Episode 8: Bioengineered Blood Vessels: Exploring Potential Improvements in Dialysis Access for Patients with Dr. Laura Niklason of Humacyte
Dr. Laura Niklason, co-founder of Humacyte, joins Field Notes to discuss the exciting potential of her company’s human acellular vessel, which could transform vascular access for dialysis patients.

Brad Puffer: Welcome, everyone, to this episode of Field Notes. I'm Brad Puffer on the Medical Office Communications Team at Fresenius Medical Care North America and your host for this discussion today. Here we interview the experts, researchers, physicians, and caregivers who bring experience, compassion, and insight into the work we do every day. And this episode is no different as we'll explore a new bioengineered blood vessel in development. This medical innovation seeks to transform vascular access for dialysis patients-- something that is critically important.

In 2018, Fresenius Medical Care announced a global partnership and major investment in a company called Humacyte, which is leading this work. Humacyte has created an investigational human acellular vessel called HAV, which is currently in phase 3 clinical trials in the US and Europe. We are fortunate to have the co-founder of Humacyte join us today.

Dr. Laura Niklason is the Nicholas M. Green professor at Yale University in anesthesia, and biomedical engineering, and a true pioneer in biomedical research and development. Through her research on regenerative strategies for cardiovascular and lung tissues, she has helped Humacyte become a world leader in tissue engineering innovation. Dr. Niklason, thank you very much for being here, and welcome to Field Notes.

Dr. Laura Niklason: Yes, it's wonderful to be here, Brad. Thank you so much.

Brad Puffer: Well, first, for everyone just learning about your company and this technology, what exactly is a bioengineered blood vessel?

Dr. Laura Niklason: An engineered blood vessel is really fundamentally different from a transplant, which might be a vein or an artery taken from the patient, or maybe taken from another patient. It's also very different from a synthetic vessel that might be made out of Dacron, or Teflon, or even an animal-based vessel. A bioengineered vessel is really a tissue that's grown in the laboratory, typically, from human cells, and it's a human engineered tissue product that is meant to function as a high-functioning vessel in the patient for a variety of applications.

Brad Puffer: Sounds really exciting and very futuristic on its phase. I want to step back though before we get too much further along on this exciting work. How did you get to where you are now? What did you see as a need in health care when you started the company?

Dr. Laura Niklason: Well, our work on engineered vessels really started almost 25 years ago when I was doing my training at a hospital in Boston. As an anesthesiologist and ICU physician, I took care of many patients with severe vascular disease. In many cases, these patients had no replacement blood vessels to revascularize their heart, or their limbs, or their internal organs, either because they didn't have vein or because a synthetic wouldn't work. So I became very interested even in the mid-1990s in trying to develop ways of using human cells as building blocks to make functional arteries. And I began this work in MIT again in around 1995.

Brad Puffer: So how do you create this human acellular vessel or engineered blood vessel? How does it actually come together and get created?

Dr. Laura Niklason: Well, we start with cells that are grown out of human tissue samples. These tissue samples typically come from organ donors. When a patient dies, and their kidneys are donated to one person, and their liver is donated to another person, for some of these patients, their blood vessels are donated to us, and we isolate vascular cells from those blood vessels.

We then grow the vascular cells in the laboratory, so that we have many millions or billions of cells. And then we take these cells, and we seed them on to a polymer scaffold. And this scaffold is shaped like the artery we want to grow. If we want to grow an artery that's 40 centimeters in length and 6 millimeters in diameter, we shape this polymer scaffolding to be of those dimensions. We then seed the cells onto that scaffolding, and we grow the cells in culture, in a bioreactor in the laboratory.

Over about a two-month period, what happens is the cells proliferate and secrete proteins like collagen. And while this is happening, the scaffold dissolves. After two months, we have an engineered vessel that's really just made out of human cells and their proteins that they secreted.

In the final step, we wash the cells away, and the reason we do that is to remove the immune properties of the tissue. Our goal is to make engineered blood vessels that just contain human proteins but don't contain any human cells nd the goal there is to make a tissue that can be transplanted into anybody and not be rejected.

Brad Puffer: Well, I know that the partnership with Fresenius has really been focused around vascular access. And it sounds like there are other ways, potentially, these type of blood vessels could be used, but the research we're working on together is around vascular access. Why are you focused on vascular access as an initial technology or initial way to use this technology? And how important is a good vascular access for our dialysis patients?

