How to repair a damaged heart? A blockage in one of the arteries that brings blood to the heart leads to an ischemia, restricting the flow of essential nutrients and damaging cardiac muscle, with lasting effects on heart function. Researchers in the BRAV3 project are working to develop a personalised, biological device to support a damaged heart, as Dr Manuel Mazo Vega explains. The effective function of cardiac muscle depends on a continuous supply of nutrients, in particular oxygen, and an occlusion or blockage in the arteries that bring blood to the heart can rapidly have serious consequences. During a myocardial infarction an arterial blockage causes an ischemia, which restricts the flow of blood and essential nutrients to the heart. “When an artery is occluded cardiac muscle starts dying within minutes,” explains Dr Manuel Mazo Vega, coordinator of the Regenerative Medicine Research Group at the University of Navarra in Spain. While most patients in developed countries survive a myocardial infarction, it does affect their long-term heart function. “When cardiac muscle dies the organism starts a repair process very similar to what happens when you cut your skin. It creates some blood clots, then fibroblasts – which are like stromal cells – that synthesise the extracellular matrix. So they create a scar, which prevents the heart from bursting,” continues Dr Mazo Vega. “However, this scar is there permanently, and the heart has less muscle to contract, so function declines. This leads to a series of problems that become chronic.” BRAV3 project This issue is central to the work of the BRAV3 project, an EU-funded initiative bringing together partners across Europe, coordinated by Prof. Felipe Prósper from the University of Navarra. The aim in the project is to essentially develop a new method of repairing a heart damaged by ischemic cardiomyopathy and restoring its function, building on earlier research into induced pluripotent stem cells (iPSCs). “iPSC technology was developed in 2006. With this technology we can take any cell – usually a blood cell or a skin cell – and turn it into a stem cell that will later be transformed into a cardiac cell,” says Dr Mazo Vega. This opens up the possibility of producing cardiac cells, which can then potentially be injected back into a damaged heart, yet Dr Mazo Vega says this approach is not very effective. “Around 90-95 percent of the cells injected
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iPSC-derived cardiomyocytes interacting with fibres in a 3D printed scaffold.
into the heart disappear within 24 hours,” he explains. “Over the last 20-25 years there’s been increasing interest in building tissues and organs in the lab. People are trying to get input from different fields, including stem cells, tissue engineering, and cardiology for example, to build something meaningful in terms of treating patients.”
throughout its thickness. This is how the heart has evolved over millions of years in order to pump blood as efficiently as possible,” he outlines. Researchers are using magnetic resonance imaging (MRI) on pigs’ hearts to determine this structure to a high degree of precision, which can then provide a solid basis for designing and producing
are oriented in the ideal way, which Dr Mazo Vega says is crucial to the effectiveness of the BioVAD in helping to restore cardiac function. “We can develop cardiomyocytes in the lab, muscles which contract. But if you have one cell contracting in one direction, and others contracting in different directions, then the sum of all these forces is going to be very minor,” he points out. The orientation of cardiac layers varies across the thickness of the heart, which is what researchers in the project are seeking to replicate. “With our 3D printing technology we can build scaffolds with very different geometries. This geometry is then going to affect the functionality of the tissue that we build,” continues Dr Mazo Vega. “We can build very, very thin fibres that can help cells to align themselves in certain orientations.” The project team have investigated a variety of different geometries, and the results have been put into computational models, which provide deeper insights into how cellular orientation affects function. So far this work has centered on relatively thin layers of the myocardium, with researchers planning to investigate thicker layers of tissue in future, which will add a further degree of complexity. “Vascularisation is an important consideration in this respect.
2022 BRAV3 consortium meeting in Lisbon, hosted by iBET.
When we have a thicker layer of the myocardium, we will want to connect with the endogenous blood supply,” says Dr Mazo Vega. There are a variety of different types of cells in the heart, so the project team are working to identify the right combinations and proportions, alongside pursuing several other avenues of research. “In the project we have been investigating what the cardiac structure is like on a very precise level, then we want to translate this structure into 3-D printed scaffolds,” outlines Dr Mazo Vega. “What types of cells do we need to put on the scaffolds to develop the most therapeutically efficient tissue?”
Long-lasting support This work is currently in progress, with researchers aiming to develop a device that can provide long-lasting support for people who have suffered cardiac damage, potentially enhancing quality of life and relieving the heavy burden that heart disease places on healthcare organisations. The initial aim is to develop a device that works effectively in pigs, bypassing testing on rodents, which Dr Mazo Vega says is not always a reliable guide to its effectiveness in larger animals. “We’ve seen that when new devices are tried on mice and rats they often work very well. But when this
Over the last 20-25 years there’s been increasing interest in building tissues and organs in the lab. People are trying to get input from different fields, including stem cells, tissue engineering, and cardiology, to build something meaningful in terms of treating patients. The BRAV3 project is now working towards this wider goal, with Dr Mazo Vega and his colleagues bringing together these different strands of research to develop a device called BioVAD (Biological Ventricular Assisting Device), which will be tested on pigs. Evidence shows that for such a device to work effectively in the heart, it needs to closely resemble natural structures, so Dr Mazo Vega says the BioVAD has to mimic the structure of the cardiac tissue that it is going to replace on a 3-dimensional level. “The orientation of the different layers of tissue in the heart changes slightly
the BioVAD. “We can then use 3-D printing, and other materials and technologies, to structure stem cells in such a way that they can produce this tissue in a way that mimics the structure we see from the MRI images,” says Dr Mazo Vega. A lot of input is being provided here by computational models, which help researchers identify the key points that need to be addressed within the structure of the BioVAD, without the need for expensive tests. Cells in the device are arranged on a polymeric scaffold, and a lot of attention in the project is focused on ensuring the cells
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