Biomaterials and the foreign body reaction: Surface chemistry dependent macrophage adhesion, fusion, apoptosis, and cytokine production

The foreign body reaction has proven to be a hindrance to the functionality of implanted biomedical devices. The ability to direct this reaction, inflammation, and wound healing via the material-dependent control of key cellular components, macrophages and foreign body giant cells (FBGCs), is vital to the development of future biomedical devices. This dissertation addresses the hypothesis that surface chemistry directs adherent macrophage/FBGC behavior. Specifically, this research endeavored to elucidate the relationship of surface hydrophobicity, hydrophilicity, and ionic chemistry with macrophage adhesion, activation, fusion into FBGCs, apoptosis, and production of cytokines, chemokines, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs) using model material systems. In addition, a dynamic mathematical model was developed in order to further understand and predict these relationships.; Utilizing an in vitro human monocyte culture system and surface-modified biomaterials displaying hydrophobic, hydrophilic, and/or ionic chemistries, it has been demonstrated that material surface chemistry influences macrophage adhesion and fusion ultimately directing the cytokines/chemokines/MMPs/TIMPs released from biomaterial-adherent macrophages/FBGCs. Hydrophilic/neutral surfaces significantly inhibited adhesion and fusion in comparison to the hydrophobic and hydrophilic/ionic surfaces. Adherent cells on these cell-limiting hydrophilic/neutral surfaces produced greater quantities of each protein analyzed in comparison to the adhesion supporting surfaces indicating an increased activation state in these cells. This finding directly contradicts previous dogma that cell activation correlates with cellular adhesion prompting additional analysis into this phenomenon. In addition, the cytokine/chemokine profiles produced by adherent cells at earlier timepoints shifted from a more classically activated state to an alternatively activated state at later timepoints suggesting that a phenotypic switch occurs in these biomaterial-adherent cells.; Subsequent analysis using surface-modified polyurethanes confirmed that FBGC formation was promoted by hydrophobic chemistry modifications, in vitro and in vivo. Macrophage apoptosis was promoted at earlier timepoints in vivo, while fusion was promoted at later timepoints supporting the theory that macrophages fuse as a mechanism to escape apoptosis.; This pivotal study clearly presents evidence that material surface chemistry can differentially affect macrophage/FBGC adhesion, activation, fusion, and apoptosis and the cytokine/chemokine/MMP/TIMP profiles derived from activated macrophages/FBGCs adherent to biomaterial surfaces.