The effect of Rho kinase inhibition on capsule formation using local delivery of Y-27632

Abstract

Introduction. Despite current developments in surgery and manufacturing technology, capsular contracture is still the most common late complication associated with breast implant surgery. This proposed study was designed to investigate the effect of Rho kinase inhibition on capsule formation. Rho kinases are pivotal regulators of several aspects of cell behavior and contribute to reorganization of the actin cytoskeleton, formation of stress fibers, and cell migration in the wound environment. They activate NF-κB by inducing I-κB kinase, which lead to activation of inflammatory pathways during wound healing. However, these responses may yield to extensive inflammatory effect which triggers an uncontrolled synthetic process, as seen in burns. We hypothesized that Rho kinase signaling pathway is up regulated in capsular contracture, which leads to excessive fibrosis, and inhibition of this pathway prevents contracture. This study aims to demonstrate the dynamic interaction between Rho kinase pathway and capsular contracture. Methods. Forty adult, Sprague-Dawley rats were utilized for this project. Animals were classified into two main groups: Group A ( n = 20): Only Silicon Implant; and Group B ( n = 10): Silicon Implant + Rho kinase Inhibitor (Y-27632). Silicon hemispheric implants of 2.5 cm in diameter were placed dorsally beneath the panniculus carnosus away from the incision into 20 Sprague-Dawley rats . Y-27632 was delivered by a biodegradable drug delivery method which is Polylactic-coglycolic acid/polyethylene glycol (PLGA/PEG) microspheres to provide long-term inhibition of the rho kinase signaling system. One milliliter of 10 mM Y-27632 was delivered into the vicinity of implant in 10 rats utilizing PLGA/PEG microspheres. Animals were sacrificed after 2 and 4 weeks for tissue processing. Obtained capsules were stained by Hematoxylin--Eosin and Masson’s trichrome stain to demonstrate architectural changes in capsules. Statistical analysis was performed using Student’s t-test ( P < 0.05). Results. Capsule formation was noted in both groups at 2 and 4 weeks. Capsule thickness was not significantly different between groups. However, histological analysis of Masson’s trichrome stained capsule specimens revealed that rho kinase inhibition led to a significant decrease in collagen deposition in Rho kinase inhibited group, an important architectural change in the capsule. Morphometric analysis using ImagePro software demonstrated that this change in collagen deposition was statistically significant ( P < 0.05). Conclusions. Down regulation of Rho kinase activity results in alterations in capsule architecture. These findings suggest that Rho kinase-mediated signaling pathway is a promising new target for prevention capsular contracture.