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

In the paper

“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.”

In the paper

“Rather, macrophage phenotype has been described as occurring along a continuum between the M1 and M2 extremes [12].”

What the sources say

• Not checked yetcites [12] Mosser, 2008, Exploring the full spectrum of macrophage activation, Nat Rev Immunol source

In the paper

“Macrophages, like the monocytes from which they derive, are a heterogeneous cell population each with different markers and functions [1,8–12].”

What the sources say

• Not checked yetcites [1] Gordon, 2005, Monocyte and macrophage heterogeneity, Nat Rev Immunol source
• Not checked yetcites [8] Mantovani, 2004, The chemokine system in diverse forms of macrophage activation and polarization, Trends Immunol source
• Not checked yetcites [9] Mantovani, 2002, Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes, Trends Immunol source
• Not checked yetcites [10] Mills, 2000, M-1/M-2 macrophages and the Th1/Th2 paradigm, J Immunol source
• Not checked yetcites [11] Mosser, 2003, The many faces of macrophage activation, J Leukoc Biol source
• Not checked yetcites [12] Mosser, 2008, Exploring the full spectrum of macrophage activation, Nat Rev Immunol source

In the paper

“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].”

What the sources say

• Not checked yetcites [34] Balkwill, 2005, Smoldering and polarized inflammation in the initiation and promotion of malignant disease, Cancer Cell source
• Not checked yetcites [35] Mantovani, 2010, Macrophages, innate immunity and cancer: balance, tolerance, and diversity, Curr Opin Immunol source
• Not checked yetcites [36] Sica, 2008, Macrophage polarization in tumour progression, Semin Cancer Biol source

In the paper

“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].”

What the sources say

• Not checked yetcites [37] Porta, 2011, Mechanisms linking pathogens-associated inflammation and cancer, Cancer Lett source
• Not checked yetcites [38] Mantovani, 2008, Cancer-related inflammation, Nature source

In the paper

“Thus, early tumor development is, in many cases, characterized by a polarized inflammatory, M1-like, environment.”

What the sources say

• Not checked yetcites [37] Porta, 2011, Mechanisms linking pathogens-associated inflammation and cancer, Cancer Lett source
• Not checked yetcites [38] Mantovani, 2008, Cancer-related inflammation, Nature source

In the paper

“Similarly, cells exposed to M2 polarizing signals can be readily induced to express genes characteristic of an M1 phenotype by exposure to LPS or IFNγ.”

In the paper

“Similar to cancer, atherosclerosis has an etiology that has, for many years, been recognized to include the involvement an inflammatory cell population, in particular macrophages [45–47].”

What the sources say

• Not checked yetcites [45] Johnson, 2009, Macrophage heterogeneity in atherosclerotic plaques, Curr Opin Lipidol source
• Not checked yetcites [46] Moore, 2011, Macrophages in the pathogenesis of atherosclerosis, Cell source
• Not checked yetcites [47] Mantovani, 2009, Macrophage diversity and polarization in atherosclerosis: a question of balance, Arterioscler Thromb Vasc Biol source

In the paper

“As will be discussed in the section which follows, dysregulation of macrophage phenotype and the inability to resolve polarized M1 or M2 states and return to tissue specific baselines is increasingly recognized to have an important role in chronic inflammatory and disease states, as well as adverse tissue remodeling following injury [31].”

What the sources say

• Not checked yetcites [31] Nathan, 2010, Nonresolving inflammation, Cell source

In the paper

“These changes are dependent upon the type, concentration and duration of the polarizing signals.”

In the paper

“Mature tumors are also characterized by significant infiltration of mononuclear cells; however, the cells commonly observed in mature tumors are of a more suppressive, M2-like, phenotype [36,39].”

