Improving the biocompatibility of intravascular devices

Abstract

Event Abstract Back to Event Improving the biocompatibility of intravascular devices Guillaume Le Saux1, Laurent Plawinski1, Sylvain Nlate1 and Marie-Christine Durrieu1 1 CBMN-UMR5248, France Introduction: Continuous glucose monitoring is an efficient method for the management of diabetes and in limiting the complications induced by large fluctuations in glucose levels. For this, intravascular systems may be useful in producing more reliable and accurate devices. However, biocompatibility remains the key issue to be addressed for optimal performance [1]. In particular, inflammation and neo-vascularization are key factors to be addressed. Currently, the most commonly used method to overcome these obstacles is the use of drug releasing implants [2]. We believe that this paradigm should be reconsidered in view of their limited lifetime. In this scope, the perennial modification of the surface of a gold-based implant with pro-angiogenic and/or anti-inflammatory principles holds some promise. Gold is widely used in medical devices due to its excellent biocompatibility. The objective of this study is to investigate the impact of surface modified with the anti-inflammatory molecule α-Melanocyte Stimulating Hormone [3] (α-MSH) as well as the pro-angiogenic peptide sequence GDSVVYGLR [4] on Human Umbilical Vein Endothelial Cell (HUVEC) behavior in vitro. Experimental Methods: Functionalization – Our model is based on self-assembled monolayers (SAMs) of thiol–bound carboxyethyl terminated hepta(ethylene oxide) (EO7-COOH) on gold. Following this, α-MSH is grafted using a thiol-maleimide bond, thus yielding EO7-MSH surfaces, while GDSVVYGLR is coupled by peptide linkage to obtain EO7-SVV surfaces. Peptide surface density was quantified using XPS and PM-IRRAS. Biological studies – HUVEC proliferation was investigated after 96h. To discriminate the effect of surface grafted SVVYGLR from Vascular endothelial Growth Factor (VEGF), experiments were performed in cell culture media containing either 0.1% or 0% VEGF. Finally, ERK1/2 signaling was investigated. HUVEC inflammatory response was assessed by quantifying the impact of the EO7-MSH surfaces on the production of the pro-inflammatory cytokine IL-6. A comparative study of the effect of soluble versus immobilized α-MSH on IL-6 production was also performed. Results And Discussion: Surface characterisation – Using XPS and PM-IRRAS we found that the EO7-COOH surfaces are compact, homogeneous and have a structure analogous to crystalline poly(ethylene oxide). EO7-SVV and EO7-MSH were successfully produced with surface densities of SVVYGLR and α-MSH of 1.6 and 3.5 pmol/mm² respectively. Proliferation – HUVECs proliferated more on the EO7-SVV surfaces, regardless of VEGF concentration. Importantly, in VEGF deprived conditions, surface grafted SVV was able to maintain adhesion and proliferation via activation of the ERK1/2 signaling pathway. Inflammation – We observed that IL-6 production was significantly reduced on the EO7-MSH surface. In addition surface bound α-MSH was found to be as efficient as physiological levels of soluble α-MSH in reducing IL-6 expression. Conclusion: Summary – Bioactive gold surfaces with controlled surface density were produced and characterized. These were used to assess HUVEC response with regards to proliferation and inflammation. We found that HUVECs respond to the presence of bioactive molecules by proliferating on surfaces presenting the SVVYGLR peptide, via activation of a pro-angiogenic pathway. We also observed that surface bound α-MSH is beneficial in limiting HUVEC inflammation and that it is as potent as equivalent levels in solution in reducing inflammation. Perspectives – Future work includes simultaneously modifying gold surfaces with both anti-inflammatory and pro-angiogenic molecules and to test their effect on cell behavior in vitro, with ultimately the prospect of an in vivo study. ANR-10-LABX-0042-AMADEus