Coronary stents represent an important tool in the armamentarium available to treat symptomatic atherosclerotic plaques, with over 1 million procedures performed annually in the US alone. The delayed endothelialization of the artery following percutaneous interventions can predispose to acute thrombosis, while the associated injury leads to neo-intimal hyperplasia, both linked to significant clinical events. We are proposing a novel way of addressing this problem by employing endoluminal cellular paving of the stented surface with cells capable of regenerating functional endothelium. To achieve this we are harnessing on the physics of acoustic radiation force, which essentially states that compressible objects in an ultrasound field are displaced away from the energy source due to absorption of the sound wave momentum. This effect is particularly strong with gas-filled lipid microbubbles used as ultrasound contrast agents. By coating the progenitor cells with microbubbles, which can act as the driving engine, the cells can be forced to marginalize and interact with the injured arterial surface when passing by a centrally placed intravascular US catheter. We have a substantial in vitro and in vivo body of data demonstrating the feasibility of the concept for vascular endoluminal cell painting. The current methods for vascular cell seeding require prolonged period of flow cessation, a problem that our current approach minimizes. In collaboration with a multidisciplinary team at the Center for Ultrasound Molecular Imaging and Therapeutics at University of Pittsburgh we will test the therapeutic efficacy of this idea in a step wise fashion testing both autologous endothelial progenitor cells (EPC) and allogeneic mesenchymal stem cells (MSCs), and using electrostatic interaction for cell:bubble association.
Under Specific Aim 1, we will define the optimal conditions for delivery of cells to the wall of a vascular phantom in terms of flow conditions, optimal microbubble coating and ultrasound parameters. Potential detrimental effects of the microbubbles and/or ultrasound on cell viability will be tested as well. Using an existing FDA approved ultrasound catheter, we will then translate this approach under Specific Aim 2 to a rabbit model of arterial injury, and test the efficacy of each cell in promoting re-endothelialization and using the 2 different types. Again, the safety of the ultrasound delivery in vivo will be specifically addressed. If successful, these translational experiments could represent the basis developing clinically relevant strategies for accelerated re-endothelialization of coronary stents.

Public Health Relevance

Percutaneous intervention with stents has made a major impact in the treatment of symptomatic atherosclerotic blockages in the coronary arteries. One of the current issues with these vascular scaffolds is the slow healing and tissue integration, in particular with drug coated stents, requiring prolonged treatment with blood thinners. The current application explore a novel way of paving the inside of the stent-treated arteries with progenitor cells, using acoustic energy generated by a catheter inside the vessel, harnessed to selectively push the cells to their target. The progenitor cells will then have the potential to regenerate the normal endothelial lining of healthy arteries, thus preventing clot formation inside the stent, and at the same time inhibit the tissue ingrowth associated with restenosis. This is an entirely new concept, and we will develop the cellular paving method from the bench top to a translational model emulating the proposed clinical application.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Lee, Albert
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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