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Cited by 927Immune cells in cancerTissue Engineering and Regenerative MedicineWound Healing and Treatments

Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine

Open access
Brown, Bryan N., Ratner, Buddy D., Goodman, Stuart B., Amar, Salomon, Badylak, Stephen F.·2012·Biomaterials
DOI 10.1016/j.biomaterials.2012.02.034PMC PMC3727238
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Abstract

The host response to biomaterials has been studied for decades. Largely, the interaction of host immune cells, macrophages in particular, with implanted materials has been considered to be a precursor to granulation tissue formation, the classic foreign body reaction, and eventual encapsulation with associated negative impacts upon device functionality. However, more recently, it has been shown that macrophages, depending upon context dependent polarization profiles, are capable of affecting both detrimental and beneficial outcomes in a number of disease processes and in tissue remodeling following injury. Herein, the diverse roles played by macrophages in these processes are discussed in addition to the potential manipulation of macrophage effector mechanisms as a strategy for promoting site-appropriate and constructive tissue remodeling as opposed to deleterious persistent inflammation and scar tissue formation.

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Written from the paper’s full text.

TL;DR

This review argues that macrophages are not simply drivers of the foreign body reaction; their context-dependent M1/M2 polarization can determine whether injury or implanted biomaterials lead to scarring or constructive tissue remodeling. It proposes that biomaterial properties and regenerative strategies could be designed to steer macrophage phenotype toward M2-like, pro-repair states.

Key findings

  • Macrophages are plastic and exist along an M1/M2 continuum rather than as fixed subsets. M1, or classically activated, macrophages are induced by IFNγ alone or with LPS/TNFα and are pro-inflammatory; M2, or alternatively activated, macrophages are induced by IL-4, IL-13, IL-10, immune complexes, glucocorticoids, or vitamin D3 and are associated with Th2-like, pro-repair responses. A timely M1-to-M2 switch appears necessary for functional remodeling, while failure to resolve polarization is linked to cancer, atherosclerosis, obesity/insulin resistance, periodontal disease, and fibrosis.
  • In tissue remodeling, the default mammalian response to injury often ends in scar tissue. Skin wound healing showed early upregulation of a mixed M1/M2 gene cluster (11 M1 genes and 7 M2 genes) and later upregulation of a predominantly M2 cluster (1 M1 gene and 9 M2 genes). Skeletal muscle repair requires an M1-to-M2 transition; blocking M2-associated gene expression in a mouse necrotic muscle injury model produced highly fibrotic tissue and decreased myofiber size, whereas wild-type mice recovered. In spinal cord injury, a predominantly M1 response persisted, and M2-conditioned media improved neuronal survival and neurite extension compared with M1-conditioned media.
  • Following biomaterial implantation, macrophage phenotype is associated with outcome. Retrieved periprosthetic tissues from loose total joint replacements with osteolysis showed predominantly M1 macrophages, while synovium from osteoarthritic joints treated by primary joint replacement showed more M2 macrophages. Porous synthetic implants with 30–40 mm pores healed with less fibrosis, greater vascularity, and higher M2/M1 ratios than non-porous controls. Extracellular matrix scaffolds promoted a switch from predominantly M1 cells immediately after implantation to an M2-enriched population by 7–14 days; crosslinking that delayed degradation inhibited the M2 response and led to scar tissue.
  • Adipose tissue macrophages illustrate disease-associated polarization shifts: they can make up as much as 10% of cells in lean tissue and as much as 40% in obese tissue, with M2-like cells in lean states and strongly M1-like cells in obesity.

Methods

  • Narrative review, not a primary study; no new experiments, systematic search, or meta-analysis are described.
  • The paper synthesizes literature on macrophage biology, disease pathogenesis, tissue remodeling after injury, and host responses to biomaterials, using selected examples from animal models, human tissue retrieval studies, and in vitro work.
  • Main analysis is conceptual and thematic, organizing evidence around M1/M2 polarization, plasticity, and the potential for biomaterials to modulate macrophage phenotype.

Limitations

  • Stated: the exact factors and mechanisms controlling macrophage differentiation and polarization switching are not fully identified; few studies have specifically evaluated macrophage polarization after biomaterial implantation; further studies are needed to define M1/M2 involvement in conditions such as periodontal disease and to develop strategies for controlling phenotype.
  • Evident: as a narrative review, the selection of examples is not systematic and no quantitative synthesis is provided; many cited findings come from animal models or in vitro systems, which limits direct clinical generalizability.

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Integrity signals

Registry

Crossref · 10.1016/j.biomaterials.2012.02.034

Cites

161 of 161 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 198 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    Macrophages, depending on context-dependent polarization profiles, can affect both detrimental and beneficial outcomes in disease processes and in tissue remodeling after injury.

    “it has been shown that macrophages, depending upon context dependent polarization profiles, are capable of affecting both detrimental and beneficial outcomes in a number of disease processes and in tissue remodeling following injury.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ultimate functional success or failure of implantable materials is a function of the host tissue response and associated remodeling at each anatomical site.
  • Premisecitation

    Macrophage phenotype occurs along a continuum between M1 and M2 extremes.

    “Rather, macrophage phenotype has been described as occurring along a continuum between the M1 and M2 extremes [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Mosser, 2008, Exploring the full spectrum of macrophage activation, Nat Rev Immunol source

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  • Premisecitation

    Macrophages are a heterogeneous cell population with different markers and functions.

    “Macrophages, like the monocytes from which they derive, are a heterogeneous cell population each with different markers and functions [1,8–12].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [1] Gordon, 2005, Monocyte and macrophage heterogeneity, Nat Rev Immunol source

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    • cites [8] Mantovani, 2004, The chemokine system in diverse forms of macrophage activation and polarization, Trends Immunol source

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    • cites [9] Mantovani, 2002, Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes, Trends Immunol source

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    • cites [10] Mills, 2000, M-1/M-2 macrophages and the Th1/Th2 paradigm, J Immunol source

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    • cites [11] Mosser, 2003, The many faces of macrophage activation, J Leukoc Biol source

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    • cites [12] Mosser, 2008, Exploring the full spectrum of macrophage activation, Nat Rev Immunol source

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  • Premisecitation

    There is a well-established link between inflammatory cells, especially macrophages, and cancer.

