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Cardiac tissue engineering is an emerging field providing tools to treat and study cardiovascular diseases (CVDs). In the past years, the integration of stem cell technologies with micro- and nanoengineering techniques has enabled the creation of novel engineered cardiac tissues (ECTs) with potential applications in disease modeling, drug screening, and regenerative medicine. However, a major unaddressed limitation of stem cell-derived ECTs is their immature state, resembling a neonatal phenotype and genotype. The modulation of the cellular microenvironment within the ECTs has been proposed as an efficient mechanism to promote cellular maturation and improve features such as cellular coupling and synchronization. The integration of biological and nanoscale cues in the ECTs could serve as a tool for the modification and control of the engineered tissue microenvironment. Here we present a proof-of-concept study for the integration of biofunctionalized gold nanoribbons (AuNRs) with hiPSC-derived isogenic cardiac organoids to enhance tissue function and maturation. We first present extensive characterization of the synthesized AuNRs, their PEGylation and cytotoxicity evaluation. We then evaluated the functional contractility and transcriptomic profile of cardiac organoids fabricated with hiPSC-derived cardiomyocytes (mono-culture) as well as with hiPSC-derived cardiomyocytes and cardiac fibroblasts (co-culture). We demonstrated that PEGylated AuNRs are biocompatible and do not induce cell death in hiPSC-derived cardiac cells and organoids. We also found an improved transcriptomic profile of the co-cultured organoids indicating maturation of the hiPSC-derived cardiomyocytes in the presence of cardiac fibroblasts. Overall, we present for the first time the integration of AuNRs into cardiac organoids, showing promising results for improved tissue function. 

Cardiovascular diseases, including myocardial infarction (MI), persist as the leading cause of mortality and morbidity worldwide. The limited regenerative capacity of the myocardium presents significant challenges specifically for the treatment of MI and, subsequently, heart failure (HF). Traditional therapeutic approaches mainly rely on limiting the induced damage or the stress on the remaining viable myocardium through pharmacological regulation of remodeling mechanisms, rather than replacement or regeneration of the injured tissue. The emerging alternative regenerative medicine-based approaches have focused on restoring the damaged myocardial tissue with newly engineered functional and bioinspired tissue units. Cardiac regenerative medicine approaches can be broadly categorized into three groups: cell-based therapies, scaffold-based cardiac tissue engineering, and scaffold-free cardiac tissue engineering. Despite significant advancements, however, the clinical translation of these approaches has been critically hindered by two key obstacles for successful structural and functional replacement of the damaged myocardium, namely: poor engraftment of engineered tissue into the damaged cardiac muscle and weak electromechanical coupling of transplanted cells with the native tissue. To that end, the integration of micro- and nanoscale technologies along with recent advancements in stem cell technologies have opened new avenues for engineering of structurally mature and highly functional scaffold-based (SB-CMTs) and scaffold-free cardiac microtissues (SF-CMTs) with enhanced cellular organization and electromechanical coupling for the treatment of MI and HF. In this review article, we will present the state-of-the-art approaches and recent advancements in the engineering of SF-CMTs for myocardial repair.