Periodic Reporting for period 4 - BRAV3 (Computational biomechanics and bioengineering 3D printing to develop a personalized regenerative biological ventricular assist device to provide lasting functional support to damaged hearts)
Reporting period: 2024-01-01 to 2025-06-30
What is the problem/issue being addressed?
Ischemic heart disease (IHD) is the leading single cause of death in the EU. It is a chronic malady, imposing an enormous burden on patients, society and healthcare systems. Acute medical intervention and medication are able to preserve the patient´s life but the chronic presence of a stiff fibrotic scar coupled with the decrease in myocardial muscle mass results in a diminished functionality. Chronically affected individuals will be eventually faced with the dichotomy of transplant versus death.
Why is it important for society?
The role of IHD as the first single cause of death in the EU has already been mentioned. As per 2015, over 22 million EU citizens were living with the disease, with approximately 3 million new cases on that very year. It imposes an enormous burden on society and jeopardizes the work structure. In terms of economic cost, the total burden of IHD for EU economies is estimated at €59 billion/year. Of these, €19 billion are directly related to healthcare cost, while €20 billion are linked to productivity losses, and the remainder €20 billion to the value of indirect care.
What are the overall objectives?
The overall project ambition is to deliver a novel solution for the unresolved problem of IHD. Our consortium is committed to the translation of the project´s findings and in consequence, the objectives of the project are much wider than the medical/scientific ones.
Specifically:
Objective 1: To complete the design-to-trial road for the first human-sized BioVAD
Objective 2: To develop the technological and regulatory framework for the clinical translation of the BioVAD.
Objective 3: To gain basic knowledge on the biology of cardiac development and physiology.
Objective 4: To work on the economic viability of BRAV∃ BioVADs.
Objective 5: To ensure patients have a voice.
Ischemic heart disease (IHD) is the leading single cause of death in the EU. It is a chronic malady, imposing an enormous burden on patients, society and healthcare systems. Acute medical intervention and medication are able to preserve the patient´s life but the chronic presence of a stiff fibrotic scar coupled with the decrease in myocardial muscle mass results in a diminished functionality. Chronically affected individuals will be eventually faced with the dichotomy of transplant versus death.
Why is it important for society?
The role of IHD as the first single cause of death in the EU has already been mentioned. As per 2015, over 22 million EU citizens were living with the disease, with approximately 3 million new cases on that very year. It imposes an enormous burden on society and jeopardizes the work structure. In terms of economic cost, the total burden of IHD for EU economies is estimated at €59 billion/year. Of these, €19 billion are directly related to healthcare cost, while €20 billion are linked to productivity losses, and the remainder €20 billion to the value of indirect care.
What are the overall objectives?
The overall project ambition is to deliver a novel solution for the unresolved problem of IHD. Our consortium is committed to the translation of the project´s findings and in consequence, the objectives of the project are much wider than the medical/scientific ones.
Specifically:
Objective 1: To complete the design-to-trial road for the first human-sized BioVAD
Objective 2: To develop the technological and regulatory framework for the clinical translation of the BioVAD.
Objective 3: To gain basic knowledge on the biology of cardiac development and physiology.
Objective 4: To work on the economic viability of BRAV∃ BioVADs.
Objective 5: To ensure patients have a voice.
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.
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.
The project has resulted in several significant advances in different areas, due to its highly interdisciplinary nature. These include:
(1) Novel information on cardiac architecture and mechanics, in health and disease, on a clinically-relevant model (pig), including data on mechanical properties, electrical activity, architecture and function.
(2) Advanced computational models, for the first time on large engineered human cardiac tissue, and its interaction with natural myocardium, non-existing up to now.
(3) A new trizonal MEW scaffold designs, considering the specific architecture, mechanics and physiology of the diseased heart.
(4) A novel methodology for the cost-effective (80% Cost of goods reduction) expansion of hiPSC-derived cardiomyocytes and their preservation for shipment
(5) New devices for the electrical, mechanical and electromechanical maturation and culture of large human engineered myocardium.
(6) Novel and mutidimensional (including gene expression, structure, electrophysiology, etc) information on the generated cells and tissues
(7) Pre-clinical validation of the effectiveness of BioVADs as a therapy for cardiac disease, through the first transplant of a large scale MEW-based tissues (BioVADs) on a large animal model of cardiac ischemia (pig).
Ischemic heart disease is the number one killer worldwide, posing a cumbersome economic and human threat to healthcare systems: over 22 million people live with the disease in the EU, with 3 additional patients per year, and a total calculated cost of over €59 billion/year. Currently, it is an incurable disease caused by the death of a portion of the affected myocardium, which does not naturally regenerate. The BioVAD developed by BRAV3 will contribute to halt this pandemic by reversing the pathological situation. It will also set the EU as a world leader in the field.
(1) Novel information on cardiac architecture and mechanics, in health and disease, on a clinically-relevant model (pig), including data on mechanical properties, electrical activity, architecture and function.
(2) Advanced computational models, for the first time on large engineered human cardiac tissue, and its interaction with natural myocardium, non-existing up to now.
(3) A new trizonal MEW scaffold designs, considering the specific architecture, mechanics and physiology of the diseased heart.
(4) A novel methodology for the cost-effective (80% Cost of goods reduction) expansion of hiPSC-derived cardiomyocytes and their preservation for shipment
(5) New devices for the electrical, mechanical and electromechanical maturation and culture of large human engineered myocardium.
(6) Novel and mutidimensional (including gene expression, structure, electrophysiology, etc) information on the generated cells and tissues
(7) Pre-clinical validation of the effectiveness of BioVADs as a therapy for cardiac disease, through the first transplant of a large scale MEW-based tissues (BioVADs) on a large animal model of cardiac ischemia (pig).
Ischemic heart disease is the number one killer worldwide, posing a cumbersome economic and human threat to healthcare systems: over 22 million people live with the disease in the EU, with 3 additional patients per year, and a total calculated cost of over €59 billion/year. Currently, it is an incurable disease caused by the death of a portion of the affected myocardium, which does not naturally regenerate. The BioVAD developed by BRAV3 will contribute to halt this pandemic by reversing the pathological situation. It will also set the EU as a world leader in the field.