    “Now commonly described as “smoldering inflammation”, these observations have led to a well-established link between inflammatory cells, macrophages in particular, and cancer [34–36].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] Balkwill, 2005, Smoldering and polarized inflammation in the initiation and promotion of malignant disease, Cancer Cell source

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    • cites [35] Mantovani, 2010, Macrophages, innate immunity and cancer: balance, tolerance, and diversity, Curr Opin Immunol source

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    • cites [36] Sica, 2008, Macrophage polarization in tumour progression, Semin Cancer Biol source

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  • Premisecitation

    The extrinsic pathway of tumorigenesis is initially characterized by a chronic pro-inflammatory environment from persistent microbial infection, autoimmune disease, or unknown etiology.

    “This “extrinsic pathway” is initially characterized by a chronic pro-inflammatory environment resulting from a persistent microbial infection, autoimmune disease, or other etiology of unknown origin [37,38].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Porta, 2011, Mechanisms linking pathogens-associated inflammation and cancer, Cancer Lett source

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    • cites [38] Mantovani, 2008, Cancer-related inflammation, Nature source

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  • Classified as probably not a substantial claim. 11
  • May combine two claims. 48
  • The quote only partly states this claim. 1

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    Premisenone given

    Macrophages assume diverse and context-dependent phenotypes defined by functional properties and gene expression.

    “Macrophages assume diverse and context dependent phenotypes, which are defined by their functional properties and patterns of gene expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Macrophages possess remarkable functional plasticity and can play both positive and negative roles in disease pathogenesis and tissue remodeling.

    “These studies indicate that macrophages possess remarkable functional plasticity and, therefore, can play both positive and negative roles in the pathogenesis of disease and tissue remodeling.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ultimate functional success or failure of implantable materials is a function of the host tissue response and associated remodeling at each anatomical site.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Polarized macrophages are broadly referred to as M1 or M2, mimicking Th1/Th2 nomenclature.

    “Broadly, polarized macrophages are referred to as having either an M1 or an M2 phenotype, mimicking the Th1/Th2 nomenclature which has been described for T helper cells [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Mills, 2000, M-1/M-2 macrophages and the Th1/Th2 paradigm, J Immunol source

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    Premisenone given

    M1 macrophages have a pro-inflammatory phenotype characterized by high IL-12 and IL-23, low IL-10, arginine metabolism, high iNOS, secretion of reactive oxygen/nitrogen intermediates and inflammatory cytokines, and Th1 effector roles.

    “In general, M1 activated macrophages express interleukin (IL)-12high, IL-23high, IL-10low; metabolize arginine, produce high levels of inducible nitric oxide synthase (iNOS); secrete toxic reactive oxygen and nitric oxygen intermediates and inflammatory cytokines such as IL-1β, IL-6, and TNFα; and are inducer and effector cells in Th1 type inflammatory responses.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    M2 macrophages include three sub-populations (M2a, M2b, M2c) with distinct inducers, markers, and functions.

    “While the term ‘M2’ encompasses all non-classically activated macrophages, M2 macrophages have been shown to include three well recognized sub-populations (M2a, M2b, and M2c), each with its own distinct inducers, markers, and functions.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Mantovani, 2004, The chemokine system in diverse forms of macrophage activation and polarization, Trends Immunol source

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    • cites [12] Mosser, 2008, Exploring the full spectrum of macrophage activation, Nat Rev Immunol source

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    • cites [13] Gordon, 2003, Alternative activation of macrophages, Nat Rev Immunol source

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  • May combine two claims.

    Premisecitation

    Macrophages have dynamic and plastic phenotypes that change with local microenvironmental signals, unlike lymphocytes whose phenotype is relatively fixed upon differentiation.

    “It has been shown that unlike lymphocytes, where cellular phenotype is relatively fixed upon differentiation, macrophages have dynamic and plastic phenotypes that change with local microenvironmental signals [5,14–16].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [5] Sunderkotter, 2004, Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response, J Immunol source

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    • cites [14] Stout, 2009, Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages, J Leukoc Biol source

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    • cites [15] Porcheray, 2005, Macrophage activation switching: an asset for the resolution of inflammation, Clin Exp Immunol source

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    • cites [16] Stout, 2005, Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences, J Immunol source

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  • May combine two claims.

    Premisenone given

    M2 macrophages have an anti-inflammatory phenotype characterized by low IL-12 and IL-23, high IL-10, high scavenger/mannose/galactose receptors, arginase production, and Th2 involvement.

    “M2 activated macrophages express IL-12low, IL-23low, and IL-10high; have high levels of scavenger, mannose, and galactose receptors; produce arginase in the place of arginine, subsequently producing ornithine and polyamines; and are involved in polarized Th2 reactions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    M1 macrophages are induced by IFNγ alone or with LPS or TNFα.

    “M1, or “classically activated” pro-inflammatory macrophages are induced by interferon (IFN)γ alone or in combination with lipopolysaccharide (LPS, endotoxin) or tumor necrosis factor (TNF)α.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    TAM profile leads to inability to mount tumor-destructive Th1 response, drives T-reg recruitment, and creates tumor-permissive environment.

    “This profile leads to an inability to mount a tumor-destructive Th1 type response while also driving the recruitment and development of T-regulatory cells (T-regs) and leading to a more tumor-permissive environment.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    TAMs are found largely in hypoxic tumor regions and drive angiogenic response required for tumor survival and metastasis.

    “Interestingly, TAMs are found largely within hypoxic regions of tumors and have been shown drive the angiogenic response that is required for tumor survival and metastasis [40,41].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Lin, 2006, Macrophages regulate the angiogenic switch in a mouse model of breast cancer, Cancer Res source

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    • cites [41] Lin, 2007, Tumor-associated macrophages press the angiogenic switch in breast cancer, Cancer Res source

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    Premisecitation

    TAMs produce large amounts of IL-10, low inflammatory cytokines/ROS, and have poor antigen presenting capabilities.