What the sources say

• Not checked yetcites [36] Sica, 2008, Macrophage polarization in tumour progression, Semin Cancer Biol source
• Not checked yetcites [39] Porta, 2007, Tumor promotion by tumor-associated macrophages, Adv Exp Med Biol source

In the paper

“Therefore, it is not surprising that interrogation of the macrophage population at any given point in time may show a mixture of macrophage phenotypes and/or macrophages in a state of transition that express markers of both M1 and M2 phenotypes.”

In the paper

“All activated macrophages, regardless of polarization state, express high levels of the transcription factors runt-related transcription factor 1 (RUNX1) and PU.1, which are thought to represent global regulators of macrophage phenotypic expression [20–22].”

What the sources say

• Not checked yetcites [20] Rosenbauer, 2007, Transcription factors in myeloid development: balancing differentiation with transformation, Nat Rev Immunol source
• Not checked yetcites [21] Olson, 1995, PU. 1 is not essential for early myeloid gene expression but is required for terminal myeloid differentiation, Immunity source
• Not checked yetcites [22] Nerlov, 1998, PU.1 induces myeloid lineage commitment in multipotent hematopoietic progenitors, Genes Dev source

In the paper

“Macrophage polarization and plasticity have been shown to play important roles in a diverse spectrum of disease processes [32,33].”

What the sources say

• Not checked yetcites [32] Murray, 2011, Protective and pathogenic functions of macrophage subsets, Nat Rev Immunol source
• Not checked yetcites [33] Pollard, 2009, Trophic macrophages in development and disease, Nat Rev Immunol source

In the paper

“Briefly, in atherosclerosis, circulating monocytes are recruited to sites of fatty deposit accumulation within the vascular intima and subintima via CCR2 and endothelial adhesion mediated mechanisms [49–52].”

What the sources say

• Not checked yetcites [49] Galkina, 2007, Leukocyte influx in atherosclerosis, Curr Drug Targets source
• Not checked yetcites [50] Ley, 2007, Getting to the site of inflammation: the leukocyte adhesion cascade updated, Nat Rev Immunol source
• Not checked yetcites [51] Boring, 1998, Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis, Nature source
• Not checked yetcites [52] Tacke, 2007, Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques, J Clin Invest source

In the paper

“Also similar to cancer, a macrophage phenotypic switch is observed to occur with disease progression, albeit with significantly different pathologic sequelae [45–48].”

What the sources say

• Not checked yetcites [45] Johnson, 2009, Macrophage heterogeneity in atherosclerotic plaques, Curr Opin Lipidol source
• Not checked yetcites [46] Moore, 2011, Macrophages in the pathogenesis of atherosclerosis, Cell source
• Not checked yetcites [47] Mantovani, 2009, Macrophage diversity and polarization in atherosclerosis: a question of balance, Arterioscler Thromb Vasc Biol source
• Not checked yetcites [48] Woollard, 2010, Monocytes in atherosclerosis: subsets and functions, Nat Rev Cardiol source

In the paper

“Indeed, TAM presence and number has been directly correlated with prognosis in a number of cancer types and model systems [42–44].”

What the sources say

• Not checked yetcites [42] Imtiyaz, 2010, Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation, J Clin Invest source
• Not checked yetcites [43] Steidl, 2010, Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma, N Engl J Med source
• Not checked yetcites [44] Ahn, 2010, Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment, Proc Natl Acad Sci USA source

In the paper

“Specifically, TAMs produce cytokines that drive cellular recruitment and proliferation, angiogenesis, matrix production and remodeling. These cytokines include epidermal growth factor (EGF), basic fibroblast growth factor (b-FGF), transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), among others.”

In the paper

“Thus, cancer can be thought to represent a disease in which an inability to resolve macrophage polarization, first M1 and then M2, results in pathologic outcomes.”

In the paper

“While the mechanisms that underlie this observed plasticity are not well understood, recent studies have shown that a number of mutually exclusive and feed forward signaling pathways may play a role [19].”

What the sources say

• Not checked yetcites [19] Lawrence, 2011, Transcriptional regulation of macrophage polarization: enabling diversity with identity, Nat Rev Immunol source

In the paper

“Adipose tissue macrophages (ATM) have been shown to comprise a significant proportion of the cellular component of adipose tissue in both lean and obese states [60–63].”

