Controlled Drug Release Technology
Transcript of Part 3: Biomaterials for Drug Delivery Systems and Tissue Engineering
00:00:07.15 My name is Bob Langer, 00:00:09.02 and I'd now like to over my third lecture, 00:00:10.22 which is Biomaterials and Biotechnology: 00:00:12.20 the development of controlled drug delivery systems 00:00:15.05 and the foundation of tissue engineering. 00:00:18.17 In my last lecture, I went over the fact that 00:00:21.28 numerous angiogenesis inhibitors 00:00:24.07 were approved by regulatory authorities 00:00:26.16 and are now in clinical use, 00:00:28.09 and that controlled drug delivery systems 00:00:30.03 actually helped in creating the bioassays 00:00:32.09 that enabled many of them to be isolated. 00:00:35.29 Also, I went over the fact 00:00:37.27 that one could create new smart materials 00:00:39.25 like nanoparticles and even smart microchips 00:00:43.06 that could be externally activated 00:00:45.00 and used in the body. 00:00:46.29 Now, what I'd like to do 00:00:48.19 is turn to some of the materials themselves 00:00:51.07 and some of the issues with those. 00:00:53.06 So, as I mentioned in my second lecture, 00:00:56.16 I worked in a hospital for a number of years, 00:00:58.22 and one of the things that I was curious about 00:01:00.14 as a chemical engineer 00:01:02.05 was how did materials 00:01:04.21 find their way into medicine? 00:01:06.26 And I though, naively, 00:01:08.15 that it must be chemists and materials scientists 00:01:10.08 and engineers that did that, 00:01:12.05 but when I looked into this I found out 00:01:13.16 that was almost never the case. 00:01:15.13 It was almost always clinicians, 00:01:16.23 and what they did is they would usually go to their house 00:01:19.22 to find some object that resembled the organ or tissue 00:01:22.13 they were trying to fix, 00:01:24.07 and they'd use it in the person. 00:01:26.09 For example, in the case of the artificial heart, 00:01:28.21 in 1967 some of the clinicians at NIH 00:01:32.01 wanted to make a heart 00:01:35.12 and they wanted something with a good flex life 00:01:37.05 and they said, "Well, what object has that?" 00:01:38.29 And they said, "A ladies girdle." 00:01:40.17 So, they took the material in a ladies girdle 00:01:42.15 and made the artificial heart out of that, 00:01:44.11 and that's actually not only what was used in 1967, 00:01:47.23 it's what used today. 00:01:49.15 But, one of the problems is 00:01:51.27 that when one starts down that path from a regulatory standpoint... 00:01:54.16 you really... it's very hard to change it, 00:01:57.27 and when people designed the artificial heart, 00:01:59.28 many times is hasn't worked that well, 00:02:02.01 because when blood hits the surface of the artificial heart, 00:02:04.01 the ladies girdle material, it could form a clot, 00:02:06.18 that clot could go to the patient's brain, 00:02:08.12 they get a stroke and they may die. 00:02:10.26 And yet, to me, it's not that surprising 00:02:12.27 that something that was designed to be a ladies girdle material 00:02:15.09 might not be the optimal blood contacting material, 00:02:18.00 and this problem really pervades all of medicine. 00:02:20.28 Dialysis tubing was sausage casing. 00:02:23.04 Vascular graft, that's an artificial blood vessel, 00:02:25.10 was a surgeon in Texas going to a clothes store 00:02:27.26 to see what he could sew well with, 00:02:29.28 and breast implants, one of those was a lubricant, 00:02:32.10 another actually was a mattress stuffing. 00:02:35.08 Being a chemical engineer I thought, 00:02:37.05 well, maybe there's a different way. 00:02:38.24 One of the things you learn about in chemical engineering is design, 00:02:41.06 and so I thought, why couldn't we ask the question, 00:02:43.06 what do we really want in a material 00:02:44.29 from an engineering standpoint, 00:02:46.22 chemistry standpoint, 00:02:48.07 and biology standpoint, 00:02:49.27 and then could we synthesize it from first principles? 00:02:52.04 So, we picked an example. 00:02:53.27 When I started, the only material that was FDA approved 00:02:57.14 that was synthetic and degradable 00:03:00.07 were the polyester sutures, 00:03:02.09 and they dissolve by a process we call bulk erosion, 00:03:04.25 which means that as you look at the top part 00:03:07.28 it's intact, but then over time it gets spongy 00:03:10.11 all the way through, 00:03:12.11 and then it just breaks apart. 