WEBVTT - Making Blood Vessels in a Factory 0:00:15.356 --> 0:00:22.196 Pushkin. When the war in Ukraine broke out a few 0:00:22.276 --> 0:00:26.876 years ago, Laura Nicholson started hearing from Ukrainian doctors who 0:00:26.916 --> 0:00:29.756 were treating soldiers at frontline hospitals. 0:00:29.676 --> 0:00:33.356 When patients would present to the hospital. In many cases, 0:00:33.476 --> 0:00:37.476 these were soldiers who had been injured in the war, 0:00:37.716 --> 0:00:41.916 typically with blast injuries and shrapnel injuries, because you know, 0:00:42.076 --> 0:00:45.436 ied explosions are really one of the you know, that's 0:00:45.516 --> 0:00:49.196 modern warfare. People lose limbs, and one of the reasons 0:00:49.236 --> 0:00:52.676 they lose limbs is because the blood flow gets damaged 0:00:52.716 --> 0:00:55.756 and cut off, and it's very hard to restore that 0:00:55.796 --> 0:00:59.636 blood flow, especially since the wounds are very contaminated. That 0:01:00.156 --> 0:01:04.076 these these limbs are filled with shrapnel and metal and soil, 0:01:04.276 --> 0:01:07.196 and it's just it's very horrific. 0:01:07.236 --> 0:01:10.116 In some cases, the doctors were getting in touch with 0:01:10.196 --> 0:01:13.396 Laura because she and her colleagues had spent more than 0:01:13.436 --> 0:01:16.956 twenty years figuring out how to use human cells to 0:01:17.036 --> 0:01:21.436 create new blood vessels outside the human body. The idea 0:01:21.676 --> 0:01:24.316 is to create a supply of vessels that surgeons can 0:01:24.436 --> 0:01:28.076 have on hand to implant into patients. She calls these 0:01:28.156 --> 0:01:33.876 vessels havs, or human acellular vessels. The havs have not 0:01:34.036 --> 0:01:38.036 yet been approved by the FDA, but the Ukrainian surgeons 0:01:38.076 --> 0:01:40.956 thought they would be helpful, so after getting approval from 0:01:40.996 --> 0:01:44.276 the Ukrainian Ministry of Health, Laura and her colleagues sent 0:01:44.556 --> 0:01:47.956 havs to several frontline hospitals in Ukraine. 0:01:48.156 --> 0:01:53.036 So when these patients would present to the hospital, if 0:01:53.076 --> 0:01:56.996 the surgeon felt that the best treatment for that patient 0:01:57.196 --> 0:02:00.996 was using the engineered vessel to rapidly restore blood flow, 0:02:01.476 --> 0:02:04.516 he would do that. And so that means, you know, 0:02:05.436 --> 0:02:07.996 cleaning out the wound. You know, the patients asleep at 0:02:07.996 --> 0:02:10.676 this time, and they're having other injuries fixed as well, 0:02:11.556 --> 0:02:15.636 but cleaning out the wound, isolating the damaged artery and 0:02:15.676 --> 0:02:19.236 then replacing the damage segment with our engineered vessel. 0:02:19.676 --> 0:02:20.516 And how did it go? 0:02:21.796 --> 0:02:26.156 Well? The outcomes in Ukraine went very well. We treated 0:02:26.156 --> 0:02:30.516 a total of nineteen patients over a year long humanitarian effort, 0:02:30.876 --> 0:02:34.356 and in fact we're still following those patients now. But 0:02:34.476 --> 0:02:37.196 what we found is that in the first month, which 0:02:37.236 --> 0:02:40.916 is really the most important time after somebody gets injured, 0:02:41.036 --> 0:02:43.756 it's how things go in the first month. What we 0:02:43.836 --> 0:02:47.116 found in the first month is that of the nineteen 0:02:47.156 --> 0:02:52.396 patients we treated. Every single limb was salvaged. There was 0:02:52.476 --> 0:02:54.916 no loss of limb, there was no loss of life. 0:02:55.796 --> 0:02:58.356 And this is true even though some of the patients 0:02:58.396 --> 0:03:01.036 we treated were very badly injured. And in fact, one 0:03:01.076 --> 0:03:03.916 of the patients, the surgeon told us later that he 0:03:04.036 --> 0:03:08.236 was quite sure this man would die, but he survived 0:03:08.316 --> 0:03:10.436 and he walked out of the hospital on his own leg. 0:03:11.116 --> 0:03:15.716 So I believe in my heart