Session 8: Controlled Drug Release Technology

00:00:07.14 So, my name is Bob Langer.
00:00:09.07 I'm a professor at MIT,
00:00:10.27 and I'm going to be discussing,
00:00:13.03 in this first lecture,
00:00:14.19 to give you an overview
00:00:16.10 of this area of controlled drug delivery technology,
00:00:20.18 and in the second lecture...
00:00:23.05 I've listed the lectures here...
00:00:25.01 I'll be talking about
00:00:27.00 some of our own work
00:00:29.27 that lead to some of these drug delivery systems
00:00:32.07 and also some future work
00:00:34.15 in nanotechnology and other areas
00:00:36.09 that I think will be exciting for the future of drug delivery.
00:00:38.23 And, in the third and final lecture,
00:00:40.08 I'll be talking about biomaterials and biotechnology
00:00:43.13 and I'll give an example, in particular,
00:00:46.06 of how one can create new materials,
00:00:48.02 and I also will discuss
00:00:49.29 how one can combine materials with cells,
00:00:52.07 which helped to lay the foundation
00:00:53.28 of tissue engineering.
00:00:56.03 So, I'll start out by just going over,
00:00:59.06 as is mentioned here,
00:01:01.04 this whole field of controlled release technology,
00:01:03.05 and it's a field that actually
00:01:05.02 now affects hundreds of millions of patients
00:01:08.09 around the world
00:01:10.01 and yet it's still a very new field.
00:01:11.22 Maybe the easiest way to start
00:01:13.12 is to just go over how people generally take drugs.
00:01:15.26 Generally, you take a pill
00:01:18.05 or you might take an injection,
00:01:21.05 but whenever you take any of these drugs
00:01:24.17 what happens is, as we can see in the slide...
00:01:28.14 there are these blue lines
00:01:30.14 which give you a desired range...
00:01:32.17 if you're above that range the drug could be toxic,
00:01:34.28 if you're below it's not effective.
00:01:37.13 One example I sometimes just use is a sleeping pill.
00:01:39.29 If somebody took too much
00:01:43.00 they would die - that's obviously toxic.
00:01:44.26 And, if you took too little then it doesn't work,
00:01:46.28 you don't fall asleep.
00:01:49.05 So, for any drug,
00:01:51.05 you have this desired range,
00:01:53.06 and what happens in a lot of cases
00:01:55.21 is you get this what I'll call peak-and-valley delivery
00:01:58.24 which you see here,
00:02:00.14 meaning that when you first take the drug
00:02:02.10 it starts out at a very low level,
00:02:04.04 then it keeps going up,
00:02:06.05 and then it goes down.
00:02:07.26 And so, you would have to take it again,
00:02:10.13 and there are really two or three problems with this.
00:02:12.13 One is the problem that I just mentioned,
00:02:14.08 that you could get these toxic effects
00:02:15.29 or it may not work.
00:02:17.28 The second effect, the big effect
00:02:20.00 is that people have what are called very poor compliance.
00:02:23.13 People usually don't do what they're supposed to do
00:02:25.23 and they often don't take the drugs
00:02:28.09 when they're supposed to,
00:02:30.07 and that has led to hospitalizations
00:02:32.07 and all kinds of other kinds of problems.
00:02:34.20 So, what somebody would like to do is,
00:02:37.28 when you look at those lines,
00:02:40.00 is to have a pill or an injection or whatever
00:02:43.29 that starts out low but then goes into the desired range.
00:02:47.19 In a way, people have tried to do this for over 100 years.
00:02:52.18 The earliest examples of these
00:02:54.28 are what we called sustained release.
00:02:57.08 Sustained release systems,
00:02:58.23 and people have heard about these probably,
00:03:00.14 are things like tiny time pills
00:03:02.04 and things like that,
00:03:04.00 so rather than what you might have seen in the last slide,
00:03:06.11 where you took, say, a pill maybe every four hours,
00:03:08.25 sustained release probably it lasts for twelve hours,
00:03:11.26 and it kind of blunts those peaks.
00:03:13.25 But, what happens is that you still...
00:03:18.20 you still have to keep taking them,
00:03:21.05 and also you really are not in the desired range.
00:03:24.28 I mean, you're in the desired range
00:03:26.16 maybe longer, but not long enough.
00:03:29.02 So, the way these have been achieve,
00:03:32.00 these sustained release systems,
00:03:34.01 involves different types of chemistry and chemical engineering,
00:03:37.20 like you can have what's called a complex.
00:03:39.23 For example,
00:03:41.20 you want to slow the release down,
00:03:43.13 and the way you might slow the release down
00:03:45.22 is by adding a salt or even complexing it
00:03:48.09 to what's called an ion-exchange resin.
00:03:50.20 Another way of slowing it down
00:03:52.26 is to put what are called slowly dissolving coatings around it.
00:03:55.21 For example, there's something called an enteric coating,
00:03:57.22 and if you have a pill with an enteric coating,
00:04:01.16 the stomach, which often has a lot of acid,
00:04:04.15 will not dissolve that coating,
00:04:07.04 so you won't get release until later...
00:04:10.15 wait until you go past the stomach
00:04:12.21 and the acidity is neutralized.
00:04:16.16 You can also do things like suspensions or emulsions,
00:04:19.25 that decreases the availability of the drug
00:04:22.22 to the body,
00:04:24.22 and even something as simple as a compressed tablet
00:04:26.23 slows release down because the drug
00:04:28.29 won't dissolve as fast.
00:04:30.24 Still, as we look at the bottom part of this slide,
00:04:34.01 what sustained release systems...
00:04:36.07 release drugs generally for short periods of time, like hours,
00:04:39.19 and they require repeated administration.
00:04:41.24 Also, the release rates are very strongly influenced
00:04:44.02 by your environmental conditions.
00:04:46.15 For example, I mentioned,
00:04:48.09 you know, release in the stomach.
00:04:50.05 Well, your stomach pH
00:04:52.03 is very dependent on when you ate your last meal,
00:04:53.25 so there's a lot of variability
00:04:55.23 when you take these kinds of systems.
00:04:57.17 And, with that in mind,
00:04:59.05 what's happened over the last 40 years
00:05:01.04 is the advent of what we now call
00:05:03.02 controlled release formulations.
00:05:04.22 These are often polymers or pumps.
00:05:08.08 They can release the drug
00:05:09.27 for really long periods of times,
00:05:11.23 like not only days but in some cases, as I 'll go over,
00:05:14.19 up to 5 years from a single tiny system.
00:05:17.16 Also, the release rates are only weakly
00:05:19.28 or not at all influenced by the environmental conditions,
00:05:23.01 so you get a fixed predetermined release pattern
00:05:28.05 for a definite period of time.
00:05:30.23 This is just a graph
00:05:32.23 that shows you an idealized case of that.
00:05:35.03 So, rather than getting this kind of peak-and-valley delivery
00:05:38.10 that I mentioned before,
00:05:40.07 what you can get is the drug starts out
00:05:42.15 in a low range, then it goes to the desired range,
00:05:45.09 and it stays there for as long as you want.
00:05:47.24 This is kind of the ideal case.
00:05:50.02 One other thing that I wanted to mention,
00:05:53.08 that's very exciting in this area of drug delivery,
00:05:56.08 is not only the idea of controlling the duration
00:05:59.00 of the drug and controlling its level,
00:06:02.10 but actually in some cases
00:06:04.09 targeting it right to where you want it to go,
00:06:06.17 and there's a lot of research going on in that area.
00:06:10.05 It's still very early,
00:06:11.24 but I'll mention some of this in my second talk,
00:06:15.06 but what people are doing
00:06:17.29 is they're looking at the little fatty particles called liposomes
00:06:21.09 that you can direct to certain cell types.
00:06:24.12 They're also looking at microspheres and microcarriers
00:06:28.00 that you can decorate in certain ways
00:06:30.12 to target them to specific places in the body.
00:06:33.04 And finally,
00:06:35.03 you can attach a drug to a carrier,
00:06:36.28 which might be an antibody or a polymer,
00:06:38.18 to hopefully, again,
00:06:40.12 target it to where you want to go.
00:06:42.12 So, all these are very exciting areas of
00:06:45.04 how you can take drugs
00:06:47.12 and make them do things they could never do before.
00:06:50.13 I thought in this lecture
00:06:52.13 what I want to do is go over
00:06:56.01 the general mechanisms by which this takes place,
00:06:58.13 and generally there's three mechanisms.
00:07:00.26 Diffusion is the first one,
00:07:02.13 and there are two geometries that people often use.
00:07:05.02 What's called a reservoir,
00:07:06.22 and I'll show you a picture of that in a minute,
00:07:08.18 and what's called matrix.
00:07:10.05 The second mechanism involves a chemical reaction,
00:07:14.00 and in the case of the chemical reaction
00:07:15.25 it might cause the polymer to erode, bioerode,
00:07:18.22 which will enable the drug to come out,
00:07:20.20 or you might have what we call a pendant chain system,
00:07:23.22 where the drug is attached to a polymer,
00:07:26.05 let's say,
00:07:28.08 and something comes along and cleaves it off.
00:07:30.14 The third mechanism is the solvent does something.
00:07:33.04 The solvent might cause the polymer to swell,
00:07:36.04 so the drug might be locked into place,
00:07:37.29 but when it swells,
00:07:39.19 now the drug comes out.
00:07:41.06 Or, as I'll show you,
00:07:42.14 there's some very clever ways using what's called osmosis
00:07:44.19 to actually deliver drugs.
00:07:47.04 Finally, and on top of all that,
00:07:49.23 you can actually in some cases
00:07:51.12 make even a smart delivery system,
00:07:53.07 where you can activate it externally
00:07:55.05 and make more drug come out at certain periods of time,
00:07:57.27 and I'll go over that...
00:08:02.08 a little bit of an example of that in my second lecture.
00:08:04.11 So, I'll just go over each of these three fundamental mechanisms.
00:08:08.19 First, diffusion,
00:08:11.11 and the most common way that people set up drug delivery
00:08:14.19 by diffusion is what's shown here,
00:08:16.16 a reservoir.
00:08:18.03 A reservoir,
00:08:19.18 and people have probably seen these,
00:08:21.06 could be a capsule, could be a microcapsule,
00:08:23.23 could be hollow fibers,
00:08:25.13 or the drug could be placed in between two membranes,
00:08:27.29 but basically what we see,
00:08:29.16 and the little dots in this slide
00:08:31.17 illustrate the drug,
00:08:33.03 the blue illustrates the membrane, let's say,
00:08:35.26 or the capsule,
00:08:37.15 and this is just a cross-section.
