BRAV3 has delivered the first 3D engineered cardiac tissue designed under the specifications of natural myocardium. For this, a through characterisation of a human-sized model (pig), at the mechanical, electrical, architectural and functional levels. This novel information has been employed for the development of advanced computational models, allowing not only the prediction of experimental outcomes, but also informing the engineered tissue biofabrication. To allow a tailored replication of the required zonal design, melt electrowriting (MEW) was employed, due to the small fibre size achiavable, its high precision and translability (use of medical-grade materials). Biolocal ventricular assist device (BioVAD) was designed with 3 distinct zones, replying to the needs of regeneration, force-transmission and tissue attachment. This advanced designed was fully characterised. Concomitantly, a portfolio of different biomaterial hydrogels was explored, to sustain the survival and function of human induced pluripotent stem cell (hiPSC)-derived cardiac cells, whilst upscaled methods for cellular production, with significantly reduced Cost of Goods, were developed and implemented. Finally, the first clinical-scale culture and maturation bioreactor, able to provide mechanical and electrical stimulation, was designed, fabricated and tested. Bringing all these advances together, human-scale BioVADs were fabricated employing MEW-trizonal scaffolds, fibrin hydrogels and hiPSC-derived cardiomyocytes and cardiac fibroblasts. These were characterised in vitro using confocal microscopy, advanced transcriptomics (bulk, single cell and spatial RNAseq), mechanical tests and optical mapping of action potentials and calcium transients, amongst others. This has provided a holistic understanding on the BioVAD, proving its advanced maturation. Finally, BioVADs where transplanted in a clinically relevant pig model of cardiac ischemia-reperfusion, showing a significant capacity to improve cardiac function of damaged hearts and halting adverse remodelling, in comparison with non-cellularised controls.
The results from the project have been protected if possible, resulting in a patent and the generation of a unique expertise supporting further translation. Widespread dissemination activities to specialised and lay audiences have been performed, resulting in over 100 actions.