that there are soldiers 0:03:15.716 --> 0:03:19.076 in Ukraine who are walking and breathing now who would 0:03:19.076 --> 0:03:20.716 not be if it weren't for the AHAV. 0:03:26.916 --> 0:03:29.436 I'm Jacob Goldstein and this is What's Your Problem, the 0:03:29.476 --> 0:03:31.596 show where I talk to people who are trying to 0:03:31.636 --> 0:03:36.476 make technological progress. My guest today is Laura Nicholson. She's 0:03:36.556 --> 0:03:40.396 the co founder and CEO of Humo site. Laura's problem 0:03:40.516 --> 0:03:43.676 is this, can you use human cells to create a 0:03:43.676 --> 0:03:47.076 blood vessel that is better, at least for some patients 0:03:47.356 --> 0:03:51.556 than any other options available today. Laura has both a 0:03:51.596 --> 0:03:55.436 PhD and an MD. She's worked as a physician in 0:03:55.476 --> 0:03:58.796 the intensive care unit. So to start, I asked her 0:03:58.916 --> 0:04:01.236 how she got into the blood vessel business in the 0:04:01.276 --> 0:04:01.836 first place. 0:04:03.716 --> 0:04:07.636 Well, you know, I started working trying to grow arteries 0:04:07.676 --> 0:04:12.196 from scratch. In the mid nineteen nineties, I was training 0:04:12.516 --> 0:04:16.156 for my residency at mass General Hospital. I was taking 0:04:16.196 --> 0:04:19.116 care of patients in the operating room. I was an 0:04:19.156 --> 0:04:23.356 antithesiologist and an intensive care unit doctor, and I took 0:04:23.396 --> 0:04:26.356 care of a lot of patients who had vascular disease 0:04:26.436 --> 0:04:29.756 in their heart or their legs or elsewhere. And you know, 0:04:30.156 --> 0:04:34.876 diseases of arteries are still the biggest killers of people 0:04:34.916 --> 0:04:37.876 in the Western world, more so than cancer, more so 0:04:37.956 --> 0:04:38.796 than anything else. 0:04:38.956 --> 0:04:41.596 Right, Sometimes we call it heart disease, right, but it's 0:04:41.636 --> 0:04:46.356 cardiovascular disease. And the vascular piece there is vessels, right. 0:04:46.516 --> 0:04:49.756 Yes, So it can be any artery supplying any part 0:04:49.796 --> 0:04:53.956 of your body, and when those fail or clot or 0:04:54.996 --> 0:04:59.076 dilate or become infected, they need to be bypassed or replaced. 0:04:59.156 --> 0:05:04.236 And it's a universal thing in all of healthcare. And 0:05:04.276 --> 0:05:09.836 what I learned during my training is that typically when 0:05:09.836 --> 0:05:13.516 we need to repair or replace an artery, we rob 0:05:13.596 --> 0:05:17.036 Peter to pay Paul. In other words, we cut open 0:05:17.076 --> 0:05:19.636 one part of your body and take a vein out 0:05:19.716 --> 0:05:21.636 or an artery out, and then we move it over 0:05:21.796 --> 0:05:25.196 and use that vein or artery to repair the artery 0:05:25.236 --> 0:05:26.276 that's broken. 0:05:26.316 --> 0:05:29.916 Like the classic as somebody's getting a bypass surgery for 0:05:29.996 --> 0:05:32.356 the blood vessels around their heart, and the surgeon takes 0:05:32.436 --> 0:05:34.916 vessels from their leg, right, you take vessels from the 0:05:34.956 --> 0:05:36.596 thid and you put it next to the heart. 0:05:37.516 --> 0:05:42.916 Yes, yes, And as you might imagine, that always injures 0:05:42.956 --> 0:05:45.356 the patient in the process of trying to fix the patient. 0:05:46.036 --> 0:05:50.236 But importantly, not everybody has veins and arteries hanging around 0:05:50.276 --> 0:05:53.396 in their body that are spare, that are the right 0:05:53.556 --> 0:05:56.556 quality and the right size and shape to fix the 0:05:56.636 --> 0:06:00.916 problem at hand. And when that happens, surgeons are forced 0:06:00.956 --> 0:06:04.316 to use plastic tubes, tubes made out of teflon, for example. 0:06:05.036 --> 0:06:07.396 And as you might imagine, if you sew a teflon 0:06:07.516 --> 0:06:11.516 tube into your vein ascular system, that often doesn't work 0:06:11.676 --> 0:06:15.716 very well. It clots, it gets infected, it can be problematic. 