00:08:39.05 So, what you see is if you go
00:08:47.00 from the left-hand one to the right-hand one
00:08:49.14 is that the little dots...
00:08:52.13 the left-hand one is the system at time 0,
00:08:57.04 but what happens is over time,
00:08:59.07 the dots keep coming out by diffusion.
00:09:01.01 They diffuse through the polymer,
00:09:02.26 and that will keep coming out over really long periods of time.
00:09:06.27 There are a number of polymers that are very commonly
00:09:09.17 used to make these systems,
00:09:11.07 like silicone rubber, EVA,
00:09:12.20 which is ethylene-vinyl acetate copolymer,
00:09:15.09 or different hydrogels.
00:09:17.19 For polymer chemists,
00:09:19.08 one good example would be
00:09:21.12 poly(2-hydroxyethyl methacrylate),
00:09:23.10 but just in general, hydrogels are materials
00:09:25.15 that are used in soft contact lenses
00:09:27.15 and they're very biocompatible.
00:09:29.21 These systems have a number of advantages,
00:09:32.08 you can make them release at relatively constant rates,
00:09:35.24 but one possible disadvantage
00:09:38.02 is if you had a leak,
00:09:39.23 let's say there was a tear in the blue,
00:09:41.23 the drug could dump out.
00:09:43.24 So, what that might mean is if you had a potentially toxic drug
00:09:46.13 like a cancer drug or insulin,
00:09:48.28 you wouldn't probably use a reservoir system,
00:09:51.16 but if you were delivering...
00:09:53.14 let's say you were delivering human growth hormone,
00:09:55.14 or things like that,
00:09:57.13 this would probably be fine.
00:09:59.12 The second system
00:10:01.11 that's also diffusion-based
00:10:03.25 is what we call a matrix system,
00:10:05.20 and again the blue dots represent the drug,
00:10:09.14 and the yellow that you see there,
00:10:12.08 the yellow-green,
00:10:14.22 that's the outside of the polymer matrix.
00:10:17.14 So, in the case of a non-erodible matrix,
00:10:20.08 the drug is uniformly distributed through that matrix,
00:10:23.09 and we see that on the top,
00:10:25.01 but then when we go to the bottom
00:10:27.01 we see the drug diffusing out.
00:10:29.11 And again,
00:10:31.15 it diffuses out through the polymer,
00:10:33.10 but now, because this geometry is different,
00:10:35.11 other things happen.
00:10:37.04 For example, this is not as easy to get steady release,
00:10:39.24 but on the positive side,
00:10:41.24 let's say there was a tear in this matrix...
00:10:44.26 not much more drug would come out
00:10:46.27 because it's embedded throughout this entire matrix.
00:10:49.27 So, this is the first mechanism, is diffusion.
00:10:52.04 The second mechanism, as I mentioned,
00:10:53.25 is a chemical reaction,
00:10:56.06 and one of the very common ways of doing this
00:10:58.20 is a bioerodible system.
00:11:01.15 So, in the case of a bioerodible system,
00:11:04.15 it basically would look, in the beginning,
00:11:06.25 essentially identical to what I showed you on the matrix,
00:11:10.25 but now the yellow, rather than staying the same,
00:11:16.14 in other words, rather than the matrix staying the same size,
00:11:19.26 it actually shrinks and ultimately completely dissolves,
00:11:23.01 and as it dissolves
00:11:25.00 what we see is all those blue dots come out and are released.
00:11:27.22 So, bioerosion
00:11:30.01 provides a whole second mechanism of being released,
00:11:32.13 and the big advantage of bioerosion,
00:11:34.13 thinking about it from the patient's standpoint,
00:11:36.15 if you had an implant and it didn't dissolve,
00:11:40.04 you have to go in and take it out.
00:11:42.24 That's gonna be done in some cases,
00:11:44.05 as I'll mention later,
00:11:46.19 but that's still a disadvantage.
00:11:48.18 It certainly would be preferable for the patient
00:11:50.11 to just have one injection or one implant
00:11:52.10 and never have to worry about it again.
00:11:54.26 So, one mechanism for chemical reaction is erosion.
00:12:00.20 The second mechanism is the idea of the polymer
00:12:03.14 containing a pendant chain,
00:12:05.23 and now what happens is the drug is attached
00:12:08.03 to the polymer backbone,
00:12:10.03 but water or enzyme, as we see in the bottom,
00:12:12.28 comes along and basically breaks the bond
00:12:15.26 and then the drug is released.
00:12:18.06 One of the advantages of this
00:12:19.26 is that you can add a lot of drug to these,
00:12:22.29 but a possible disadvantage
00:12:25.17 is that these are what are called new chemical entities.
00:12:28.13 We've chemically modified the drug by attaching it,
00:12:30.29 so it's a new chemical entity,
00:12:32.14 so you'd have to do a lot more toxicology
00:12:34.13 to eventually get approval,
00:12:36.06 whereas the earlier systems that I talked about,
00:12:38.10 there is no change in the drug,
00:12:39.27 it's just physically embedded.
00:12:42.15 The third mechanism
00:12:44.26 is the solvent does something,
00:12:47.14 and so here we're looking at swelling having an effect,
00:12:50.08 and the idea of swelling is you,
00:12:53.20 again, if we look at the left-hand panel,
00:12:56.18 the drug is dissolved in the polymer
00:12:58.23 and we see it just looking blue,
00:13:00.27 but now, as we go the right-hand panel,
00:13:04.28 what happens is the water goes in
00:13:08.15 and the outer part of the matrix actually swells.
00:13:11.27 So, the drug was locked into place,
00:13:14.02 but now since it's swelling, it can come out,
00:13:18.02 and that takes place over time
00:13:20.15 and that gives you the opportunity
00:13:25.06 to deliver the drug simply based on water.
00:13:27.13 Also, one of the other things
00:13:29.07 that people have sometimes done in the case of swelling systems
00:13:31.17 is make them swell so much
00:13:33.21 that they might stay in the stomach a little longer,
00:13:35.21 and that might also give you a way, if you took an oral system,
00:13:38.25 of maybe making it act longer as well.
00:13:42.07 And, the final mechanism for solvents,
00:13:45.07 and of the one's I'm gonna talk about,
00:13:48.08 is osmotic pressure.
00:13:50.09 And, the idea of osmosis is that what happens is,
00:13:53.04 if you have... let's just say I had two sites,
00:13:58.22 I have site 1 where I have water and a lot of salt in it,
00:14:02.08 like table salt,
00:14:04.16 and I have site 2 that just has water in it,
00:14:07.26 and then they're connected by a membrane.
00:14:10.04 There's a whole field called thermodynamics
00:14:12.20 where what happens is,
00:14:14.16 if you have these two sites
00:14:16.10 and they're separated by the membrane
00:14:18.11 and water can permeate,
00:14:20.03 what they wanna do is have what's called
00:14:22.03 the same thermodynamic activity,
00:14:23.14 so what happens is water will actually
00:14:26.24 rush in from one to the other to actually dilute it,
00:14:29.04 so you'll actually hopefully someday
00:14:31.06 have the same salt concentration on both sides.
00:14:34.12 But, when that happens,
00:14:35.29 that is what leads to osmotic pressure,
00:14:39.21 because water is actually rushing in
00:14:41.18 and there's a certain amount of pressure
00:14:43.23 that is caused by that.
00:14:45.21 That same thing is manifested here in this final mechanism
00:14:48.12 of osmosis,
00:14:50.23 where the drug is dissolved in the polymer,
00:14:53.07 but now water rushes in
00:14:55.08 because the drugs not on the outside and water wants to...
00:14:58.24 the water wants to come in to dilute that drug,
00:15:01.04 and you see these cracks form, these porous openings,
00:15:04.00 and those permit release.
00:15:05.26 Now, one of the issues with this particular system
00:15:08.27 is it's not so reproducible.
00:15:12.07 It's getting cracks...
00:15:13.24 it's not easy to make reproducible cracks,
00:15:15.28 but I want to show you what I think is a very clever approach
00:15:19.06 that has been done
00:15:21.18 where you can actually make an osmotic pump,
00:15:23.26 and what's interesting about this pump...
00:15:25.21 I think when people generally think about pumps
00:15:27.28 you think about pumps that involve mechanical parts
00:15:31.28 and electricity and things like that.
00:15:34.03 The pump I'm gonna show you here
00:15:35.25 has none of that.
00:15:37.15 It's a totally-driven pump,
00:15:39.24 and it can actually give you very, very precise release rates.
00:15:42.12 So, when we look at this slide,
00:15:45.06 let's take a look first at the top left,
00:15:47.23 that's a front cross-section,
00:15:50.03 and the way this has been designed
00:15:52.19 is you've got an outer membrane
00:15:55.02 that's rigid but it's water permeable,
00:15:57.13 so water can go through it
00:15:59.08 and yet the system won't expand.
00:16:01.20 Immediately below that
00:16:04.12 there's another chamber where you see the salt.
00:16:06.17 That salt could be like sodium chloride or potassium chloride.
00:16:10.08 That salt is, again,
00:16:12.11 what's going to cause the osmotic pressure,
00:16:14.10 because there's not much salt on the outside,
00:16:16.03 so water is going to want to rush in to that salt.
00:16:19.17 And, actually you load the salt
00:16:21.18 at a pretty high level
00:16:23.18 so that it's always going to be above it's solubility level,
00:16:26.17 so water will actually rush in at a constant rate.
00:16:29.22 Now, the next chamber,
00:16:31.24 as we keep going to the inside,
00:16:33.29 is a compressible membrane,
00:16:35.24 but that compressible membrane is exactly the opposite
00:16:38.06 of the rigid membrane on the outside.
00:16:40.18 That compressible membrane is water impermeable,
00:16:42.23 in other words water can't get through it,
00:16:44.27 and yet it's compressible, it's not rigid.
00:16:47.17 You might of it like a balloon.
00:16:49.27 And, inside that chamber,
00:16:53.15 you have the dissolved drug.
00:16:55.23 So, the only other thing
00:16:57.23 that I wanted to point out as we look at this top section
00:17:01.20 is now if we looked at a side view,
00:17:03.20 there's actually a laser-drilled hole
00:17:05.13 in the very front of this system,
00:17:07.11 and that is how the drug's gonna come out.