00:03:13.26 Which is okay for some drugs, but for others 00:03:15.21 it could lead to bursts of drug release 00:03:17.17 and that could be fatal if you had 00:03:19.21 a possibly dangerous drug like an anti-cancer drug. 00:03:22.15 So we said, and others have said, 00:03:25.22 what you really want in a polymer 00:03:30.27 to degrade is not bulk erosion, but surface erosion. 00:03:33.23 That would be layer by layer erosion, 00:03:35.14 and if that could happen kind of the way a bar of soap might dissolve 00:03:38.12 then you wouldn't have this problem of dose dumping. 00:03:40.27 The challenge was, how could you do that? 00:03:43.05 How could you create a polymer to do this? 00:03:45.28 So, we went through 00:03:48.06 a very detailed engineering design analysis 00:03:50.25 to try to figure that out. 00:03:52.15 We'd start out with different design questions, 00:03:54.12 like what should cause the polymer degradation? 00:03:57.04 Should it be enzymes? 00:03:58.20 Should it be water or something else? 00:04:00.12 Our thinking is, well, everybody may have different enzyme levels, 00:04:02.09 but everybody has excess water, 00:04:04.06 so let's build into the polymer 00:04:06.08 the ability to be degraded by water 00:04:09.03 as a first step. 00:04:10.21 And then what we did is we figured out 00:04:12.08 what the right building blocks are 00:04:14.12 to make those polymers 00:04:15.25 that would keep water out, 00:04:17.20 because you want to keep water confined to the surface. 00:04:20.00 And then we tried to figure out 00:04:21.16 what would be the right chemical bonds 00:04:23.10 that would break apart in the right way 00:04:24.19 and we came up with the anhydride bond. 00:04:26.20 And then we tried to figure out 00:04:28.14 what would be the specific units in the polymer 00:04:31.00 that would be safe in the body, 00:04:34.13 and ultimately we came up with this polymer. 00:04:37.11 It's what's called a copolymer, 00:04:38.28 there's two units to it: 00:04:40.26 PCPP, that's carboxyphenoxy-propane, 00:04:43.09 and sebacic acid. 00:04:45.02 And our thinking was 00:04:47.06 that by changing the ratios of these 00:04:49.06 we could make the polymer last for different times, 00:04:51.01 and if we used this anhydride bond 00:04:53.04 to connect everything, 00:04:55.09 then we might be able to get the surface erosion. 00:04:58.11 We made some of these; 00:05:00.17 we synthesized these polymers. 00:05:02.17 It's a good deal of work but we synthesized them, 00:05:05.00 and what you see is 00:05:07.23 they actually did come quite close to this surface erosion, 00:05:09.23 but if you change the ratio of one to the other... 00:05:12.04 the 79, 55, 15, and 0 00:05:17.01 all referring to the amount of sebacic acid, 00:05:19.04 what happens is you can make these last 00:05:21.15 for almost any length of time. 00:05:23.03 You can go from the 79% one 00:05:25.16 that lasts for about 2 weeks. 00:05:27.03 The 0% one will last for 3 or 4 years. 00:05:29.20 So, you can simply dial in the ratio of these 00:05:32.09 and make them last for almost any length of time you want. 00:05:35.19 Well, one of the things that I always want to try to do 00:05:38.12 is not just write the paper, 00:05:40.11 but to try to see if we can use these materials that we create 00:05:44.04 to do something useful, 00:05:46.09 and in 1985, Henry Brem, 00:05:47.27 a young neurosurgeon at Johns Hopkins, 00:05:49.21 came to visit me 00:05:51.20 and wanted to see if we might be able to help him 00:05:53.25 come up with a different way to treat brain cancer. 00:05:56.27 Henry is now chairman of neurosurgery at Johns Hopkins. 00:06:00.05 But just briefly, 00:06:02.06 these were some of the statistics at the time. 00:06:04.14 With glioblastoma multiforme 00:06:06.10 it was a uniformly fatal disease. 