Dr. Laura Niklason: Well, as we know, there's hundreds of thousands of hemodialysis patients in the US, and this number grows every year. One of the biggest health challenges for dialysis patients is the quality and the sustainability of their access. A patient, who has access that frequently fails or and access that becomes infected, is a patient that suffers a lot of unhappiness and a lot of morbidity and we had really seen this. I had seen this during my years as a clinician both in Boston and in North Carolina.

Dialysis patients, who have difficulties with their access, often returned to the OR very frequently and just suffer a lot of complications. Our goal was really to first figure out whether the engineered acellular vessel could be more useful for these patients, and could function better, and perhaps function longer and certainly, we would hope it would be able to resist infection because it really is a tissue rather than a synthetic polymer or a piece of plastic.

Brad Puffer: Well, it mentioned that you're currently in a stage 3 clinical trial, so this process has been going on for quite a while. What have you learned through the development of this bioengineered vessel and how it works?

Dr. Laura Niklason: Well, we've learned a lot as you say. We implanted our first patient in December of 2012. And since that time, you know, we've certainly been very grateful to all of the patients, who've participated in these trials and all of our investigators. We've worked now with probably 50 different investigative sites in the US and Europe, and we've implanted over 400 patients. Roughly, 350 of these patients have been dialysis patients, although, some have been patients with peripheral arterial disease and other types of arterial injury.

I will say that we've learned that the vessel seems to be very robust. It's mechanically very strong. In some patients, we've seen that they can dialyze through this vessel for 5, 6, 7 years, and that's with the vessel being cannulated with large bore needles three times a week. So the vessel for many patients seems to be very robust.

We've also learned that the vessel seems to really be resistant to infection. We've published infection rates in a couple of papers now, which are very, very low and it's really been gratifying to see that these engineered tissues seem to protect patients against developing an abscess infection, which can really be a devastating complication.

Brad Puffer: Oh, must be really exciting for you to see this vision you had way back then start to get closer and closer to reality. I want to take you back to when you first had that first patient, where you had a bioengineered vessel implanted. What was that like? That must have been incredibly exciting.

Dr. Laura Niklason: I would say it was incredibly exciting but also incredibly stressful. Though our first patient was implanted at the end of 2012, we had been implanting these human vessels in large animals, in pigs and in primates, for four or five years before that, but still, we had never implanted these in a human and because this is a first in class product, we really had nothing to compare it to.

All we had was our animal data and our laboratory data, but fundamentally, it was difficult to predict how this would function in man. It was exciting and gratifying, but I'll tell you, it was also nerve wracking. In fact, I developed a pinched nerve in my neck and I couldn't turn my head for about a month because I was so stressed out about this event.

Brad Puffer: Wow.

Dr. Laura Niklason: Anyway-- it was it was exciting. Our first patient actually went on to do very well, and his conduit lasted, I think, for roughly six years. It's been an interesting journey. And again, I'm just so grateful to the patients and investigators who've worked with us.

Brad Puffer: You know, we're talking beyond dialysis. In some cases, you're looking at how these blood vessels can be used in different ways. And my understanding is you've actually worked with the military in some cases as well. Is that correct?

Dr. Laura Niklason:  We've been working with the defense department in partnership, both studying the vessel in animal models and also in humans, for close to 10 years now. In fact, our partnership began with some investigators in Texas with the military. They were interested in seeing if the engineered vessel could work in a pig model of vascular trauma that sort of mimics the trauma that can occur in the battlefield.

Some of these Defense Department investigators were really very pleased to see that the engineered vessel worked quite well in a model of pig vascular injury that really mimicked battlefield injury. Those initial animal results led to ongoing partnership with the Defense Department and they've funded a clinical trial studying our engineered vessel in peripheral arterial disease and in vascular trauma in the United States. It's been a wonderful partnership that's really been very durable.

Brad Puffer: Right now, we're talking about vessels and the HAV that is not yet cleared by the FDA but is in this stage 3 trial. What is the process left between now and trying to actually be able to commercialize a product?