00:17:09.19 But, let me just now go over how it works,
00:17:11.14 and it's really going to be looking at the bottom part
00:17:14.18 of this slide that shows you how that happens.
00:17:18.03 So, what happens is,
00:17:20.12 as I mentioned before, water is going to want to rush in
00:17:23.06 at a constant rate through that rigid membrane
00:17:25.27 and what happens is,
00:17:27.19 as water rushes in at a constant rate,
00:17:30.25 the outer membrane doesn't expand,
00:17:32.14 the whole system doesn't expand, but...
00:17:35.29 so the only thing that can happen
00:17:38.08 is the chamber where we have the salt,
00:17:40.07 that does expand inward
00:17:42.25 because that's the only place the water can go.
00:17:45.16 So, water rushes in at a constant rate,
00:17:48.11 diluting the salt,
00:17:50.13 and it compresses that compressible membrane.
00:17:52.17 It can't get inside that membrane, but it can compress it,
00:17:55.07 and it gets smaller and smaller,
00:17:57.15 and it's kind of almost like squishing a tube of toothpaste,
00:18:00.06 and as you squish it
00:18:02.07 the only thing that can happen
00:18:04.08 is the contents in the center, the solution,
00:18:06.08 go out that laser-drilled hole
00:18:08.16 where you see the drug coming out at the bottom.
00:18:11.02 So, you squish this by osmotic pressure
00:18:13.03 at an exactly constant rate,
00:18:14.21 the drug comes out at an exactly constant rate,
00:18:17.25 and the patient gets steady delivery.
00:18:22.19 So, what's novel about this is
00:18:24.25 this is I think a very interesting example of
00:18:27.13 where different chemical and physical principles
00:18:29.24 are used to design a steady delivery system,
00:18:34.04 and it's actually been widely used.
00:18:36.06 These kinds of systems are used for delivery systems
00:18:38.25 and studying different biological things in animals,
00:18:41.26 and actually variations of it
00:18:43.28 are pills that most people probably take.
00:18:46.09 They may not realize it,
00:18:47.29 but sometimes if you look down
00:18:50.06 very carefully at the pill, you can see a little laser-drilled hole right
00:18:52.26 where they have the label.
00:18:55.01 So, what I've gone over so far
00:18:57.01 are some of the different mechanisms by which these work.
00:19:00.08 Now, I thought I'd turn and show you how they're actually used
00:19:02.08 in different applications.
00:19:04.20 Well, the eye was actually one of the earliest places
00:19:07.21 where people used controlled release.
00:19:10.02 They used it in glaucoma,
00:19:12.19 which is a leading cause of blindness,
00:19:14.11 and in artificial tears, which is very uncomfortable.
00:19:17.06 I’ll go over each of these.
00:19:18.25 This was one of the earliest systems
00:19:20.25 developed in controlled release.
00:19:22.12 This was in the 70s, and it was called the Ocusert,
00:19:26.04 and it's a little device that you just put into your eye,
00:19:29.24 which you see here,
00:19:31.22 it's actually a reservoir system that lasts for one week.
00:19:38.04 Normally, somebody, it they had this disease,
00:19:40.10 would have had to take 28 eye drops.
00:19:44.21 The way it's designed is shown here.
00:19:47.01 It's a reservoir system,
00:19:48.27 just like the very first thing that I went over
00:19:50.28 on those three different types,
00:19:52.22 so you have pilocarpine, that's the drug.
00:19:55.01 It's surrounded by two membranes
00:19:57.00 that really control the rate of diffusion,
00:19:59.21 and what they've done,
00:20:01.09 just so people can visualize it better,
00:20:03.10 is they've put an annular ring right here
00:20:06.17 that's got titanium dioxide in it,
00:20:08.20 and that makes it easy for the patient to see.
00:20:11.03 That's why when you looked at it on the last slide
00:20:13.07 it had this little ring around it on the bottom.
00:20:16.18 So, depending on the thickness of those two membranes
00:20:20.25 that actually controls the rate of release,
00:20:22.22 so what's been done
00:20:24.24 is to make one that releases at 40 µg/hour
00:20:27.09 after an initial burst,
00:20:29.07 and another that releases at 20 µg/hour
00:20:31.17 after an initial burst.
00:20:33.06 But really, again, by using engineering
00:20:35.03 you can make them release at any rate you want,
00:20:37.00 just by controlling the thickness of those membranes,
00:20:39.18 so these are just two common ones that have been used.
00:20:43.17 The next system I wanted to mention was artificial tears.
00:20:46.09 If somebody had dry eye
00:20:48.07 that can be very painful,
00:20:50.12 and the goal is to put something in the eye
00:20:53.16 that might last for a long time,
00:20:55.12 rather than have somebody take eye drops, you know,
00:20:57.15 really every 20 minutes sometimes.
00:20:59.08 So, what's been done is to create an applicator,
00:21:01.24 shown here,
00:21:03.25 which you can use to pick up a little polymer
00:21:07.15 and then drop it in the eye
00:21:10.11 and basically, when you do,
00:21:13.18 it might last for up to 18 hours
00:21:15.23 and hold on to corneal moisture.
00:21:17.29 It's not a perfect system by any means,
00:21:19.28 because one of the things that happens sometimes
00:21:22.02 for some patients is they get blurred vision,
00:21:24.10 but it's an illustration of what you can do,
00:21:26.02 and actually I think it's a challenge for the future
00:21:28.21 to be able to do systems like this
00:21:32.01 that will not have any change in visual acuity.
00:21:36.19 Probably one of the biggest areas
00:21:38.11 where this whole field of controlled release
00:21:40.10 has been used worldwide
00:21:42.12 is in contraceptive systems.
00:21:44.06 There are a number of ways
00:21:46.01 that people have done this:
00:21:47.23 non-erodible subdermal implants, erodible ones,
00:21:52.01 steroid releasing intra-uterine devices,
00:21:53.22 and vaginal rings.
00:21:55.28 I'll go over them briefly.
00:21:57.27 Probably the most widely-known system
00:22:00.18 for contraception using controlled release
00:22:03.02 is a system called the Norplant.
00:22:05.12 It's actually shown here.
00:22:07.22 This is a woman's finger
00:22:09.20 and she has these six sticks,
00:22:11.17 now actually they've designed them so you can just have two of them,
00:22:14.28 but they're very small, they're like matchstick-size.
00:22:17.28 They can be placed underneath the skin
00:22:20.24 and they'll deliver the drug for 5 years.
00:22:22.24 It's just slow diffusion through the polymer,
00:22:25.08 through the reservoir system like I mentioned,
00:22:27.15 and it'll last for 5 years.
00:22:29.05 Here is an example of that,
00:22:31.00 where we're looking at release curves for different patients,
00:22:33.19 and it goes for 2000 days
00:22:35.26 even though it's as small as what I showed you.
00:22:38.16 Another system, also a reservoir system,
00:22:41.27 is what's called the Progestasert,
00:22:45.21 and this system...
00:22:47.22 again, very small, it's an intra-uterine device.
00:22:50.10 These again are a woman's fingers
00:22:52.16 and, again, you put the drug
00:22:55.22 in the center of the system,
00:22:57.29 just like I showed earlier
00:23:00.01 with the picture where the drug was the dots
00:23:03.10 and then it will diffuse out,
00:23:05.15 and here's an example of that,
00:23:07.19 where look at the core matrix.
00:23:09.17 The dots here, again, represent the drug,
00:23:11.19 and the drug will diffuse out
00:23:14.03 over a 365 day period.
00:23:17.01 This is just a curve, it's not exactly constant,
00:23:20.00 but it basically will vary from,
00:23:23.05 over a 400 day period,
00:23:26.05 it's pretty close to 50 µg/day over that period.
00:23:30.21 So, this is a second way that people do it,
00:23:33.14 and there are other controlled release systems as well
00:23:36.12 that have been worked on for contraception.
00:23:40.25 A third area that's been very important
00:23:43.14 is dentistry, actually,
00:23:45.18 that people use controlled release for.
00:23:47.22 If one looks at the percentage of patients
00:23:50.02 who have periodontal disease,
00:23:52.00 it's maybe 25% of the population.
00:23:55.13 To tell if you have periodontal disease,
00:23:57.07 the way I always know is if I go to the dentist
00:23:59.21 and, you know, they brush your teeth a lot harder
00:24:01.24 than we do, or I do at least,
00:24:03.20 and if they start bleeding
00:24:05.24 then you probably have some periodontal disease.
00:24:07.20 It's not pleasant, 2-3% of the people
00:24:10.02 who have periodontal disease require surgery.
00:24:12.19 If you have no treatment
00:24:14.25 the result is no teeth.
00:24:16.11 That's not a very good outcome.
00:24:18.03 If you do surgery, that's painful, it's expensive.
00:24:21.04 There are drugs that people use,
00:24:22.26 like tetracycline, but they make you incredibly sick
00:24:24.21 to your stomach.
00:24:26.20 So, what's been done
00:24:28.26 is to actually make fibers
00:24:32.04 with tetracycline or other drugs,
00:24:34.05 and here you're delivering the drug locally.
00:24:36.27 So, because you're delivering the drug locally,
00:24:38.24 rather than throughout the whole body,
00:24:40.16 the body doesn't get as much
00:24:42.24 and so it's effective,
00:24:45.03 but with much lower dosage,
00:24:46.24 like in this case it's effective with less than 1/1000-th the dose,
00:24:49.23 and the dentist can apply them very quickly,
00:24:51.22 like 3 minutes per tooth.
00:24:53.28 You can barely see them, I'll show you a picture.
00:24:55.26 They get rid of the problem, the spirochetes,
00:24:58.05 and they don't cause irritation.
00:24:59.24 I'll just show you a couple pictures.
00:25:01.26 Here is a picture of the general idea
00:25:05.15 of the hollow fiber in the bottom,
00:25:08.08 just covering the tooth,
00:25:10.12 and it will deliver the drug over time.
00:25:13.01 And, let me just even go further
00:25:15.01 and show you what was done.
00:25:17.06 Originally, they used a reservoir system,
00:25:19.15 this is a hollow fiber,
00:25:21.01 where the drug was placed in the center,
00:25:22.20 but they got some leaks.
00:25:24.13 So, then they went to the matrix system
00:25:26.02 where they uniformly distribute it,
00:25:27.29 and tetracycline is kind of a yellowish drug,
00:25:30.07 so now it's in these fibers
00:25:33.02 but they're uniformly distributed,
00:25:34.27 and what the dentist did,
00:25:37.00 and I'll just show you some pictures...