00:06:08.23 The mean lifespan, 00:06:10.10 regardless of how you treated it, 00:06:11.29 was generally less than a year. 00:06:13.24 The drug that people used at that time 00:06:16.01 in the 1980s was this one, BCNU. 00:06:19.11 It's effective but very, 00:06:22.19 you know, toxic drug. 00:06:25.09 And, what Henry and I talked about was this idea: 00:06:28.07 rather than give it intravenously, 00:06:30.14 which was always what was done before, 00:06:33.01 could we introduce this paradigm 00:06:34.28 of what I'lll call local chemotherapy? 00:06:37.04 Could we allow the neurosurgeon, like Dr. Brem, 00:06:40.04 to operate on the patient 00:06:43.12 to remove as much of the tumor as he could, 00:06:45.24 but before he closes the patient, 00:06:47.18 could he line the surgical cavity 00:06:49.14 with little wafers containing this drug and polymer? 00:06:53.26 Now, this polymer, the drug I should say, 00:06:57.09 normally lasts just for 12 minutes, 00:06:59.17 but if you put it in the polymer it's protected. 00:07:01.05 It'll last as long as the polymer lasts. 00:07:03.10 So, the neurosurgeons like Dr. Brem, 00:07:06.07 they wanted it to last for a month, 00:07:09.05 and we could do that by changing the chemistry. 00:07:11.15 So basically, what we were able to do 00:07:14.02 is make these wafers, 00:07:16.05 make it last for a month, 00:07:17.29 and also what was important to the neurosurgeons 00:07:20.20 is they're putting the wafers in the brain, 00:07:22.24 so they're exposing only the cells, largely, 00:07:25.13 they wanted to to the drug, 00:07:27.10 and the rest of the body is really spared these high concentrations 00:07:29.08 of chemotherapy. 00:07:31.09 So... 00:07:33.24 so, that was the idea and, 00:07:36.18 well, what happened is that 00:07:39.16 whenever you're in academia, a professor, 00:07:41.11 you have to raise money, 00:07:42.27 and so what we would do to try to raise money 00:07:44.29 to move this forward, 00:07:46.22 first to create the new materials and everything, 00:07:48.11 is I'd write grants and I'd write them 00:07:50.21 to like the National Institutes of Health of other places, a 00:07:52.13 nd then they'd have professors at other universities 00:07:54.18 review them and say what they thought. 00:07:56.22 And we did terribly. 00:07:58.16 We did very, very badly. 00:08:00.18 When I first wrote the grants, 00:08:02.25 the reviewers, the chemists said, 00:08:05.06 well, we'll never be able to synthesize the polymers. 00:08:07.28 But, I had a very good graduate student at the time 00:08:10.00 named Howie Rosen. 00:08:11.21 Howie later became president of the ALZA corporation, 00:08:13.08 a 12 billion dollar corporation, 00:08:15.16 and also has been elected to the National Academy of Engineering, 00:08:18.10 and he synthesized the polymers. 00:08:20.14 So, we sent the grant back 00:08:22.07 and the reviewers said, well, 00:08:23.24 we still shouldn't fund it even if you can synthesize them. 00:08:26.22 The polymers are gonna... 00:08:28.15 they have these anhydride bonds, 00:08:29.13 they'll react with whatever drug you put in. 00:08:30.00 But, another couple postdocs, 00:08:32.19 Bob Linhardt, who's now Constellation Professor of Chemistry 00:08:35.28 at RPI, 00:08:37.20 and Kam Leong, who's a James Duke Professor of Bioengineering 00:08:40.05 at Duke University, 00:08:41.18 also was elected to the National Academy of Engineering, 00:08:44.02 and they showed there was no reaction. 00:08:46.08 So, we sent it back again, 00:08:47.26 and the reviewers said, 00:08:49.26 well, you know, okay... 00:08:51.10 that's not a problem, 00:08:52.13 but these polymers are low molecular weight, 00:08:54.18 they're fragile, they'll break in the body. 00:08:57.18 But I had another couple postdocs, 00:08:58.28 Edith Mathiowitz, she's now a full professor of Bioengineering 00:09:01.25 at Brown University, 00:09:03.15 she's been elected to the National Academy of Inventors, 00:09:05.25 and Avi Domb, 00:09:07.01 who later became Chairman of Medicinal Chemistry 00:09:09.09 at Hebrew University, 00:09:10.28 and they made polymers that were very strong, 00:09:13.05 high molecular weight polymers 00:09:14.20 and, you know, wouldn't break. 