Dr. Laura Niklason: Well, as you said, we have a number of phase 3 trials underway both in dialysis access, and we're in the process of converting a vascular trauma trial into a phase 3 trial. Once those trials are completed and we have the data readout, then we would submit that data to the FDA as part of a biological licensing application or a BLA. The BLA has the clinical data, but it also has a tremendous amount of data around our manufacturing process, and the stability of the product, and a lot of laboratory investigations. And then after the FDA reviews that BLA application, hopefully, they'll issue an approval.

Brad Puffer: Closer to seeing this in reality, which is certainly very exciting, tell us a little bit about the partnership with Fresenius Medical Care. Why was this partnership so important to you, and how was it been going?

Dr. Laura Niklason: Well, we were really delighted to have this partnership with Fresenius. And in fact, we began speaking with physicians in the Fresenius network even before we implanted our first patient with an HAV for dialysis in 2012. So while the partnership was officially signed in 2018, in fact, it was the result of several years of discussions, updates and communications.

And I think Fresenius was excited by the technology as being one of the few really fundamental and really new potential improvements for dialysis access that's come along for their patients in a very long time. For us, it was a tremendous vindication and validation of our data and our platform, because Fresenius' position in the world of dialysis is so preeminent that certainly, regulators, and investors, and analysts, who have observed our partnership with four seniors have been very impressed by that-- because it's just the strongest possible outside validation of what we're trying to do.

Brad Puffer: Well, I know there's still a lot of work to ensure that, not only is this bioengineered vessel fully safe, but functions the way you hope it will function, so that we do eventually see approval and commercialization of this new vessel, but it is very exciting to think about where this might go. When we talk about the future of bioengineered vessels beyond just what you're working on with Fresenius Medical Care, what is the potential? I know other companies are looking at similar technologies, and from what I understand, you're even at Yale working on engineering artificial lungs, correct?

Dr. Laura Niklason: The world of tissue engineering, and cell therapy, and regenerative medicine, is just an exciting place to work right now. In fact, I often tell colleagues that I feel very fortunate to be working on this topic in this era. There's a tremendous amount that we've learned in cell biology and tissue development just in the last 5, 10, 20 years. That's really enabled this field to become a reality.

I see engineered tissues, including engineered arteries but also engineered skin, and cartilage, and bladder, and bone. I see many tissues that are either very close to clinical approval or in fact have already been clinically approved here and outside the US. For many types of tissue therapies, we already are very close to having products on the market.

For more complex tissues and organs, for example, engineered lungs, I have been working on that in my laboratory at Yale for almost 15 years. And I would say we've got another 10 to 20 years of work before this would be suitable for human trial, but what's exciting is that we are making progress. Obviously, a lung is a lot more complicated than an artery, but many of the engineering principles that we've learned over the last 20 years in growing blood vessels actually apply to our lung work and to all other types of complex tissues.

Brad Puffer: That's where I was hoping to end, which was looking 20 to 30 years down into the future. You kind of hinted at it. Perhaps, seeing a clinical trial for an engineered artificial lung, where do you see this technology taking off? What is the potential 30 years from now?

Dr. Laura Niklason: Well, I do think that there are some organs that are going to be a minimal to rebuilding. If I had to guess, I would say the organs most likely to succeed might be the lung, certainly the liver, perhaps spleen, and perhaps pancreas. Kidneys are hard. It's hard to grow a kidney.

The kidney structure is pretty complex, although there are certainly people who are trying, and heart is hard. Myocardial it is very difficult, although there are many people who are working there, but I can probably point to a 4, 5, or 6 organs that I think could be in use in the clinic, at least in trials 20 years from now. And that just makes this such an exciting place to work.

Brad Puffer: Well, we certainly wish you luck in that clinical stage 3 trial that's under way. And to remind everybody, this is an investigational human acellular vessel we're talking about, still in clinical trial, but we are going to be watching you very closely, Dr. Niklason and Humacyte to see where this goes in the next few years. And we hope you could come back to us in the future with an exciting update.

Dr. Laura Niklason: I would love to do that. I always love talking about the technology. Thank you so much.

Brad Puffer: Well, it's been a pleasure speaking with you, and thank you so much for taking the time.

To our audience, you can find Field Notes on the Apple Store, or Google Play, or right here at fmcna.com, or you can also find our annual medical report, and other feature articles. We hope you'll come back and join us as we discuss more important issues in the weeks ahead. Until next time, I'm Brad Puffer, and you've been listening to Field Notes by Fresenius Medical Care. Take care, everyone.