These studies focus on the interactions of inflammatory cells with biomedical materials and target the currently unknown role(s) of lymphocytes in modulating recognized critical activities of adherent macrophages and foreign body giant cells (FBGCs) at the host/biomaterial interface. Our working hypothesis is that biomaterial surface chemistry controls the outcomes of macrophage interactions with lymphocytes, including lymphocyte responses, macrophage behavior, and lymphokine-induced FBGC formation on biomaterials. These innovative studies, which exploit well-characterized model surface- modified materials to elucidate specific roles of lymphocytes and lymphokines in the foreign body response to implanted biomaterials in vivo and in vitro, feature four strategically integrated specific aims that address (1) lymphocyte effects on biomaterial-adherent macrophage behavior, (2) biomaterial-adherent macrophage and FBGC modulation of lymphocyte behavior, (3) mechanisms of biomaterial-dependent lymphokine- induced FBGC formation, and (4) the physiological significance of lymphokine-induced FBGC formation on implanted biomaterials toward defining a biomaterials-induced macrophage activation phenotype. Our established and well-characterized in vitro human monocyte/macrophage and FBGC culture system has been extended to include co-cultures with autologous human lymphocytes. In vitro discoveries will be validated in the in vivo environment with our established mouse cage and subcutaneous implant systems. Our analyses will exploit state-of the-art methods, including proliferation assays, enzyme-linked immunosorbent assays (ELISA), flow cytometry with fluorescence-activated cell sorting (FACS), fluorescence confocal laser scanning microscopy, and immunohistochemistry. Significantly, the combined results from these studies will provide new and crucial perspectives of complex inflammatory cell/biomaterial interactions and will thereby foster novel design and/or management criteria for future biomedical implant materials and tissue-engineered surfaces.

Public Health Relevance

Lymphocyte interactions with macrophages and foreign body giant cells (FBGC) play a far greater role in the inflammatory response to implanted materials than previously appreciated. This investigation is designed to illuminate the significant and incompletely understood relationships between inflammatory cell behaviors on biomaterials and host response mechanisms. Target areas of focus are direct and indirect effects of lymphocytes on critical macrophage/FBGC behaviors, macrophage/FBGC modulation of lymphocyte behaviors, mechanisms of lymphokine-induced macrophage fusion, and the physiological significance of lymphokine-induced FBGC formation. New knowledge from these studies will provide greater perspectives on host responses to implanted biomedical devices, prostheses, and tissue- engineered materials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB000282-16
Application #
8514597
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Hunziker, Rosemarie
Project Start
1996-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
16
Fiscal Year
2013
Total Cost
$333,115
Indirect Cost
$120,940
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
McNally, Amy K; Anderson, James M (2015) Phenotypic expression in human monocyte-derived interleukin-4-induced foreign body giant cells and macrophages in vitro: dependence on material surface properties. J Biomed Mater Res A 103:1380-90
Rujitanaroj, Pim-on; Jao, Brian; Yang, Junghoon et al. (2013) Controlling fibrous capsule formation through long-term down-regulation of collagen type I (COL1A1) expression by nanofiber-mediated siRNA gene silencing. Acta Biomater 9:4513-24
McNally, Amy K; Anderson, James M (2011) Foreign body-type multinucleated giant cells induced by interleukin-4 express select lymphocyte co-stimulatory molecules and are phenotypically distinct from osteoclasts and dendritic cells. Exp Mol Pathol 91:673-81
Chang, David T; Colton, Erica; Matsuda, Takehisa et al. (2009) Lymphocyte adhesion and interactions with biomaterial adherent macrophages and foreign body giant cells. J Biomed Mater Res A 91:1210-20
Rodriguez, Analiz; Meyerson, Howard; Anderson, James M (2009) Quantitative in vivo cytokine analysis at synthetic biomaterial implant sites. J Biomed Mater Res A 89:152-9
Rodriguez, Analiz; Macewan, Sarah R; Meyerson, Howard et al. (2009) The foreign body reaction in T-cell-deficient mice. J Biomed Mater Res A 90:106-13
Brodbeck, William G; Anderson, James M (2009) Giant cell formation and function. Curr Opin Hematol 16:53-7
Anderson, James M; Rodriguez, Analiz; Chang, David T (2008) Foreign body reaction to biomaterials. Semin Immunol 20:86-100
Rodriguez, Analiz; Voskerician, Gabriela; Meyerson, Howard et al. (2008) T cell subset distributions following primary and secondary implantation at subcutaneous biomaterial implant sites. J Biomed Mater Res A 85:556-65
Chang, David T; Jones, Jacqueline A; Meyerson, Howard et al. (2008) Lymphocyte/macrophage interactions: biomaterial surface-dependent cytokine, chemokine, and matrix protein production. J Biomed Mater Res A 87:676-87

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