0:06:15.996 --> 0:06:20.156 So so I became really interested during my training thirty 0:06:20.236 --> 0:06:23.956 years ago in whether or not we could make new 0:06:24.116 --> 0:06:27.636 arteries for patients that would behave like their own veins 0:06:27.676 --> 0:06:31.236 and arteries, but whether we could we could manufacture them, 0:06:31.356 --> 0:06:34.636 you know, make basically spare parts that would be available 0:06:34.676 --> 0:06:35.276 off the shelf. 0:06:36.476 --> 0:06:41.316 How how is that idea received at that time, so. 0:06:43.076 --> 0:06:47.556 People people viewed it as very much like science fiction, 0:06:47.836 --> 0:06:53.116 but also maybe not in a good way. So some 0:06:53.356 --> 0:06:55.556 some of my some of even my close friends, when 0:06:55.596 --> 0:06:58.196 I started working on this, they kind of stepped back 0:06:58.236 --> 0:07:02.596 and looked at me funny, like, are you really serious here? 0:07:02.716 --> 0:07:04.236 Is this something you're really going to try to do? 0:07:04.476 --> 0:07:06.396 You know, grow an artery in a jar? You know, 0:07:06.836 --> 0:07:09.836 nobody will take you seriously if you try to do that. So, yes, 0:07:09.956 --> 0:07:12.716 that was absolutely the vibe in the nineteen nineties. 0:07:13.436 --> 0:07:17.756 So you're a medical resident, your physician, learning you know, 0:07:17.876 --> 0:07:19.916 the clinical skills you need to be a practicing physician. 0:07:19.996 --> 0:07:22.196 Then you get this idea, you want to grow blood 0:07:22.236 --> 0:07:28.196 vessels in a jar. How do you even do that? Like, 0:07:28.396 --> 0:07:29.916 they're not doing that at Mass General. 0:07:32.236 --> 0:07:35.236 Yeah, so the idea of wanting to grow a vessel 0:07:35.316 --> 0:07:38.356 in a jar, You're right, it's not an obvious idea 0:07:38.436 --> 0:07:42.116 that pops into somebody's head. But I was fortunate enough 0:07:43.156 --> 0:07:45.796 to be able to work in the laboratory of Robert Langer, 0:07:45.836 --> 0:07:49.596 who's still a very accomplished investigator, one of the most 0:07:49.636 --> 0:07:53.756 famous investigators at MIT. And as you may know, MIT 0:07:53.996 --> 0:07:56.516 is right across the river from mass General where I 0:07:56.676 --> 0:08:00.556 was doing my residency, and Langer's lab was really one 0:08:00.596 --> 0:08:05.756 of the pioneers in developing this whole concept of tissue engineering, 0:08:06.116 --> 0:08:11.316 basically growing tissues from scratch. So I developed this sort 0:08:11.356 --> 0:08:15.516 of hybrid identity where I would do my clinical training 0:08:15.636 --> 0:08:18.276 during the day at mass General, and then after I 0:08:18.476 --> 0:08:21.316 was done with my cases, I take the subway and 0:08:21.676 --> 0:08:24.236 go across the river and then work in Langer's lab 0:08:24.316 --> 0:08:26.476 in the afternoon and evening and try to figure out 0:08:26.676 --> 0:08:29.196 how you grow an artery and a jar. So I 0:08:29.316 --> 0:08:33.836 got very excited about this and joined his lab in 0:08:33.996 --> 0:08:37.356 ninety five and worked for about three and a half years, 0:08:37.916 --> 0:08:41.956 and then was able to demonstrate and publish really the 0:08:42.116 --> 0:08:47.516 first functional engineered artery in a large animal. We published 0:08:47.516 --> 0:08:51.156 that in nineteen ninety nine, where I took cells from 0:08:51.316 --> 0:08:55.316 pigs and grew arteries for those pigs and then implanted 0:08:55.356 --> 0:08:58.596 them back and they worked, and we published that in 0:08:58.676 --> 0:09:01.076 Science and at the time that made quite a splash. 