# What becomes of the broken hearted? Blueprint of a donor-free world using custom heart technologies

Advances in 3D-printing technology have the potential to lower the cost and increase the availability of organ transplants.

April 4, 2018
Blueprint reading, a practical manual of instruction (source: Internet Archive on Flickr)

Imagine feeling like you ran a marathon when you’re actually just getting off the couch. Imagine the extreme anxiety you might experience from living with bouts of dizziness, chest pain, and accelerated heartbeat until a doctor explains to you that these symptoms are not “nothing”, and that in fact, you have cardiomyopathy. This condition could lead to heart failure and eventually a heart transplant, but this desperately needed organ may not be available in time.

Organ transplants are in high demand in the United States. The heart is the third most requested organ, with 4,000 candidates on the waitlist and over 2,000 heart transplant surgeries performed in 2017.

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Heart transplantation is an exorbitantly expensive procedure (Table 1-1) with a myriad of potential complications. Rejection is an unsolved problem and has remained for all these years a major risk of all organ transplants.

Table 1-1. Estimated US average of billed charges per heart transplant in 2017 (Milliman research report, 2017 U.S. organ and tissue transplant cost estimates and discussion)
Per heart transplant Cost (US dollars)
30 days pre-transplant $43,300 Procurement$102,100
Hospital admission $887,400 Physician during transplant admission$92,300
180 days post-transplant $222,800 Immuno-suppressants & other$34,500
Total $1,382,400 If a heart substitute could be developed, capable of emulating a human heart, this would address a critical need for patients in these dire straits. Moreover, a lab-grown heart might be free of rejection issues if a patient’s own cells are used, thus economizing the total cost of heart transplant from$1,382,400 to $1,245,800 by eliminating procurement, the surgery to remove the organ from the donor, and immuno-suppressants (Table 1-1). This$136,600 per transplant saving translates to approximately $300 million from the 2,000 surgeries performed in 2017. Given the 4,000 patients on the waitlist, a rough estimate of the market size of a human heart substitute could reach nearly$1 billion per year for the custom heart industry in the US.

Scientists have been working to address the gap in the shortage of tissue transplants. New opportunities have opened in the past decades as many of the technological limitations have been overcome by important innovations in stem cell biology.

Stem cells are highly pluripotent, with the ability to differentiate into any cell type in the body. Breakthroughs in induced pluripotent stem cells (iPSC) allow for reprograming somatic cells and have made it possible to obtain pluripotent, embryonic-like stem cells without embryos. Cells derived from iPSCs can serve as building blocks for tissues, turning the idea of growing organs outside of the body from science fiction to reality.

While we are able to grow pieces of heart muscle iPSCs to patch small, damaged areas (like Nenad Bursac’s group at Duke University did)—an achievement in itself—there are many obstacles to overcome when building a replica of the human heart due to its complex structure and composition.

Nevertheless, building something that is functionally identical to a heart may be possible. Many interesting approaches are currently being explored to produce adequate, artificial replacements for this most critical organ.

## Recycling an Unusable Heart

Time is critical in organ transplantation. When a donor heart becomes available, it can only be preserved for a short time for transplantation. As a result, 20% of donated hearts go to waste because they cannot be transplanted to a recipient in time.

What can we do with these “unusable” hearts? Harald Ott’s group at Harvard Medical School and Massachusetts General Hospital found a way to give them new life.

Using a detergent solution, the researchers first strip the cells, DNA and lipids from the heart, leaving an intact, complex acellular cardiac extracellular matrix (ECM) scaffold.

This cell-free scaffold is a mesh that holds the heart together and contains blood vessels that can transport oxygen, nutrients, and waste. Next, they re-seed the ECM with new cardiomyocytes derived from iPSCs to form the muscular wall of the heart.

The re-cellularized ECM is incubated in a bioreactor which could provide all nutrients and mechanical stimulations needed for tissue development. After two weeks, the ECM is covered with layers of cardiomyocytes and exhibits functional contraction upon electrical stimulation.

Several challenges remain to be addressed in this approach, including ensuring that the right number of cells are in the right combination for proper heart function, as well as engineering a bioreactor that better mimics the human body. Despite these obstacles, this approach has served as a convincing proof-of-concept that functional hearts can be re-grown in labs on existing cardiac ECMs

## Building a Vegetarian Heart

As an alternative to using ECMs from animal sources, a multi-institutional collaboration among Worcester Polytechnic Institute, the University of Wisconsin-Madison, and Arkansas State University-Jonesboro seeks to develop plant-based ECM scaffolds.

This idea is far from intuitive, given the vast differences between animals and plants. However, plant vascular structures follow many of the similar physiological laws as the cardiovascular systems of animals. More importantly, an ECM from plants is mainly composed of biocompatible materials, making it an ideal candidate for a lab-grown organ.

In a procedure analogous to the one just described, scientists first wash away the cellular material from a spinach leaf to obtain an acellular ECM with functional veins. The spinach ECM is then coated with human endothelial cells on the leaf vasculature and seeded with human cardiomyocytes.

After a few days, the cells attach to the spinach ECM and contract in the same way as cells grown in a tissue culture. This demonstrates the possibility of culturing human cells on a plant scaffold. However, how well plant veins can sustain human tissue and the immune response against the plant scaffold still requires further investigation.

## Exploiting a Pig’s Heart

While the heart is a delicate and complicated machine, it is hardly unique to humans. Could we substitute human heart with a heart from an animal? This process is known as xenotransplantation.

In the mid-20th century, severe immune responses made all xenotransplantation between nonhuman primates and humans fatal. However, in recent years, with better understanding of the human immune system, xenotransplantation has gradually regained attention and consideration.

Among all of the possible animal donors, the pig is considered to be the best candidate, as it is widely accessible, genetically similar to humans, and has organs of approximately the same size.

The creation of a genetically engineered pig lacking the gal gene, a main trigger of human immune reaction, has significantly extended the survival time of baboons receiving these porcine organ transplants.

Muhammad Mohiuddin’s group at the National Heart, Lung, and Blood Institute, took a step further with the gal knockout pigs. By inserting two human proteins that prevent host cell damage and blood coagulation into the gal-free pig genome, his group was able to keep a porcine heart alive in a baboon for over two years.

Delayed rejection ultimately happened and led to the death of the baboon, but modifying pig genes, altering the types and expression levels of human genes in pigs, and optimizing anti-rejection drugs may lead to a viable system of xenotransplantation.

In addition to rejection complications, viral infection is another concern for xenotransplantation. Genes from ancient infections from porcine endogenous retroviruses (PERV) are scattered throughout a pig’s genome.

Although it is not clear whether PERVs could actually produce viral particles capable of infecting humans, the presence of those viral remnants still generates concerns among the scientific community and casts a shadow on the use of xenotransplantation.

To overcome this problem, eGenesis, a Boston-based startup, has devoted its expertise in genome editing to make PERV-free pigs. Founded in 2015 by geneticists Luhan Yang and George Church from Harvard Medical School, the company’s mission is to use genome editing to make safe human tissues and organs for transplant.