    “These cells, termed “tumor associated macrophages” (TAM), are characterized by production of large amounts of IL-10, low production of inflammatory cytokines and reactive oxygen intermediates, and poor antigen presenting capabilities.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Sica, 2008, Macrophage polarization in tumour progression, Semin Cancer Biol source

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    • cites [39] Porta, 2007, Tumor promotion by tumor-associated macrophages, Adv Exp Med Biol source

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    Premisecitation

    Chronic production of inflammatory mediators can lead to tumor cell proliferation/survival or genetic instability in normal cells, resulting in oncogene expression and immune suppressive cytokines.

    “The chronic production of large quantities of inflammatory mediators in these cases can lead, through a number of pathways, to tumor cell proliferation and survival or to the induction of genetic instabilities in normal cells, with resultant expression of oncogenes and production of immune suppressive cytokines [37,38].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Porta, 2011, Mechanisms linking pathogens-associated inflammation and cancer, Cancer Lett source

      Not checked in the free run.

    • cites [38] Mantovani, 2008, Cancer-related inflammation, Nature source

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  • May combine two claims.

    Premisecitation

    Initial infiltrating macrophage population in early atherosclerosis is heterogeneous but predominantly M2-like.

    “A number of recent studies have begun to assess the polarization profile of plaque infiltrating macrophages, suggesting that the initial infiltrating population in early atherosclerosis is heterogeneous, but possesses a predominantly M2-like phenotype [28,45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Bouhlel, 2007, PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties, Cell Metab source

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    • cites [45] Johnson, 2009, Macrophage heterogeneity in atherosclerotic plaques, Curr Opin Lipidol source

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    Premisecitation

    LPS-stimulated classically activated macrophages become TLR-tolerant and unable to produce similarly elevated pro-inflammatory cytokines upon second LPS exposure, but retain ability to produce anti-inflammatory cytokines like IL-10.

    “For example, in vitro experiments have shown that LPS stimulated, classically activated macrophages, become Toll-like receptor (TLR)-tolerant and unable to produce similarly elevated levels of pro-inflammatory cytokines upon second exposure to LPS [16–18].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Stout, 2005, Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences, J Immunol source

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    • cites [17] Biswas, 2009, Endotoxin tolerance: new mechanisms, molecules and clinical significance, Trends Immunol source

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    • cites [18] Foster, 2007, Gene-specific control of inflammation by TLR-induced chromatin modifications, Nature source

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  • May combine two claims.

    Premisecitation

    STAT1 and IRF5 are involved in M1 polarization/maintenance; STAT6, IRF4, CREB-C/EBPβ, and PPARγ are involved in M2 polarization/maintenance.

    “Specifically, STAT1 and IRF5 have been shown to be involved in polarization and maintenance of an M1 phenotype while STAT6, IRF4, CREB-C/EBPβ, and PPARγ are involved in polarization and maintenance of an M2 phenotype [23–30].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [23] Darnell, 1994, Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins, Science source

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    • cites [24] Ruffell, 2009, A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair, Proc Natl Acad Sci USA source

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    • cites [25] Satoh, 2010, The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection, Nat Immunol source

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    • cites [26] Takeda, 1996, Essential role of Stat6 in IL-4 signalling, Nature source

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    • cites [27] Ohmori, 1997, IL-4-induced STAT6 suppresses IFN-gamma-stimulated STAT1-dependent transcription in mouse macrophages, J Immunol source

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    • cites [28] Bouhlel, 2007, PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties, Cell Metab source

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    • cites [29] Odegaard, 2007, Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance, Nature source

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    • cites [30] Savitsky, 2010, Regulation of immunity and oncogenesis by the IRF transcription factor family, Cancer Immunol Immunother source

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  • May combine two claims.

    Premisereasoning

    Macrophages can play both beneficial and detrimental roles in tissue remodeling, and an efficient timely phenotypic switch is essential for appropriate functional remodeling versus scar tissue outcome.

    “That is, macrophages can play both beneficial and detrimental roles in the process of tissue remodeling and, in many cases, an efficient and timely phenotypic switch is essential for appropriate and functional remodeling as opposed to a deleterious or scar tissue outcome with a loss of function.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Periodontal disease has a complex multifactorial etiology including host immune response and environmental factors, likely involving multiple cell types.

    “Overall, a complex multifactorial etiology of periodontal disease including the host immune response and environmental factors has been suggested likely involving multiple cell types [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Cullinan, 2003, Acquisition and loss of Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans and Prevotella intermedia over a 5-year period: effect of a triclosan/copolymer dentifrice, J Clin Periodontol source

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  • May combine two claims.

    Premisecitation

    Foam cell macrophages exhibit highly activated phenotype producing pro-inflammatory mediators and MMPs that destabilize plaques, potentially leading to thromboembolism.

    “Foam cell macrophages exhibit a highly activated phenotype leading to production of pro-inflammatory mediators and MMPs that destabilize the plaques, potentially leading to thromboembolism [56].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Newby, 2005, Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture, Physiol Rev source

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    Premisecitation

    Periodontal disease has mechanistic parallels and links to atherosclerosis and obesity.

    “Importantly, periodontal disease has been shown to have many mechanistic parallels and links to the pathogenic processes of atherosclerosis and obesity [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Zelkha, 2010, Periodontal innate immune mechanisms relevant to atherosclerosis and obesity, Periodontol 2000 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The default response to tissue injury occurs in four stages: hemostasis, inflammation, proliferation, and remodeling.

    “The default response to tissue injury has been described as occurring in four stages: hemostasis, inflammation, proliferation, and remodeling [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Diegelmann, 2004, Wound healing: an overview of acute, fibrotic and delayed healing, Front Biosci source

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    Premisecitation

    These macrophages are predominantly pro-inflammatory and secrete cytokines/chemokines that promote further leukocyte recruitment.