What the sources say

• Not checked yetcites [60] Boyle, 2003, Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms, Arterioscler Thromb Vasc Biol source
• Not checked yetcites [61] Chen, 2005, Diet induction of monocyte chemoattractant protein-1 and its impact on obesity, Obes Res source
• Not checked yetcites [62] Weisberg, 2006, CCR2 modulates inflammatory and metabolic effects of high-fat feeding, J Clin Invest source
• Not checked yetcites [63] Olefsky, 2010, Macrophages, inflammation, and insulin resistance, Annu Rev Physiol source

In the paper

“This accumulation of cells with a pro-remodeling and proangiogenic phenotypic profile likely contributes to the formation, expansion, and stabilization of the plaque.”

In the paper

“Additional studies suggest that, while systemic levels of these same pro-inflammatory mediators are lower than those observed locally, these tissue cytokines may “leak” into the circulation and affect other tissues and organs.”

In the paper

“A number of free fatty acid products released from necrotic adipocytes have been shown to cause pro-inflammatory activation of macrophages through TLR-2 and TLR-4 signaling pathways, suggesting a potential mechanism by which obesity-induced inflammation may occur [73,74].”

What the sources say

• Not checked yetcites [73] Nguyen, 2007, A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways, J Biol Chem source
• Not checked yetcites [74] Shi, 2006, TLR4 links innate immunity and fatty acid-induced insulin resistance, J Clin Invest source

In the paper

“Additionally, each of these scenarios involves some form of phenotypic switch from M1 to M2 or vice versa.”

In the paper

“Specifically, if the host innate immune response becomes suppressed or tolerant (i.e. unable to mount an appropriate M1 type macrophage response) following low-level stimulation of critical pattern recognition receptors, this may lead to a muted local immune response, thus enabling periodontal disease-associated bacteria such as Porphyromonas gingivalis (P. gingivalis) to evade the host immune”

What the sources say

• Not checked yetcites [83] Muthukuru, 2005, Oral mucosal endotoxin tolerance induction in chronic periodontitis, Infect Immun source
• Not checked yetcites [84] Tanabe, 2008, Macrophage tolerance response to Aggregatibacter actinomycetemcomitans lipopolysaccharide induces differential regulation of tumor necrosis factor-alpha, interleukin-1 beta and matrix metalloproteinase 9 secretion, J Periodontal Res source

In the paper

“Indeed, in obese individuals, similar accumulations of M1 activated macrophages are observed in both muscle and the liver [63].”

What the sources say

• Not checked yetcites [63] Olefsky, 2010, Macrophages, inflammation, and insulin resistance, Annu Rev Physiol source

In the paper

“The proliferative phase of wound healing involves cellular proliferation, angiogenesis, new ECM deposition, and the formation of granulation tissue – processes that are largely mediated via the effects of the local microenvironment including pH and oxygen tension, and cytokines secreted by macrophages, T lymphocytes, and other cells within the wound site [91,98,99].”

What the sources say

• Not checked yetcites [91] Werner, 2003, Regulation of wound healing by growth factors and cytokines, Physiol Rev source
• Not checked yetcites [98] Knighton, 1983, Oxygen tension regulates the expression of angiogenesis factor by macrophages, Science source
• Not checked yetcites [99] LaVan, 1990, Oxygen and wound healing, Clin Plast Surg source

In the paper

“However, concurrent with lesion progression and expansion, a switch to a predominantly M1 phenotype has been observed [53].”

What the sources say

• Not checked yetcites [53] Matthijsen, 2009, Macrophage-specific expression of mannose-binding lectin controls atherosclerosis in low-density lipoprotein receptor-deficient mice, Circulation source

In the paper

“The default mammalian host response following tissue injury is a well-documented series of events that typically result in the deposition of dense fibrous connective tissue (i.e., scar tissue) within the site of injury [85–87].”

