnier, C. (2001). Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol. Biol. Cell 12, 2730–2741. doi:10.1091/mbc.12.9.2730
Holt, D. J., Chamberlain, L. M., and Grainger, D. W. (2010). Cell-cell signaling in co-cultures of macrophages and fibroblasts. Biomaterials 31, 9382–9394. doi:10.1016/j.biomaterials.2010.07.101
Hu, W. J., Eaton, J. W., Ugarova, T. P., and Tang, L. (2001). Molecular basis of biomaterial-mediated foreign body reactions. Blood 98, 1231–1238. doi:10.1182/blood.v98.4.1231
Hu, M., Liang, C., and Wang, D. (2024). Implantable bioelectrodes: challenges, strategies, and future directions. Biomater. Sci. 12, 270–287. doi:10.1039/d3bm01204b
Huang, Y.-J., Hung, K.-C., Hung, H.-S., and Hsu, S.-H. (2018). Modulation of macrophage phenotype by biodegradable polyurethane nanoparticles: possible relation between macrophage polarization and immune response of nanoparticles. ACS Appl. Mater Interfaces 10, 19436–19448. doi:10.1021/acsami.8b04718
Işıktekin, E., Acuner, B., Torun Karadere, M., Doğan Gün, B., and Kargı, A. E. (2025). The effect of suture materials on the development of capsular contracture in silicone implants. Aesthet. Surg. J. 45, 1198–1205. doi:10.1093/asj/sjaf140
ISO (2006). Biological evaluation of medical devices – part 20: principles and methods for immunotoxicology testing of medical devices. Geneva, Switzerland: ISO, 10993–10996.
ISO (2016). Biological evaluation of medical devices – part 6: tests for local effects after implantation. Geneva, Switzerland: ISO, 10993–10996.
ISO (2021). Biological evaluation of medical devices – part 20: principles and methods for immunotoxicology testing of medical devices. Geneva, Switzerland: ISO, 10993–10996.
Jannasch, M., Gaetzner, S., Weigel, T., Walles, H., Schmitz, T., and Hansmann, J. (2017a). A comparative multi-parametric in vitro model identifies the power of test conditions to predict the fibrotic tendency of a biomaterial. Sci. Rep. 7, 1689. doi:10.1038/s41598-017-01584-9
Jannasch, M., Weigel, T., Engelhardt, L., Wiezoreck, J., Gaetzner, S., Walles, H., et al. (2017b). In vitro chemotaxis and tissue remodeling assays quantitatively characterize foreign body reaction. ALTEX 34, 253–266. doi:10.14573/altex.1610071
Jannasch, M., Gaetzner, S., Groeber, F., Weigel, T., Walles, H., Schmitz, T., et al. (2019). An in vitro model mimics the contact of biomaterials to blood components and the reaction of surrounding soft tissue. Acta Biomater. 89, 227–241. doi:10.1016/j.actbio.2019.03.029
Jones, J. A., Chang, D. T., Meyerson, H., Colton, E., Kwon, I. K., Matsuda, T., et al. (2007). Proteomic analysis and quantification of cytokines and chemokines from biomaterial surface-adherent macrophages and foreign body giant cells. J. Biomed. Mater. Res. A 83, 585–596. doi:10.1002/jbm.a.31221
Kalashnikov, N., Barralet, J., and Vorstenbosch, J. (2025). Implantable medical devices, biomaterials, and the foreign body response: a surgical perspective. J. Biomed. Mater. Res. A 113, e37983. doi:10.1002/jbm.a.37983
Khandwekar, A., and Rho, C. K. (2012). Modulation of cellular responses on engineered polyurethane implants. J. Biomed. Mater. Res. A 100, 2211–2222. doi:10.1002/jbm.a.34146
Kim, J. H., Nam, S. E., Sung, J. Y., Song, K. Y., Bang, B. S., and Lee, E. K. (2022). The value of capsule thickness on breast ultrasound as an indicator of the severity of capsular contracture and its correlation with the baker classification. Aesthetic Plast. Surg. 46, 621–629. doi:10.1007/s00266-021-02544-5