00:25:39.28 here's a patient with periodontal disease,
00:25:42.01 notice the red gums.
00:25:44.15 Then, what the dentist does
00:25:47.17 is he puts... she puts
00:25:50.13 the matrix systems that are on the teeth
00:25:54.00 like you see them here,
00:25:56.21 and so they are actually on several of the teeth,
00:25:59.12 and that will release the drug,
00:26:01.23 say, over a 10 day period,
00:26:03.12 and when you're done with that,
00:26:05.18 notice the difference in the gums.
00:26:07.17 The problem has gone away.
00:26:09.15 And, there have been many different variations
00:26:11.07 of these that people have used
00:26:13.06 to help people with this problem.
00:26:15.08 Another really powerful example of local delivery
00:26:18.10 is the drug-eluting stent.
00:26:20.26 If somebody has cardiovascular disease,
00:26:23.02 one of the most common ways
00:26:25.08 of treating cardiovascular disease today
00:26:27.19 is to basically prop open the blood vessel
00:26:29.21 with a system like this.
00:26:31.17 This is a stent,
00:26:33.10 and it basically looks like a Chinese finger puzzle.
00:26:35.18 It props open the blood vessel,
00:26:37.06 but unfortunately about 50% of the time
00:26:39.27 when you do this you get a lot of cells,
00:26:42.17 smooth muscle cells proliferating,
00:26:44.16 and they'll block off the blood vessel itself,
00:26:48.02 which isn't good and in the worst case somebody could die,
00:26:51.22 but even short of that
00:26:54.05 you'll have to go in and do another operation.
00:26:56.02 So, what's been done is to take some fairly toxic anti-cancer drugs
00:26:59.26 like Taxol,
00:27:01.27 coat them with a polymer on these stents,
00:27:05.07 and these anti-cancer drugs are anti-proliferative,
00:27:08.15 they prevent the smooth muscle cells
00:27:10.25 from dividing the same way,
00:27:13.26 and basically they keep the blood vessel open,
00:27:16.03 and probably close to a million patients use this every year.
00:27:20.26 Now, I'm gonna move a little bit
00:27:23.20 from local delivery like the teeth and stent
00:27:26.15 to systemic delivery,
00:27:28.20 and again go over a couple of examples.
00:27:31.04 One of the other I think really important areas
00:27:33.28 for controlled release
00:27:36.06 is a lot of times people have come up with new drugs
00:27:38.01 like peptides and proteins
00:27:40.01 in the last 20 or 30 years.
00:27:41.26 One of those was what's called
00:27:43.15 a luteinizing hormone-releasing hormone analog,
00:27:45.22 and that has been shown to be very effective
00:27:48.08 in treating certain diseases
00:27:50.05 like prostate cancer, endometriosis,
00:27:52.10 and other diseases.
00:27:53.24 The problem was,
00:27:55.17 since it's a peptide of 1200 molecular weight,
00:27:57.22 there was no good way to give it to the patient.
00:28:00.02 If the patient tried to swallow it,
00:28:02.02 it's destroyed in the stomach and the GI tract
00:28:05.14 by enzymes.
00:28:06.23 Also, it's too big to get absorbed.
00:28:08.25 They also tried to give it through the nasal passages
00:28:10.24 and other things but, again,
00:28:12.06 none got into the body.
00:28:14.08 So, they injected it,
00:28:16.04 but the problem when you inject it is that enzymes
00:28:18.08 destroyed it right away,
00:28:19.27 so what's now done
00:28:21.20 is to put it in little microspheres
00:28:23.10 like one of those matrix systems,
00:28:24.27 actually a bioerodible matrix system,
00:28:26.24 and what happens is you can actually release it for many days.
00:28:29.25 This is a graph of it,
00:28:31.23 but now Lupron Depot,
00:28:33.08 which has been used by many, many millions of patients...
00:28:36.15 most of these last for about four months.
00:28:39.02 So, you give a single injection every four months
00:28:41.20 for the patient and it will deliver the drug.
00:28:44.23 Another example that's widely used
00:28:48.09 is for patients that have schizophrenia.
00:28:50.19 If somebody has schizophrenia
00:28:52.07 there are also drugs like Risperdal
00:28:54.23 which are quite good for the patient,
00:28:56.29 but a lot of times people forget to take them,
00:29:00.26 and so what's been done
00:29:03.02 is to put them in another type of microsphere,
00:29:06.23 bioerodible system like I was talking about,
00:29:09.20 and they're injected every two weeks.
00:29:11.28 Now, actually, they've come up with one
00:29:14.01 that will be injected every four weeks,
00:29:15.24 again using these kind of principles
00:29:17.12 that I mentioned earlier.
00:29:19.01 And, that's had a huge effect
00:29:22.01 on helping patients that have schizophrenia.
00:29:25.23 It's decreased the amounts of hospitalizations,
00:29:29.21 it's decreased suicides,
00:29:32.08 and probably about five million patients have taken these.
00:29:37.00 Another example, recently approved,
00:29:39.02 is another molecule
00:29:41.08 that may be useful in this case for type 2 diabetes.
00:29:43.10 This is a glucagon-like peptide,
00:29:45.20 and what happened was when it came out
00:29:48.27 it was effective in terms of improving blood sugar
00:29:51.16 after food intake,
00:29:53.24 but you had to give injections twice a day.
00:29:56.05 Now it's put into one of these microspheres,
00:29:58.03 again, one of these bioerodible systems
00:29:59.27 that I mentioned,
00:30:01.23 and it's given once a week
00:30:03.20 from a degradable system called PLGA,
00:30:05.19 which is poly(lactic-glycolic acid).
00:30:10.02 The last area that I wanted to talk about
00:30:13.02 to illustrate some of these points
00:30:14.17 are what are called transdermal systems.
00:30:16.10 For many years, people would have never thought
00:30:18.17 that you could deliver drugs through the skin
00:30:20.22 because you'd think that that might be...
00:30:23.00 you know, if things could get through the skin easily
00:30:25.09 that might be very bad,
00:30:26.25 like somebody could get infected.
00:30:28.15 But what's been found out
00:30:30.28 is that some molecules can actually get through the skin,
00:30:32.22 and what's been done is to make, again,
00:30:35.29 another reservoir system,
00:30:37.15 diffusion-based system, shown here,
00:30:39.22 and the way this is designed
00:30:41.18 is you've got a backing membrane,
00:30:43.13 a drug reservoir which is shown in the middle,
00:30:45.27 a rate controlling membrane,
00:30:47.27 and finally an adhesive.
00:30:49.16 And you just put this reservoir system,
00:30:51.19 diffusion controlled reservoir,
00:30:53.22 on the skin and it will release the drug,
00:30:56.00 and these may last anywhere
00:30:58.11 from a day to a week.
00:31:00.20 The key issue in terms of getting drugs
00:31:03.13 through the skin
00:31:05.09 is pretty much all the resistance
00:31:07.05 in terms of getting the drugs through the skin
00:31:08.25 is the outermost skin layer.
00:31:10.09 It's called the stratum corneum,
00:31:12.10 and actually if you looked at it under a microscope
00:31:14.07 it looks like a brick wall.
00:31:16.09 There are dead cells called keratinocytes
00:31:18.05 and then there are lipid bilayers in between them,
00:31:20.28 and that provides a very tight barrier
00:31:23.10 that makes it very hard for things to get through,
00:31:26.04 but if some molecule has just the right characteristics,
00:31:29.10 like the right molecular size
00:31:31.06 and the right, let's say lipophilicity,
00:31:33.10 meaning how fat soluble it is,
00:31:35.05 actually it can get through.
00:31:37.10 So, I though I'd make a few general comments
00:31:39.12 about transdermal systems.
00:31:41.11 The skin, as I mentioned,
00:31:42.26 is generally impenetrable
00:31:44.20 and the principle resistance
00:31:46.27 is the stratum corneum,
00:31:49.03 which is actually dead skin,
00:31:51.03 but it has this tight sheath, as I mentioned,
00:31:53.19 of keratinocytes and lipid bilayers.
00:31:57.22 The permeability of a drug
00:32:01.16 correlates with its water solubility,
00:32:03.09 its molecular weight,
00:32:05.01 you'd like it to be fairly small,
00:32:06.24 and its oil/water partition coefficient,
00:32:09.07 because if the drug is more what's called lipid-like
00:32:11.09 it's more likely to, you know,
00:32:13.16 if you take the principle "like-dissolves-like",
00:32:15.19 it's more likely to be able to penetrate through the lipid bilayers
00:32:17.25 that I showed you in the last slide.
00:32:20.08 And finally, it's useful...
00:32:22.05 transdermal systems are useful for drugs
00:32:24.01 that have a low dose requirement,
00:32:26.04 the lower the better because of this permeability issue,
00:32:28.06 and also for drugs that have high skin permeability.
00:32:32.09 One of the big areas of transdermal research
00:32:35.10 is the fact that
00:32:37.27 you can enhance permeability by using certain compounds,
00:32:41.07 chemical compounds,
00:32:42.28 and just to give an example,
00:32:44.28 when people have put estradiol in a patch,
00:32:47.23 for postmenopausal women,
00:32:50.20 the flux is not very high,
00:32:52.11 but what they found is that you can take ethanol
00:32:55.10 and you can put it in it,
00:32:57.05 and that will increase the flux by a factor of 20,
00:32:59.13 and what that means for the patient
00:33:01.14 is that they can go from having this giant patch
00:33:03.14 to a much smaller patch,
00:33:05.06 a factor of 20 smaller,
00:33:07.00 and that makes it practical.
00:33:08.16 Also, these transdermal systems
00:33:11.06 are easy to apply and easy to remove.
00:33:15.12 One of the biggest advantages
00:33:17.05 is the fact that when you do something transdermally,
00:33:20.10 rather than orally,
00:33:22.09 you really tremendously reduce the first pass effect.
00:33:25.01 For example, there's lots of drugs that,
00:33:26.15 when you take them orally,
00:33:28.11 they're destroyed by the liver,
00:33:30.17 and that leads to low amounts in the blood
00:33:32.14 and also variability,
00:33:34.19 but transdermal systems can reduce that tremendously.