    “These cells are of a predominantly pro-inflammatory phenotype and secrete cytokines and chemokines that promote the further recruitment of leukocytes to the site of injury [89,91].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] Barrientos, 2008, Growth factors and cytokines in wound healing, Wound Repair Regen source

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    • cites [91] Werner, 2003, Regulation of wound healing by growth factors and cytokines, Physiol Rev source

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  • May combine two claims.

    Interpretationreasoning

    Pathogenesis of disease results from inappropriate macrophage polarization, inhibition of polarization, or inability to resolve chronic M1/M2 polarization.

    “In each case, the pathogenesis of disease results from inappropriate macrophage polarization, an inhibition of macrophage polarization, or an inability to resolve a chronic polarization towards the M1 or M2 extreme.”
    Quote in the paperSubstantial claim

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    Premisecitation

    TLR-4 deficient mice are not protected from diet-induced obesity but are protected from obesity-induced insulin resistance.

    “A number of studies have shown that TLR-4 deficient mice are not protected from diet-induced obesity, but are protected from obesity-induced insulin resistance [74,76,77].”
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    • cites [74] Shi, 2006, TLR4 links innate immunity and fatty acid-induced insulin resistance, J Clin Invest source

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    • cites [76] Tsukumo, 2007, Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance, Diabetes source

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    • cites [77] Saberi, 2009, Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice, Cell Metab source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In normal rodents and humans, ATMs make up as much as 10% of cellular constituents; in obese subjects, up to 40%.

    “In normal rodents and humans, ATMs make up as much as ten percent of the cellular constituents of the tissue [62]. In comparison, it has been shown that in obese subjects that number rises to as much as 40% [62].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Weisberg, 2006, CCR2 modulates inflammatory and metabolic effects of high-fat feeding, J Clin Invest source

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    Premisecitation

    DAMPs such as heat shock proteins from dead adipocytes may signal through TLR pathways, activating NLRP3 inflammasome and promoting pro-inflammatory phenotype.

    “Additionally, damage associated molecular pattern molecules, such as heat shock proteins, released from dead or dying adipocytes may signal through TLR pathways, producing activation of the NLRP3 inflammasome and promotion of a pro-inflammatory phenotype [75].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Vandanmagsar, 2011, The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance, Nat Med source

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    Premisecitation

    Clodronate treatment does not reduce size of established plaques, suggesting it may be most effective early.

    “However, clodronate treatment was not shown to reduce the size of plaques that were already established prior to treatment, suggesting that such a treatment may be most effective in the early stages of disease progression [59].”
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    • cites [59] Stoneman, 2007, Monocyte/macrophage suppression in CD11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques, Circ Res source

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    Premisecitation

    Obese ATMs produce high levels of TNFα, IL-6, and IL-1β, also elevated in insulin resistant individuals.

    “These cells produce high levels of TNFα, IL-6, and IL-1β, all of which are also observed in increased levels of adipose tissue from insulin resistant individuals.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [63] Olefsky, 2010, Macrophages, inflammation, and insulin resistance, Annu Rev Physiol source

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    • cites [69] Zelkha, 2010, Periodontal innate immune mechanisms relevant to atherosclerosis and obesity, Periodontol 2000 source

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    • cites [70] Lumeng, 2007, Obesity induces a phenotypic switch in adipose tissue macrophage polarization, J Clin Invest source

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    • cites [71] Prieur, 2011, Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice, Diabetes source

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    Premisecitation

    Macrophages remove apoptotic neutrophils, and this phagocytosis may lead to a change toward reparative M2 phenotype and resolution of inflammation.

    “Macrophages also remove apoptotic neutrophils, the phagocytosis of which may lead to a change toward a more reparative (M2) macrophage phenotype and the resolution of the inflammatory phase of wound healing [94–96].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [94] Erwig, 2007, Immunological consequences of apoptotic cell phagocytosis, Am J Pathol source

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    • cites [95] Fadok, 1998, Regulation of macrophage cytokine production by phagocytosis of apoptotic and post-apoptotic cells, Biochem Soc Trans source

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    • cites [96] Sylvia, 2003, The role of neutrophil apoptosis in influencing tissue repair, J Wound Care source

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  • May combine two claims.

    Premisecitation

    PPARγ deficient mice exhibit impaired M2 macrophage function and susceptibility to diet-induced inflammation and insulin resistance.

    “Studies in PPARγ deficient mice exhibit impaired M2 macrophage function and susceptibility to diet-induced inflammation and insulin resistance [29,65–67].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [29] Odegaard, 2007, Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance, Nature source

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    • cites [65] Pascual, 2007, Macrophage peroxisome proliferator activated receptor gamma as a therapeutic target to combat Type 2 diabetes, Expert Opin Ther Targets source

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    • cites [66] Hevener, 2007, Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones, J Clin Invest source

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    • cites [67] Norris, 2003, Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones, J Clin Invest source

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  • May combine two claims.

    Interpretationreasoning

    Therapies preventing M2 to M1 switch or depleting M1 macrophages may stabilize atherosclerotic plaques.

    “These observations suggest that therapies which prevent the M2 to M1 switch or deplete M1 macrophages selectively may be of clinical utility for the stabilization of atherosclerotic plaques.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In CNS injury, in the absence of blood-brain barrier breach, tissue remodeling largely involves local microglia at early time points, which possess a predominantly pro-inflammatory phenotype that propagates tissue damage and scar deposition.

    “These cells have been shown to possess a predominantly pro-inflammatory phenotype following injury, resulting in a microenvironment that is cytotoxic and propagates tissue damage and scar tissue deposition [128].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Kigerl, 2009, Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord, J Neurosci source

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    Premisecitation

    In a spinal cord injury study, a predominantly M1 phenotype was induced immediately and persisted in lesions; M2 macrophages were seen early but not later, suggesting the M1 to M2 shift does not occur in the same way as in other tissues.

