Biomaterials elicit a distinct inflammatory response leading to the formation of destructive foreign body giant cells (FBGC) that participate in the encapsulating foreign body response (FBR). We have described the participation of the chemokine MCP1 in the formation of FBGC and fibrotic encapsulation; the latter in a tissue- specific manner. Specifically, we found that MCP1 is critical for FBGC formation in both subcutaneous (SC) and intraperitoneal (IP) implantation models and for fibrosis only in the latter. Our findings prompted us to investigate the activation phenotype of WT and MCP1 KO macrophages in the context of the FBR IP. In preliminary studies, we have discovered a reduction in the levels of TNF-? and low activation of the NF?B pathway in vitro and in vivo. Moreover, these defects were associated with reduced levels of TGF- and attenuated fibrosis. Therefore, our findings suggest that MCP1 is a critical determinant of macrophage polarization/activation in the FBR. To gain greater inside into the mechanism of biomaterial-induced macrophage activation and fusion, we initiated high throughput analysis of cDNA and micro inhibitory RNA (miRNA) arrays with a focus on identifying genes and miRNAs that are differentially regulated in WT and MCP1 macrophages. In addition, we have explored macrophage signaling by focusing on activation of kinases and preliminary studies indicate a defect in ERK1/2 activation in MCP1 KO macrophages. In this application, we propose studies to explore and exploit macrophage activation and identify mechanistic links between this process and the progression of the FBR in various tissues. In addition, we aim to expand and translate some of our findings into bioengineering approaches that should provide proof-of-principle for the modulation of macrophage phenotype as a strategy to attenuate the FBR. Accordingly, the specific aims of this application are: 1) to test the hypothesis the MCP1-specific signaling modulates the function of biomaterial-adherent macrophages; 2) to test the hypothesis that biomaterial-induced macrophage activation is a critical determinant of implant fibrosis; and 3) to test the hypothesis that biomaterial-induced macrophage activation and/or fusion is regulated by specific miRNAs.

Public Health Relevance

Implantation of biomaterials, devices, and tissue engineered constructs into vascularized tissues elicits an inflammatory response the can lead to implant failure. A hallmark of this response is the fusion of inflammatory cells on the implant surface to form multinucleated giant cells that can be destructive. In addition, the inflammatory response leads to the eventual encapsulation of the implant resulting in lack of integration. In this application we propose to explore the molecular signals that regulate the activation of inflammatory cells and the formation of giant cells and develop biomaterials with the inherent ability to modulate the inflammatory response they elicit. Completion of this project should lead to a greater understanding of the events at the interface between living tissues and biomaterials.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072194-13
Application #
9394013
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Somers, Scott D
Project Start
2005-04-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
13
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kunkemoeller, Britta; Kyriakides, Themis R (2017) Redox Signaling in Diabetic Wound Healing Regulates Extracellular Matrix Deposition. Antioxid Redox Signal 27:823-838
Moore, Laura Beth; Sawyer, Andrew J; Saucier-Sawyer, Jennifer et al. (2016) Nanoparticle delivery of miR-223 to attenuate macrophage fusion. Biomaterials 89:127-35
Sawyer, Andrew J; Kyriakides, Themis R (2016) Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization. Adv Drug Deliv Rev 97:56-68
Morris, Aaron H; Chang, Julie; Kyriakides, Themis R (2016) Inadequate Processing of Decellularized Dermal Matrix Reduces Cell Viability In Vitro and Increases Apoptosis and Acute Inflammation In Vivo. Biores Open Access 5:177-87
Padmanabhan, Jagannath; Augelli, Michael J; Cheung, Bettina et al. (2016) Regulation of cell-cell fusion by nanotopography. Sci Rep 6:33277
Padmanabhan, Jagannath; Kyriakides, Themis R (2015) Nanomaterials, inflammation, and tissue engineering. Wiley Interdiscip Rev Nanomed Nanobiotechnol 7:355-70
Moore, Laura Beth; Sawyer, Andrew J; Charokopos, Antonios et al. (2015) Loss of monocyte chemoattractant protein-1 alters macrophage polarization and reduces NF?B activation in the foreign body response. Acta Biomater 11:37-47
Moore, Laura Beth; Kyriakides, Themis R (2015) Molecular Characterization of Macrophage-Biomaterial Interactions. Adv Exp Med Biol 865:109-22
Sawyer, Andrew J; Tian, Weiming; Saucier-Sawyer, Jennifer K et al. (2014) The effect of inflammatory cell-derived MCP-1 loss on neuronal survival during chronic neuroinflammation. Biomaterials 35:6698-706
Padmanabhan, Jagannath; Kinser, Emily R; Stalter, Mark A et al. (2014) Engineering cellular response using nanopatterned bulk metallic glass. ACS Nano 8:4366-75

Showing the most recent 10 out of 38 publications