00:09:16.29 So then we sent it back again 00:09:18.23 and the reviewers said, well, you know, 00:09:20.12 new materials are certainly gonna be toxic, 00:09:22.16 but I had another graduate student, 00:09:24.08 Cato Laurencin, 00:09:26.04 Cato later became Dean of Medicine at the University of Connecticut, 00:09:28.12 and he's been elected to actually both the 00:09:30.22 Institute of Medicine of the National Academy of Sciences 00:09:33.10 as well as the National Academy of Engineering, 00:09:36.00 and he showed that they were very, very safe. 00:09:38.19 Anyhow, this kept going on and on until 1996, 00:09:41.07 when the FDA approved the treatment. 00:09:43.05 It was actually the first time 00:09:45.01 in over 20 years they approved a new treatment for brain cancer, 00:09:47.28 and the first time they ever approved 00:09:49.28 this idea of polymer-based chemotherapy for cancer. 00:09:53.28 You can probably tell from the way I'm speaking 00:09:56.15 that I'm very proud of... 00:09:58.05 well, all the graduate students and postdocs 00:10:00.08 that they became chairpeople of departments, 00:10:03.17 presidents of large corporations, 00:10:05.29 received all kinds of honors, 00:10:07.23 whereas the reviewers... 00:10:09.29 they haven't done that well. 00:10:12.13 Now, I'd like to actually show 00:10:15.09 what the operation looks like, 00:10:16.15 but these are gonna be fairly bloody slides, 00:10:18.25 so people shouldn't look 00:10:20.28 if they don't want to, 00:10:22.21 but this is gonna be a little wafer going into the human brain, 00:10:26.14 and you can see that here, 00:10:28.18 it's the white part, 00:10:30.00 and usually they put 6 or 7 in and then close up the brain. 00:10:33.17 So, I should point out that, 00:10:37.28 you know, it's very hard to get good advice when I give a talk, 00:10:40.24 but my wife once came to one of the talks I gave 00:10:42.28 and I asked her about it... 00:10:44.19 this was a talk to a group of engineers at MIT, 00:10:46.16 and she told me that 00:10:48.23 I had left those two bloody slides on for 10 minutes 00:10:51.06 explaining all the details, 00:10:53.09 and unfortunately all of the engineers got, 00:10:55.10 I guess, very ill, 00:10:57.11 and I should have noticed that. 00:10:59.05 So, now I don't leave them on very long 00:11:01.11 when I talk to engineers, so I apologize for that. 00:11:04.20 At any rate, 00:11:07.11 this was some of the clinical data 00:11:09.05 that was published in Neurosurgery 00:11:11.06 and from the European clinical trials. 00:11:13.12 It's what called a Phase 3 clinical trial, 00:11:15.29 and what you see is at the end of two years 00:11:20.18 you do see significantly increased survival. 00:11:24.00 It's not a cure by any means, 00:11:26.03 but what's been exciting is that now... 00:11:31.09 for patients who have, you know, sometimes localized tumors, 00:11:34.20 this treatment has been approved by the FDA, 00:11:36.23 it's been used in over 30 countries 00:11:38.21 for the last 18 years, 00:11:40.07 and it created a new paradigm 00:11:41.25 for how one would think about local chemotherapy. 00:11:45.17 Not only might you use it in cancer, 00:11:48.01 and people are studying it in other kinds of cancer, 00:11:50.06 but you might also use it in other diseases, 00:11:52.14 and in fact one of my other graduate students, 00:11:54.27 former graduate students, 00:11:56.14 Elazer Edelman, who's now a professor at Harvard and MIT, 00:11:59.29 as well as a number of companies 00:12:01.19 like Boston Scientific, 00:12:03.14 have used these ideas in the area of drug-eluting stents, 00:12:06.08 and that's been a huge area in interventional cardiology. 00:12:09.17 Today, if somebody has heart disease, 00:12:11.18 one of the things that are often done 00:12:14.04 is to prop open the blood vessel 00:12:16.12 by putting a stent in, 00:12:18.07 it's like a Chinese finger puzzle, 00:12:20.02 but about half the time 00:12:22.06 what happens is it closes off 00:12:24.06 because of smooth muscle cell proliferation. 00:12:26.23 And now what's done is to coat these stents 00:12:29.02 with a polymer 00:12:31.00 that locally delivers a drug like another anti-cancer drug by Taxol, 00:12:35.01 and that prevents that proliferation, 00:12:37.00 and these are used in about a million patients every year 00:12:39.07 and have had very profound effects. 00:12:41.20 Now, what I'd like to do 00:12:45.12 is go the second part of the talk, 00:12:47.01 where I'd like to talk to you about 00:12:49.05 using materials to create new tissues and organs 00:12:51.23 by combining materials with cells. 