    “The results of the study showed that a predominantly M1 phenotype was induced immediately following injury and persisted within spinal cord lesions. A small number of M2 macrophages were also seen in the site of injury at early time points; however, these cells were not observed at later time points in the remodeling process, suggesting that the M1 to M2 phenotype shift does not occur in the same”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Kigerl, 2009, Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord, J Neurosci source

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    Premisecitation

    Diabetes and advanced age are associated with delayed or impaired wound healing and with a reduced ability to transition from an M1 to an M2 macrophage phenotype.

    “It is interesting to note that diabetes and advanced age are also associated with delayed or impaired wound healing, and with a reduced ability to transition from an M1 to an M2 macrophage phenotype [63,108].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [63] Olefsky, 2010, Macrophages, inflammation, and insulin resistance, Annu Rev Physiol source

      Not checked in the free run.

    • cites [108] Mahbub, 2012, Advanced age impairs macrophage polarization, J Interferon Cytokine Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In models of muscular dystrophy, macrophage polarization may play an important role in muscle wasting; progenitor cells are recruited to sites of mixed M1/M2 inflammation, and the lack of an M1 to M2 switch leads to ineffective remodeling and depletion of progenitor reserves.

    “Studies have also suggested that macrophage polarization may play an important role in the process of muscle wasting which occurs in models of muscular dystrophy [124,126,127].”
    • Also stated in: § 3.2. The role of macrophage polarization in tissue remodeling · plain
      “Unlike the normal process of muscle tissue remodeling, this environment is not characterized by a switch from M1 to M2. Rather, the mixed polarization state persists, constantly recruiting progenitor cells which then fail to differentiate along normal pathways resulting in ineffective remodeling and depletion of progenitor cell reserves within the tissue.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [124] Villalta, 2011, Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype, Hum Mol Genet source

      Not checked in the free run.

    • cites [126] Villalta, 2009, Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy, Hum Mol Genet source

      Not checked in the free run.

    • cites [127] Villalta, 2011, IFN-gamma promotes muscle damage in the mdx mouse model of Duchenne muscular dystrophy by suppressing M2 macrophage activation and inhibiting muscle cell proliferation, J Immunol source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In a study of human cutaneous wound healing, two gene clusters associated with M1/M2 polarization were transiently upregulated: an early cluster with mixed M1 and M2 genes (11 M1, 7 M2) and a later cluster predominantly M2 (1 M1, 9 M2).

    “Of note, however, investigators identified two clusters of genes, associated with macrophage M1/ M2 polarization, which were upregulated transiently during the wound healing process.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Deonarine, 2007, Gene expression profiling of cutaneous wound healing, J Transl Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Skeletal muscle repair events fall into three stages: proliferation, early differentiation, and terminal differentiation.

    “Briefly, the events that occur during skeletal muscle repair are thought to fall into three well defined stages including (1) proliferation, (2) early differentiation, and (3) terminal differentiation [110].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Le Grand, 2007, Skeletal muscle satellite cells and adult myogenesis, Curr Opin Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-10 secreted by M2 macrophages drives the M1 to M2 transition and promotes fusion and maturation of myotubes.

    “For example, IL-10 secreted by M2 macrophages is known both to drive a transition from an M1 to an M2 phenotype as well as to promote the fusion and maturation of myotubes [112,125].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [112] Arnold, 2007, Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis, J Exp Med source

      Not checked in the free run.

    • cites [125] Strle, 2007, Novel activity of an anti-inflammatory cytokine: IL-10 prevents TNFalpha-induced resistance to IGF-I in myoblasts, J Neuroimmunol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cytokines involved in the proliferative phase include EGF, b-FGF, TGF-α, TGF-β, VEGF, and others depending on the injured tissue.

    “These cytokines include EGF, b-FGF, TGF-α, TGF-β, VEGF, and others depending on the nature of the injured tissue [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Diegelmann, 2004, Wound healing: an overview of acute, fibrotic and delayed healing, Front Biosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mechanisms of the M1 to M2 switch during dermal remodeling are not well described but are thought to include phenotypic changes caused by phagocytosis of apoptotic cells and debris by M1 macrophages.

    “The mechanisms of this switch from an M1 to an M2 phenotype during dermal remodeling are not well described, but are thought to include phenotypic changes caused by the phagocytosis of apoptotic cells and debris by M1 macrophages [94–96].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [94] Erwig, 2007, Immunological consequences of apoptotic cell phagocytosis, Am J Pathol source

      Not checked in the free run.

    • cites [95] Fadok, 1998, Regulation of macrophage cytokine production by phagocytosis of apoptotic and post-apoptotic cells, Biochem Soc Trans source

      Not checked in the free run.

    • cites [96] Sylvia, 2003, The role of neutrophil apoptosis in influencing tissue repair, J Wound Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Depletion of circulating monocytes reduces removal of cellular debris and delays muscle tissue remodeling after injury.

    “A number of studies have shown that reduction of the number of monocytes available to participate in the response following muscle injury via depletion of circulating cells results in slowed removal of cellular debris and delayed muscle tissue remodeling [112–114].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [112] Arnold, 2007, Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis, J Exp Med source

      Not checked in the free run.

    • cites [113] Summan, 2006, Macrophages and skeletal muscle regeneration: a clodronate-containing liposome depletion study, Am J Physiol Regul Integr Comp Physiol source

      Not checked in the free run.

    • cites [114] Tidball, 2007, Macrophages promote muscle membrane repair and muscle fibre growth and regeneration during modified muscle loading in mice in vivo, J Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After the initial pro-inflammatory phase, a switch to an M2 phenotype and resolution of inflammation occurs with the initial differentiation of muscle satellite cells.

    “Following the initial pro-inflammatory phase, a switch to an M2 macrophage phenotype and resolution of the inflammatory response has been shown to occur with the initial stages of differentiation of muscle satellite cells into differentiated skeletal muscle cells [123].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] St Pierre, 1994, Differential response of macrophage subpopulations to soleus muscle reloading after rat hindlimb suspension, J Appl Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, muscle progenitor cells proliferate, express early differentiation markers (MyoD, Myf5), and fuse into mature myotubes with a contractile phenotype without immune cells or their secreted products.