00:33:38.20 One possible drawback, however, of a transdermal system
00:33:41.26 is that it takes time to reach a steady state,
00:33:44.09 like maybe 2-6 hours in some cases,
00:33:47.17 and what that means is that
00:33:49.14 probably if you had an acute problem,
00:33:51.04 like say, sudden pain,
00:33:52.27 an oral system would be better than a transdermal system,
00:33:55.15 but if you have a chronic situation
00:33:58.03 transdermal is actually quite good.
00:34:01.04 This slide simply shows
00:34:04.13 the flux of different drugs
00:34:07.05 and melting points,
00:34:08.28 but in particular what I wanted to note
00:34:10.29 is if you look at the drug on the top,
00:34:12.19 like say nitroglycerin, scopolamine, fentanyl...
00:34:14.16 all of which are used clinically
00:34:17.21 in transdermal systems,
00:34:19.07 their fluxes are pretty high,
00:34:21.06 but if you go down closer to the bottom
00:34:23.14 and you look at estradiol,
00:34:25.15 estradiol has a lower flux,
00:34:27.11 so the only way to really get that to
00:34:29.24 become a useful transdermal system
00:34:31.18 is you have to have a permeation enhancer,
00:34:34.21 and that would move estradiol up higher
00:34:38.25 so it would be more like the scopolamine,
00:34:40.15 fentanyl, and nitroglycerin fluxes.
00:34:44.14 On the final slide,
00:34:46.04 I just wanted to expand that point a little bit further
00:34:48.18 and go over methods of enhancement.
00:34:51.03 This is a big area probably for the future,
00:34:54.16 because most drugs...
00:34:55.28 right now there's only about 20-25 drugs
00:34:57.21 or drug combinations
00:34:59.19 that are given transdermally,
00:35:01.17 even though they're used by millions of patients.
00:35:04.09 We'd like to expand the numbers of drugs
00:35:07.16 that could be given this way,
00:35:09.26 so one way of doing it
00:35:12.05 that people are looking at is electric fields
00:35:14.05 like by iontophoresis.
00:35:15.29 Could you actually take an electric field
00:35:18.21 and apply it to a drug
00:35:21.18 so that the drug could go through the hair follicles or sweat ducts?
00:35:24.29 And, this is experimental,
00:35:26.28 but may some time be useful for delivering peptides,
00:35:30.01 for example, in patches.
00:35:31.25 Electroporation, that's a second method,
00:35:34.11 and it also involves electricity,
00:35:36.06 but it involves creating new pathways,
00:35:37.29 new pores in the skin that are just temporarily there,
00:35:41.01 and even though it's an early stage
00:35:43.07 it's shown very, very large increases,
00:35:45.09 like 10^4 increases in permeation
00:35:48.08 and is in clinical trials in some situations.
00:35:51.06 The third are is ultrasound.
00:35:52.25 Ultrasound... actually
00:35:54.13 there has already been an ultrasound system approved by the FDA
00:35:57.07 for delivering pain medications,
00:35:59.08 and one of things the ultrasound does
00:36:01.21 is it gets rid of any type of lag time,
00:36:04.03 but also tremendously increases permeation of drugs,
00:36:07.24 and people are exploring it for
00:36:10.19 different types of large molecules.
00:36:13.02 For all of these three,
00:36:14.24 iontophoresis, electroporation,
00:36:16.05 and ultrasound,
00:36:18.08 one of big challenges is engineering
00:36:20.08 and miniaturizing
00:36:22.14 and making less expensive the units,
00:36:24.09 so that you could make a small patch
00:36:26.09 that the patient could conveniently wear.
00:36:28.17 In addition to these methods,
00:36:30.08 there are chemical methods like making a drug more lipophilic
00:36:33.27 by making what's called a prodrug,
00:36:35.23 that means attaching something lipophilic to the drug
00:36:38.18 and, as I mentioned, penetration enhancers.
00:36:41.00 So, drug delivery, in summary,
00:36:43.26 is actually a very, very broad area.
00:36:45.13 It involves a lot of chemical
00:36:47.22 and physical and biological principles.
00:36:49.15 It's been very, very important
00:36:51.01 for delivering all kinds of drug up until now,
00:36:54.09 and I believe it will probably be even more important
00:36:56.15 in the future as we come up with...
00:36:58.13 and the world comes up with new drugs
00:36:59.29 like siRNA, mRNA, DNA, gene editing,
00:37:05.21 all kinds of approaches
00:37:08.01 where really I think the delivery
00:37:10.03 will end up being critical
00:37:12.15 to getting these important molecules
00:37:14.10 into the cells where you want them.
00:37:16.10 Thank you very much.

00:00:07.17 My name is Bob Langer
00:00:08.28 and I'd like to now go over the second lecture,
00:00:11.19 which is Drug Delivery Technology:
00:00:13.13 Present and Future,
00:00:15.15 but I should briefly summarize
00:00:17.28 what I went over in my first lecture.
00:00:19.27 And, in that first lecture,
00:00:21.08 I discussed the fact that controlled release systems
00:00:23.02 offer long-term drug release
00:00:25.10 with release rates primarily determined
00:00:27.09 by the system itself,
00:00:28.29 and I went over some different ways that one could achieve that,
00:00:32.04 and I in particular went over
00:00:34.20 how one might design certain polymer systems
00:00:37.10 or pump-based systems to do that.
00:00:40.17 Now what I'd like to do is actually go back in time
00:00:42.17 and tell you how I got involved in this area in the first place,
00:00:46.13 and then talk to you about
00:00:49.07 some of the systems we developed
00:00:50.28 and even some of the ones we're developing for the future.
00:00:54.03 So, when I got done with my doctorate it was 1974
00:01:00.05 and I was in chemical engineering,
00:01:01.26 and most of my friends at the time
00:01:03.28 went into the oil industry, there was a gas shortage then
00:01:06.09 and they had lots of jobs,
00:01:08.12 but I got a lot of job offers from the oil companies
00:01:10.24 but I wasn't very excited about it,
00:01:12.28 and I was looking for a way to try to use my chemically engineering background
00:01:16.01 to either help in education or human health,
00:01:19.17 and I was very fortunate that Judah Folkman,
00:01:21.28 who was a surgeon,
00:01:23.25 offered me a job in his lab
00:01:26.14 on something very, very different,
00:01:28.06 but that I felt was incredibly exciting.
00:01:30.10 And I though I'd start out and just show you a picture,
00:01:34.08 actually from the New York Times, in 1971,
00:01:37.07 of Dr. Folkman's vision of how tumors grow,
00:01:40.29 and what he proposed is that a tumor cell
00:01:45.18 would somehow be created
00:01:47.29 and it would grow to a 3-dimensional mass,
00:01:49.25 and it would never get larger than say about a millimeter cubed,
00:01:53.12 because it ran into a nutrition problem.
00:01:55.17 Cells in the center would die
00:01:57.15 because they couldn't get nutrients or get rid of wastes.
00:02:01.07 Well, what he said is that somehow the tumor
00:02:04.02 is able to solve that problem
00:02:06.12 because the tumor would create a chemical signal
00:02:08.21 which he called TAF, tumor angiogenesis factor,
00:02:12.08 that would diffuse to the surrounding blood vessels
00:02:14.23 which normally didn't do anything,
00:02:16.22 but when the TAF was there
00:02:19.02 it would cause them to multiply and grow,
00:02:21.11 and grow right to the tumor,
00:02:22.29 and that would cause a second phase of growth,
00:02:25.14 which you see here.
00:02:27.05 And, in that second phase of growth,
00:02:29.07 the tumor is vascularized
00:02:31.00 and that solves the nutrition problem for the tumor.
00:02:34.03 It gets bigger and bigger
00:02:36.10 and ultimately can spread through those blood vessels,
00:02:38.03 a process called metastasis,
00:02:39.29 and eventually kill.
00:02:41.24 Dr. Folkman's idea, which is I didn't realize
00:02:44.10 but was very controversial at the time,
00:02:46.08 was that it you could stop the blood vessels from growing,
00:02:48.17 achieve anti-angiogenesis,
00:02:51.04 maybe that would be a whole new way of thinking
00:02:53.05 about stopping cancer.
00:02:55.18 So, when I came to his lab in 1974
00:03:01.02 there was no such thing as an angiogenesis inhibitor,
00:03:03.20 and he asked me to isolate, actually,
00:03:06.03 what would become the first of these.
00:03:09.03 How do you think about a problem like that?
00:03:11.05 Well, we kind of broke it up into two parts.
00:03:13.06 First, where could you find something
00:03:15.13 that might stop blood vessels from growing,
00:03:17.13 and one of the things that we thought about was cartilage,
00:03:19.24 which is in your nose and your knee,
00:03:21.24 and cartilage doesn't have blood vessels.
00:03:24.04 So, I was able to get some cartilage
00:03:28.11 from the little rabbits we had in the lab,
00:03:30.00 but I couldn't get that much.
00:03:31.29 So then, I started thinking,
00:03:34.07 you know, well where can I get more?
00:03:35.27 ...you know, and I found a slaughterhouse
00:03:38.07 that had cows and I got some of their bones,
00:03:41.03 but still I could only get a couple bones.
00:03:43.08 So, I found out, where do all of the cow bones
00:03:47.09 in the Northeast go,
00:03:49.02 and they go it turns out to a slaughterhouse,
00:03:51.01 to some meatpacking places in south Boston.
00:03:53.08 So I made an arrangement with them to get all their bones
00:03:55.10 and I'd bring them back to the lab
00:03:57.20 and I would process them,
00:03:59.15 meaning that I would scrape meat off of the bones,
00:04:03.26 I'll actually just show you one.
00:04:06.07 Here's a bone and if you look at the top of it,
00:04:07.23 that's where the cartilage it.
00:04:09.13 And so I'd scrape the meat off the top,
00:04:11.09 which I did in this case,
00:04:13.00 and then I'd slice off the cartilage,
00:04:15.11 and then I'd put it through various extraction
00:04:17.26 and purification procedures
00:04:19.14 so that at the end of several years
00:04:21.08 I maybe had 50 or 100 different what are called fractions
00:04:24.04 that I wanted to study
00:04:26.01 and test to see if they would stop blood vessels from growing.
00:04:28.11 But, that then brings up the second problem.
00:04:30.12 How do you study something
00:04:32.01 like blood vessel growth?
00:04:33.25 And, if you look back at the history of medicine,
00:04:37.23 one of the biggest challenges
00:04:39.29 whenever somebody comes up with a new factor
00:04:41.24 or substance
00:04:43.20 is often finding a bioassay, a way to study it.
