Biomaterial Encapsulation Is Enhanced in the Early Stages of the Foreign Body Reaction During Conditional Macrophage Depletion in Transgenic Macrophage Fas-Induced Apoptosis Mice.

Macrophages are pivotal cells during the foreign body reaction (FBR), as they orchestrate the proinflammatory microenvironment inside and around biomaterials by secretion of inflammatory mediators. Furthermore, they are responsible for the degradation of biomaterials and are thought to instruct the fibroblasts that generate a fibrous capsule around implanted biomaterials. In this study, we investigated the events during the FBR when macrophages are not present. Hexamethylenediisocyanate crosslinked collagen scaffolds were implanted in "Macrophage Fas-Induced Apoptosis" mice, which allow "on demand" macrophage depletion. We observed that macrophage depletion completely inhibited inflammatory ingrowth into the scaffolds and resulted in an increased capsule size. Quantitative polymerase chain reaction analysis revealed decreased expression levels of proinflammatory mediators such as TNFα and IL1β, and increased expression levels of collagens and fibroblast-stimulating growth factors such as EGF, FGF1, FGF2, and TGFα. Our results indicate that macrophages are indeed crucial for the generation of a proinflammatory microenvironment inside implanted biomaterials, leading to inflammatory ingrowth. In contrast, macrophages do not appear to be important for the generation of a fibrous capsule around implanted biomaterials. In fact, our data suggest that the macrophages present in the capsule might instruct the surrounding fibroblasts to produce less fibroblast-stimulating factors and less collagens.

[1]  D. Grainger,et al.  Extracellular matrix-based biomaterial scaffolds and the host response. , 2016, Biomaterials.

[2]  T. Wynn,et al.  Macrophages in Tissue Repair, Regeneration, and Fibrosis. , 2016, Immunity.

[3]  Li Tang,et al.  Biomaterial Strategies for Immunomodulation. , 2015, Annual review of biomedical engineering.

[4]  N. Câmara,et al.  Macrophages During the Fibrotic Process: M2 as Friend and Foe , 2015, Front. Immunol..

[5]  Yong Wang,et al.  Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates , 2015, Nature materials.

[6]  Douglas A. Simonetto,et al.  Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. , 2014, Gastroenterology.

[7]  U. Klueh,et al.  Impact of macrophage deficiency and depletion on continuous glucose monitoring in vivo. , 2014, Biomaterials.

[8]  H. Anders,et al.  Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. , 2013, Biochimica et biophysica acta.

[9]  S. V. van Putten,et al.  Macrophage phenotypes in the collagen-induced foreign body reaction in rats. , 2013, Acta biomaterialia.

[10]  R. Bank,et al.  Cell plasticity in wound healing: paracrine factors of M1/ M2 polarized macrophages influence the phenotypical state of dermal fibroblasts , 2013, Cell Communication and Signaling.

[11]  S. Akira,et al.  Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages , 2013, Nature.

[12]  A. Bergman,et al.  CD169+ macrophages provide a niche promoting erythropoiesis under homeostasis and stress , 2013, Nature Medicine.

[13]  S. Rivella,et al.  Macrophages support pathological erythropoiesis in Polycythemia Vera and Beta-Thalassemia , 2013, Nature Medicine.

[14]  D. Grijpma,et al.  Biodegradable nanocomposite hydrogel structures with enhanced mechanical properties prepared by photo-crosslinking solutions of poly(trimethylene carbonate)-poly(ethylene glycol)-poly(trimethylene carbonate) macromonomers and nanoclay particles. , 2012, Acta biomaterialia.

[15]  B. Brown,et al.  Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. , 2012, Biomaterials.

[16]  S. Gaines,et al.  The Mouse , 2011 .

[17]  J. Simon,et al.  Immune responses to implants - a review of the implications for the design of immunomodulatory biomaterials. , 2011, Biomaterials.

[18]  S. V. van Putten,et al.  Endotoxin contamination delays the foreign body reaction. , 2011, Journal of biomedical materials research. Part A.

[19]  Daniel G. Anderson,et al.  Real-time in vivo detection of biomaterial-induced reactive oxygen species. , 2011, Biomaterials.

[20]  D. Grainger,et al.  Cell-cell signaling in co-cultures of macrophages and fibroblasts. , 2010, Biomaterials.