    “That is, when placed into culture, muscle progenitor cells proliferate, express early markers of differentiation along a muscle phenotype (MyoD, Myf5), and then fuse and form mature myotubes with a contractile phenotype in the absence of immune cells or their secreted products [110].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Le Grand, 2007, Skeletal muscle satellite cells and adult myogenesis, Curr Opin Cell Biol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In vivo, the response to muscle injury includes a significant number of infiltrating inflammatory cells, which can exceed 100,000 cells/mm3 of tissue.

    “In vivo, however, the response following muscle tissue injury has been shown to include a significant number of infiltrating inflammatory cells which can exceed 100,000 cells/mm3 of tissue [111].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Wehling, 2001, A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice, J Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The remodeling phase begins after deposition of significant ECM (mainly collagens I and III) and is characterized by MMP- and TIMP-mediated degradation and remodeling of new collagen, generally resulting in scar tissue formation or maturation.

    “Following the deposition of significant amounts of ECM (predominantly collagens type I and III) during the proliferative phase, the remodeling phase of wound healing begins. This phase is characterized by MMP- and tissue inhibitor of metalloproteinase (TIMP)-mediated degradation and remodeling of the newly deposited collagen, generally resulting in scar tissue formation/maturation [86,100].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [86] Diegelmann, 2004, Wound healing: an overview of acute, fibrotic and delayed healing, Front Biosci source

      Not checked in the free run.

    • cites [100] Gill, 2008, Metalloproteinases and their inhibitors: regulators of wound healing, Int J Biochem Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The M2 environment attenuates inflammation and cytotoxic nitric oxide and drives differentiation and fusion of cells.

    “The transition to an M2 environment not only serves to attenuate the inflammatory response and potentially cytotoxic production of nitric oxide, but also to drive the differentiation and fusion of cells [114,124].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [114] Tidball, 2007, Macrophages promote muscle membrane repair and muscle fibre growth and regeneration during modified muscle loading in mice in vivo, J Physiol source

      Not checked in the free run.

    • cites [124] Villalta, 2011, Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype, Hum Mol Genet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a mouse model of necrotic muscle injury, deletion of two binding sites in the CREB-C/EBPβ pathway blocked induction of M2 associated genes (Msr1, IL-10, IL-13ra, Arg-1) without affecting M1 gene expression; these mice showed fibrotic tissue and decreased myofiber size, unlike wild-type mice with full recovery.

    “In this study it was shown that the deletion of two of the binding sites in the CREB-C/EBPβ pathway blocked the induction of M2 associated genes (Msr1, IL-10, IL-13ra, and Arg-1), while M1 gene (IL-1, IL-6, IL-12b, TNFα) expression was not affected.”
    • Also stated in: § 3.2. The role of macrophage polarization in tissue remodeling · plain
      “However, the tissue that formed within the site of remodeling was highly fibrotic and associated with a decrease in myofiber size. This result was in direct contrast to wild-type mice that exhibited full recovery of the injured muscle.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Ruffell, 2009, A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Proinflammatory cytokines may inhibit muscle progenitor cell differentiation, and reactive oxygen species (nitric oxide) from M1 cells can be cytotoxic in sufficient quantities, requiring resolution of the proinflammatory response for muscle recovery.

    “However, it has also been shown that proinflammatory cytokines may inhibit muscle progenitor cell differentiation and that the reactive oxygen species that are produced by M1 cells (nitric oxide) can be cytotoxic if present in sufficient quantities, demonstrating the need for resolution of the proinflammatory response for muscle recovery to proceed beyond this initial stage [120–122].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [120] Nguyen, 2003, Interactions between neutrophils and macrophages promote macrophage killing of rat muscle cells in vitro, J Physiol source

      Not checked in the free run.

    • cites [121] Szalay, 1997, TNF inhibits myogenesis and downregulates the expression of myogenic regulatory factors myoD and myogenin, Eur J Cell Biol

      Not checked in the free run.

    • cites [122] Tsujinaka, 1996, Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice, J Clin Invest source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    This phenotypic transition impairment suggests a potential link between defective macrophage polarization switching or pro-inflammatory disposition and impaired tissue remodeling.

    “This phenotypic transition impairment suggests a potential, but as yet unexplored, link between defective macrophage polarization switching or disposition towards a pro-inflammatory phenotype and impaired tissue remodeling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    This bimodal outcome suggests the default CNS injury response is a chronic pro-inflammatory M1 response that decreases neuronal viability, and inducing a more M2 response may promote constructive remodeling.

    “This bimodal outcome scenario suggests that the default response following CNS injury is a chronic pro-inflammatory, M1 type response which leads to decreased viability of the neurons within the site of injury, and that induction of a more M2 type response may be capable of promoting a more constructive tissue remodeling type environment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Wear byproducts from total joint replacements include particulate polymeric, ceramic, and metallic debris and metallic ions, which cause pro-inflammatory responses that can persist for the life of the implant.

    “The byproducts of wear include particulate polymeric, ceramic and metallic debris (mostly in the nano, submicron, and micron size range) and in the case of metal-on-metal implants, metallic ions [143]. These byproducts are well known to cause pro-inflammatory responses which can persist for the life of the implant [144,145].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [143] Shanbhag, 1994, Composition and morphology of wear debris in failed uncemented total hip replacement, J Bone Jt Surg Br source

      Not checked in the free run.

    • cites [144] Goodman, 2007, Wear particles, periprosthetic osteolysis and the immune system, Biomaterials source

      Not checked in the free run.

    • cites [145] Ingham, 2005, The role of macrophages in osteolysis of total joint replacement, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that study, M1 and M2 macrophages had distinct effects on neuron survival and neurite outgrowth: M1-conditioned media decreased viability and neurite length, while M2-conditioned media improved survival and neurite extension.