Klinge, U., Dievernich, A., Tolba, R., Klosterhalfen, B., and Davies, L. (2020). CD68+ macrophages as crucial components of the foreign body reaction demonstrate an unconventional pattern of functional markers quantified by analysis with double fluorescence staining. J. Biomed. Mater. Res. B Appl. Biomater. 108, 3134–3146. doi:10.1002/jbm.b.34639
Klopfleisch, R. (2016). Macrophage reaction against biomaterials in the mouse model - phenotypes, functions and markers. Acta Biomater. 43, 3–13. doi:10.1016/j.actbio.2016.07.003
Kondyurina, I., and Kondyurin, A. (2023). Foreign body reaction (immune response) for artificial implants can be avoided: an example of polyurethane in mice for 1 week. J. Funct. Biomater. 14, 432. doi:10.3390/jfb14080432
Kyriakides, T. R., Foster, M. J., Keeney, G. E., Tsai, A., Giachelli, C. M., Clark-Lewis, I., et al. (2004). The CC chemokine ligand, CCL2/MCP1, participates in macrophage fusion and foreign body giant cell formation. Am. Journal Pathology 165, 2157–2166. doi:10.1016/S0002-9440(10)63265-8
Kyriakides, T. R., Kim, H.-J., Zheng, C., Harkins, L., Tao, W., and Deschenes, E. (2022). Foreign body response to synthetic polymer biomaterials and the role of adaptive immunity. Biomed. Mater. 17. doi:10.1088/1748-605X/ac5574
Larsen, A., Timmermann, A. M., Kring, M., Weltz, T. K., Ørholt, M., Vester-Glowinski, P., et al. (2024). A histological assessment tool for breast implant capsules validated in 480 patients with and without capsular contracture. Aesthetic Plast. Surg. 49, 497–508. doi:10.1007/s00266-024-04128-5
Larsen, A., Fritz, B. G., Weltz, T. K., Tran, J. V. Q., Bak, E. E. F., Hemmingsen, M. N., et al. (2025). Transcriptome of capsular contracture around breast implants mimics allograft rejection: a matched case-control study. Plast. Reconstr. Surg. 156, 59e–72e. doi:10.1097/PRS.0000000000011938
Lehká, K., Starigazdová, J., Mrázek, J., Nešporová, K., Šimek, M., Pavlík, V., et al. (2023). An in vitro model that mimics the foreign body response in the peritoneum: study of the bioadhesive properties of HA-based materials. Carbohydr. Polym. 310, 120701. doi:10.1016/j.carbpol.2023.120701
Liang, N. E., Parker, J. B., Lu, J. M., Januszyk, M., Wan, D. C., Griffin, M., et al. (2024). Understanding the foreign body response via single-cell meta-analysis. Biol. (Basel) 13, 540. doi:10.3390/biology13070540
Liu, W., Xiong, S., Du, J., Song, Y., Wang, T., Zhang, Y., et al. (2022). Deciphering key foreign body reaction-related transcription factors and genes through transcriptome analysis. Front. Mol. Biosci. 9, 843391. doi:10.3389/fmolb.2022.843391
Lotti, F., Ranieri, F., Vadalà, G., Zollo, L., and Di Pino, G. (2017). Invasive intraneural interfaces: foreign body reaction issues. Front. Neurosci. 11, 497. doi:10.3389/fnins.2017.00497
Majd, H., Scherer, S. S., Boo, S., Ramondetti, S., Cambridge, E., Raffoul, W., et al. (2015). Novel micropatterns mechanically control fibrotic reactions at the surface of silicone implants. Biomaterials 54, 136–147. doi:10.1016/j.biomaterials.2015.03.027
McClatchey, P. M., McClain, E. S., Williams, I. M., Malabanan, C. M., James, F. D., Lord, P. C., et al. (2019). Fibrotic encapsulation is the dominant source of continuous glucose monitor delays. Diabetes 68, 1892–1901. doi:10.2337/db19-0229