0:09:02.276 --> 0:09:07.156 So what was the state of tissue engineering more generally 0:09:07.316 --> 0:09:10.356 at that time people do at that time? 0:09:11.956 --> 0:09:14.876 Well, the state of tissue engineering in the nineteen nineties 0:09:15.676 --> 0:09:20.156 was really there had been some successes in what I 0:09:20.196 --> 0:09:24.436 would call sort of simpler connective tissues. So just to 0:09:24.476 --> 0:09:28.716 step back a little bit, our bodies are divided into 0:09:28.916 --> 0:09:33.436 connective tissues and non connective or organ tissues. And connective 0:09:33.476 --> 0:09:36.116 tissues are any tissues that hook one part of the 0:09:36.156 --> 0:09:41.836 body to the other, so that's skin, bone, blood, vessel, tendon, 0:09:42.036 --> 0:09:46.076 what have you. And then organs are obviously heart, liver, kidney, 0:09:46.236 --> 0:09:50.116 stuff like that. So there had been some successes even 0:09:50.196 --> 0:09:54.436 in the nineteen nineties in growing engineered tissues, for example, 0:09:54.596 --> 0:09:58.916 skin and cartilage, and in fact, engineered skin and cartilage 0:09:59.156 --> 0:10:01.396 by the mid to late nineteen nineties were already on 0:10:01.516 --> 0:10:07.236 the market, they were being used in patients, and so 0:10:07.996 --> 0:10:11.876 the early feasibility with some simpler connective tissues had really 0:10:11.956 --> 0:10:13.716 already been demonstrated by that time. 0:10:14.476 --> 0:10:17.876 So, okay, this is whatever twenty five ish years ago. 0:10:18.956 --> 0:10:20.996 Just at the end of last year, at the end 0:10:21.036 --> 0:10:25.316 of twenty twenty three, you applied for FDA approval. You're 0:10:25.436 --> 0:10:28.356 likely to hear back in the next few months. So 0:10:28.596 --> 0:10:30.636 what were a few of the things you had to 0:10:30.716 --> 0:10:33.636 figure out to get from where you were twenty five 0:10:33.716 --> 0:10:35.156 years ago to where you are now. 0:10:35.636 --> 0:10:38.956 So it has been a long journey. Initially we thought, oh, well, 0:10:39.076 --> 0:10:42.596 we'll take a small biopsy from a patient who needs 0:10:42.596 --> 0:10:45.036 an artery and will grow their cells, and then we'll 0:10:45.076 --> 0:10:46.996 make that patient a new artery and then give it 0:10:47.116 --> 0:10:47.596 back to them. 0:10:47.796 --> 0:10:49.396 So it's custom, it's bespoke. 0:10:50.036 --> 0:10:54.596 It was bespoke tissue engineering. The problem with that, though, 0:10:54.876 --> 0:10:58.276 is twofold one. It takes a long time. Yes, so 0:10:58.436 --> 0:11:01.316 if you're a patient with chest pain or. 0:11:01.356 --> 0:11:04.356 Who just got blown up by an IED, or who 0:11:04.516 --> 0:11:04.876 just got. 0:11:04.836 --> 0:11:07.196 Blown up by an IED, you don't really have three 0:11:07.276 --> 0:11:09.036 or four months to wait around for a new art 0:11:10.716 --> 0:11:14.036 So that's fundamentally a problem. But also what we found, 0:11:15.116 --> 0:11:17.356 and this was during some work that I did while 0:11:17.356 --> 0:11:20.556 I was still in academia at Duke University, what we 0:11:20.716 --> 0:11:24.836 found is that for older patients who have vascular disease, 0:11:25.716 --> 0:11:28.556 if we try to take those cells from those patients 0:11:28.636 --> 0:11:31.996 and grow new arteries for those patients, it actually doesn't 0:11:32.036 --> 0:11:35.396 work very well. You know, their vessels are old and 0:11:35.516 --> 0:11:40.236 their cells are old. And we found that and publish that, 0:11:40.316 --> 0:11:43.156 and we have a whole series of papers on that. 0:11:43.676 --> 0:11:46.796 But that really led us to a fundamental pivot, which 0:11:46.996 --> 0:11:51.436 was the insight that we could use young, healthy cells 0:11:51.556 --> 0:11:56.716 from humans, use those to grow arteries. But then after 0:11:56.836 --> 0:12:01.276 we grew the arteries from scratch, we would wash the 0:12:01.396 --> 0:12:04.636 cells out of the engineer tissue. And what that leaves 0:12:04.836 --> 0:12:08.996 behind is extracellular matrix, which can then be implanted into anybody. 0:12:09.556 --> 0:12:11.796 I mean, that's essentially where you arrived and what you 0:12:11.916 --> 0:12:15.196 are doing now, right, And so I want to talk 0:12:15.236 --> 0:12:19.396 about that in a little more detail. Basically, how it works, 0:12:19.956 --> 0:12:23.236 how you make the thing that you make. So where 0:12:23.236 --> 0:12:23.676 do you start. 