What the sources say

• Not checked yetcites [85] Robbins, 2010
• Not checked yetcites [86] Diegelmann, 2004, Wound healing: an overview of acute, fibrotic and delayed healing, Front Biosci source
• Not checked yetcites [87] Guo, 2010, Factors affecting wound healing, J Dent Res source

In the paper

“Additional studies have suggested dysregulation of innate immunity as a key event in the progression of periodontal disease [82].”

What the sources say

• Not checked yetcites [82] Slots, 1984, Black-pigmented Bacteroides species, Capnocytophaga species, and Actinobacillus actinomycetemcomitans in human periodontal disease: virulence factors in colonization, survival, and tissue destruction, J Dent Res source

In the paper

“These studies suggest that inhibition of the recruitment of M1 macrophages may hold promise.”

In the paper

“However, the ability to target these interventions to specific locales without impacting essential systemic immune function remains difficult.”

In the paper

“However, macrophage accumulation in obese adipose tissue has been observed to be localized around necrotic or apoptotic adipocytes [72].”

What the sources say

• Not checked yetcites [72] Cinti, 2005, Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans, J Lipid Res source

In the paper

“By 48–72 h post-injury, however, macrophages begin to dominate the cell population at the site of injury [93].”

What the sources say

• Not checked yetcites [93] Adamson, 2009, Role of macrophages in normal wound healing: an overview, J Wound Care source

In the paper

“The T lymphocyte population also plays an important late regulatory role in the resolution of the inflammatory process through local secretion of cytokines and chemokines, many of which are known to affect macrophage polarization [97].”

What the sources say

• Not checked yetcites [97] Keen, 2008, A review of research examining the regulatory role of lymphocytes in normal wound healing, J Wound Care source

In the paper

“Indeed, depletion of circulating monocytes via injection of clodronate laden liposomes have been shown to reduce the formation of atherosclerotic plaques in rabbits [58].”

What the sources say

• Not checked yetcites [58] Ylitalo, 1994, Effects of clodronate (dichloromethylene bisphosphonate) on the development of experimental atherosclerosis in rabbits, J Lab Clin Med

In the paper

“It seems likely that high levels of pro-inflammatory mediators locally impair the function of resident insulin processing cells.”

In the paper

“While the ATMs present in healthy lean adipose tissue are primarily of an M2 phenotype, those that accumulate in the adipose tissue during obesity have a strongly polarized pro-inflammatory, M1 phenotype [63,69–71].”

What the sources say

• Not checked yetcites [63] Olefsky, 2010, Macrophages, inflammation, and insulin resistance, Annu Rev Physiol source
• Not checked yetcites [69] Zelkha, 2010, Periodontal innate immune mechanisms relevant to atherosclerosis and obesity, Periodontol 2000 source
• Not checked yetcites [70] Lumeng, 2007, Obesity induces a phenotypic switch in adipose tissue macrophage polarization, J Clin Invest source
• Not checked yetcites [71] Prieur, 2011, Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice, Diabetes source

In the paper

“An increasing number of studies in multiple animal models and organ systems have shown similar phenomena also occur during the course of remodeling which occurs following tissue injury.”

In the paper

“In normal, non-obese subjects ATMs have a polarized M2 phenotype characterized by increased baseline STAT6 and PPARγ expression [29].”

What the sources say

• Not checked yetcites [29] Odegaard, 2007, Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance, Nature source

In the paper

“Importantly, and as will be discussed in the following examples, macrophage participation and polarization during this stage may have significant implications for the outcome of the following remodeling phase.”

In the paper

“These cells have been shown to possess a phenotype that switches from M1 to M2 during the course of muscle remodeling [109].”

What the sources say

• Not checked yetcites [109] Tidball, 2010, Regulatory interactions between muscle and the immune system during muscle regeneration, Am J Physiol Regul Integr Comp Physiol source

In the paper

“A recent study showed that depletion of macrophages during the proliferative phase of wound healing resulted in a defective transition to the remodeling phase and impaired healing [106,107].”