[21]  George P McCabe,et al.  Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component. , 2009, Biomaterials.

[22]  S. V. van Putten,et al.  The downmodulation of the foreign body reaction by cytomegalovirus encoded interleukin-10. , 2009, Biomaterials.

[23]  S. Badylak,et al.  Macrophage phenotype as a determinant of biologic scaffold remodeling. , 2008, Tissue engineering. Part A.

[24]  James M. Anderson,et al.  Foreign body reaction to biomaterials. , 2008, Seminars in immunology.

[25]  Il Keun Kwon,et al.  Proteomic analysis and quantification of cytokines and chemokines from biomaterial surface-adherent macrophages and foreign body giant cells. , 2007, Journal of biomedical materials research. Part A.

[26]  M. Harmsen,et al.  Material dependent differences in inflammatory gene expression by giant cells during the foreign body reaction. , 2007, Journal of biomedical materials research. Part A.

[27]  M. Harmsen,et al.  Cytokine and chemokine dynamics differ between rats and mice after collagen implantation , 2007, Journal of tissue engineering and regenerative medicine.

[28]  J. Fallowfield,et al.  Scar-Associated Macrophages Are a Major Source of Hepatic Matrix Metalloproteinase-13 and Facilitate the Resolution of Murine Hepatic Fibrosis1 , 2007, The Journal of Immunology.

[29]  M. Harmsen,et al.  The correlation between difference in foreign body reaction between implant locations and cytokine and MMP expression. , 2006, Biomaterials.

[30]  M. Harmsen,et al.  Cellular and molecular dynamics in the foreign body reaction. , 2006, Tissue engineering.

[31]  D. Cohen,et al.  Development of peritoneal adhesions in macrophage depleted mice. , 2006, The Journal of surgical research.

[32]  J. Cailhier,et al.  Conditional Macrophage Ablation Demonstrates That Resident Macrophages Initiate Acute Peritoneal Inflammation1 , 2005, The Journal of Immunology.

[33]  Jiayou Zhang,et al.  Conditional macrophage ablation in transgenic mice expressing a Fas‐based suicide gene , 2004, Journal of leukocyte biology.

[34]  S. Grinstein,et al.  Phagocytosis by neutrophils. , 2003, Microbes and infection.

[35]  C. Overall.  Molecular determinants of metalloproteinase substrate specificity , 2002, Molecular biotechnology.

[36]  P. Waring,et al.  Cell death induced by the Fas/Fas ligand pathway and its role in pathology , 1999, Immunology and cell biology.

[37]  L. Creemers,et al.  Participation of intracellular cysteine proteinases, in particular cathepsin B, in degradation of collagen in periosteal tissue explants. , 1998, Matrix biology : journal of the International Society for Matrix Biology.

[38]  C. Peschle,et al.  Expression of growth factor receptors in unilineage differentiation culture of purified hematopoietic progenitors. , 1996, Blood.

[39]  C. Haslett,et al.  Apoptotic neutrophils are phagocytosed by fibroblasts with participation of the fibroblast vitronectin receptor and involvement of a mannose/fucose-specific lectin. , 1994, Journal of immunology.

[40]  J. Pollard,et al.  Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. , 1994, Development.

[41]  J. Feijen,et al.  Biocompatibility and tissue regenerating capacity of crosslinked dermal sheep collagen. , 1994, Journal of biomedical materials research.

[42]  Julie H. Campbell,et al.  Stem Cells , Tissue Engineering and Hematopoietic Elements Cellular Plasticity of Inflammatory Myeloid Cells in the Peritoneal Foreign Body Response , 2017 .

[43]  Vineet Agrawal,et al.  Damage associated molecular patterns within xenogeneic biologic scaffolds and their effects on host remodeling. , 2012, Biomaterials.

[44]  J. Babensee,et al.  Macrophage and dendritic cell phenotypic diversity in the context of biomaterials. , 2011, Journal of biomedical materials research. Part A.

[45]  N. Van Rooijen,et al.  Liposomes for specific depletion of macrophages from organs and tissues. , 2010, Methods in molecular biology.

[46]  Jacqueline A. Jones,et al.  Matrix metalloproteinases and their inhibitors in the foreign body reaction on biomaterials. , 2008, Journal of biomedical materials research. Part A.