00:12:53.27 Here, I've worked very closely with Jay Vacanti. 00:12:56.02 Jay is head of the pediatric surgery program 00:12:58.20 at Massachusetts General Hospital, 00:13:00.24 and he and I have been working on this 00:13:04.02 for, now, over 30 years, 00:13:06.05 and the reason this came about is he would see patients 00:13:08.07 who had liver failure, like this little boy, 00:13:11.06 who were dying, 00:13:12.24 and there was no way to treat them other than a transplant 00:13:14.27 and there weren't nearly enough transplants. 00:13:17.13 And so, he and I started talking about this 00:13:19.12 and asked, could we come up with a way 00:13:22.00 to maybe use the patients own cells 00:13:24.02 or a relative's cells or someone's cells, 00:13:27.00 combined with materials, 00:13:28.18 to create new tissues and organs? 00:13:30.25 The specific idea we had is shown here. 00:13:33.17 This is from a paper we wrote in Science many years ago, 00:13:36.24 and the idea was you could take these cell types, 00:13:40.07 you see osteoblasts, which are bone cells, 00:13:42.11 or chondrocytes, which are cartilage cells, 00:13:44.18 hepatocytes, which are liver cells, 00:13:46.14 and so forth, 00:13:47.28 and you'd dissociate them... 00:13:49.27 today, you might also consider using stem cells 00:13:52.16 and converting them to one of these, 00:13:54.19 but if you take these cells 00:13:56.10 and inject them at random in the body, 00:13:58.04 not much happens. 00:13:59.16 But, the cells are small and people, 00:14:01.04 for example at Berkeley, 00:14:03.05 have shown that you can take mammary epithelial cells 00:14:05.09 and put them close together 00:14:07.09 and when you do that, they're smart enough 00:14:08.29 to actually make acini and make milk, 00:14:11.16 and our theory was that if we could create 00:14:14.02 the right kind of polymer 00:14:15.22 and biodegradable scaffold, 00:14:17.11 and the cells would be close enough together, 00:14:19.09 and they were grown under the right in vitro tissue culture conditions 00:14:23.01 in what we call bioreactors, 00:14:24.22 maybe we could make a new tissue 00:14:26.12 and ultimately put it in the body. 00:14:28.20 There are a number of components to this, 00:14:31.09 as one sees on this slide. 00:14:32.24 The first component was having the right materials, 00:14:34.20 and we would generally use degradable materials 00:14:37.06 that had been shown to be safe in people, 00:14:38.26 and in many cases we synthesized new materials ourselves. 00:14:42.23 We might then convert them to fibers, 00:14:44.21 where we could put cells on 00:14:46.19 like you can see in this scanning electron micrograph, 00:14:49.06 but also the way this field is going, 00:14:51.21 we also thought that you might someday 00:14:53.27 be able to even use techniques 00:14:56.08 like CAD/CAM techniques, 00:14:58.17 computer-aided design is what I basically mean, 00:15:01.14 and just to illustrate that, 00:15:03.12 this is work that Prasad Shastri, who was a postdoc with us, did. 00:15:07.02 He basically was thinking about 00:15:10.09 making new structures like a nose, which you see here, 00:15:13.14 and so he basically designed a nose 00:15:16.01 with a foaming technique... 00:15:17.27 you could also use 3-D printing, 00:15:19.28 other ones of my former postdocs like Linda Griffith 00:15:22.12 have done things like that, 00:15:24.10 she's a professor at MIT now... 00:15:26.14 and the idea is that 00:15:29.12 you could make basically a nose. 00:15:33.09 It's 98% porous, 00:15:36.09 but it's made of a polymer of, in fact, poly(L-lactic acid), 00:15:40.06 and you could make this nose into any shape, 00:15:41.19 so I've just speculated 30 or 40 years from now, 00:15:44.19 maybe they'll be a computer printout 00:15:47.13 that somebody could pick, 00:15:49.03 when they're going to a plastic surgeon, 00:15:51.10 whatever nose shape they want. 00:15:52.24 So, they could have a regular nose shape, 00:15:55.01 or maybe they'd want an upturned nose shape, 00:15:57.04 which wouldn't be hard, you'd just take a little bit of this off. 00:15:59.28 You can even give a hooked nose shape... 