Engineered cardiac tissue patch maintains structural and electrical properties after epicardial implantation

Abstract

Functional cardiac tissue engineering holds promise as a candidate therapy for myocardial infarction and heart failure. Generation of "strong-contracting and fast-conducting" cardiac tissue patches capable of electromechanical coupling with host myocardium could allow efficient improvement of heart function without increased arrhythmogenic risks. Towards that goal, we engineered highly functional 1 cm × 1 cm cardiac tissue patches made of neonatal rat ventricular cells which after 2 weeks of culture exhibited force of contraction of 18.0 ± 1.4 mN, conduction velocity (CV) of 32.3 ± 1.8 cm/s, and sustained chronic activation when paced at rates as high as 8.7 ± 0.8 Hz. Patches transduced with genetically-encoded calcium indicator (GCaMP6) were implanted onto adult rat ventricles and after 4-6 weeks assessed for action potential conduction and electrical integration by two-camera optical mapping of GCaMP6-reported Ca transients in the patch and RH237-reported action potentials in the recipient heart. Of the 13 implanted patches, 11 (85%) engrafted, maintained structural integrity, and conducted action potentials with average CVs and Ca transient durations comparable to those before implantation. Despite preserved graft electrical properties, no anterograde or retrograde conduction could be induced between the patch and host cardiomyocytes, indicating lack of electrical integration. Electrical properties of the underlying myocardium were not changed by the engrafted patch. From immunostaining analyses, implanted patches were highly vascularized and expressed abundant electromechanical junctions, but remained separated from the epicardium by a non-myocyte layer. In summary, our studies demonstrate generation of highly functional cardiac tissue patches that can robustly engraft on the epicardial surface, vascularize, and maintain electrical function, but do not couple with host tissue. The lack of graft-host electrical integration is therefore a critical obstacle to development of efficient tissue engineering therapies for heart repair.

A multi-cellular 3D bioprinting approach for vascularized heart tissue engineering based on HUVECs and iPSC-derived cardiomyocytes

“…These medical challenges have raised the need for innovative and more effective cell-based approaches that are currently the subject of numerous research studies 12 , 13 . To this aim, the tissue engineering and regenerative medicine approaches revealed great potential as alternative options, creating constructs for repairing or replacing macroscopic part of cardiovascular tissue 14 – 17 . Moreover, modern technologies for the transplantation of human organs - with their countless challenges and high costs - are ripe for making a revolution to innovation and process optimization.…”

ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure

“…19,69 The underlying process of in vivo maturation are however not well understood and further optimization of engineering paradigms may benefit from further mechanistic insight. A possible implementation of engineering systems to overcome these shortcomings may consist in using biomaterial fabrication criteria supporting coordinated multi-layered vascular and myocardial cell growth, 100 systems favouring electro-mechanical coupling of cells in the patch 101,102 and, finally, materials with defined biophysical characteristics (e.g. stiffness) promoting maturation of myocyte action potential propagation.…”

Cardiomyocyte Induction and Regeneration for Myocardial Infarction Treatment: Cell Sources and Administration Strategies

“…[107] Jackman et al fabricated a 1 cm × 1 cm cardiac patch by placing mixture of neonatal rat ventricular cells and fibrin/matrigel composite hydrogel into a reusable polydimethysiloxane (PDMS) mold, the patch can robustly engraft to the host epicardial surface, vascularize and maintain structural integrity, but lack electrical integrity with host tissue. [108] A cardiac stromal cell-laden microneedle patch was fabricated from aqueous solution of PVA using a silicon micromold, which consists of 20 by 20 microneedle array and the conical needle has a base diameter of 300 µm, a tip diameter of 5 µm and a height of 600 µm. The microneedle patch creates "channels" between host myocardium and the engrafted cardiac stromal cells (CSCs) and allows release of regenerative factors se-creted by CSCs to the infarcted area to promote heart repair (Figure 4); in vivo application of cell-laden microneedle patches in rat and pig MI models reveal enhanced angiomyogenesis and improved cardiac function, [109] indicating microneedle cardiac patch a novel delivery system of therapeutic cells and factors for MI repair.…”