Role of protein kinase C in the monocyte‐derived macrophage‐mediated biodegradation of polycarbonate‐based polyurethanes

Abstract

Polycarbonate-polyurethanes (PCNUs) elicit a foreign body reaction during the initial tissue contact, partly mediated by the respiratory burst in monocytes, during which protein kinase C (PKC) activates NADPH (nicotinamide adenine dinucleotide phosphate) oxidase. Using an in vitro cell system, monocytes were differentiated into monocyte-derived macrophages (MDMs) and then reseeded onto three PCNUs (HDI431, HDI321, or MDI321): hexane (HDI) or 4,4-methylene bis-phenyl (MDI) diisocyanates synthesized with poly(1,6-hexyl 1,2-ethyl carbonate) diol (PCN) and 14C-labeled butanediol (BD) in the ratios 4:3:1 or 3:2:1 (diisocyanate/PCN/BD). MDM-mediated degradation was assessed by radiolabel release in the presence of a PKC activator (phorbol myristate acetate), inhibitor (H7), and a catalase/peroxidase inhibitor (NaN3). Activating PKC decreased biodegradation and esterase activity in MDMs on HDI431 and HDI321 but not MDI321, whereas H7 and NaN3 inhibited the MDM degradation of MDI321 only. Pretreatment of the PCNUs with H2O2 inhibited esterase-mediated radiolabel release from HDI431 and HDI321 but stimulated radiolabel release from MDI321. The difference in the effect of H2O2 on the HDI versus MDI PCNUs contributes to explaining the effect of PKC activation on material degradation. Understanding the mechanism by which this pathway is linked to PCNU chemistry may assist in designing materials with tailored biodegradation rates.

The interaction between hydrolytic and oxidative pathways in macrophage‐mediated polyurethane degradation

“…19 Another study of these PCNUs showed that MDM-mediated degradation of HDI431 was affected differently from the degradation of HDI321 (after the addition of the PKC inhibitor H-7). 25 These studies suggest that MDM can differentiate and react differently to material surfaces that have identical chemical moieties and differ by only 3% in hard segment concentration. 3 Therefore, although other studies have suggested that oxidation is the most dominant activity in the degradation of PUs, 38 this does not hold true for PUs in general and even for specific classes of PUs (i.e., polyetherPUs, PCNUs, etc.)…”

“…Previously, oxidation of a PCNU by H 2 O 2 pretreatment did show changes in its susceptibility to hydrolytic cleavage by CXE. 25 Since neutrophils, monocytes, and MDM all release ROS it is possible in vivo for MDM to attach to an implanted material that has previously been oxidized. There were significant differences in the response of the MDM adherent to the oxidized PCNUs.…”

“…24 In a recent study, it was shown that H 2 O 2 pretreatment of the two HDI PCNUs inhibited subsequent CXEmediated degradation, whereas pretreatment of MDI321 did not reduce degradation. 25 When MDM were cultured with phorbol myristate acetate (PMA), MDM-mediated degradation of HDI PCNUs was inhibited; however, the degradation of MDI321 was unaffected. 25 It was suggested that PMA activation of PKC was responsible for this result since the release of ROS might inhibit susceptibility to hydrolysis of the HDI PCNUs because of oxidation of the surface.…”

“…25 When MDM were cultured with phorbol myristate acetate (PMA), MDM-mediated degradation of HDI PCNUs was inhibited; however, the degradation of MDI321 was unaffected. 25 It was suggested that PMA activation of PKC was responsible for this result since the release of ROS might inhibit susceptibility to hydrolysis of the HDI PCNUs because of oxidation of the surface. These studies suggest that oxidation of the material can alter the surface chemistry, making fewer or more susceptible bonds available for hydrolytic cleavage, or perhaps modulating the MDM response to the altered surface.…”

“…Although it appeared in a previous study that oxidation of the surface affected subsequent hydrolysis, 25 no determination of the ROS released from MDM on the different materials was made. For the first time, this study quantified the ROS produced by MDM in response to the PCNU surfaces with and without the PMA activation of PKC, and these findings were discussed in terms of structural changes to the surfaces following treatment with H 2 O 2 , the latter being the end product of the respiratory burst in MDM.…”