Protein kinase C and the respiratory burst in the macrophage-mediated biodegradation of polyurethanes: Dependence on material surface chemistry

Abstract

Polyurethanes are versatile materials used in the manufacture of diverse medical devices. Monocytes attach to the material surface and differentiate to monocyte-derived macrophages (MDM)s during the foreign body response. MDMs degrade polyurethanes by releasing reactive oxygen species (ROS) and hydrolytic enzymes (cholesterol esterase and monocyte-specific esterase (MSE)) by an unknown mechanism. To study this mechanism, model polycarbonate-based polyurethanes (PCNU)s have been made with hexane (HDI) or methylene bisphenyl diisocyanate (MDI) with poly (1,6-hexyl carbonate) diol (PCN) and 1,4-butanediol (BD) in a 4:3:1 ratio of HDI:PCN:BD (HDI431) or a 3:2:1 ratio of HDI:PCN:BD or MDI:PCN:BD (HDI321 or MDI321 respectively). HDI431 is the most degradable by MDM- and esterase-mediated degradation followed by HDI321 and MDI321. Manuscript#1 investigated the effects of phorbol myristate acetate (PMA) on MDM-mediated degradation of model PCNUs. In this study PMA inhibited the degradation of HDI PCNUs correlating with decreased esterase activity and MSE, but had no effect on the degradation of MDI321. Manuscript#2 suggested that H2O 2 treatment degraded PCNUs and affected subsequent MDM-mediated degradation, esterase and acid phosphatase activity in a material surface specific manner. In addition, this study found that material surface stimulated ROS production in MDM. PMA affected ROS production in MDM differently based on material surface. Manuscript#3 investigated the role of protein kinase C (PKC) activation and the respiratory burst in MDM-mediated PCNU degradation. This study showed that the PMA inhibition of MDM-mediated degradation of HDI PCNUs, esterase activity and MSE protein were dependent on PKC activation. The activation marker high molecular weight group box 1 protein secretion was highest on HDI431 and was prevented by PMA, matching the decreased degradation. A degradative pathway in MDM on MDI321 was triggered with PKC inactive PMA, ROS scavengers or PMA with a PKC inhibitor. This thesis proposes that material degradation by hydrolytic and oxidative pathways are channeled by MDM in varying amounts depending on material chemistry, supporting the theory that MDM respond to material chemistry first and then to environmental factors. Therefore these studies suggest that each polyurethane be tested under physiologically appropriate conditions in order to determine if it is suitable for the desired application and implant location.