    “Neurons which were exposed to media conditioned by M1 macrophages were shown to exhibit a decrease in viability as well as a decrease in neurite length, while those cells exposed to media conditioned by M2 macrophages showed improved survival and a greater degree of neurite extension.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Kigerl, 2009, Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages regulate fibrosis through production of cytokines that activate fibroblasts (TGF-β, PDGF, IGF-1), production of MMPs and TIMPs that drive ECM remodeling, and M1 factors (IL-1b) that drive feed-forward inflammation.

    “Briefly, macrophages regulate the process of fibrosis through the production of cytokines which directly activate fibroblasts (TGF-β, PDGF, insulin like growth factor (IGF)-1), the production of MMPs and TIMPs which drive ECM remodeling, and M1 factors which drive a “feed-forward” state of inflammation and remodeling (IL-1b) [102].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Wynn, 2008, Cellular and molecular mechanisms of fibrosis, J Pathol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Materials with pores of 30-40 mm healed with minimal fibrosis and highest vascularity, and these pores were heavily infiltrated by macrophages but not foreign body giant cells.

    “It was noted that those materials possessing pores of 30–40 mm healed with minimal fibrosis and the highest vascularity [149]. These pores were also found to be heavily infiltrated by macrophages, but not foreign body giant cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Fukano, 2010, Epidermal and dermal integration into sphere-templated porous poly(2-hydroxyethyl methacrylate) implants in mice, J Biomed Mater Res A source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In total joint replacements, chronic inflammation and foreign body reaction to wear debris result in periprosthetic bone resorption (osteolysis), which can lead to chronic synovitis, loosening, and pathologic fracture.

    “In the case of TJR, these processes result in periprosthetic bone resorption (osteolysis) which undermines the bony foundation of the implant and can lead to chronic synovitis, loosening and pathologic fracture [144].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Goodman, 2007, Wear particles, periprosthetic osteolysis and the immune system, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The optimal time for injection of these cells was one week post-injury, suggesting early M1 polarization may play a beneficial role in CNS remodeling similar to skeletal muscle.

    “It was also shown that the optimal time for injection of these cells was one week post-injury, suggesting that early M1 polarization may play a beneficial role in CNS remodeling following injury, similar to that observed in skeletal muscle [136].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Ziv, 2006, Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A major complication after implantation of any material is the foreign body reaction, which encapsulates the material and generally impairs device function.

    “While the specific mode of failure is highly context dependent, a major complication following the implantation of any material is the development of a foreign body reaction (FBR).”
    • Also stated in: § 4.1. The role of macrophage polarization following the implantation of long-term medical devices · boosted
      “The FBR consists of a set of well known and overlapping processes (reviewed in [141,142]) that result in the encapsulation of the material, thus isolating it from the surrounding tissues and, generally, negatively impacting the ability of the device to function as intended.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [141] Anderson, 2007, Phenotypic dichotomies in the foreign body reaction, Biomaterials source

      Not checked in the free run.

    • cites [142] Anderson, 2008, Foreign body reaction to biomaterials, Semin Immunol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Macrophage phenotype can be modulated by biomaterials, leading to improved tissue remodeling and long-term functional outcomes.

    “An increasing number of studies in the field of regenerative medicine have begun to apply these paradigms and concepts, and have shown that macrophage phenotype can be modulated by biomaterials with improved tissue remodeling and long-term functional outcomes as a result.”
    Quote in the paperSubstantial claim
57 of 57

  • The paper relies on this without support.

    The ultimate functional success or failure of implantable materials is a function of the host tissue response and associated remodeling at each anatomical site.

    “However, the ultimate functional success or failure of such materials is invariably a function of the host tissue response to the presence of the materials and the associated remodeling process at each anatomical site.”

  • The paper relies on this without support.

    Surface structure, both topographical and chemical, are critically important determinants of downstream events at the material-tissue interface.

    “Therefore, surface structure, both topographical and chemical, are critically important determinants of downstream events.”

  • The paper relies on this without support.

    The specific factors and exact mechanisms controlling macrophage differentiation upon entering tissues have not been fully identified.

    “However, the specific factors and exact mechanisms which control macrophage differentiation upon entering tissues have not yet been fully identified.”

  • The paper relies on this without support.

    The M1/M2 paradigm provides a useful simplified framework for deciphering macrophage roles in disease and tissue remodeling.

    “However, the M1/M2 paradigm provides a simplified framework from which to begin deciphering the complex and context dependent roles of macrophages in disease and tissue remodeling.”

  • The paper relies on this without support.

    Manipulating macrophage effector mechanisms can promote site-appropriate constructive tissue remodeling rather than persistent inflammation and scar formation.

    “Herein, the diverse roles played by macrophages in these processes are discussed in addition to the potential manipulation of macrophage effector mechanisms as a strategy for promoting site-appropriate and constructive tissue remodeling as opposed to deleterious persistent inflammation and scar tissue formation.”

  • The paper relies on this without support.

    Few studies have assessed the role of specific macrophage sub-populations in dermal wound healing remodeling.

    “However, despite the understanding that macrophages play an important and potentially determinant role in dermal wound healing, few studies to date have assessed the role of specific macrophage sub-populations in the remodeling process.”

  • The paper relies on this without support.

    Every material used in implantable medical devices, tissue engineered constructs, or scaffold-based approaches will evoke a host response beginning immediately upon implantation.

    “Every material used in implantable medical devices, tissue engineered constructs, or scaffold-based approaches to regenerative medicine will evoke a host response which begins immediately upon implantation.”

  • The paper relies on this without support.

    Few studies have evaluated macrophage polarization specifically with respect to biomaterials implantation.

    “However, few studies have evaluated macrophage polarization specifically with respect to biomaterials implantation.”

  • The paper relies on this without support.

    In periprosthetic tissues from loose, revised implants with osteolysis, M1 macrophages predominate, whereas M2 macrophages are more prevalent in synovium from osteoarthritic joints treated by primary total joint replacement.

    “In the former tissues, an M1 macrophage phenotype predominated, whereas M2 macrophages were more prevalent in the latter tissues, indicating that macrophage phenotype may play an important role in outcomes following TJR.”