00:04:46.24 And there was no such bioassay,
00:04:48.21 really, for studying angiogenesis,
00:04:50.17 so we had to create one.
00:04:53.05 And, one of the things that we thought about was,
00:04:57.03 as we started to think about creating them, was...
00:05:00.04 one of the big issues was that almost everywhere you go
00:05:02.08 in the body or any organism there are background blood vessels,
00:05:05.07 so we wanted to find a place where there weren't,
00:05:07.05 and so we thought about the eye of a rabbit.
00:05:09.16 And, it turns out that Michael Gimbrone had shown
00:05:12.13 that if you put tumors, certain types of tumors like B2 carcinomas
00:05:16.12 in the eyes of rabbit,
00:05:18.17 they will cause, over about a 2-3 month period,
00:05:21.02 blood vessels to grow from the edge of the cornea,
00:05:23.11 the limbus, to the tumor.
00:05:25.07 So, we thought we could take an ophthalmic microscope
00:05:27.13 and actually measure the length of the longest blood vessel,
00:05:31.10 but the problem was,
00:05:32.18 if we wanted to now find an inhibitor,
00:05:34.16 we had to also put the inhibitor in the eye
00:05:37.04 and the inhibitors would quickly diffuse away.
00:05:39.16 So, we thought a way to solve that
00:05:41.18 is to have what we call a controlled release polymer
00:05:43.27 that could take any of the things we isolated from cartilage,
00:05:46.24 all of which were fairly large molecules,
00:05:49.07 and deliver them to the eye and to the tumor
00:05:53.10 and to the blood vessels over this 2-3 month period.
00:05:57.14 So, one of the big challenges, then,
00:05:59.21 became to try to develop such a polymer...
00:06:02.28 and they didn't exist,
00:06:05.11 and in fact Dr. Folkman, he was on the board of the one company, ALZA,
00:06:08.23 working in this area,
00:06:11.06 and he went out to ask them if they could help us.
00:06:13.01 But they said no, they said
00:06:15.17 that large molecules can't slowly diffuse through solid polymers.
00:06:19.18 It's kind of like saying, could any of us walk through a wall?
00:06:22.25 In fact, the literature said similar things,
00:06:25.23 that the use of polymer matrices
00:06:27.19 has been virtually restricted to small molecules.
00:06:30.11 The only thing I really had going for me is
00:06:32.26 I just didn't know any of that,
00:06:35.06 so I went ahead and tried to do it anyhow.
00:06:37.09 I experimented in the lab and I...
00:06:40.20 kind of almost Edisonian-like...
00:06:42.29 and I actually found over 200 different ways
00:06:45.04 to get this to not work.
00:06:47.18 But eventually, I was able to make little microspheres,
00:06:51.16 those shown here and one shown here
00:06:54.14 and then the other's cut in half,
00:06:57.10 and we were able to show
00:06:59.22 that by making these the right way
00:07:01.19 we could actually get release,
00:07:03.12 this is from a paper in Nature in 1976,
00:07:05.25 for over 100 days,
00:07:08.08 for really any molecule.
00:07:10.15 And that enabled us to start to
00:07:13.20 think about doing these bioassays
00:07:18.01 and to do controlled release as well.
00:07:21.05 Later on, one of the challenges
00:07:23.05 was to get constant release,
00:07:25.04 and we worked out some ways, using some engineering models
00:07:28.06 where we could predict certain shapes or drug distributions,
00:07:30.26 where we could get constant release,
00:07:32.17 and here's an example of that.
00:07:36.04 When I first presented some of this work,
00:07:40.03 people were very, very skeptical about it.
00:07:42.28 I remember giving a talk at a major meeting in 1976,
00:07:48.24 and I practiced this talk for many weeks before
00:07:53.12 because I was a very young guy,
00:07:55.01 I was a postdoc and there were all these very famous
00:07:58.00 polymer chemists and engineering in it,
00:08:00.05 and when I got done with the talk
00:08:02.06 I actually felt I did alright,
00:08:04.03 but what happened was all these older scientists,
00:08:06.01 when I got done,
00:08:07.16 they came up to me and they said,
00:08:08.27 "We don't believe anything you said."
00:08:10.22 They were just very skeptical
00:08:12.09 that you could release these large molecules.
00:08:14.23 But what happens, of course, in science
00:08:16.26 is the key is whether people reproduce what you do,
00:08:19.05 and it turned out that over the next couple of years
00:08:21.00 a number of groups did,
00:08:22.23 and the question shifted to how could this happen.
00:08:24.23 So, to understand the way this happened,
00:08:27.25 I had a graduate student, Rajan Bawa,
00:08:30.01 when I was at MIT,
00:08:31.12 and we cut thin sections through the polymer with a cryomicrotome.
00:08:34.29 Here, for example, is one of those thin sections.
00:08:37.12 It's a 5 micron thin section of a polymer we used
00:08:40.11 called ethylene-vinyl acetate copolymer.
00:08:43.07 And, if you had a molecule that was
00:08:46.04 300 molecular weight or greater,
00:08:48.02 it would not be able to diffuse from one side of this to the other.
00:08:51.00 So, how could the molecules get through?
00:08:53.18 Well, now we cut a second section.
00:08:55.23 This section has a red drug in it,
00:08:58.03 actually a red protein, myoglobin,
00:09:00.14 and this is cut before any release has taken place.
00:09:04.01 And we see what we call, in this case,
00:09:05.27 a phase separation.
00:09:07.19 You see the red myoglobin chunks here,
00:09:10.23 and then you see the white polymer here,
00:09:14.04 and you see that throughout.
00:09:16.14 So, this is what happened before any release.
00:09:18.27 Now, let's say you released it for a year
00:09:21.03 and then you cut a thin section.
00:09:22.28 What you'd see is left behind...
00:09:25.16 where the drug was,
00:09:27.19 are these pores,
00:09:29.29 and these pores are large enough so that molecules even millions of
00:09:32.12 molecular weight can get through,
00:09:34.05 but what happens is...
00:09:35.21 we did a lot of serial sectioning
00:09:37.13 and also scanning electron microscopy...
00:09:39.12 and what happens is it turns out that these pores
00:09:41.21 are interconnected, they have tight constrictions between them,
00:09:45.01 and they're incredibly winding and tortuous,
00:09:47.21 so it takes a really long time
00:09:49.20 for the molecules to get through them.
00:09:51.20 One way, when I try to explain this to people
00:09:53.27 when I give lectures around the world,
00:09:55.17 is I sometimes say it's kind of like driving a car through Boston.
00:09:59.04 Boston has,
00:10:01.18 what we call in chemical engineering terms,
00:10:03.20 which I'm a chemical engineer,
00:10:05.11 is Boston and these structures
00:10:07.07 have what we call a very high tortuosity.
00:10:09.19 And, if you have a high tortuosity,
00:10:11.23 that you can use to slow release down,
00:10:13.26 and over the years our graduate students and postdocs
00:10:16.19 have worked out ways
00:10:18.27 to create all kinds of these porous tortuous structures
00:10:21.20 and to even develop mathematical models
00:10:23.27 to predict how to make these,
00:10:25.23 and so you can make these last anywhere
00:10:27.20 from days to years, or any time in between.
00:10:33.11 So now, we were able to go back
00:10:35.22 and try to address the problem,
00:10:37.16 the angiogenesis problem,
00:10:40.04 because now we have these polymers that could deliver
00:10:42.06 molecules of any size
00:10:44.03 and we also were able to make these polymers in a way
00:10:46.18 that would not cause irritation to the eye,
00:10:48.11 which was also a big challenge.
00:10:50.15 So this was the assay I mentioned we wanted to create.
00:10:53.08 The tumor is there
00:10:55.25 and the polymer,
00:10:58.03 and what we did is we put different fractions,
00:11:00.16 we probably did close to 2000 eyes,
00:11:03.02 and when we did...
00:11:06.15 most of them didn't work.
00:11:08.05 There were all different fractions that we isolated
00:11:09.22 and most of them didn't work.
00:11:11.15 I should also almost all but one didn't work.
00:11:14.05 And I'll just show you some pictures
00:11:15.22 of what they look like.
00:11:17.13 So, this is from a paper we wrote in Science in 1976
00:11:21.11 with this what's called rabbit corneal pocket assay.
00:11:23.23 If you didn't have the cartilage-derived inhibitor,
00:11:26.00 that's what I call CDI,
00:11:27.28 if you didn't have it...
00:11:30.28 over, this is about 9 weeks after the start of the experiment,
00:11:34.01 you get a sheet of blood vessels
00:11:36.03 growing from the bottom of the eye
00:11:38.24 over the polymer to the tumor.
00:11:40.19 You can actually see the tumor...
00:11:42.19 where the tumor is it's a little bit cloudy.
00:11:44.26 And, if you looked at this eye,
00:11:46.26 or any eye like it 2-3 weeks after this,
00:11:49.15 what would happen is it would be...
00:11:53.01 the tumor would be 3-dimensional.
00:11:54.16 It would be out of the orbit of the eye...
00:11:56.14 we sacrificed the animals before that,
00:11:58.13 but nonetheless you see the rapid blood vessel growth.
00:12:01.07 In contrast, if you look at the next panel
00:12:04.24 where we put the CDI in the polymer,
00:12:06.19 the cartilage-derived inhibitor,
00:12:08.06 notice how the blood vessels are lower:
00:12:10.10 they avoid the polymer,
00:12:12.12 they don't grow into the tumor.
00:12:14.09 This is at exactly the same time,
00:12:16.04 and it turns out that about 40-50% of the time,
00:12:19.00 the tumors on the right will never grow,
00:12:21.03 whereas 100% of the time the tumors grew on the left,
00:12:24.09 and like I say, we did hundreds, thousands of eyes
00:12:27.26 over the years to look at this.
00:12:31.07 So, that actually enabled us
00:12:33.13 to isolate the first angiogenesis inhibitor.
00:12:35.16 It did a couple of important things,
00:12:37.09 I like to think.
00:12:39.00 One, is that we did develop an assay
00:12:42.09 that people could use in the future
00:12:44.25 for all future angiogenesis inhibitors.
00:12:46.23 Secondly, I like to think that this
00:12:48.22 really established there were angiogenesis inhibitors
00:12:51.05 that were chemical, and they did exist.
00:12:53.22 And then we had this first one.
00:12:56.09 Now, what happened is of course it took...
