Roles for biomaterial surface and shear stress effects in the development of cardiovascular device infection

Modern medicine has made rapid advances towards the efficacious use of implantable devices in the treatment of cardiovascular maladies. However, catastrophic device infection still occurs despite inherent host defenses. This study intended to identify effects resulting from biomaterial interactions with bacteria and phagocytic leukocytes, in simulated dynamic flow conditions generated by a rotating disk system. Adhesion of Staphylococcus epidermidis and human neutrophils to a polyetherurethane urea (PEUU) over time was quantified. Bacterial adhesion in the shear stress range of 0–18 dynes/cm2 was substantial regardless of shear level, while neutrophil adhesion decreased with increasing shear. Nonadherent neutrophils transiently exposed to PEUU under shear stress displayed no cellular dysfunction as determined by superoxide release, a result which focused subsequent studies on adherent cells. Comprehensive characterization of cellular alterations occurring in adherent neutrophils exposed to shear stress for 1 hour yielded striking conclusions. It was ascertained that adherent neutrophils are sentenced to a rapid death through the induction of apoptosis in a shear-dependent fashion resulting in complete neutrophil death at shear levels above 6 dynes/cm 2. Cells displayed morphological (cytoplasm, nucleus) and biochemical (membrane, cytoskeleton, nucleus) alterations indicative of apoptosis, in addition to diminished phagocytic ability. Enzymatic caspase activity was detected in adherent cells, and immunoblotting of neutrophil extracts confirmed that caspase-3 participates in shear-induced apoptosis. Comparative static studies with PEUU-adherent neutrophils succeeded in inducing apoptosis with TNF-α and cycloheximide, but to a much lesser extent than shear stress. Caspase-3 activity was detected in TNF-α induced apoptosis. The microbicidal responsibilities of neutrophils are shared by monocytes, motivating studies of monocyte responses to shear stress following adhesion to PEUU. Whereas monocytes displayed identical morphological and biochemical shear-induced alterations as neutrophils, the extent of monocyte shear strew-induced apoptosis after 4 hours was less. Importantly, comparative static studies utilizing untreated and TNF-α induced monocytes revealed material dependencies between apoptosis of cells adherent to PEUU and a dimethyl-modified glass, and again enzymatic caspase activity was identified. This investigation has revealed much regarding the complex interactions occurring between bacteria, leukocytes, and biomaterials, and emphasizes that mechanisms by which shear strew and material surfaces foster the persistence of cardiovascular device infections should not be overlooked in device design.