Mechanisms of Endothelial Cell Attachment, Proliferation, and Differentiation on 4 Types of Platinum-Based Endovascular Coils

Objective

A subarachnoid hemorrhage is neurologically devastating, with 50% of patients becoming disabled or deceased. Advent of Guglielmi detachable coils in 1995 permitted endovascular treatment of cerebral aneurysms. Coiling is efficacious and safe, but durability needs improvement, as nearly 20% of patients require further invasive intervention secondary to aneurysm recurrence. The aim of this study is to develop an in vitro model of endothelial cell (EC) proliferation and differentiation on four types of platinum-based coils, using gene expression profiling to understand EC biology as they colonize and differentiate on coils.

Methods

Human umbilical vein ECs were grown in vitro on platinum coil segments. Growth patterns were assessed as a function of coil type. Gene expression profiles for coil attached versus coil unattached ECs were determined using immunohistochemistry and gene array analysis.

Results

ECs showed rapid, robust attachment to all coil types. Some detachment occurred within 24–48 hours. Significant growth of remaining attached cells occurred during the next week, creating a confluence on coils and within coil grooves. Similar growth curve results were obtained with human brain ECs on platinum-based coil surfaces. Differentiation markers in attached cells (α₁, α₂, β₁ integrins) were expressed on immunostaining, whereas microarray gene expression revealed 48 up-regulated and 68 down-regulated genes after 24-hour growth on coils. Major pathways affected as a function of time of colonization on coils and coil type included those involved in regulation of cell cycle and cell signaling.

Conclusions

We developed an in vitro model for evaluating endothelialization of platinum coils to optimize coil design to support robust EC colonization and differentiation.

Introduction

Thirty-five thousand patients suffer from aneurysmal subarachnoid hemorrhage yearly within the United States. The International Subarachnoid Aneurysm Trial (ISAT) reported a lower probability of death and disability for patients undergoing coiling of cerebral aneurysms as opposed to microsurgery (15). Although ISAT built the platform for launching endovascular treatment of cerebral aneurysms as a mainstay therapy, the durability of this treatment method remains inferior to that of microsurgery. Based on follow-up cerebral angiography, 10%–30% of all coiled aneurysms will show recurrence 1, 18. Recurrence of coiled aneurysms leads to increased morbidity secondary to retreatments, angiographic follow-up, and the real risk of rerupture.

The goal of endovascular occlusion of aneurysms is to introduce platinum-based coils into the cerebral aneurysm until the entire aneurysm volume is filled with thrombus and coils. Volumetric analysis shows that most aneurysms are only filled 20%–40% with coils, and the rest represents acute thrombus (1). Histopathologic analyses based on autopsy of patients who harbored coiled aneurysms show that within the first 4 weeks, the aneurysm houses organized thrombus, which then develops into minimal fibrous tissue. Endothelial proliferation seems to occur at 3 months after embolization 3, 4, 21. At 12 months after the procedure, coils seem to be embedded in fibrous tissue with endothelialization occurring over the neck of the aneurysm 3, 4, 21. Recurrence takes place when the endothelialization process does not occur across the neck of the aneurysm and thus, the pulsatility is transmitted to the coil/thrombus mass leading to coil compaction as the thrombus dissolves. Our goal is to understand the interaction of platinum coils with endothelial cells (ECs), with the future aim of creating an intra-aneurysmal environment for EC proliferation across the neck of the aneurysm.