00:16:02.02 probably nobody would want that, but you could do it. 00:16:04.03 And then maybe you take the patients own cells 00:16:06.11 and put that on the scaffold, 00:16:08.16 and so these are just some examples. 00:16:11.22 So, I thought I would go through a few examples 00:16:14.23 just to illustrate some of the challenges 00:16:16.18 and some of what we and others do. 00:16:19.00 So, let's say you want to make a new blood vessel. 00:16:20.28 That's been very challenging; 00:16:22.10 there's not been a way to make small diameter blood vessels. 00:16:25.11 So, one of our students, 00:16:27.02 David Mooney, who is now a professor at Harvard, 00:16:30.03 made these little tubes 00:16:31.28 out of a polymer that are also about 97-98% porous, 00:16:36.14 and then Jinming Gao, another postdoc, 00:16:39.27 he's now a professor at Texas Southwestern, 00:16:42.15 modified polyglycolic acid (PGA) 00:16:45.24 so that you could get a high attachment density 00:16:48.07 of what are called smooth muscle cells, 00:16:51.02 and the person who led this project 00:16:53.17 was Laura Niklason, 00:16:55.10 she was a fellow with us and now is a full professor at Yale, 00:16:58.07 and her idea was, 00:17:00.05 you know, nobody had ever been able to make a blood vessel before 00:17:02.24 and we and others had tried making these to try to grow them, 00:17:06.12 but the way you actually culture something is important. 00:17:09.08 Normally, when people grow cells 00:17:11.08 it's sitting in a petri dish that's stationary, 00:17:13.04 maybe there's a little bit of movement, 00:17:15.05 but what Laura said, you know, 00:17:16.24 that's not what happens in the body. 00:17:18.13 In the body, a blood vessel doesn't just stay there, 00:17:20.11 it's actually hooked up to a pulsatile pump, 00:17:22.13 your heart. 00:17:23.26 So she said, to get this to work, 00:17:25.13 we're gonna need to make a bioreactor 00:17:27.09 that really mimics that, 00:17:28.21 and so would create what we call pulsatile radial stress. 00:17:31.28 So, she did that. 00:17:33.13 She figured out the right medium 00:17:35.05 and had the pulsatile pump, 00:17:36.19 and over a several month period, 00:17:38.11 would pump that media in this pulsatile fashion, 00:17:40.15 165 beats per minute, 00:17:43.08 and try to make blood vessels. 00:17:45.05 And she was able to do that, 00:17:46.26 this was published in Science, 00:17:48.25 and made these tiny little blood vessels, 00:17:51.14 and when she characterized them 00:17:53.24 they were very, very similar 00:17:55.29 to regular blood vessels: 00:17:57.16 50% collagen, 00:17:59.01 their rupture strengths are greater than 2000 mm of mercury, 00:18:02.11 you can suture them in 00:18:04.20 and they're very strong, 00:18:06.09 and they show the same pharmacology 00:18:08.09 as a regular blood vessel. 00:18:12.23 We worked with Bill Abbott to try to put these into pigs, 00:18:15.24 which is considered the best model for blood vessels, 00:18:18.08 and here you see an angiogram 00:18:20.08 where the blood vessels are open, months later. 00:18:24.09 And Laura has actually taken this work a lot farther, 00:18:26.18 she actually started a company on this 00:18:28.27 and actually they're in multiple clinical trials, 00:18:31.05 actually using a variation of this, 00:18:33.16 a decellularized construct, 00:18:36.15 meaning she's taken the cells off 00:18:38.27 after she's made it, 00:18:42.27 and so that's now been used in a number of patients. 00:18:49.04 Now, I want to move on to cartilage as another tissue, 00:18:54.00 and this work was done with Lisa Freed, 00:18:56.06 Gordana Vunjak, 00:18:57.12 Chuck Vicanti, 00:18:58.23 and Jay Vicanti, 00:19:00.10 and here what we did is we took nude mice 00:19:03.19 and basically mimicked what someday might 00:19:06.10 happen in a person. 00:19:09.00 So, what happened here 00:19:11.05 is that you could take the cartilage, 00:19:13.06 and you could take it from an animal and redo it, 00:19:16.10 and if you look at the animal on the right, 00:19:18.07 we've redone his skull. 00:19:21.10 If you go to the next set of animals 00:19:22.27 and you look at the animal on your left, 00:19:25.13 we've redone his cheek. 00:19:27.03 If you open the animal and look at it, 00:19:28.17 it's pure white, glistening cartilage. 