Modulation of Tissue Microenvironment Following Myocardial Infarction

Abstract

Significant progress has been made in methods for cardiac repair and regeneration within the past few decades; however, the diseased microenvironment of the infarct remains a limitation in the efficacy of therapies. A breadth of research is currently aiming to reverse this environment, focusing on immunomodulation, scavenging of oxidative species, and increasing oxygen levels within the tissue, either directly using materials or oxygen therapy or secondarily via angiogenesis and neovascularization techniques. Herein, an overview of the current methods for reversal of infarcted cardiac tissue to a less-diseased state, via biomaterials such as electrospun scaffolds, gels or nanoparticles, stem cells, and derived exosomes, drugs, or bioactive molecules such as growth factors, is provided. Often, combinations of therapies are complementary and induce a superior response. Finally, a brief summation of recent clinical trials is provided.

Effects of electrospun fibers containing ascorbic acid on oxidative stress reduction for cardiac tissue engineering

“…Research suggests that modulating the infarcted microenvironment toward a less diseased state may enhance the efficacy of these interventions. 5 It has been established that high doses of AA (reported as greater than 6 g per day, or 75 mg per kg per day), are safe in human populations. 64 Clinical trials have suggested infusing AA prior to reperfusion improves cardiac function, 22,23 however there are issues in traditional antioxidant therapy regarding obtaining therapeutic concentrations within the diseased tissue.…”

“…Despite promising results in vivo, regenerative therapies for myocardial infarction have shown limited success in clinical trials. Research suggests that modulating the infarcted microenvironment toward a less diseased state may enhance the efficacy of these interventions 5 …”

“…4 Regulation of this microenvironment toward a healthier state may increase the efficacy of current regenerative therapies and directly improve cardiac function. 5 One treatment pathway is using exogenous antioxidants such as ascorbic acid (AA), α-tocopherol and N-acetylcysteine, which reduce overall oxidative stress via the direct scavenging of ROS or inhibiting their generation. 6 Antioxidant therapies following myocardial infarction have been reviewed extensively 3,[6][7][8][9][10] ; while preclinical studies administering exogenous antioxidants have reported reductions in infarct size and improvements in cardiac function, clinical trials have yielded limited success.…”

“…The subsequent oxidative stress causes a cascade of myocardial injury; cells undergo apoptosis due to DNA damage and protein oxidation, and the infiltration of M1 macrophages and production of pro‐inflammatory cytokines occurs 4 . Regulation of this microenvironment toward a healthier state may increase the efficacy of current regenerative therapies and directly improve cardiac function 5 . One treatment pathway is using exogenous antioxidants such as ascorbic acid (AA), α‐tocopherol and N ‐acetylcysteine, which reduce overall oxidative stress via the direct scavenging of ROS or inhibiting their generation 6 …”

Recent Methods for Modifying Mechanical Properties of Tissue-Engineered Scaffolds for Clinical Applications

“…Tissue engineering is a rapidly expanding field which aims to design constructs which supplement or replace damaged biological tissue. The fabrication of a tissue-engineered graft can be undertaken in a variety of ways, including phase separation, bioprinting, gas foaming and electrospinning techniques [ 18 , 19 , 20 , 21 , 22 , 23 ]. From these methods, a dense interconnected network of material may be formed, which is termed a scaffold [ 24 ].…”