  • The paper relies on this without support.

    Exact strategies for eliciting an M2 response and the ability of such strategies to prevent osteolysis have yet to be explored.

    “However, exact strategies for eliciting this type of response and the ability of such strategies to prevent osteolysis have yet to be explored.”

  • The paper relies on this without support.

    Studies examining specific effects of macrophage polarization following implantation of synthetic or naturally derived biomaterials in regenerative medicine have been few.

    “To date, studies examining the specific effects of macrophage polarization following implantation of synthetic or naturally derived biomaterials in regenerative medicine have been few.”

  • The paper relies on this without support.

    Exact mechanisms underlying the observed responses of porous biomaterials remain largely unknown.

    “Although the exact mechanisms which underlie the observed responses still remain largely unknown, such biomaterials mediated control of macrophage phenotype has significant implications for improving outcomes in regenerative medicine.”

  • The paper relies on this without support.

    Mechanisms by which ECM-based scaffold materials promote M1 to M2 transition remain unknown.

    “The mechanisms by which ECM based scaffold materials promote the M1 to M2 transition remain unknown.”

  • The paper relies on this without support.

    Exact surface ligands responsible for macrophage-surface interactions have yet to be identified.

    “While the exact surface ligands responsible have yet to be identified, a better understanding of macrophage-surface ligand interaction has significant potential to inform future biomaterial design and applications.”

  • The paper relies on this without support.

    Exact contributions of specific M1 and M2 populations in fibrosis are not well defined.

    “The exact contributions of specific M1 and M2 populations in fibrosis are not well defined.”
15 of 15

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • M2c macrophages orchestrate matrix remodeling by releasing MMPs and TIMPs.

    “Among several types of M2 macrophages, M2c macrophages are known to orchestrate matrix remodeling by releasing MMPs and TIMPs (tissue inhibitors of metalloproteinase)15,39.”

    From Bioengineered liver crosslinked with nano-graphene oxide enables efficient liver regeneration via MMP suppression and immunomodulation (2023) · cites this paper as [15]

    Section 3.2.5 says macrophages produce MMPs and TIMPs that drive extracellular-matrix remodeling. Section 3.2 also suggests an M2a-to-M2c transition may aid late-stage muscle repair, but it does not attribute MMP and TIMP release specifically to M2c macrophages; it says the contributions of specific M1 and M2 populations are not well defined. Page numbers were not available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Circulating monocytes are recruited into tissues and differentiated into macrophages, which dictate inflammatory responses and tissue remodeling in implants.

    “circulating monocytes are also recruited into the tissues and differentiated into macrophages, which dictate both inflammatory responses and tissue remodeling in the implants12,15.”

    From Bioengineered liver crosslinked with nano-graphene oxide enables efficient liver regeneration via MMP suppression and immunomodulation (2023) · cites this paper as [15]

  • Prolonged M1 presence leads to severe foreign body response, granuloma and fibrous encapsulation, resulting in chronic inflammatory events and failure of biomaterial integration.

    “In the context of biomaterial implantation, while the initial presence of M1 macrophages promotes a necessary inflammatory response, a prolonged M1 presence leads to a severe FBR, granuloma and fibrous encapsulation resulting in chronic inflammatory events and failure of biomaterial integration.”

    From Biomaterial based modulation of macrophage polarization: a review and suggested design principles (2015) · cites this paper as [8]

  • Physical properties (substrate stiffness, topography, pore size, size of wear debris), chemical properties (surface chemistry, ligand presentation, release of growth factors), and temporal properties (degradation rates) all influence cell behavior.

    “Physical properties such as substrate stiffness, topography, pore size and size of wear debris; chemical properties such as surface chemistry, ligand presentation and release of growth factors; and temporal properties, such as degradation rates, all influence the behavior of cells [8,9].”

    From Biomaterial based modulation of macrophage polarization: a review and suggested design principles (2015) · cites this paper as [8]

  • A subsequent transition to the M2 phenotype, which promotes tissue remodeling and repair, is generally believed to be a favorable adaptation.

    “Therefore, a subsequent transition to the M2 phenotype -which promotes tissue remodeling and repair -is generally believed to be a favorable adaptation [8].”

    From Biomaterial based modulation of macrophage polarization: a review and suggested design principles (2015) · cites this paper as [8]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • TLR-4 obesity claim conflicts with a cited reference

    Minor

    The text says TLR-4 deficiency does not protect against diet-induced obesity, but the title of cited reference 76 says a TLR-4 loss-of-function mutation prevents it.

1 of 1

Cites

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5 of the 166 references couldn’t be matched to a known paper.

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Related

Authors
Brown, B. N., Ratner, B. D., Goodman, S. B., Amar, S., & Badylak, S. F.
Affiliations
  • University of Pittsburgh (US)
  • University of Washington (US)
  • Stanford Medicine (US)
  • Boston University (US)
Corresponding author
Badylak, Stephen F.
ORCID
Venue
Biomaterials
Publisher
Elsevier BV
Published
2012-05
Volume
33
Issue
15
Pages
3792-3802
ISSN
0142-9612 (ISSN-L)
DOI
10.1016/j.biomaterials.2012.02.034
PMC
PMC3727238
OpenAlex
W2055901626
Cited by
926
References
166
Citations by year
2026: 53 · 2025: 53 · 2024: 69 · 2023: 63 · 2022: 77 · 2021: 98 · 2020: 84 · 2019: 64 · 2018: 68 · 2017: 82 · 2016: 65 · 2015: 52 · 2014: 54 · 2013: 33 · 2012: 9
FWCI
4.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomaterials (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Touro Scholar (Touro College) (submittedVersion)
Funders
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR063717, R01AR055650)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
Keywords
macrophage polarization, foreign body reaction, granulation tissue, tissue remodeling, scar formation, chronic inflammation, regenerative medicine, biomaterial implantation
MeSH terms
Animals, Biocompatible Materials, Humans, Macrophages, Cell Polarity, Treatment Outcome, Prostheses and Implants, Regenerative Medicine

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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