00:12:59.12 this was just the start.
00:13:01.04 It took the work of many companies,
00:13:03.16 particularly Genentech and others,
00:13:06.04 to really move this field forward,
00:13:09.17 so it's wasn't...
00:13:11.24 you know, many years later.
00:13:13.09 So, it wasn't until 2004
00:13:15.21 when the first angiogenesis inhibitor got approved,
00:13:19.07 and this is just a list of angiogenesis...
00:13:22.18 and it's not even a complete list,
00:13:24.12 that have gotten approved since 2004.
00:13:28.15 Avastin, which is a Genentech drug,
00:13:30.09 is one of the biggest, most widely-used
00:13:33.19 biotech drugs in history,
00:13:35.07 but there are many others as well
00:13:37.08 and they've been, as we can see in this slide,
00:13:39.00 been used for all kinds of cancers.
00:13:41.08 And, not just cancer,
00:13:43.01 but many people have different...
00:13:44.27 of what's called...
00:13:46.13 an eye disease called macular degeneration,
00:13:48.09 where you get blood vessels
00:13:50.02 growing into the back of the eye
00:13:51.21 causing hemorrhage.
00:13:53.11 And, before this, the only way to treat them
00:13:55.01 was to use lasers to do what's called photocoagulation.
00:13:58.15 Now, you can use these inhibitors
00:14:02.01 like Eylea or Lucentis or Macugen
00:14:04.25 to actually stop the blood vessels from growing
00:14:07.16 and even reverse macular degeneration.
00:14:10.01 What's happened is angiogenesis,
00:14:14.01 this whole area
00:14:15.25 has become a quite large area.
00:14:17.19 Now, about 20 million patients
00:14:19.05 have been treated with angiogenesis inhibitors
00:14:21.07 and the FDA has said that there are four kinds of ways of treating cancer:
00:14:25.23 angiogenesis treatment,
00:14:27.02 chemotherapy,
00:14:28.18 surgery,
00:14:29.22 and radiation,
00:14:31.05 and sometimes these are used together.
00:14:33.04 But it also seemed to me that not only might this be useful...
00:14:36.06 the controlled release systems for angiogenesis,
00:14:38.06 but they might be useful...
00:14:40.08 studies...
00:14:42.17 but they might be also useful in their own right,
00:14:44.25 for delivering all kinds of drugs.
00:14:48.18 And, as a proof of principle, Larry Brown,
00:14:50.20 one of my graduate students,
00:14:52.12 just took a molecule, insulin,
00:14:54.06 and again I'm simplifying this,
00:14:56.12 it was actually his whole doctoral thesis,
00:14:58.24 but he put insulin in these pellets,
00:15:00.17 designed a certain way,
00:15:02.28 and was able to get three months release
00:15:06.06 of a fairly large molecule.
00:15:08.07 So, we thought, both Dr. Folkman and I,
00:15:10.16 that this might be, you know...
00:15:12.22 really open up the door
00:15:17.18 to all kinds of new delivery systems.
00:15:19.20 So, I was working at Children's Hospital
00:15:21.04 when I started this work
00:15:23.06 and Dr. Folkman said to me one day,
00:15:24.25 he said, "Bob, we should file for a patent on this."
00:15:27.06 And, it's interesting,
00:15:29.08 I'd never had a patent before at the time,
00:15:31.14 and Dr. Folkman actually said
00:15:33.13 the entire Children's Hospital never had a patent at the time.
00:15:36.02 So, we worked with a lawyer and filed the patent,
00:15:39.09 and five years in a row
00:15:41.00 the patent examiner turned it down
00:15:43.03 and, you know, we felt he didn't understand it,
00:15:44.23 but it really didn't matter.
00:15:46.02 The patent examiner was the one calling the shots.
00:15:48.08 So, the lawyer said to me around 1982,
00:15:51.17 we started this process in 1976,
00:15:54.10 the lawyer said to me, he said,
00:15:55.21 "Bob, you know, you're wasting a lot of money for the hospital,
00:15:57.22 you should just give up."
00:15:59.14 But, I don't like to give up,
00:16:01.07 so I was thinking,
00:16:02.25 how could we convince the examiner,
00:16:04.29 you know legally of course,
00:16:07.05 that the patent... you know that this was novel.
00:16:10.08 And I thought, you know, when I first started talking about this work
00:16:13.27 everybody told me it was impossible, it couldn't work.
00:16:16.10 I remember getting my first nine grants turned down.
00:16:19.29 There was just this enormous skepticism
00:16:22.03 about whether it could work,
00:16:23.18 and I wondered whether anybody ever wrote anything down.
00:16:26.06 So, I actually did what's called the science citation search,
00:16:29.12 meaning that I could go back to our original paper,
00:16:31.08 which we wrote in Nature in 1976,
00:16:33.27 and see who wrote stuff about it
00:16:35.13 and what they said,
00:16:37.05 and it was actually fascinating.
00:16:38.29 I found a number of quotes,
00:16:40.25 but this one in particular was very useful,
00:16:42.25 and I'll just read this.
00:16:44.25 It was by five of the leading polymer scientists in the world,
00:16:48.10 and what they said,
00:16:50.15 and they were describing this field is,
00:16:52.04 "Generally the agent to be released
00:16:53.23 is a relatively small molecule
00:16:55.13 with a molecular weight no larger than a few hundred.
00:16:58.16 One would not expect that macromolecules,
00:17:01.02 e.g. proteins,
00:17:02.29 could be released by such a technique
00:17:05.01 because of their extremely small permeation rates
00:17:07.14 through polymers.
00:17:09.01 However, Folkman and Langer
00:17:10.28 have reported some surprising"
00:17:12.14 ... that surprising word is a very good word for a patent examiner...
00:17:16.14 "have reported some surprising results
00:17:18.09 that clearly demonstrate the opposite."
00:17:20.20 So, I showed this to our lawyer
00:17:22.13 and he was very excited.
00:17:23.22 He said, "I'm gonna fly down to Washington
00:17:25.05 and show it to the examiner."
00:17:26.24 And he did, and the examiner said,
00:17:28.24 he said, "I had no idea".
00:17:30.08 He said, "I'll tell you what,
00:17:31.25 I will allow this patent if Dr. Langer
00:17:33.22 can get written affidavits from these five authors
00:17:35.27 that they really wrote that quote."
00:17:38.07 So, I did that.
00:17:39.15 I wrote each of them, and they were all kind enough to write me back
00:17:41.05 that they really did write that,
00:17:43.04 and then we got this very broad patent issued,
00:17:46.01 and that was the first one in the history of Children's Hospital
00:17:49.00 and then the hospital would license that out
00:17:51.22 to other people
00:17:53.18 and, today, many companies have developed all kinds of products
00:17:55.28 based on either the patent or these ideas,
00:17:59.10 and these are just a few of them shown here.
00:18:01.25 For example, if somebody has certain peptides
00:18:07.00 that you might want to take, l
00:18:10.00 ike leuprolide acetate...
00:18:12.00 people have not figured out ways to give it orally
00:18:14.01 or by skin patches because the molecule is just so big.
00:18:18.01 If it's injected it's destroyed right away.
00:18:20.15 So now, what happens is
00:18:23.14 it's put in little microspheres, just like I showed you,
00:18:25.22 that are injected under the skin
00:18:27.16 and actually deliver the drug for four months.
00:18:29.25 And there are many other too.
00:18:31.24 This is just pictures of different ones.
00:18:33.27 There's systems that can deliver
00:18:37.07 anti-schizophrenic drugs for several weeks.
00:18:40.00 There's systems that can deliver drugs
00:18:41.22 to treat alcoholism for a month,
00:18:43.16 to treat narcotic addiction for a month,
00:18:45.21 so you give the injections once a month,
00:18:47.23 to treat type 2 diabetes,
00:18:50.18 for where you give an injection once a week,
00:18:52.23 and this is really just the start of this.
00:18:54.17 There are many, many others
00:18:56.12 that end up affecting the lives of tens of millions
00:18:58.23 of patients around the world.
00:19:01.03 So, so far what I've done is I've gone over, now,
00:19:04.20 how you can take systems like this,
00:19:07.21 deliver them at steady rates
00:19:09.21 or maybe slightly decreasing rates
00:19:12.09 over long periods of time.
00:19:14.01 And so, what these systems allow you to do
00:19:16.14 is it allows you to control the level of the drug
00:19:18.24 and the duration of the drug,
00:19:20.24 and generally these are given intramuscularly or subcutaneously.
00:19:25.04 But we want to even go further,
00:19:26.16 and now I'd like to sort of turn to nanotechnology
00:19:29.10 and even some of the systems for the future,
00:19:31.15 or at least that I hope will be the future.
00:19:34.07 So, could you actually make these...
00:19:36.21 use a lot of the same principles...
00:19:38.14 but make these even smaller,
00:19:40.29 so that you could put them in the bloodstream
00:19:42.22 so they'll be able to go around the bloodstream
00:19:44.11 and find their way to particular cells
00:19:46.09 that you want them to go to.
00:19:48.24 How could you do this?
00:19:51.04 So, what we published,
00:19:53.23 this was about 20 years ago,
00:19:55.29 it was one of the earliest papers on medical nanotechnology,
00:19:59.07 is that the challenge is
00:20:01.10 if you make a particle
00:20:03.05 that you want to put drugs in,
00:20:04.20 and you inject it into the bloodstream,
00:20:06.20 almost always what will happen quite quickly
00:20:08.29 is macrophages, cells in the body,
00:20:11.01 will eat those particles.
00:20:13.04 So, what we had to do
00:20:14.20 was figure out a disguise for those particles, the nanoparticles,
00:20:17.26 so that that wouldn't happen,
00:20:19.11 and of course you need to get past the macrophages.
00:20:21.09 In a way, you can think of the macrophages
00:20:23.06 as kind of like the guardian.
00:20:24.23 If you could get past the macrophages
00:20:26.20 then maybe you can get to the cells you want,
00:20:28.11 if you can figure out the right other things
00:20:30.14 to add to the nanoparticle.
00:20:33.04 So, what we did is we made this disguise.
00:20:35.06 We picked a substance called polyethylene glycol
00:20:38.28 that we could add to the outside of the nanoparticles,
00:20:42.21 and our thinking was
00:20:44.19 is that takes up a lot of water,
00:20:46.23 and if the cell sees water, well,
00:20:48.22 it's used to seeing water
00:20:50.22 and it doesn't eat water up.
