Multilevel Assessment of Stent-Induced Inflammation in the Adjacent Vascular Tissue

Abstract

A recent U.S. Food and Drug Administration report presented the currently available scientific information related to biological response to metal implants. In this work, a multilevel approach was employed to assess the implant-induced and biocorrosion-related inflammation in the adjacent vascular tissue using a mouse stent implantation model. The implications of biocorrosion on peri-implant tissue were assessed at the macroscopic level via in vivo imaging and histomorphology. Elevated matrix metalloproteinase activity, colocalized with the site of implantation, and histological staining indicated that stent surface condition and implantation time affect the inflammatory response and subsequent formation and extent of neointima. Hematological measurements also demonstrated that accumulated metal particle contamination in blood samples from corroded-stetted mice causes a stronger immune response. At the cellular level, the stent-induced alterations in the nanostructure, cytoskeleton, and mechanical properties of circulating lymphocytes were investigated. It was found that cells from corroded-stented samples exhibited higher stiffness, in terms of Young’s modulus values, compared to noncorroded and sham-stented samples. Nanomechanical modifications were also accompanied by cellular remodeling, through alterations in cell morphology and stress (F-actin) fiber characteristics. Our analysis indicates that surface wear and elevated metal particle contamination, prompted by corroded stents, may contribute to the inflammatory response and the multifactorial process of in-stent restenosis. The results also suggest that circulating lymphocytes could be a novel nanomechanical biomarker for peri-implant tissue inflammation and possibly the early stage of in-stent restenosis. Large-scale studies are warranted to further investigate these findings.

A Predictive Toxicokinetic Model for Nickel Leaching from Vascular Stents

“…The three stent types (V1HT, V1EP, and V2EP) were tested in vivo to establish the time-dependent concentration of the released Ni ions in tissues, organs, and body fluids. Drug treatment and surgical procedures were carried out as per the reported experimental protocol by Kapnisis et al, 48 which describes in detail a method for stent implantation in mouse carotid artery. In brief, following general anesthesia, a small median incision is performed at the ventral neck area, and the left common carotid artery (LCCA) is exposed.…”

“…Vascular tissue surrounding explanted stents was removed through a digestion process in a 1 M solution of NaOH, according to the protocol described in Kapnisis et al 48 Whole blood was collected via retro-orbital bleeding, and untainted urine specimens were collected via terminal direct bladder puncture using a glass Pasteur pipette. To avoid issues and variations arising from handling errors, the tissue-digested solution, the harvested organs, and the body fluid samples were collected and pooled ( n = 3 per stent type and time point) for more accurate estimates.…”