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3496 Mesenchymal Stem Cell Extracellular Vesicle Delivery in a Shear-Thinning Hydrogel For Therapy in an Acute Myocardial Infarction Model: A Comparative Analysis

Published online by Cambridge University Press:  26 March 2019

Drew Goldberg
Affiliation:
University of Pennsylvania School of Medicine
Ann Gaffey
Affiliation:
University of Pennsylvania School of Medicine
Minna Chen
Affiliation:
University of Pennsylvania School of Medicine
Elizabeth Li
Affiliation:
University of Pennsylvania School of Medicine
Samuel Kim
Affiliation:
University of Pennsylvania School of Medicine
Zoe Tran
Affiliation:
University of Pennsylvania School of Medicine
Jason Burdick
Affiliation:
University of Pennsylvania School of Medicine
Pavan Atluri
Affiliation:
University of Pennsylvania School of Medicine
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Abstract

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OBJECTIVES/SPECIFIC AIMS: The primary aim is to assess differences in therapeutic effect between MSC and EPC EVs on acute ischemic rat hearts through delivery in a biocompatible and shear-thinning hydrogel. Primary outcomes for therapeutic assessment include an in-vitro angiogenesis assay and in-vivo hemodynamic analysis, mainly identifying differences in ejection fraction and contractility. Secondary hemodynamic outcomes include cardiac output, stroke volume, and end-diastolic pressure volume relationship (EDPVR). Secondary structural outcomes include post-mortem scar analysis and immunohistochemistry (IHC) staining for angiomyogenesis. METHODS/STUDY POPULATION: MSCs and EPCs will be cultured according to previously published protocols. EVs will be isolated from cultured cell lines through precipitation methods with polyethylene glycol. EVs will be qualitatively analyzed with nanoparticle tracking analysis (NTA) and flow cytometry. The shear thinning hydrogel (STG) will be constructed using a hyaluronic backbone conjugated to adamantane or beta-cyclodextrin, ultimately facilitating guest-host interactions with shear thinning properties. Controls and treatment groups mixed with the hydrogel will be injected into the border zone of infarcted Wistar rat hearts immediately following a left anterior descending artery ligation. Hemodynamic assessment will be performed at four weeks through left ventricular catheter based pressure-volume recordings. Ex-vivo analysis will include scar thickness assessment using Masson collagen staining and IHC stain for vessel (anti-vonWillebrand factor; anti-Isolectin) and myocyte formation (anti-cardiac Troponin I). RESULTS/ANTICIPATED RESULTS: We hypothesize that, in-vitro, MSC-EVs will demonstrate non-inferior angiogenic potential as compared to EPC-EVs. We posit that MSC-EVs will demonstrate superior therapeutic effect to EPC-EVs in-vivo as measured by functional hemodynamics and structural assessment. We have successfully isolated MSC and EPC EVs and have validated uniformity across EV populations (Figure 1). Preliminary data from the angiogenesis assay (n=3) demonstrated that MSC-EV and EPC-EV produce non-significantly different angiogenic potential as measured by number of vascular meshing extremes (p=0.144) and length of master vascular segment (p=0.193), with significant differences compared to either positive or negative controls. DISCUSSION/SIGNIFICANCE OF IMPACT: Novel regenerative therapies are needed for patients with a history of AMI given current limitations to therapy and sequelae of ischemic heart disease. Delivery of extracellular vesicles through a shear-thinning gel is a novel “off-the-shelf” translational approach to address the current clinical need.

Type
Mechanistic Basic to Clinical
Creative Commons
Creative Common License - CCCreative Common License - BYCreative Common License - NCCreative Common License - ND
This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (http://creativecommons.org/licenses/by-ncnd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.
Copyright
© The Association for Clinical and Translational Science 2019