What the sources say

• Not checked yetcites [106] Lucas, 2010, Differential roles of macrophages in diverse phases of skin repair, J Immunol source
• Not checked yetcites [107] Mirza, 2009, Selective and specific macrophage ablation is detrimental to wound healing in mice, Am J Pathol source

In the paper

“Additional studies have suggested that transition from specific M2a to M2c sub-populations may also play an important role in directing late stage differentiation and functional recovery [126].”

What the sources say

• Not checked yetcites [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

In the paper

“Briefly, a number of studies have shown that the chemokines and cytokines (TNF-α, IL-1β, IL-6) produced by initially infiltrating M1 macrophages are chemoattractant and mitogenic for muscle progenitor cells, including Pax7+ satellite cells [115–119].”

What the sources say

• Not checked yetcites [115] Lolmede, 2009, Inflammatory and alternatively activated human macrophages attract vessel-associated stem cells, relying on separate HMGB1- and MMP-9-dependent pathways, J Leukoc Biol source
• Not checked yetcites [116] Torrente, 2003, Tumor necrosis factor-alpha (TNF-alpha) stimulates chemotactic response in mouse myogenic cells, Cell Transplant source
• Not checked yetcites [117] Wang, 2008, Effects of interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor on the proliferation and differentiation of adult human myoblasts, Cell Mol Neurobiol source
• Not checked yetcites [118] Serrano, 2008, Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy, Cell Metab source
• Not checked yetcites [119] Li, 2003, TNF-alpha is a mitogen in skeletal muscle, Am J Physiol Cell Physiol source

In the paper

“The results of this study suggest a role for M1/M2 polarization in the process of cutaneous wound healing.”

In the paper

“That is, the selective activation of components of the inflammatory, proliferation, and remodeling phase can result in a constructive and functional outcome as opposed to scar tissue formation.”

In the paper

“Macrophages, however, have been recognized as the most long-lived and central cell population that plays a role in dermal wound healing largely through the production of the cytokines, growth factors, and MMPs described above [93,103,104].”

What the sources say

• Not checked yetcites [93] Adamson, 2009, Role of macrophages in normal wound healing: an overview, J Wound Care source
• Not checked yetcites [103] Koh, 2011, Inflammation and wound healing: the role of the macrophage, Expert Rev Mol Med source
• Not checked yetcites [104] Rodero, 2010, Skin wound healing modulation by macrophages, Int J Clin Exp Pathol

In the paper

“Elimination of these cytokines in vivo has been shown to diminish muscle repair [118].”

What the sources say

• Not checked yetcites [118] Serrano, 2008, Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy, Cell Metab source

In the paper

“A small number of blood-derived monocytes have been observed to participate in the default tissue remodeling response in the CNS at late time points following injury, even in the absence of a breach of the blood–brain barrier [129,130].”

What the sources say

• Not checked yetcites [129] Rolls, 2009, The bright side of the glial scar in CNS repair, Nat Rev Neurosci source
• Not checked yetcites [130] Shechter, 2009, Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice, PLoS Med source

In the paper

“In some cases, as will be discussed in further detail, prolonged inflammation and remodeling leading to fibrosis or hypertrophic scar formation may occur due to dysregulation of the default healing process [32,86,101,102].”

What the sources say

• Not checked yetcites [32] Murray, 2011, Protective and pathogenic functions of macrophage subsets, Nat Rev Immunol source
• Not checked yetcites [86] Diegelmann, 2004, Wound healing: an overview of acute, fibrotic and delayed healing, Front Biosci source
• Not checked yetcites [101] Wynn, 2010, Macrophages: master regulators of inflammation and fibrosis, Semin Liver Dis source
• Not checked yetcites [102] Wynn, 2008, Cellular and molecular mechanisms of fibrosis, J Pathol source

In the paper

“With respect to these events, the macrophage plays a key role in determining the remodeling characteristics and functional outcome at the interface between the implant and the surrounding bone and soft tissues.”

