Discrete microstructural cues for the attenuation of fibrosis following myocardial infarction

Abstract

Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. We have developed a therapeutic materials strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructures to mechanically alter the microenvironment. Polymeric microstructures were fabricated using photolithographic techniques and studied in a three-dimensional culture model of the fibrotic environment and by direct injection into the infarct zone of adult rats. Here, we show dose-dependent down-regulation of expression of genes associated with the mechanical fibrotic response in the presence of microstructures. Injection of this microstructured material into the infarct zone decreased levels of collagen and TGF-β, increased elastin deposition and vascularization in the infarcted region, and improved functional outcomes after six weeks. Our results demonstrate the efficacy of these discrete anti-fibrotic microstructures and suggest a potential therapeutic materials approach for combatting pathologic fibrosis.

Localized delivery of mechano-growth factor E-domain peptide via polymeric microstructures improves cardiac function following myocardial infarction

“…The use of the MRS engineered with these specifications was based on previous data showing that the empty MRS can inhibit NIH 3T3 fibroblast proliferation and down regulate expression of myofibroblast markers (collagen I, VI and α-smooth muscle actin) when seeded in a 3D culture system [17]. These studies were recently extended by showing that intramyocardial delivery of the empty MRS alone is sufficient to limit fibrosis to an ischemia-reperfusion model in vivo [32]. Moreover, studies examining cardiac myocyte remodeling in 3D cultures showed that the presence of microrods influence cardiac myocyte size, protein content, myofibrillar alignment and gene expression, indicating that the physical cues of the microenvironment can play a significant role in regulating cellular function [33,34].…”

Concise Review: Reduction of Adverse Cardiac Scarring Facilitates Pluripotent Stem Cell-Based Therapy for Myocardial Infarction

“…Although several biomaterials have been identified to reduce tissue stiffness or inhibit cardiac fibrosis, it remains to address whether they can be synergistically used in PSC‐based therapies. Microstructures of hyaluronic acid or hydrogel (fabricated by photolithography) were shown to anchor fibroblasts and mitigate cardiac fibrosis . MMPs (e.g., MMP2, MMP9, and MMP13) are required to correctly degrade the implanted scaffolds and endogenous natural ECM, allowing for stem cell migration and angiogenesis .…”

Probing the luminal microenvironment of reconstituted epithelial microtissues

“… 10 . For a detailed description of how cuboidal or rod-like PEG-microparticles were fabricated via photolithography, see refs 12 and 27 , respectively.…”