Periodic Reporting for period 3 - 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: 2022-07-01 to 2023-12-31
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.
In the past 12 months, the project has seen good progress in all areas, in spite of the challenges imposed by the pandemic. Specifically, the BRAV3 Consortium has developed new computational mechanical and electrical models of the heart. These will allow us to generate cardiac tissue in the lab that better resembles the native myocardium. At the same time, we have applied similar principles to the mechanical behaviour of 3D printed scaffolds in order to improve their capacity to later perform when transplanted. Similarly, four of our groups have aligned their procedures to generate human cardiac cells from stem cells in the lab, which are being used to pilot the generation of large-scale myocardium. On the purely technological level, this first year has seen the designing and prototyping of the new devices that will be later on applied to the BioVAD. Closing the loop, work on the human-sized animal model is feeding the computational activities in order to perfect the models and making more specific and personalized. In parallel to all this more scientific part, we have also progressed in assessing how to make our proposed therapy a reality, through working on the economic viability of BioVADs. Finally, the project has been in contact with patient´s associations, to ensure their voice is heard.
During the last months, our Consortium has progressed towards the project goals. On the pig animal model, we have characterized both healthy and infarcted hearts, using a wide portfolio of techniques completing what is probably the most comprehensive analysis of human-scale cardiac tissue. This information has contributed to the perfection of computational models of natural myocardium (2.0 models), whilst also simulations for bioartificial human cardiac tissue are progressing. Three D printing activities have finalised a BioVAD architecture fulfilling the initial fabrication requirements for our specific animal model. Production of human cardiac cells in the lab has managed to deliver all needed cell types, and has started scaling-up for the later human-sized BioVAD production. A working prototype of the electromechanical bioreactor has been fabricated and delivered to UNAV. Also, surgeons in the project have started planning the procedure for BioVAD transplant. Finally, the end-user map has been finalised, as well as the process of identifying of key exploitable results.
In the recent period, work has continued toward the achievement of BRAV3´s overarching and specific aims. A first series of pilot BioVAD 1.0 transplants have been performed. Under the short follow up (1 week), we have obtained confirmation on the treatment´s safety (no unmanageable arrhythmias) and the viability of the employed immunosuppression regime. Computational models for the natural and the engineered myocardium (BioVAD) have been refined with experimental data from mechanical and electrical tests. These models are performing the first in silico experiments, delivering results that help steer the project empirical approach. A complex MEW reinforcing structure has been coded, printed and tested. This designed has taking into account all the gathered information and expertise on cardiac mechanics and physiology. Large scale differentiation protocols for cardiomyocyte and fibroblast differentiation and expansion from hiPSCs have been developed and implemented, and are now being used to deliver the cells needed for the generation of BioVADs (2.0 designs). Electromechanical maturation is underway, using purpose-built devices. Finally, multidimensional characterisation of BioVADs is underway, in order to determine new avenues for improvement.
During the last months, our Consortium has progressed towards the project goals. On the pig animal model, we have characterized both healthy and infarcted hearts, using a wide portfolio of techniques completing what is probably the most comprehensive analysis of human-scale cardiac tissue. This information has contributed to the perfection of computational models of natural myocardium (2.0 models), whilst also simulations for bioartificial human cardiac tissue are progressing. Three D printing activities have finalised a BioVAD architecture fulfilling the initial fabrication requirements for our specific animal model. Production of human cardiac cells in the lab has managed to deliver all needed cell types, and has started scaling-up for the later human-sized BioVAD production. A working prototype of the electromechanical bioreactor has been fabricated and delivered to UNAV. Also, surgeons in the project have started planning the procedure for BioVAD transplant. Finally, the end-user map has been finalised, as well as the process of identifying of key exploitable results.
In the recent period, work has continued toward the achievement of BRAV3´s overarching and specific aims. A first series of pilot BioVAD 1.0 transplants have been performed. Under the short follow up (1 week), we have obtained confirmation on the treatment´s safety (no unmanageable arrhythmias) and the viability of the employed immunosuppression regime. Computational models for the natural and the engineered myocardium (BioVAD) have been refined with experimental data from mechanical and electrical tests. These models are performing the first in silico experiments, delivering results that help steer the project empirical approach. A complex MEW reinforcing structure has been coded, printed and tested. This designed has taking into account all the gathered information and expertise on cardiac mechanics and physiology. Large scale differentiation protocols for cardiomyocyte and fibroblast differentiation and expansion from hiPSCs have been developed and implemented, and are now being used to deliver the cells needed for the generation of BioVADs (2.0 designs). Electromechanical maturation is underway, using purpose-built devices. Finally, multidimensional characterisation of BioVADs is underway, in order to determine new avenues for improvement.
The project progress during the first year has seen the grounding of the basic principles on which the future progress is founded. However, we have also managed to gather new knowledge and technology. On computational models, we have advanced towards the generation of more accurate models, through the gathering of novel data from the animals. At the same time, we have generated the first models of the BioVAD. Similarly, the application of new analytical approaches and models are already improving how we 3D print the scaffolds. The new devices prototyped in the project will see an advancement in the field and permit a faster translation, which is expected to be aided by the work invested on ensuring the economic viability of the proposed therapy. With a wider perspective and given the high socio-economic impact of cardiac disease, we anticipate this work will have important implications.
Advances in the following years in the development of the project include: (1) novel information on cardiac architecture and mechanics, in health and disease, on a clinically-relevant model (pig), (2) advanced computational models, for the first time on large engineered human cardiac tissue, and its interaction with natural myocardium, (3) new MEW scaffold designs, considering the specific architecture, mechanics and physiology of the diseased heart, (4) a new method for the cost-effective 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 and (7) crucial information on the first transplant of large scale MEW-based tissues (BioVADs) on a large animal model of cardiac ischemia (pig).
Advances in the following years in the development of the project include: (1) novel information on cardiac architecture and mechanics, in health and disease, on a clinically-relevant model (pig), (2) advanced computational models, for the first time on large engineered human cardiac tissue, and its interaction with natural myocardium, (3) new MEW scaffold designs, considering the specific architecture, mechanics and physiology of the diseased heart, (4) a new method for the cost-effective 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 and (7) crucial information on the first transplant of large scale MEW-based tissues (BioVADs) on a large animal model of cardiac ischemia (pig).