Construction of a Vascularized Hydrogel for Cardiac Tissue Formation in a Porcine Model.

Replacing cardiac tissues lost to myocardial infarction remains a therapeutic goal for regenerative therapy in recovering cardiac function. We assessed the feasibility of constructing a macrosized human cardiac tissue construct using pluripotent stem cell-derived cardiomyocytes or control fibroblasts infused fibrin/collagen hydrogel and performed ectopic implantation in peripheral vascular system of a porcine model for 3weeks. Finally, an optimized vascularized cardiac construct was explanted and grafted onto porcine myocardium for 2weeks. Myocardial-grafted human cardiac constructs showed a nascent tissue-like organization with aligned cardiomyocytes within the remodelled collagen matrix. Nevertheless, no significant changes in intraconstruct density of cardiomyocytes were observed in the myocardial-grafted constructs (human embryonic stem cell [hESC]-derived cardiomyocyte [n=4]: 70.5 +/- 22.8 troponin I+ cardiomyocytes/high power field [HPF]) as compared to peripherally implanted constructs (hESC-derived cardiomyocyte [n=4]: 59.0 +/- 19.6 troponin I+ cardiomyocytes/HPF; human induced pluripotent stem cell-derived cardiomyocyte [n=3]: 50.9 +/- 8.5 troponin I+ cardiomyocytes/HPF, p=ns). However, the myocardial-grafted constructs showed an increased in neovascularization (194.4 +/- 24.7 microvessels/mm(2) tissue, p<.05), microvascular maturation (82.8 +/- 24.7 mature microvessels/mm(2), p<.05), and tissue-like formation whereas the peripherally implanted constructs of hESC-derived cardiomyocyte (168.3 +/- 98.2 microvessels/mm(2) tissue and 68.1 +/- 33.4 mature microvessels/mm(2)) and human induced pluripotent stem cell-derived cardiomyocyte (86.8 +/- 57.4 microvessels/mm(2) tissue and 22.0 +/- 32.7 mature microvessels/mm(2)) were not significantly different in vascularized response when compared to the control human fibroblasts (n=3) constructs (65.6 +/- 34.1 microvessels/mm(2) tissue and 30.7 +/- 20.7 mature microvessels/mm(2)). We presented results on technical feasibility and challenges of grafting vascularized centimetre-sized human cardiac construct that may spur novel approaches in cardiac tissue replacement strategy.