This investigation seeks to develop greater understanding of the complexity of host/material interactions that comprise the inflammatory cell responses to biomaterials and to acquire the fundamental knowledge and perspective necessary for the design of new biomaterials. These studies will focus on the differential participation of Th1 and Th2 lymphocyte subsets in monocyte/macrophage (MO/MC)-mediated inflammatory responses and the development of foreign body giant cells (FBGC) at the tissue/biomaterial interface.
The specific aims of the proposed project are: 1) to evaluate the polymer surface property dependence and control of lymphokine-mediated MC activation and FBGC formation; (2) to investigate the material surface-dependent phenomenon of interleukin-4 (IL-4)- induced FBGC formation and the material surface property- independent phenomenon of Langhans giant cell formation, and to utilize these findings to establish a cytoskeletal/adhesive structural basis for the major morphological differences between giant cells; (3) to evaluate the effects of surface properties on the production of lymphocyte-derived cytokines that induce MC fusion to form FBGCs or Langhans giant cells; (4) to elucidate the molecular mechanism of IL-4-induced FBGC formation and to determine the host tissue protective role for IL-4 in biomaterial/tissue interactions; and (5) to investigate the functional significance of the existence of morphologically- distinguishable types of multinucleated giant cells. Experimental methods to address these specific aims are provided in an interrelated network of in vitro human MC and lymphocyte cell culture studies and in vivo mouse studies. Techniques to address lymphocyte/MC/FBGC interactions with biomaterials include immunoassays for cytokine identification/quantitation, receptor- targeted inhibition studies to evaluate the participation of specific cell surface molecules in giant cell formation, and confocal scanning laser microscopy (CSLM) to correlate the patterns of cytoskeletal protein organization and cytoplasmic adhesion structures promoted during FBGC formation on the surfaces. Emphasis is place on elucidating material surface property effects on lymphokine-induced macrophage cytoskeletal reorganization during FBGC formation. Materials to be investigated in our studies are divided into three groups: 1) modified polystyrene surfaces; 2) neutral and ionic hydrophilic surfaces; and 3) molecular engineered surfaces. Rationale and justification for the choice of these materials are presented within the application. The molecular engineered surfaces are specifically designed to exploit CSLM to probe the relationships between MC and FBGC cytoskeletal and adhesive structural organization, and MC membrane receptor/material surface interactions.
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