0:12:24.796 --> 0:12:28.956 So we start with human cells and the cells that 0:12:29.716 --> 0:12:33.636 we use. So right now human site has banks of 0:12:33.716 --> 0:12:36.316 human cells, and in fact, we have enough cells banked 0:12:36.876 --> 0:12:40.196 to support tissue production for the next thirty or forty years. 0:12:40.876 --> 0:12:42.836 We've got a lot of cells. But where those cells 0:12:42.916 --> 0:12:47.756 come from is actually they come from organ and tissue donors. 0:12:48.476 --> 0:12:51.916 So if a patient dies and they become an organ donor, 0:12:52.596 --> 0:12:54.916 their heart might go somewhere and their liver might go 0:12:55.036 --> 0:13:00.116 somewhere else, but there's actually no transplantation use for their 0:13:00.156 --> 0:13:05.476 blood vessels. So we worked with organ procurement organizations and 0:13:05.636 --> 0:13:11.076 we obtained consent from donor families, and we obtained large 0:13:11.076 --> 0:13:15.956 blood vessels aortas from hundreds of different organ donors. We 0:13:16.116 --> 0:13:18.596 isolated cells from those donors, and then we did a 0:13:18.716 --> 0:13:24.196 tremendous amount of screening to identify which cells would really 0:13:24.276 --> 0:13:28.676 be optimal for growing new arteries, and then we established banks. 0:13:29.156 --> 0:13:32.956 So actually we have banks of donor cells now that 0:13:33.036 --> 0:13:34.316 are derived from organ donors. 0:13:34.636 --> 0:13:38.556 So it's like vials of cells in fluid in the 0:13:38.636 --> 0:13:40.116 refrigerator or something like that. 0:13:40.396 --> 0:13:44.076 It's vials of cells stored in liquid nitrogen, so they're 0:13:44.156 --> 0:13:47.756 extremely cold, but that means that the cells can store 0:13:47.836 --> 0:13:48.476 for decades. 0:13:49.756 --> 0:13:54.236 Okay, so very good. That's step one. Get a lot 0:13:54.316 --> 0:13:59.156 of nice, healthy or to cells. And just to be clear, 0:13:59.396 --> 0:14:03.356 by the way, that our blood vessel cells the same 0:14:03.476 --> 0:14:05.756 in all of the vessels. Dumb question, But are the 0:14:05.796 --> 0:14:07.676 cells of the order the same as the cells in 0:14:07.836 --> 0:14:08.956 whatever other blood vessel. 0:14:09.716 --> 0:14:14.236 The cells even within your aorta, there's different flavors of cells, 0:14:14.916 --> 0:14:18.276 and the cells differ between arteries and veins and big 0:14:18.396 --> 0:14:21.716 arteries and small arteries and capillaries. So that was really 0:14:21.836 --> 0:14:25.556 part of the challenge for us, was really identifying which 0:14:25.716 --> 0:14:29.316 subset of cells in the aortas was really the most 0:14:31.356 --> 0:14:35.836 productive for growing new arteries. As it turns out, some 0:14:35.996 --> 0:14:37.956 of the cells in your body, even if you're an 0:14:37.956 --> 0:14:42.076 older person still have this sort of progenitor or stem 0:14:42.316 --> 0:14:47.076 like capability. And those cells we found could grow extensively 0:14:47.956 --> 0:14:50.916 in our process and could grow large numbers of new arteries. 0:14:52.396 --> 0:14:55.156 Great, so you got not only a lot of cells, 0:14:55.196 --> 0:14:56.876 you got a lot of the right kind of cells. 0:14:57.396 --> 0:15:00.116 What do you do with them? Well, when we want 0:15:00.196 --> 0:15:02.996 to grow a batch of arteries. Right now, we grow 0:15:03.076 --> 0:15:06.716 two hundred arteries at a time in a highly automated 0:15:06.796 --> 0:15:10.636 system that we've designed and built over many years. 0:15:11.796 --> 0:15:12.676 Artery factory. 0:15:12.836 --> 0:15:16.316 It's an artery factory, yes, yes, In fact, we have 0:15:17.636 --> 0:15:21.196 eight installed units now. Each unit, which we call a 0:15:21.316 --> 0:15:23.996 Luna two hundred unit, can grow two hundred vessels at 0:15:23.996 --> 0:15:24.316 a time. 0:15:24.796 --> 0:15:26.116 A unit is like a machine. 