McNally, A. K., Macewan, S. R., and Anderson, J. M. (2008). Foreign body-type multinucleated giant cell formation requires protein kinase C beta, delta, and zeta. Exp. Mol. Pathol. 84, 37–45. doi:10.1016/j.yexmp.2007.10.005
Milde, R., Ritter, J., Tennent, G. A., Loesch, A., Martinez, F. O., Gordon, S., et al. (2015). Multinucleated giant cells are specialized for complement-mediated phagocytosis and large target destruction. Cell Rep. 13, 1937–1948. doi:10.1016/j.celrep.2015.10.065
Mooney, J. E., Rolfe, B. E., Osborne, G. W., Sester, D. P., van Rooijen, N., Campbell, G. R., et al. (2010). Cellular plasticity of inflammatory myeloid cells in the peritoneal foreign body response. Am. Journal Pathology 176, 369–380. doi:10.2353/ajpath.2010.090545
Moore, L. B., Sawyer, A. J., Charokopos, A., Skokos, E. A., and Kyriakides, T. R. (2015). Loss of monocyte chemoattractant protein-1 alters macrophage polarization and reduces NFκB activation in the foreign body response. Acta Biomater. 11, 37–47. doi:10.1016/j.actbio.2014.09.022
Morris, A. H., Mahal, R. S., Udell, J., Wu, M., and Kyriakides, T. R. (2017). Multicompartment drug release system for dynamic modulation of tissue responses. Adv. Healthc. Mater. 6. doi:10.1002/adhm.201700370
Noskovicova, N., Hinz, B., and Pakshir, P. (2021a). Implant fibrosis and the underappreciated role of myofibroblasts in the foreign body reaction. Cells 10, 1794. doi:10.3390/cells10071794
Noskovicova, N., Schuster, R., van Putten, S., Ezzo, M., Koehler, A., Boo, S., et al. (2021b). Suppression of the fibrotic encapsulation of silicone implants by inhibiting the mechanical activation of pro-fibrotic TGF-β. Nat. Biomed. Eng. 5, 1437–1456. doi:10.1038/s41551-021-00722-z
Novak, M. T., and Reichert, W. M. (2015). Modeling the physiological factors affecting glucose sensor function in vivo. J. Diabetes Sci. Technol. 9, 993–998. doi:10.1177/1932296815593094
Pakshir, P., and Hinz, B. (2018). The big five in fibrosis: macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. 68-69, 81–93. doi:10.1016/j.matbio.2018.01.019
Park, S., Park, M., Kim, B. H., Lee, J. E., Park, H. J., Lee, S. H., et al. (2015). Acute suppression of TGF-ß with local, sustained release of tranilast against the formation of fibrous capsules around silicone implants. J. Control Release 200, 125–137. doi:10.1016/j.jconrel.2014.12.021
Poppler, L., Cohen, J., Dolen, U. C., Schriefer, A. E., Tenenbaum, M. M., Deeken, C., et al. (2015). Histologic, molecular, and clinical evaluation of explanted breast prostheses, capsules, and acellular dermal matrices for bacteria. Aesthet. Surg. J. 35, 653–668. doi:10.1093/asj/sjv017
Ratner, B. D. (2016). A pore way to heal and regenerate: 21st century thinking on biocompatibility. Regen. Biomater. 3, 107–110. doi:10.1093/rb/rbw006
Robotti, F., Bottan, S., Fraschetti, F., Mallone, A., Pellegrini, G., Lindenblatt, N., et al. (2018). A micron-scale surface topography design reducing cell adhesion to implanted materials. Sci. Rep. 8, 10887. doi:10.1038/s41598-018-29167-2
Rodriguez, A., Macewan, S. R., Meyerson, H., Kirk, J. T., and Anderson, J. M. (2009). The foreign body reaction in T-cell-deficient mice. J. Biomed. Mater. Res. A 90, 106–113. doi:10.1002/jbm.a.32050
Rostam, H. M., Singh, S., Vrana, N. E., Alexander, M. R., and Ghaemmaghami, A. M. (2015). Impact of surface chemistry and topography on the function of antigen presenting cells. Biomater. Sci. 3, 424–441. doi:10.1039/c4bm00375f
