The great scientific adventure of creating a human bioartificial heart

The world's number one "killer" of humans is acute myocardial infarction (better known as "heart attack"). Nothing kills more people, be they men or women. In fact, it is estimated that one in 4 people will die from this cause. In the United States, someone dies of a heart attack every 40 seconds. Meanwhile, in Spain, around 15,000 people die from this cause each year. Far from decreasing, these figures will increase even more over time due to the progressive aging of the western population.

When what is needed is a new heart

Advances in pharmacological and surgical treatments have considerably improved the prognosis after a heart attack. However, except for heart transplants, medical treatments are palliative and not curative. Why? Because once a region of the heart has died, this tissue will never regenerate or function again. Over time, this involves a progressive alteration of the heart muscle that was healthy with a worsening of the overall function of the heart, until seriously life-threatening due to heart failure.

The only truly curative treatment that allows cardiac function to return to normal is a heart transplant. Unfortunately, there are not enough heart donors for all those who need a transplant of this vital organ. A multitude of patients die on waiting lists in various parts of the world, after an agonizing delay of a heart that does not arrive on time.

There are not enough heart donors for all those who need a transplant

The shortage of heart donors is a phenomenon that will sharpen over time, due to the increase in people who will need one, among other factors. Furthermore, not only patients affected by a heart attack may need a transplant, certain people affected by heart conditions such as congenital malformations or hypertrophic cardiomyopathies (where the heart wall thickens and does not work as it should) may also require it.

This dark panorama has led scientists from around the world to embark on a great and ambitious adventure: the creation of a bioartificial human heart. Among the multiple strategies to achieve this, researchers in the area of ​​regenerative medicine work to develop human hearts through biological components. Although they are inspired by the most cutting-edge knowledge in biology and medicine, they also draw on technological advances for this purpose. Currently, there are three main approaches at the forefront of creating complete human hearts.

3d print

3D printers with inorganic materials and their applications have expanded so much that they have almost become an everyday thing. However, until a few years ago, 3D printing has been a closed field for regenerative medicine, especially for the creation of heart tissue. The main obstacle? Poor cell survival during printing. Muscle heart cells (cardiomyocytes) are very delicate and need certain conditions to stay alive. Just a few years ago, 3D printers killed the absolute majority of cardiomyocytes.

Fortunately, advances in 3D printing technologies have managed to solve much of this problem. Today, 3D printers create cardiac tissues, layer by layer, by injecting biotint that contains various types of cells and biomaterials. Biomaterials are essential to provide structural support and improve the properties of these tissues.

So far, relatively fine patches of heart tissue have been developed. The creation of adult human hearts is still a long way off due to 3 great challenges. On the one hand, that you can print many cells together in the shape of a heart, does not mean, far from it, that they are going to work in coordination as a heart. It is essential to get these cells to organize and work together. At the moment, we do not know how to do it.

Another great barrier is to achieve the structural stability of large soft organs during printing, without affecting functionality. From certain dimensions, 3D printing of soft organs is like playing house of cards, with a very precarious stability in which it is very easy to "collapse". Another challenge that is associated with the large dimensions of an organ such as the human heart is to ensure that, after printing, the cells do not suffocate and die malnourished. For this, it is essential that there is an integrated circulatory system that provides the oxygen and nutrients that cells need in the printed organ. Again, at the moment, how to get it is unknown.

Detachable cells: decellularization and recellularization

What if instead of trying to create hearts from scratch, as in 3D printing, we try to take advantage of Mother Nature from already created hearts? Thanks to different chemicals (such as detergents) it is possible to remove all the cells of a heart and keep only the fibrous skeleton (the extracellular matrix).

Thanks to different chemicals (such as detergents) it is possible to remove all the cells of a heart and keep only the fibrous skeleton

Thus, for example, we can remove all the cells of a pig's heart, keeping the skeleton, and then administer human cells that invade that skeleton. The use of the pig is not accidental, since the pig heart is very similar to the human in structure and function. The great advantage of having a pig heart "skeleton" is that we have already created a complex, stable and natural structure, and it is easy for cells to adhere to this matrix.

In addition, the basic structures of the blood vessels are also present, making it easier to re-develop them by injecting the typical cells that line these vessels. On the other hand, by eliminating the cells of a pig's heart, the reaction of human immune rejection decreases considerably. That, combined with the existence of transgenic pigs with more human extracellular matrices, make them an attractive possibility for the creation of human hearts.

Right now, the main obstacle in creating human hearts by combining human cells and extracellular matrices from animals like pigs is the repopularization of these matrices with human cells. In other words, how to put the cells in those cardiac "skeletons" so that they distribute as they would in a human heart and work together. Removing cells from animal hearts is very easy, but putting human cells without clumping into very specific areas presents a real challenge.

Pig-human chimeras

Chimeras are organisms that have cells with DNA from different individuals. This is something that rarely occurs in nature within the same species. However, what had never happened before were chimeras between species as different as pig and human. In 2017, scientists from the Salk Institute managed to create pig-human chimeras for the first time, thanks to genetic modification techniques. What exactly do they consist of? They are genetically altered pigs so that they do not develop certain organs during embryonic / fetal development. Instead, human stem cells are introduced that are responsible for the development of human organs.

In other words, work is being done to ensure that animals such as pigs can naturally develop human hearts during pregnancy. Thus, it is nature that does most of the work and scientists only have to "hack" the instruction manual for pig embryonic development.

Humanizing animals, albeit with the lofty goal of creating human hearts to save lives, blurs the frontier of what it means to be human.

It is still early to know how far you can go. For ethical reasons, the development of these pig-human chimeras has only been allowed until 28 days of pregnancy. And it is that this technique is not exactly without controversy. Humanizing animals, albeit with the lofty goal of creating human hearts to save lives, blurs the frontier of what it means to be human. Precisely for this reason, one of the red lines of this technique is the development of human brains in animals. Chimera animals are being prevented at all costs from developing human brains, with the theoretical possibility of developing human consciousness and intelligence.

Scientists are currently investigating how compatible the development of pigs with human stem cells is to create organs that are not typical of pigs. Furthermore, we also don't know what degree of immune rejection would be triggered by organs created in this way. Since this strategy is in its infancy, there are many details that we do not know.

But it is still missing to see them in action

Currently, none of these three strategies are contemplated to reach the clinic in the near future. There are many details to perfect and much knowledge to acquire. Yes, cardiac patches have been used in some clinical trials that have shown safety and certain benefits. In addition, the tissues created can be used as models for heart disease or for drug testing. Despite this, creating a complete human bioartificial heart is a much more ambitious goal, and reaching it is still far from everyday, but closer than science fiction.

Image | Human heart by Edward Leung
Image | Decellularized human heart

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