0:15:26.356 --> 0:15:28.676 It's a machine. It's a machine. It's about as big 0:15:28.716 --> 0:15:33.636 as a school bus, and it's essentially a large incubator 0:15:33.836 --> 0:15:38.356 where we control temperature and humidity and oxygen. But we 0:15:38.556 --> 0:15:42.636 also have inside the school bus, inside the incubator, we 0:15:42.836 --> 0:15:48.916 have bioreactor systems where where we can provide an environment 0:15:49.036 --> 0:15:53.996 for the cells while they're growing, so that the cells 0:15:54.236 --> 0:15:56.996 form new arteries. But I'm sort of jumping ahead a 0:15:57.036 --> 0:16:00.316 little bit. So when we start a batch, what we 0:16:00.436 --> 0:16:02.836 do is we take a tiny vial of cells. It's 0:16:02.876 --> 0:16:05.436 about a fifth of a tea spoon. It's a little 0:16:05.476 --> 0:16:08.436 tiny volume, and we thaw out those cells and then 0:16:08.476 --> 0:16:14.396 we grow them and we let them expand about two thousandfold, 0:16:15.516 --> 0:16:18.476 and then we take we gather all those cells and 0:16:18.636 --> 0:16:24.116 then we essentially walk over to one of our production units, 0:16:24.156 --> 0:16:27.276 one of our Luna two hundreds, and in the Luna 0:16:27.316 --> 0:16:31.836 two hundred is two hundred what we call bioreactor bags. 0:16:31.996 --> 0:16:36.356 Each bag has a has a scaffold inside of it 0:16:37.236 --> 0:16:41.076 that's sterile. And that scaffold is six millimeters in diameter 0:16:41.196 --> 0:16:44.276 and forty centimeters long, So that's the size of the 0:16:44.356 --> 0:16:45.076 artery we grow. 0:16:45.236 --> 0:16:48.276 So and it's made of like plastic or something. 0:16:48.436 --> 0:16:52.596 It's a degradable it's a degradable plastic. It's actually it's 0:16:52.716 --> 0:16:56.716 the same material that's used in degradable sutures. So each 0:16:56.836 --> 0:17:00.116 fiber is about the width of a cell, and there's 0:17:00.156 --> 0:17:02.436 a lot of empty space in between the fibers. But 0:17:02.596 --> 0:17:07.116 this this the shape of the scaffold. We can we 0:17:07.196 --> 0:17:10.316 can shape it into this six millimeter diameter tube that's 0:17:10.356 --> 0:17:14.556 forty centimeters long. And what we do is we take 0:17:14.636 --> 0:17:16.956 the cells that we grow, and we inject them into 0:17:16.996 --> 0:17:20.596 the bag and the cells stick onto the stick, stick 0:17:20.636 --> 0:17:23.276 onto the fibers of the scaffold. It's like a person. 0:17:23.396 --> 0:17:26.956 It's like a person hanging onto a metal pole on 0:17:27.116 --> 0:17:29.596 building scaffolding. If you think of it that, that's kind 0:17:29.636 --> 0:17:30.116 of what it's like. 0:17:30.316 --> 0:17:32.716 And so the cells are grabbing sort of all over 0:17:32.876 --> 0:17:35.356 this little plastic tube, all over the scalfeld. 0:17:35.756 --> 0:17:39.476 Yes, each cell grabs onto a metal pole and they 0:17:39.516 --> 0:17:44.756 hang on for dear life. And then then we basically 0:17:45.156 --> 0:17:48.836 fill the bag, the bioreactor bag, with culture medium. And 0:17:49.036 --> 0:17:52.396 then that culture medium is super secret. It has lots 0:17:52.436 --> 0:17:55.036 of yummy stuff in it that convinces the cells to 0:17:55.196 --> 0:18:00.116 grow and to while they're growing, they secrete proteins like 0:18:00.236 --> 0:18:05.716 collagen and other matrix molecules. What also happens while while 0:18:05.756 --> 0:18:08.916 the cells are growing in the culture medium is we've 0:18:08.956 --> 0:18:12.036 just sign the bioreactor bag so that we can stretch 0:18:12.156 --> 0:18:15.716 the cells as if as if the cells are in 0:18:15.836 --> 0:18:18.236 the wall of an artery and they're feeling your heart beat. 0:18:18.676 --> 0:18:22.996 Huh, because because arteries need to get wider and get 0:18:23.076 --> 0:18:26.036 narrow as the pulse of blood comes in and out. Yes, yes, 0:18:26.116 --> 0:18:28.156 so if you well, there's two different numbers in your 0:18:28.196 --> 0:18:29.796 blood pressure reading exactly. 