Congenital heart disease is the most common birth defect globally, affecting almost nine in every 1,000 babies. Tissue engineering, which involves combining regenerative cells, proteins, or drugs with biomaterials, is a promising strategy to treat congenital heart diseases. A particularly exciting development is the use of 3D printers to fabricate custom cardiac components to replace diseased tissues, such as heart valves, or create cardiac patches that can provide therapeutic benefit to cardiac tissues.
In pediatric patients this approach holds significant potential, as the possibility to print living cells means that the fabricated components could potentially grow and develop in tandem with the recipient. This means that a child wouldn’t need to have multiple surgeries to replace parts that no longer fit. In addition, using a patient’s own cells in a biomaterial-based implant means that immune rejection issues are minimized, compared with existing cardiac implants that rely on animal tissues.
These advanced cardiac therapies form some of the research of Prof. Michael Davis of Georgia Tech. Davis focuses on pediatric patients with heart failure and heart defects, and uses 3D printing technology to develop cardiac components that combine biomaterials and living cells. Medgadget had the opportunity to ask Prof. Davis some questions about his research, the answers to which are below, but first take a look at this video to get an idea of the printing process:
Conn Hastings, Medgadget: Please give us some background on congenital heart diseases and the challenges facing clinicians in dealing with these conditions.
Michael Davis, Georgia Tech: Congenital heart diseases and pediatric heart failure in general are highly variable. These can range from just a small hole in the septum that can be fixed quickly to complex disease requiring multiple surgeries. In children, it can be genetic, unknown, present on different sides of the heart, and more. Not to minimize the disease in adults, but primarily most therapies are around left-ventricular heart failure and most of them are due to a heart attack or wear and tear. It is also important to note that the same drugs that work in adults (like beta blockers) are not necessarily effective in children. This means children need more personalized therapies.
Medgadget: What approaches are currently used in treating congenital heart diseases and what drawbacks do they have?
Michael Davis: For children with complex CHD, they do not always get implants but rather surgeries to alleviate or bypass the issue. For example, in severe cases like Hypoplastic Left Heart Syndrome (children born without a functioning left ventricle), they need surgery that turns the right ventricle into the main chamber. These surgeries temporarily fix the major issue, but create long-term issues that need to be fixed later. In the above example, the right ventricle is not meant to supply the body with blood and will eventually wear down. Many of these surgeries, while wonderful and allow the child to live, create chronic problems that result in the need for transplant.
Medgadget: You are in the process of starting a clinical trial called the Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome (ACT-HLHS) Trial. Can you give us a brief overview of the targeted stem cell treatment you are going to evaluate?
Michael Davis: We are really excited about this. The heart (and many tissues) has its own pool of stem and/or progenitor cells. These cells can be extracted from waste tissue and grown up in a lab from a few dozen to millions of cells for implantation. Our research and research from others suggest that the younger the age of the patient, the more reparative the cells. This means that we are getting the most reparative cells from newborns and that is where our trial starts. Children with Hypoplastic Left Heart Syndrome have a high rate of heart failure when they get older (and a host of other problems). Because they come in for multiple surgeries when they are young, it creates ideal timing to extract the cells and then reinject them later. So that is what we are doing. When they come in for their first surgery at a few days old, we collect the tissue for cell extraction. When they come back for their second surgery in a few months, the cells will be ready for injection. It is our hope that these cells can spur the repair process and keep the tissue from breaking down over time.
Medgadget: So, what about combining cells with biomaterials? What are the advantages of 3D printing in this context, and what types of cardiac implants can you produce?
Michael Davis: Stem and progenitor cells have strong potential, but tissue has a lot of blood flow, meaning cells can be washed away quickly. Additionally, you are injecting cells usually in to a diseased environment so the implanted cells do not get good signals. By using biomaterials one can retain the cells better in the tissue (the cells are embedded within the material). Also, one can modify these materials to contain the proper signals to support the function of the cells. The advantages of 3D printing are even more control. If I am just injecting the cells in the materials, I do not have the best control over the structure. If 3D printing can be used, any number of different structures can generated, which is great for children requiring personalized therapy. With 3D printing we can make simple patches containing cells, or even complex 3D structures containing cells, blood vessels and more. There are some pretty fantastic people in this field doing some amazing things!
Medgadget: Can cells easily survive the printing process? Was it a significant challenge to optimize the process and materials so that they allow cells to survive and create a material that is suitable for implantation into the heart?
Michael Davis: It is not easy! For 3D printing of cells, one must take extra precautions to protect the cells. Biomaterials require specific solvents, temperatures, pressures, etc., that are not always compatible with the cells. If your material is too thick and you have to use a lot of pressure to 3D print, you could damage the cells with shear stress. If the material requires ultraviolet light to polymerize, you could damage the cells with free radicals. Also, just because a material can print does not mean you can control the structure easily. For each successful print we generate with a material, it can take weeks of testing different variables to get the right control over the structure while maximizing cell health. Then one has to test the material, which may behave differently when you print it from when you tested it on the bench. We spend 90% of our time optimizing and testing. Also, each cell type may behave differently, so what works for a heart cell precursor may not work for a blood vessel precursor…different signals, different functions, and different properties.
Medgadget: How do you envisage this field progressing in the next ten years? Do you think that an implant that grows with its recipient will be possible?
Michael Davis: That is the hope and that is what most people are trying to achieve. A living implant is the holy grail, one that can grow and change with the patient over time. We are seeing a lot of really cool things, like 3D printing shape memory materials. So you can create a tissue and then compress it in to a catheter, and it will re-expand after implantation. We are seeing 3D printing used to create tissues on a chip so that drugs can be tested in a realistic environment but can still be high-throughput (testing hundreds of chips). With the development of robotic printers, we are seeing the ability to print really complex materials with different cells in different orientations. With the advent of things like induced pluripotent cells and CRISPR technology, the idea of “fixing” genetically damaged tissue is becoming a reality. What was once just an idea is now being placed in to practice and technology is keeping pace at amazing rate.