00:19:30.20 And actually, biochemically, 00:19:32.01 it looks like cartilage, 00:19:33.17 but it's still not of a good enough mechanical strength 00:19:36.25 that you can help people, 00:19:38.19 at this point at least in our research, 00:19:40.11 that if they had a weight-bearing injury, 00:19:42.09 that you could do anything. 00:19:43.29 So... but it is able to help people 00:19:46.03 with various cosmetic issues, 00:19:47.28 and so we actually had been approached... 00:19:50.04 have worked with the army, 00:19:51.22 the United States Armed Forces 00:19:53.02 Institute for Regenerative Medicine, 00:19:54.25 and they have patients that come back 00:19:57.12 from like Iraq or Afghanistan, 00:19:58.28 say, without certain body parts like an ear. 00:20:01.01 So Linda Griffith, one of our former postdocs, 00:20:03.16 and I mentioned she's now a professor at MIT, 00:20:05.11 actually made a scaffold in the form of the ear. 00:20:08.03 You see that on the top, 00:20:09.16 and on the bottom you see a scanning electron micrograph of it, 00:20:12.08 and you actually see the cells 00:20:13.25 and the matrix growing, 00:20:15.14 and over time you'll see more cells and matrix growing, 00:20:18.01 and the fibers that you see, they'll disappear, 00:20:20.25 and you'll actually get an ear. 00:20:22.08 And in fact, this has not been put on patients, 00:20:26.01 but it has been put on animals and it's been shown to work. 00:20:29.09 And in fact, Jay, my colleague, 00:20:31.20 has even put some of these systems on human beings, 00:20:37.10 in what are called physician-sponsored INDs. 00:20:40.14 Here's a 12-year old boy at the time, 00:20:42.19 and if you look at him he's got no chest covering his heart, 00:20:46.03 but he, like other 12-year olds, 00:20:47.17 likes to play baseball. 00:20:49.10 But you can imagine, if he ever got hit in the chest with a baseball, 00:20:51.08 he could die. 00:20:53.07 So actually, Jay operated on him, 00:20:54.26 we made a scaffold for him, 00:20:56.12 and Jay created a whole new chest for him 00:20:58.02 and he's doing fine. 00:21:00.07 Also, we licensed the technology 00:21:02.19 that we developed to different companies, 00:21:06.04 and some of them have now made artificial skin 00:21:08.08 for burn victims, 00:21:09.22 and let me just show you that. 00:21:11.17 Here, for example, is a 2-year old boy. 00:21:14.04 He's very badly burned, 00:21:18.05 and you can create a product which has now been done, 00:21:20.26 and it's actually approved by the FDA 00:21:23.16 and been used in many patients, 00:21:25.18 but the idea is that you have a polymer scaffold, 00:21:28.15 you can put on neonatal skin fibroblasts, 00:21:32.17 and you can actually cryopreserve these, 00:21:34.22 but then you come back and you put it in the child at the time of injury, 00:21:38.25 like this. 00:21:40.29 We'll come back three weeks later 00:21:43.02 and he looks better, 00:21:45.03 and six months later he's pretty much healed. 00:21:47.05 So, these have been approved now by the FDA 00:21:49.27 for patients who have been burned 00:21:51.18 and patients who have diabetic skin ulcers. 00:21:55.01 And, the final example I wanted to give you, 00:21:57.07 which is very early, 00:21:59.08 but could you someday even help people 00:22:01.12 who have paralysis - spinal cord repair? 00:22:03.22 And this project was led... 00:22:05.23 it was started in our lab by a woman named Erin Lavik, 00:22:08.13 who's now a professor at Case Western Reserve, 00:22:11.05 and this was done in collaboration with Ted Teng, 00:22:13.14 who's a neurosurgeon, 00:22:15.06 and Evan Snyder, who's a neuronal stem cell expert at the Burnham, 00:22:18.21 and basically the idea was, 00:22:21.12 could we make a scaffold that would mimic the grey and white matter 00:22:24.13 of the spinal cord? 00:22:25.28 And have an outer part that would be 00:22:28.20 sort of microfabricated or nanofabricated in a certain way 00:22:31.28 to provide axonal guidance, 00:22:33.26 and an inner part where we could create pores 00:22:36.25 where we could put neuronal stem cells 00:22:38.27 that we got from Evan. 00:22:41.01 And, just to show some pictures, 00:22:43.25 on the top-left hand panel 00:22:45.17 you see the scaffold, macroscopically. 