In the paper

“A number of studies have shown that biologically derived scaffold materials, when prepared by tissue decellularization methods that largely preserve native structure and composition, are capable of promoting constructive tissue remodeling in a number of tissues and organs [153].”

What the sources say

• Not checked yetcites [153] Badylak, 2007, The extracellular matrix as a biologic scaffold material, Biomaterials source

In the paper

“These results suggest that interactions of host cells with ligands on the surface of the material, or their degradation products, may be responsible for the observed phenomena.”

In the paper

“Finally, localization of blood-derived macrophages to the margin of the site of injury appears to be essential to functional recovery [137].”

What the sources say

• Not checked yetcites [137] Schwartz, 2006, Immune-based therapy for spinal cord repair: autologous macrophages and beyond, J Neurotrauma source

In the paper

“The findings of these studies have shown that injection of macrophages incubated with fragments of sciatic nerve, a nerve capable of regeneration, promoted functional recovery [135].”

What the sources say

• Not checked yetcites [135] Rapalino, 1998, Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats, Nat Med source

In the paper

“Macrophages, however, can also regulate or reverse fibrosis through the secretion of matrix degrading MMPs and other M2 factors that have been shown to suppress fibrosis (IL-10, RELMα, Arg-1) [102,138–140].”

What the sources say

• Not checked yetcites [102] Wynn, 2008, Cellular and molecular mechanisms of fibrosis, J Pathol source
• Not checked yetcites [138] Pesce, 2009, Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis, PLoS Pathog source
• Not checked yetcites [139] Pesce, 2009, Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type immunity, PLoS Pathog source
• Not checked yetcites [140] Wilson, 2007, IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice, J Clin Invest source

In the paper

“Persistent or dysregulated inflammation can result in fibrosis following tissue injury or in the setting of infection [101,102].”

What the sources say

• Not checked yetcites [101] Wynn, 2010, Macrophages: master regulators of inflammation and fibrosis, Semin Liver Dis source
• Not checked yetcites [102] Wynn, 2008, Cellular and molecular mechanisms of fibrosis, J Pathol source

In the paper

“Thus, control of macrophage phenotype, with beneficial effects upon tissue remodeling, can be driven by biomaterial morphology.”

In the paper

“This constructive remodeling response has been directly linked to the ability of the material to modulate macrophage phenotype [154–157].”

What the sources say

• Not checked yetcites [154] Badylak, 2008, Macrophage phenotype as a determinant of biologic scaffold remodeling, Tissue Eng Part A source
• Not checked yetcites [155] Brown, 2011, Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials, Acta Biomater
• Not checked yetcites [156] Brown, 2009, Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component, Biomaterials source
• Not checked yetcites [157] Valentin, 2009, Macrophage participation in the degradation and remodeling of extracellular matrix scaffolds, Tissue Eng Part A source

In the paper

“In each of these cases, a delicate balance and timely switch between M1 and M2 phenotypes with resolution of the inflammatory response is essential for tissue remodeling with functional recovery.”

In the paper

“Recent studies have demonstrated that porous biomaterials of the same composition as those which, in their non-porous form, elicit an FBR and encapsulation heal with less encapsulation and more vascularity when implanted into either the dermis or into cardiac tissues [147–149].”

What the sources say

• Not checked yetcites [147] Underwood, 2011, Quantifying the effect of pore size and surface treatment on epidermal incorporation into percutaneously implanted sphere-templated porous biomaterials in mice, J Biomed Mater Res A source
• Not checked yetcites [148] Madden, 2010, Proangiogenic scaffolds as functional templates for cardiac tissue engineering, Proc Natl Acad Sci USA source
• Not checked yetcites [149] Fukano, 2010, Epidermal and dermal integration into sphere-templated porous poly(2-hydroxyethyl methacrylate) implants in mice, J Biomed Mater Res A source

In the paper

“Briefly, scaffold materials composed of extracellular matrix (ECM) have been shown to promote a switch from a predominantly M1 cell population immediately following implantation to a population enriched in M2 cells by 7–14 days post implantation [154–156].”