Rostam, H. M., Fisher, L. E., Hook, A. L., Burroughs, L., Luckett, J. C., Figueredo, G. P., et al. (2020). Immune-instructive polymers control macrophage phenotype and modulate the foreign body response in vivo. Matter 2, 1564–1581. doi:10.1016/j.matt.2020.03.018
Rujitanaroj, P., Jao, B., Yang, J., Wang, F., Anderson, J. M., Wang, J., et al. (2013). Controlling fibrous capsule formation through long-term down-regulation of collagen type I (COL1A1) expression by nanofiber-mediated siRNA gene silencing. Acta Biomater. 9, 4513–4524. doi:10.1016/j.actbio.2012.09.029
Saleh, L. S., and Bryant, S. J. (2017). In vitro and in vivo models for assessing the host response to biomaterials. Drug Discov. Today Dis. Models 24, 13–21. doi:10.1016/j.ddmod.2018.04.002
Saleh, L. S., Amer, L. D., Thompson, B. J., Danhorn, T., Knapp, J. R., Gibbings, S. L., et al. (2022). Mapping macrophage polarization and origin during the progression of the foreign body response to a poly(ethylene glycol) hydrogel implant. Adv. Healthc. Mater. 11, e2102209. doi:10.1002/adhm.202102209
Schoberleitner, I., Faserl, K., Sarg, B., Egle, D., Brunner, C., and Wolfram, D. (2023). Quantitative proteomic characterization of foreign body response towards silicone breast implants identifies chronological disease-relevant biomarker dynamics. Biomolecules 13, 305. doi:10.3390/biom13020305
Shayan, M., Padmanabhan, J., Morris, A. H., Cheung, B., Smith, R., Schroers, J., et al. (2018). Nanopatterned bulk metallic glass-based biomaterials modulate macrophage polarization. Acta Biomater. 75, 427–438. doi:10.1016/j.actbio.2018.05.051
Simoni, E., Gentilin, E., Candito, M., Borile, G., Romanato, F., Chicca, M., et al. (2020). Immune response after cochlear implantation. Front. Neurol. 11, 341. doi:10.3389/fneur.2020.00341
Stewart, C. L., Hook, A. L., Zelzer, M., Marlow, M., and Piccinini, A. M. (2024). Cellular and microenvironmental cues that promote macrophage fusion and foreign body response. Front. Immunol. 15, 1411872. doi:10.3389/fimmu.2024.1411872
Sudarsanam, P. K., Alsema, E. C., Beijer, N. R. M., van Kooten, T., and Boer, J. de (2024). Beyond encapsulation: exploring macrophage-fibroblast cross talk in implant-induced fibrosis. Tissue Eng. Part B Rev. 30, 596–606. doi:10.1089/ten.TEB.2023.0300
Svobodová, L., Rucki, M., Vlkova, A., Kejlova, K., Jírová, D., Dvorakova, M., et al. (2021). Sensitization potential of medical devices detected by in vitro and in vivo methods. ALTEX 38, 419–430. doi:10.14573/altex.2008142
Swartzlander, M. D., Barnes, C. A., Blakney, A. K., Kaar, J. L., Kyriakides, T. R., and Bryant, S. J. (2015). Linking the foreign body response and protein adsorption to PEG-based hydrogels using proteomics. Biomaterials 41, 26–36. doi:10.1016/j.biomaterials.2014.11.026
Thompson, B. J., Saleh, L. S., Carillion, E. L., Alper, S., and Bryant, S. J. (2025). Damage associated molecular patterns (DAMPs) mediate the foreign body response to poly(ethylene glycol) diacrylate hydrogels via toll like receptors. ACS Biomater. Sci. Eng. 11, 4128–4138. doi:10.1021/acsbiomaterials.4c01984
Trout, K. L., and Holian, A. (2020). Multinucleated giant cell phenotype in response to stimulation. Immunobiology 225, 151952. doi:10.1016/j.imbio.2020.151952
Williams, D. F. (2008). On the mechanisms of biocompatibility. Biomaterials 29, 2941–2953. doi:10.1016/j.biomaterials.2008.04.023
