Dr. Lawson is a professor of surgery and pathology at Duke University and vice chair of research for the department of surgery, overseeing research activities. He has worked at Duke for 23 years both scientifically as a vascular biologist involved in an array of projects including tissue and blood vessel engineering and also as a full-time vascular surgeon. Dr. Lawson discloses research funding and a consulting relationship with Humacyte.
At the 2015 International Symposium on Endovascular Therapy (ISET), Jeffrey Lawson, MD, of Duke University, delivered a keynote lecture that presented work that he performed in collaboration with Humacyte, Inc. (Research Triangle Park, NC) and Humacyte Founder Dr. Laura Niklason (Professor Biomedical Engineering and Anesthesia, Vice-Chair Anesthesia, Yale University) to engineer implantable blood vessels from donor vascular cells. The technology has received US Food and Drug Administration fast-track designation for approval, and clinical trials are under way. Vascular Disease Management spoke with Dr. Lawson about the blood vessel technology and ongoing research.
Q:Could you describe how the vessel is engineered?
A: My lecture at the ISET meeting was on a bioengineered blood vessel project that I’ve been involved with for nearly 17 years. We have gone from early prototype concepts back in the late ‘90s to the implantation of this technology in humans. We’ve been growing these over the years through a number of iterative improvements.
The basic concept is that the tube itself, the bioengineered blood vessel, is made initially on a biodegradable scaffold. Polyglycolic acid is woven into a tube you can make in an array of shapes and sizes, conceptually, and that tube is used to seed vascular smooth muscle cells onto. That tube is grown in culture medium, under flowing and pulsatile conditions. There are many things that go into getting the cells to grow right in the right configuration. It’s taken years of research that hasn’t necessarily been glamorous but is necessary to figure out those subtleties.
What we then make is a collagen-based tube out of vascular smooth muscle cells where the initial scaffold degrades away. And now it’s made up of the structure of a normal blood vessel, basically the extracellular matrix. To make that tissue universally implantable, we remove all of the cellular antigens that were the original cells that made the graft and now must be sacrificed. The cells and their associated antigenicity are removed -- what’s left is an acellular structure that allows for the incorporation of host cells so that it transitions from a scaffold structure to what we believe is the blood vessel of the host that it is implanted into.
Q: How has the vessel changed over time?
A: It has changed primarily in how robust the structure is. Initially the early prototype vessels that we worked with were very thin. I often joked that it was like trying to sew wet tissue paper. Not only with suture retention, but we had many of the early prototypes rupture shortly after implantation. As any long-term research project goes, you go back to the drawing board and start over. Much of the credit must go to Dr. Laura Niklason and Humacyte scientists, who have been partners, colleagues and co-scientists for the duration of this project. We started with Dr. Niklason’s original idea prior to coming to Duke. We all worked together to re-engineer and retest both on the bench as well as in animal models where we’ve done a whole series of structural testing of the tubes as they’ve evolved to make a bioengineered vessel that is now safe to implant into humans.
Q: Could you describe the scope of the FDA fast-track study?
A:We are in clinical trials with this bioengineered human acellular vessel, as we call it. We are in clinical trials both in the United States and Europe. We started the trial in Europe about two and a half years ago and in the United States about two years ago, and we have had ongoing follow-up from our first implants. The graft is being tested clinically primarily in vascular access for hemodialysis. There have been some arterial implants that have been done in Europe and that clinical program will be evolving both in the United States and Europe over the next few years. But the fast-track designation given by the FDA specifically is a United States development pathway where the FDA identified this technology as an unmet clinical need particularly in the area of vascular access for hemodialysis, and consider the technology promising enough that they’re willing to accelerate its approval path assuming that we continue to move forward with the clinical research that is ongoing.
So we are finishing our phase I and Phase II first-in-man implant follow-up, we’ve had our last set of patients complete 6-month follow-up. We’ve started to put together the pivotal clinical trial design, which I can’t discuss in detail, but it will set out to work with the FDA for what will be pivotal approval for this, initially in the area of vascular access for dialysis.
Q: And you see other potential applications?
A: I’d say there is the potential to have this be a vascular tissue that can be used for reconstruction anywhere in the body. It has had to enter in the vascular access space primarily for safety issues and making a relatively standard-sized conduit. We’ve already made smaller prototypes and larger prototypes that have been tested in different animal models. We’ve tested them preclinically in coronary and small-caliber arterial positions. There’s no reason to think that with some engineering modifications, depending on geometry, that we couldn’t make this tissue for any vascular reconstruction, ultimately arterial or venous, anywhere in the body. The medical opportunity is potentially significant and we’re starting where we have to be as safe as possible with respect to patients and regulatory development in the setting of vascular access for hemodialysis.
Q: Any limitations right now that could be modified in the future?
A: Like any technology that evolves, it will continue to be developed and re-engineered going forward. Currently we’ve had positive outcomes with the graft implanted in both animals and humans, meaning we’ve seen no immune rejection. We’ve seen very robust cellular repopulation both in the middle of the vessel as well as the endothelial layer. We’ve also seen very good structural stability. In fact, when we explant a graft it’s been stronger than when we implanted it.
One particular area that might be addressed in more detail in the future would be cannulation durability for dialysis. Because this was engineered to be a blood vessel, in the unique place of dialysis it also has to be cannulated three times a week with a needle. And that’s not something that it was originally designed for. Even so, this structure tends to work very well.
The other thing that would be a natural development path would be to take this vessel structure and convert it to something that would not only be surgically implanted but also potentially endovascularly deployed. So instead of bioabsorbable stents you might have a vascular device that was implanted via a different strategy that sticks to the same paradigm of host-bioengineered surfaces.
Q: Any other points you’d like to share?
A: People have thought about engineering different types of human tissues for a long time. And I think that the promise of that is just beginning to be realized. Probably this, or a technology like this, will be the first very simple organ that is engineered and implanted into people, and I think it will set the groundwork for what will become more complex tissues developed in the future. I really believe this, that the fundamental ability to make a structure, once we understand the biology and now as we begin to understand the genetic and developmental pathways, will make it possible for us to grow blood vessels and someday kidneys or hearts or all kinds of structures that are needed to replace vessels or organs throughout the body. It’s really very exciting.