What the sources say

• Not checked yetcites [154] Badylak, 2008, Macrophage phenotype as a determinant of biologic scaffold remodeling, Tissue Eng Part A source
• Not checked yetcites [155] Brown, 2011, Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials, Acta Biomater
• Not checked yetcites [156] Brown, 2009, Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component, Biomaterials source

In the paper

“Additionally, contamination with endotoxin and other bacterial byproducts may occur during the lifetime of the implant, leading to further pro-inflammatory activation and adverse outcomes [146].”

What the sources say

• Not checked yetcites [146] Bi, 2001, Adherent endotoxin on orthopedic wear particles stimulates cytokine production and osteoclast differentiation, J Bone Miner Res source

In the paper

“Materials derived from mammalian tissue sources elicit a distinctly different host response than those composed of synthetic materials due to their unique surface topologies and ligand landscapes [152].”

What the sources say

• Not checked yetcites [152] Badylak, 2008, Immune response to biologic scaffold materials, Semin Immunol source

In the paper

“Further, when compared to the non-porous control, implants with 30–40 mm pores elicited a host response which was characterized by significantly higher ratios of M2/M1 macrophages [148].”

What the sources say

• Not checked yetcites [148] Madden, 2010, Proangiogenic scaffolds as functional templates for cardiac tissue engineering, Proc Natl Acad Sci USA source

In the paper

“These results also suggest that strategies which promote polarization to an M2 anti-inflammatory, pro-tissue healing phenotype may be a potential strategy to mitigate the adverse effects of particle-induced inflammation and osteolysis around TJR.”

In the paper

“It is likely, therefore, that similar paradigms and processes apply to the remodeling which occurs following the implantation of biomaterials.”

In the paper

“Contrary to many long-held views regarding neural inflammation and tissue remodeling, these results suggest that strategies that promote the recruitment of additional circulating monocytes and macrophages may promote functional recovery as opposed to tissue damage and lesion propagation.”

In the paper

“However, modification of such scaffold materials with chemical crosslinking agents which delay or prevent macrophage mediated degradation inhibits the formation of the beneficial M2 response and results in downstream scar tissue formation [154].”

What the sources say

• Not checked yetcites [154] Badylak, 2008, Macrophage phenotype as a determinant of biologic scaffold remodeling, Tissue Eng Part A source

In the paper

“This suggests that strategies which provide control of macrophage phenotype may meet with greater success in regenerative medicine applications.”

In the paper

“Whether macrophage participation results in a positive or negative outcome depends largely upon context appropriate polarization towards an M1 or an M2 phenotype and the ability to shift and resolve polarized responses.”

In the paper

“Additional experiments by the same group showed that skin derived macrophage populations also promoted functional recovery when injected into spinal cord lesions [133].”

What the sources say

• Not checked yetcites [133] Bomstein, 2003, Features of skin-coincubated macrophages that promote recovery from spinal cord injury, J Neuroimmunol source

In the paper

“Similarly, recent studies have also shown potential modulating effects of biomaterial surface topography upon macrophage polarization [150,151].”

What the sources say

• Not checked yetcites [150] Saino, 2011, Effect of electrospun fiber diameter and alignment on macrophage activation and secretion of proinflammatory cytokines and chemokines, Biomacromolecules source
• Not checked yetcites [151] Bota, 2010, Biomaterial topography alters healing in vivo and monocyte/macrophage activation in vitro, J Biomed Mater Res A source

In the paper

“The phenotypic profile of the cells which respond to these scaffold materials at early time points has been shown to be a statistical predictor of the downstream outcome associated with their implantation [155].”

What the sources say

• Not checked yetcites [155] Brown, 2011, Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials, Acta Biomater