00:22:47.26 Next to that, 00:22:49.09 you see a scanning electron micrograph 00:22:50.29 that shows you the pores, 00:22:52.24 and you see another vision of that right next it. 00:22:55.23 Below it, 00:22:58.05 you see a scanning electron micrograph 00:22:59.26 of the outer part that Erin created, 00:23:02.01 and notice the nanopatterning 00:23:04.02 to aid in the axonal guidance. 00:23:05.28 And finally, this, on your... 00:23:09.15 here, is the experiment. 00:23:12.09 Basically, you take the spinal cord, 00:23:15.00 you remove a portion of it, 00:23:16.29 and then you do one of four things in our studies. 00:23:19.23 We basically did nothing, that's a sham operation, 00:23:23.00 or you put cells in, that's the second set of controls, 00:23:26.17 the scaffold by itself, that's third, 00:23:28.24 and the scaffold/cell combination, 00:23:31.08 which would be the experiment. 00:23:33.05 And these animals, Erin and Ted followed them 00:23:35.05 for over 400 days, 00:23:37.24 and really looked at behavioral studies 00:23:40.03 and track tracing and other things. 00:23:42.25 So, let me just show some of the results. 00:23:45.29 So first, 00:23:47.21 I'll just show a typical control animal, 00:23:50.09 and notice that he's not able to move his... 00:23:54.26 support his weight very well on the backside, 00:23:57.15 and as you'll see, 00:24:00.05 the paws are splayed are in a rather awkward fashion. 00:24:02.22 So he'd get what's called a BBB score 00:24:05.00 of about 5 out of a possible 20. 00:24:07.00 This is done 100 days 00:24:09.03 after the start of the experiment, 00:24:11.04 and we'll just look at this for a little while longer. 00:24:16.12 Now, if we go to a typical treated animal, 00:24:20.01 the mean of the treated group... 00:24:22.01 this is not a cure by any means, 00:24:23.27 but he is able to bear his own weight, 00:24:27.01 and notice how the paws 00:24:29.06 are splayed in a much more normal way. 00:24:32.08 You'll see this more clearly in a second, 00:24:35.24 and he gets a BBB score of about 14 out of 20. 00:24:38.25 Like I said, it's not a cure, but it's an improvement. 00:24:41.01 There are the paws. 00:24:44.03 And so, we basically did 52 animals, 00:24:46.15 13 in each group, 00:24:48.18 and got, you know, 00:24:51.19 good data with both the cell/polymer scaffold 00:24:53.26 and the scaffold actually by itself. 00:24:56.24 Then, this went to monkeys, 00:24:58.19 African green monkeys, 00:25:00.10 and this was done by Eric Woodard 00:25:01.28 and John Slotkin 00:25:03.11 and InVivo Therapeutics, 00:25:05.01 and here's the monkeys. 00:25:06.25 They're put on a treadmill test 00:25:08.22 and what happens is, 00:25:11.12 in the controls they're not able to move the one leg 00:25:14.02 that's been injured, 00:25:15.28 but when you give the scaffold or scaffold/cells 00:25:19.05 they do much better. 00:25:21.05 It's again not a cure, 00:25:22.17 but it's a significant improvement, 00:25:25.09 and what's happened now is, based on this, 00:25:27.21 the FDA has actually given the go-ahead 00:25:29.19 for the start of human clinical trials 00:25:31.21 at a number of hospitals around the United States, 00:25:34.04 so we'll learn more about what happens in humans, 00:25:38.27 I believe, in the next year. 00:25:40.28 So, in summary, 00:25:43.14 what I've tried to go over in this lecture 00:25:45.25 is how one can create new materials 00:25:48.22 to solve different medical problems, 00:25:51.07 and how one can create materials 00:25:53.17 and combine them with cells 00:25:55.13 to someday make new tissues and organs. 00:25:57.20 All this work in all these slides 00:25:59.25 really was made possible 00:26:01.26 by the terrific funding agencies 00:26:04.00 that have been very kind to us, 00:26:05.29 like the National Institutes of Health 00:26:07.16 and National Science Foundation, 00:26:09.04 the Gates Foundation, 00:26:10.19 and other foundations, 00:26:12.10 different companies, 00:26:13.27 and most of all, really, 00:26:15.19 it's been the terrific work 00:26:17.24 of really a wonderful group of student and postdocs 00:26:20.26 at MIT and Children's Hospital over the years 00:26:22.16 that have made this possible. 00:26:24.14 Thank you very much for having me.