Witherel, C. E., Graney, P. L., and Spiller, K. L. (2018). In vitro model of macrophage-biomaterial interactions. Methods Mol. Biol. 1758, 161–176. doi:10.1007/978-1-4939-7741-3_13
Witherel, C. E., Abebayehu, D., Barker, T. H., and Spiller, K. L. (2019). Macrophage and fibroblast interactions in biomaterial-mediated fibrosis. Adv. Healthc. Mater. 8, e1801451. doi:10.1002/adhm.201801451
Wolf, M. T., Dearth, C. L., Ranallo, C. A., LoPresti, S. T., Carey, L. E., Daly, K. A., et al. (2014). Macrophage polarization in response to ECM coated polypropylene mesh. Biomaterials 35, 6838–6849. doi:10.1016/j.biomaterials.2014.04.115
Wynn, T. A. (2008). Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199–210. doi:10.1002/path.2277
Yang, J., Jao, B., McNally, A. K., and Anderson, J. M. (2014). In vivo quantitative and qualitative assessment of foreign body giant cell formation on biomaterials in mice deficient in natural killer lymphocyte subsets, mast cells, or the interleukin-4 receptorα and in severe combined immunodeficient mice. J. Biomed. Mater. Res. A 102, 2017–2023. doi:10.1002/jbm.a.35152
Yang, L., Wang, P., Zhang, Y., Zhou, J., Bi, X., Qian, Z., et al. (2025). Hybrid cell membrane coating orchestrates foreign-body reactions, anti-adhesion, and pro-regeneration in abdominal wall reconstruction. Biomaterials 321, 123289. doi:10.1016/j.biomaterials.2025.123289
Yu, T., Wang, W., Nassiri, S., Kwan, T., Dang, C., Liu, W., et al. (2016). Temporal and spatial distribution of macrophage phenotype markers in the foreign body response to glutaraldehyde-crosslinked gelatin hydrogels. J. Biomater. Sci. Polym. Ed. 27, 721–742. doi:10.1080/09205063.2016.1155881
Zeplin, P. H., Larena-Avellaneda, A., Jordan, M., Laske, M., and Schmidt, K. (2010a). Phosphorylcholine-coated silicone implants: effect on inflammatory response and fibrous capsule formation. Ann. Plast. Surg. 65, 560–564. doi:10.1097/SAP.0b013e3181d6e326
Zeplin, P. H., Larena-Avellaneda, A., and Schmidt, K. (2010b). Surface modification of silicone breast implants by binding the antifibrotic drug halofuginone reduces capsular fibrosis. Plast. Reconstr. Surg. 126, 266–274. doi:10.1097/PRS.0b013e3181dbc313
Zhao, Q., Topham, N., Anderson, J. M., Hiltner, A., Lodoen, G., and Payet, C. R. (1991). Foreign-body giant cells and polyurethane biostability: in vivo correlation of cell adhesion and surface cracking. J. Biomed. Mater. Res. 25, 177–183. doi:10.1002/jbm.820250205
Zhou, G., Loppnow, H., and Groth, T. (2015). A macrophage/fibroblast co-culture system using a cell migration chamber to study inflammatory effects of biomaterials. Acta Biomater. 26, 54–63. doi:10.1016/j.actbio.2015.08.020
Keywords: adverse outcome pathway (AOP), biomaterials, foreign body reaction, immunotoxicology, ISO 10993, macropage, medical devices
Citation: Meseberg T, Kurz S and Spohn J (2026) Foreign body reaction: towards a macrophage-centered adverse outcome pathway for fibrotic encapsulation. Front. Toxicol. 8:1735871. doi: 10.3389/ftox.2026.1735871
Received: 30 October 2025; Accepted: 21 January 2026;
Published: 04 February 2026.
Edited by:
Sara Bridio, Joint Research Centre (JRC), ItalyReviewed by:
Amy Madl, Valeo Sciences LLC, United StatesCopyright © 2026 Meseberg, Kurz and Spohn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Tom Meseberg, dG9tLm1lc2ViZXJnQGlrdHMuZnJhdW5ob2Zlci5kZQ==