0:18:29.956 --> 0:18:32.236 There's a there's a higher pressure in a lower pressure. 0:18:32.236 --> 0:18:34.116 And if you put your if you put your finger 0:18:34.196 --> 0:18:37.116 on your wrist, you can feel your pulse. That pulse 0:18:37.236 --> 0:18:40.756 is your artery distending and then and then recoiling every 0:18:40.796 --> 0:18:43.436 time your heart beats. Well, it turns out we learned 0:18:43.556 --> 0:18:46.756 very early. We figured out when I was working in 0:18:46.916 --> 0:18:50.116 Langer's lab in the nineties that if we didn't stretch 0:18:50.196 --> 0:18:52.756 these cells while they were growing, they didn't really make 0:18:52.796 --> 0:18:55.116 an artery because they didn't know they were supposed. 0:18:54.756 --> 0:18:57.236 To do that. So they would be too like rigid, 0:18:57.276 --> 0:18:58.116 they wouldn't be able to. 0:18:58.116 --> 0:19:01.756 They would be pul they would be disorganized. Actually, they 0:19:01.796 --> 0:19:04.236 would just grow randomly because they didn't know what they 0:19:04.276 --> 0:19:05.196 were supposed to be doing. 0:19:06.716 --> 0:19:10.076 Huh. So it's like that that pulse kind of it 0:19:10.236 --> 0:19:14.276 tells them how to grow and organize themselves. That's really interesting. 0:19:14.436 --> 0:19:15.436 It's really interesting. 0:19:15.636 --> 0:19:18.916 Yeah, So so you do that in the bag? How 0:19:18.996 --> 0:19:20.596 do you get them to so you have a little 0:19:20.636 --> 0:19:23.476 sort of imitation heartbeat sort of in the bag. 0:19:23.916 --> 0:19:26.996 We have a little imitation heartbeat in the bag, Yes, 0:19:27.796 --> 0:19:30.516 and every vessel gets stretched the same amount, and they 0:19:30.596 --> 0:19:34.316 get stretched cyclically by this heartbeat for the entire two 0:19:34.396 --> 0:19:35.356 month culture duration. 0:19:36.556 --> 0:19:40.876 So they spend two months growing and learning how to 0:19:40.996 --> 0:19:46.716 be cells in an artery and filling in all the 0:19:46.836 --> 0:19:50.196 spaces on the scaffold on the little plastic tube. What 0:19:50.316 --> 0:19:52.636 happens at the end of that two months, well, at. 0:19:52.596 --> 0:19:54.876 The end of the two months, a couple things have happened. 0:19:54.996 --> 0:19:59.516 One is that that scaffolding, which I said is degradable, 0:19:59.796 --> 0:20:02.836 has mostly degraded, so it's like it's pretty much all gone. 0:20:03.436 --> 0:20:06.556 So what we have by that time is a human 0:20:06.716 --> 0:20:11.756 artery that has these cells and also the collagen matrix 0:20:12.196 --> 0:20:15.556 proteins that they made, and there's really no scaffold left. 0:20:16.236 --> 0:20:20.516 Huh So in a final step, we re drain out 0:20:20.556 --> 0:20:23.876 the culture medium that we use to convince the cells 0:20:23.916 --> 0:20:28.996 to grow, and then we replace it with detergents and 0:20:29.276 --> 0:20:33.196 we basically we spend five days and we washed the 0:20:33.316 --> 0:20:34.996 cells out of the artery. 0:20:35.556 --> 0:20:38.676 Huh So, So after two months, when you take it out, 0:20:38.876 --> 0:20:41.956 it feels like it's a lot like an artery in 0:20:42.316 --> 0:20:46.396 my body, in your body, in anybody's body. But that's 0:20:46.476 --> 0:20:48.636 not good because if you put that in a patient, 0:20:48.956 --> 0:20:51.956 you'll have an immune a bad immune response. That's presumably 0:20:52.036 --> 0:20:53.716 the problem. Why you can't just use that. 0:20:54.236 --> 0:20:57.276 That's the reason, yes, because again these are these are 0:20:57.356 --> 0:20:59.396 cells from a cell bank. So if I if I 0:20:59.476 --> 0:21:02.156 grow that artery and then I implanted in you, your 0:21:02.196 --> 0:21:03.796 body will reject it because. 