The proposed studies in this application focus on the development of a mechanistic understanding of the complexity of host/material interactions that comprise the foreign body response to biomaterials. Our working hypothesis is that lymphokine-mediated macrophage activation and foreign body gift cell (FBGC) formation on biomaterials are the result of complex extracellular and intracellular interactions that can be controlled by biomaterial surface chemistry.
The specific aims of the proposed project are: 1) to modulate and control lymphokine-mediated macrophage activation and FBGC formation through the application of molecularly-engineered surfaces designed to target critical cellular mechanisms and interactions, 2) to demonstrate that the spatial distribution and phenotype of adherent monocytes, macrophages and lymphokine-induced FBGC can be controlled by micropatterned surfaces that exert geometric constraints on these cell types, 3) to determine the effects of material surface properties on the production of specific lymphocyte-derived cytokines that promote macrophage development, activation and fusion to form FBGC or Langhans giant cells (LGC), 4) to elucidate the molecular mechanism(s) of lymphokine-induced FBGC and LGC formation and the cytoskeletal/adhesive structural organizations that underlie morphological differences between these giant cells, and 5) to determine through phenotypic characterization the potential functional significance of giant cells at sites of inflammation and foreign body reaction. Our experimental approach will utilize molecularly-engineered, micropatterned and temperature responsive surfaces to address these related and interactive specific aims. Correlative and quantitative biochemical and immunochemical techniques will be applied to our in vitro systems of FBGC and LGC formation utilizing human monocytes and lymphokines and our murine in vivo cage implant system. Fluorescence confocal scanning laser microscopy (FCSLM) will be exploited to identify extracellular and intracellular molecules and receptors that are critically important in the surface chemistry-dependent events of monocyte/macrophage adhesion and macrophage fusion to form FBGC. Material surface-dependent variations in these cell surface, intracellular, cytoskeletal and adhesive structural molecules will be evaluated. In vivo experiments will focus on identification of material-dependent lymphokine gene expression and secretion profiles and on Th1 versus Th2 lymphokine participation in FBGC formation. Results from our combined studies will lead to a greater appreciation of these complex cell/material interactions and novel design criteria for new biomaterials and tissue-engineered surfaces.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055714-06
Application #
6389547
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Kelley, Christine A
Project Start
1996-08-01
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
6
Fiscal Year
2001
Total Cost
$221,313
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Brodbeck, William G; Voskerician, Gabriela; Ziats, Nicholas P et al. (2003) In vivo leukocyte cytokine mRNA responses to biomaterials are dependent on surface chemistry. J Biomed Mater Res A 64:320-9
McNally, Amy K; Anderson, James M (2003) Foreign body-type multinucleated giant cell formation is potently induced by alpha-tocopherol and prevented by the diacylglycerol kinase inhibitor R59022. Am J Pathol 163:1147-56
Collier, Terry O; Anderson, James M; Kikuchi, Akihiko et al. (2002) Adhesion behavior of monocytes, macrophages, and foreign body giant cells on poly (N-isopropylacrylamide) temperature-responsive surfaces. J Biomed Mater Res 59:136-43
Brodbeck, William G; Patel, Jasmine; Voskerician, Gabriela et al. (2002) Biomaterial adherent macrophage apoptosis is increased by hydrophilic and anionic substrates in vivo. Proc Natl Acad Sci U S A 99:10287-92
McNally, Amy K; Anderson, James M (2002) Beta1 and beta2 integrins mediate adhesion during macrophage fusion and multinucleated foreign body giant cell formation. Am J Pathol 160:621-30
Collier, T O; Anderson, J M (2002) Protein and surface effects on monocyte and macrophage adhesion, maturation, and survival. J Biomed Mater Res 60:487-96
Brodbeck, William G; Shive, Mathew S; Colton, Erica et al. (2002) Interleukin-4 inhibits tumor necrosis factor-alpha-induced and spontaneous apoptosis of biomaterial-adherent macrophages. J Lab Clin Med 139:90-100
Brodbeck, W G; Shive, M S; Colton, E et al. (2001) Influence of biomaterial surface chemistry on the apoptosis of adherent cells. J Biomed Mater Res 55:661-8
Jenney, C R; Anderson, J M (2000) Adsorbed serum proteins responsible for surface dependent human macrophage behavior. J Biomed Mater Res 49:435-47
Nakayama, Y; Anderson, J M; Matsuda, T (2000) Laboratory-scale mass production of a multi-micropatterned grafted surface with different polymer regions. J Biomed Mater Res 53:584-91

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