Myocardial infarction from a tissue engineering and regenerative medicine point of view: A comprehensive review on models and treatments

Abstract

In the modern world, myocardial infarction is one of the most common cardiovascular diseases, which are responsible for around 18 million deaths every year or almost 32% of all deaths. Due to the detrimental effects of COVID-19 on the cardiovascular system, this rate is expected to increase in the coming years. Although there has been some progress in myocardial infarction treatment, translating pre-clinical findings to the clinic remains a major challenge. One reason for this is the lack of reliable and human representative healthy and fibrotic cardiac tissue models that can be used to understand the fundamentals of ischemic/reperfusion injury caused by myocardial infarction and to test new drugs and therapeutic strategies. In this review, we first present an overview of the anatomy of the heart and the pathophysiology of myocardial infarction, and then discuss the recent developments on pre-clinical infarct models, focusing mainly on the engineered three-dimensional cardiac ischemic/reperfusion injury and fibrosis models developed using different engineering methods such as organoids, microfluidic devices, and bioprinted constructs. We also present the benefits and limitations of emerging and promising regenerative therapy treatments for myocardial infarction such as cell therapies, extracellular vesicles, and cardiac patches. This review aims to overview recent advances in three-dimensional engineered infarct models and current regenerative therapeutic options, which can be used as a guide for developing new models and treatment strategies.

Modeling Heart Diseases on a Chip: Advantages and Future Opportunities

“…58 During myocardial infarction, the partial or complete obstruction of coronary blood flow leads to inefficient oxygen and nutrient delivery to the myocardium. 59 This is characterized by a low cardiomyocyte pH, compensatory H+/Na+ and Na+/Ca2+ exchange leading to Ca2+ overload, formation of reactive oxygen species, and cell death. 60,61 Restoration of blood flow is essential to prevent life-threatening arrhythmias and irreversible cardiac damage that can lead to heart failure.…”

Engineering the cardiac tissue microenvironment

“…Levels of miRNAs such as miR-1, miR-133, miR-208 have been shown to rise in blood quickly before and after an acute cardiac event. The advantage of identifying miRNA signatures will be earlier detection of MI than the traditional troponin assay-based methods, which only become detectable after heart muscle damage and peaks 12-48 h after onset of MI [24,132,160]. Moreover, similar algorithms have been used to decipher the miRNA signature of pulmonary arterial hypertension [296].…”

“…While ECT models are a popular topic for review, many discussions aim to focus on a single aspect of these devices, such as the utilized cells [14][15][16], constructed materials [17][18][19], or novel fabrication methods [12,20], and often convalesce to investigate the zeitgeist of models used to engineer the heart, the majority of which are bioprinting and heart-on-a-chip models [21,22]. Despite this, few articles have been published on the target applications of cardiac tissue engineering [10,23,24]. To address this, we focus on the use of cardiac tissue engineering in (i) the treatment of heart diseases, along with potential applications in the development of strategies for cardiac tissue regeneration and replacement, and (ii) creating both healthy and diseased cardiac tissue models to both enhance our understanding of the fundamental biology of heart diseases, as well as develop more biomimetic and easily accessible platforms for drug testing and discovery, and diagnosis.…”

The Role of ncRNAs in Cardiac Infarction and Regeneration

“…Ischemia leads to the necrosis and cell death of the affected myocardium. Moreover, during the reperfusion process, the sudden influx of oxygenated blood drives the generation of reactive oxygen species (ROS), promoting oxidative stress and an extra wave of cell death [ 3 ]. As it is well known, the adult human heart has low levels of cardiomyocyte proliferation, thereby limiting its healing capacity.…”

“…These two processes are well coordinated and involve fine-tuned cross-talk among different cell types, such as cardiac myocytes, neutrophils, macrophages, fibroblasts, endothelial cells, and nerve cells, among which macrophages and fibroblasts are the two cell populations with the most important roles during the post-MI response. Finally, inflammation and scar formation lead to a loss of contractile function, which eventually induces heart failure (HF) [ 3 , 5 ].…”