0:21:03.516 --> 0:21:08.396 It's certainly I'm getting a transplant. And so what is 0:21:08.596 --> 0:21:11.636 what is that final step or that that next step? 0:21:12.756 --> 0:21:16.396 So the final step we call that decellularization. So we 0:21:16.676 --> 0:21:20.476 rinse away the cells, which are really the part that 0:21:20.636 --> 0:21:24.236 creates the immune rejection. But what we leave behind, and 0:21:24.316 --> 0:21:28.636 what we're very careful not to disturb, is the extracellular 0:21:28.716 --> 0:21:31.756 matrix proteins like the collagen that I mentioned, there's actually 0:21:32.036 --> 0:21:35.916 forty or fifty proteins there. The reason that's important is 0:21:36.076 --> 0:21:40.716 because it's really the collagen and the proteins that give 0:21:40.796 --> 0:21:45.396 the vessel all of its mechanical properties. So actually washing 0:21:45.556 --> 0:21:48.716 the cells out of the tissue doesn't change how strong 0:21:48.756 --> 0:21:51.836 it is. It's still just as strong as your arteries. 0:21:52.876 --> 0:21:55.116 After we wash the cells out, the cells are really 0:21:55.196 --> 0:21:58.836 there to be little protein factories, yeah right, but they 0:21:58.916 --> 0:22:00.356 themselves are not very strong. 0:22:01.516 --> 0:22:02.116 Huh So. 0:22:02.836 --> 0:22:06.756 But because collagen is so important, like for example, your 0:22:06.836 --> 0:22:10.996 collagen and my collagen are identical. Huh, they're identical. 0:22:11.396 --> 0:22:16.036 You're saying, there's no kind of there's no potential immune response. 0:22:16.076 --> 0:22:18.636 It's just protein. It's just these exact same protein. You 0:22:18.716 --> 0:22:20.836 couldn't tell the difference, Yes, you couldn't tell who it came. 0:22:20.916 --> 0:22:23.516 Your body, Yes, your body can't tell the difference. And 0:22:23.636 --> 0:22:29.876 so we've implanted these decellularized, engineered arteries into nearly six 0:22:29.996 --> 0:22:33.596 hundred patients over the last eleven years. We've never seen 0:22:33.676 --> 0:22:35.516 a single episode of rejection. 0:22:35.916 --> 0:22:38.676 Because in an immune sense, there's nothing to reject. 0:22:39.716 --> 0:22:40.636 That's what we believe. 0:22:40.756 --> 0:22:45.676 Yes, so now it's like kind of like a dead artery, 0:22:45.676 --> 0:22:51.676 an artery without any personality, a generic artery. You put 0:22:51.716 --> 0:22:53.436 it in a person and a patient. 0:22:54.756 --> 0:22:58.276 What happens then, well, there's a couple things that happened. 0:22:58.356 --> 0:23:01.076 The first thing that happens is that the artery works 0:23:01.116 --> 0:23:04.556 as it should. So the main job of arteries is 0:23:04.636 --> 0:23:07.196 to conduct blood flow so that you can get blood 0:23:07.236 --> 0:23:10.436 from point A to point B. So that happens as 0:23:10.476 --> 0:23:12.396 soon as the surgeon sews it in and takes the 0:23:12.476 --> 0:23:15.956 clamps off. So some people worry, g we wash the 0:23:16.076 --> 0:23:16.996 cells out, will. 0:23:16.916 --> 0:23:17.716 It be leaky. 0:23:19.596 --> 0:23:24.956 That doesn't happen. We don't see that. But what's probably 0:23:25.116 --> 0:23:29.796 cooler is that over time, sells from the patient see 0:23:29.916 --> 0:23:34.436 this naked artery and to them it sort of looks 0:23:34.516 --> 0:23:39.476 like an empty apartment building. And what we've seen happen, 0:23:39.556 --> 0:23:42.956 in fact we've published this, is that cells from the 0:23:43.076 --> 0:23:50.596 patient migrate into the acellular artery and they start off 0:23:50.676 --> 0:23:54.156 being progenitor cells, but they become vascular cells. So over 0:23:54.236 --> 0:23:58.636 a period of months, this non living thing becomes a 0:23:58.796 --> 0:24:03.596 living artery and it's the patient's own. So this is really, 0:24:03.796 --> 0:24:07.476 I think this is regenerative medicine in the truest sense. 0:24:09.836 --> 0:24:13.396 Can you tell the difference whatever a year later, between 0:24:13.476 --> 0:24:16.116