Joseph Wu Director of the Stanford Cardiovascular Institute and Professor of Medicine and Radiology at Stanford University, discusses the rise of engineered cell and tissue products for use in patients. While these products are now technically advanced and better suited for the clinic, there continues to be issues around patient safety that need to be monitored and mitigated for routine use and mass production.
Joseph C. Wu, MD, PhD, Director of the Stanford Cardiovascular Institute and Professor of Medicine and Radiology at Stanford University, spoke to writer Tanuja Koppal, PhD, about the rise of engineered cell and tissue products for use in patients. While these products are now technically advanced and better suited for the clinic, there continues to be issues around patient safety that need to be monitored and mitigated for routine use and mass production.
AABME: Can you share your perspectives on the promise as well as challenges with the use of engineered cell therapy products?
Joseph Wu: A recent report from France (outlined how researchers) crafted human ES (embryonic stem cell)-derived progenitor cells into patches and then transplanted them into a patient following heart bypass surgery. This is the first study that used human ES-derived cardiac cells. My hunch is that a group in Japan will come up with a similar study to show the use of human iPS (induced pluripotent stem cell)-derived products in the next couple of years. However, one of the main safety concerns with the use of such pluripotent-derived cells in the form of injectable scaffolds, myocardial patches, or engineered heart muscles (EHM) is whether they will form a teratoma in the patient. Then there are also concerns around rejection of cells after injection or transplantation, especially for allogeneic ES-derived products. If the patients are immunosuppressed to prevent rejection of the allogeneic cells, the side-effects of immunosuppression can be quite severe. Moreover, when a lot of cells are injected and if the cells die, they can trigger ventricular arrhythmias. Finally, the cell products used must be as good, if not better than, adult stem cells such as mesenchymal cells or bone marrow cells (which are easier to work with), and also better than existing medical or surgical therapies. Some of these concerns around cell therapy products are discussed in our recent paper.
AABME: What are some of the current limitations associated with the development of these products?
JW: Every cell product has to be well-qualified in order to be approved by the FDA for patient use. The FDA is looking carefully at the addition of xenogeneic products, such as those derived from animals or viruses to human tissue-engineered products or patches being used for cell therapy. Engineers who are looking to create a product using a combination of different human cells such as cardiac cells along with fibroblasts or endothelial cells also have to make sure that every product has the exact same composition in terms of ratio of cells used. It’s important to maintain consistency during production. For example, when creating a tissue-engineered patch for the heart, if the patch is too thick there is not enough vascularization to support patch viability. On the other hand, if the patch is too thin it won’t provide the necessary mechanical support. There are also problems associated with storing and transporting these tissue-engineered products when they are mass-produced. Freezing and thawing cell products before use can lead to significant cell death and can create differences in quality and performance. These are all important practical considerations that tissue engineers and manufacturers need to think about.
More for You: Read about the latest in cell therapy treatments from AABME.org.
AABME: What are some of the strategies and technologies being used to improve the safety of human pluripotent stem cells for use in therapeutics?
JW: The challenge with using cells derived from pluripotent stem cells, whether it’s heart, muscle, or endothelial cells, is that there is always a potential risk of teratoma formation. The question is how to prevent them. Many researchers think that you can get rid of teratomas by introducing a suicide gene, which we have done in the past. However, that approach requires genetic manipulation which will require additional hurdle for demonstrating safety of these modified cell products. This creates an extra level of scrutiny to the investigator or company and an additional burden for getting the product approved. To address that, we have used non-invasive imaging techniques and biomarkers to detect and mitigate the risk of teratoma formation in cell therapy. We have shown that the level of teratoma formation can be monitored by using magnetic resonance imaging (MRI), and once detected it can be destroyed by using external beam radiation therapy (EBRT).
AABME: Do you see an increased use of computational tools for the design and scale-up of engineered cell products?
JW: In our recent study, we used computational tools to try to understand how much passive stretch is needed to induce structural and functional maturation of engineered human pluripotent stem cell-derived cardiomyocytes. We created a patch of EHMs and stretched it between two posts of varying distances. The cardiomyocytes matured over time as the muscles contracted between these two posts. Prior to our study, simple questions such as how does the spacing between the poles affect cell maturation had never been addressed. We used computational models and experimentation to show that a passive stretch of 7 mm of spacing between the posts gives a consistent formation of mature cardiomyocytes, while 5 mm or 9 mm spacing does not. Using computational models, we can also predict how the stretch can affect the cell composition, geometry, and ratio, and how that can affect the quality of the EHM.
Tanuja Koppal, PhD is a technical writer based in Randolph, NJ.