00:20:52.13 So, that was our hope,
00:20:54.01 that we could disguise these particles,
00:20:56.08 you know, to do that.
00:20:58.07 And then what we did
00:21:00.06 is Omid Farokhzadb, who was a postdoctoral fellow in our lab,
00:21:03.10 actually now is a clinician
00:21:06.07 and associate professor at Harvard Med. School,
00:21:08.24 took it even one step further.
00:21:11.00 We not only put the PEG on the nanoparticles,
00:21:13.08 but he put targeting molecules on
00:21:16.12 that might go to a tumor, for example.
00:21:18.07 Examples could be antibodies or aptamers
00:21:21.08 or things that could target things.
00:21:23.15 I realize sometimes
00:21:25.08 I don't always explain this perfectly,
00:21:27.13 but I was fortunate that
00:21:29.25 about a year or two ago Nova, the TV show,
00:21:31.21 they came to our lab and they filmed some of what we did,
00:21:34.03 and they made this video
00:21:36.02 that explains it much, much better than I do,
00:21:37.12 so I thought I'd...
00:21:39.02 I've gotten their permission to use that video,
00:21:40.16 so I thought I'd use it and show it to you
00:21:42.23 because I think it explains pretty well
00:21:44.22 how this kind of technology works.
00:21:46.24 So, let me just go to that video.
00:21:48.27 "He starts with a nanoparticle of anti-cancer drugs.
00:21:53.15 That gets incased in a plastic
00:21:55.14 that releases the drug over time.
00:21:57.28 That, in turn, gets a special wrapping
00:22:00.04 that disguises the package as a water molecule,
00:22:03.08 to fool the body's immune system.
00:22:05.22 And, last but not least,
00:22:07.26 the address where it should be delivered,
00:22:10.09 a key that will only fit the lock of cancer cells."
00:22:20.10 I should say that a lot of the clinicians
00:22:22.03 I work with tell me
00:22:24.01 it doesn't blow the cell up quite that way,
00:22:26.05 but I think it gives you an idea of what's happening.
00:22:28.19 And, then, what we did...
00:22:33.14 we actually, Omid and I got involved in even helping set up a company
00:22:37.17 that created a whole manufacturing plant to make nanoparticles,
00:22:40.13 which was a huge challenge,
00:22:43.02 and this is just a picture of that plant,
00:22:45.22 and then moved it from test tubes
00:22:48.21 to small animals
00:22:50.01 to large animals
00:22:51.16 to humans, where it is now.
00:22:53.24 And, it's been interesting and exciting, the compound...
00:22:58.10 one of the first compounds is one called BIND-014,
00:23:00.19 which is basically putting Docetaxel,
00:23:03.20 a common anti-cancer drug with some side effects, normally,
00:23:08.20 in the nanoparticles.
00:23:10.28 And what happens is,
00:23:12.15 this is a semi-log plot,
00:23:14.22 but if you look at the red dots and the red curve,
00:23:17.16 if you put the drug in by itself,
00:23:22.07 it goes to zero very, very quickly.
00:23:24.22 But, if you put just the same amount of drug
00:23:26.24 in the nanoparticle
00:23:28.20 it lasts for days, so it keeps pounding the tumor.
00:23:32.06 The consequence of that maybe
00:23:33.21 can be seen even better by looking at human pharmacokinetic data,
00:23:37.22 and in particular the thing to focus on might be,
00:23:41.19 let's look at the dose just to make these absolutely equivalent,
00:23:45.08 of BIND-014 at 30 mg
00:23:49.07 and Taxotere, the same drug, also at 30 mg.
00:23:52.17 Well, what you see when you look at the third panel,
00:23:55.12 the area under the curve,
00:23:57.13 is you could take the same drug
00:23:59.09 but we've changed it dramatically.
00:24:01.11 When you put it in the long-circulating nanoparticle,
00:24:03.15 the area under the curve is 127,280.
00:24:07.16 When you don't put it in the nanoparticle it's 512.
00:24:10.25 So, you get something that's almost
00:24:13.04 250 times higher
00:24:15.18 when you put it in the nanoparticle,
00:24:17.05 so it's just pounding the tumor,
00:24:19.05 and it's early yet but the consequence of this,
00:24:21.15 this is from some papers
00:24:23.28 we published in Science Translational Medicine,
00:24:26.21 show that there's at least some hints of efficacy.
00:24:31.24 If you look a the top CAT scan,
00:24:34.07 you look at the patient's lung before
00:24:36.17 and then maybe 42 days after.
00:24:38.27 If you look at the bottom, that's another example
00:24:41.14 where you look at the lung before and 42 days after,
00:24:44.18 and notice that the nodules, that are circled in yellow,
00:24:48.22 go away after this treatment.
00:24:51.06 Now, of course, what's happening is hundreds of patients
00:24:53.25 are being done and we'll get a better feel for where this may work,
00:24:57.13 where it may not work,
00:24:59.10 but I think it's the dawn of a whole new era
00:25:00.27 of using nanotechnology to deliver drugs.
00:25:04.09 This is a small molecule drug. W
00:25:06.08 e're also using nanotechnology
00:25:08.01 in this form and in the form of different lipid systems,
00:25:11.00 to deliver DNA,
00:25:13.05 to deliver siRNA,
00:25:15.18 to deliver mRNA,
00:25:16.29 and all these things I think are
00:25:18.21 a very, very exciting opportunity for the future
00:25:21.12 and, again, I think the problems are still unsolved,
00:25:23.22 but I hope that this is the start
00:25:26.07 of solving some of them
00:25:29.12 and bringing them into patients.
00:25:31.14 I want to mention one other idea
00:25:33.11 that also might be somewhat futuristic,
00:25:35.24 but I think also will be a part
00:25:38.08 of how drug delivery can change
00:25:40.05 how people do things.
00:25:42.16 I was watching this television show
00:25:44.17 a number of years ago
00:25:46.11 about how they made microchips in the computer industry,
00:25:49.03 and I thought when I watched it,
00:25:50.23 you know, that would be a great way
00:25:52.01 to make a drug delivery system.
00:25:53.12 Now, of course, I've spent 34 years of my life
00:25:55.25 working on drug delivery systems,
00:25:57.10 so somebody might think, you know,
00:25:59.00 any TV show I say I might think that,
00:26:00.19 and they may be right.
00:26:03.09 But, I just want to show the idea I had.
00:26:07.27 The idea I had when I watched the show
00:26:10.01 was that maybe what you could do
00:26:13.02 is make a chip,
00:26:15.06 but rather than put electrical things in it,
00:26:17.05 you could also put chemical things in it,
00:26:19.05 and what we see in this chip,
00:26:21.02 this is just a schematic
00:26:24.23 and it's a cut-away where we're just looking at...
00:26:27.05 the chip itself is fully whole
00:26:29.07 and I'll show you some in a minute...
00:26:31.12 but, when you look at it,
00:26:33.03 we have these wells
00:26:34.18 where you could put active substances in.
00:26:36.22 So, you could put different doses of the same substance in,
00:26:39.15 or your could literally, theoretically,
00:26:41.12 have what we call a pharmacy on a chip.
00:26:42.24 You could put multiple drugs in
00:26:44.21 and have them come out whenever you want,
00:26:46.24 and they're really stored in these chips indefinitely.
00:26:49.12 But, notice that the chips
00:26:51.03 have a cover which looks like a gold cover here,
00:26:53.09 it could be gold or it could be a platinum alloy,
00:26:57.16 and they are hermetically sealed
00:27:00.03 and the drugs are underneath them
00:27:02.09 but, as I'll show you, when we apply,
00:27:04.11 by remote control...
00:27:06.25 we can actually take those covers off
00:27:09.29 and the drug could come out
00:27:12.01 whenever we want to make it do so.
00:27:13.24 Let me just show you some of the work that was done.
00:27:16.17 I did this work with my collaborator
00:27:18.09 Michael Cima at MIT,
00:27:19.25 and we had a very good graduate student
00:27:21.14 John Santini,
00:27:23.23 and we made these chips using techniques
00:27:25.22 that were never used in the pharmaceutical industry,
00:27:27.26 but using techniques
00:27:29.19 that we adapted from microelectronics.
00:27:32.02 And here you see in the top two pictures,
00:27:36.26 which is both a top view and a bottom view
00:27:38.28 of one of these chips,
00:27:40.25 and it's got something like 34 wells in it,
00:27:43.09 and these are tiny little wells,
00:27:46.04 but they don't have to be.
00:27:47.20 They can be bigger or smaller,
00:27:49.08 and they don't have to be short, flat chips.
00:27:51.03 We've actually made sort of cylindrical chips
00:27:52.23 that could be injected into the body and so forth,
00:27:55.08 but just to give you a size idea,
00:27:57.27 here's a United States dime.
00:27:59.20 Let me just show you how they work.
00:28:02.00 So, here's a well, it's covered with the metal
00:28:04.11 and you can see this,
00:28:06.02 this is a scanning electron micrograph of it,
00:28:07.19 it would actually stay in the body like this for years,
00:28:09.21 but if you come along
00:28:11.22 and just give one volt by remote control,
00:28:15.21 in nanoseconds the cover comes off
00:28:18.07 and you see that happening here.
00:28:20.27 And when the cover comes off the drug comes out.
00:28:24.01 So, this is from another paper
00:28:25.28 we wrote in Nature,
00:28:27.26 where we put different amounts of drug
00:28:29.15 in different wells
00:28:31.09 and the drug comes out at different times.
00:28:32.18 This is in test tubes, in vitro.
00:28:35.00 Along the lines of the pharmacy on a chip idea,
00:28:38.19 we put multiple model drugs in
00:28:41.26 and triggered release at different times
00:28:43.21 and that's shown here.
00:28:45.23 But over time,
00:28:47.15 what John and Mike
00:28:49.21 and a little company, Microchips, that we were involved with did,
00:28:52.27 is take this all the way from test tubes,
00:28:54.22 to small animals,
00:28:56.06 to large animals,
00:28:57.17 to humans.
00:28:59.03 And what I'm going to mention now
00:29:00.22 might almost sound like space-age medicine,
00:29:02.06 but we actually did it.
00:29:03.24 What was done is you put the chips in the human body
00:29:05.11 and you can communicate with them
00:29:07.02 over a special radiofrequency
00:29:08.24 called the Medical Implant Communications Service Band.
00:29:11.22 It's been approved by both the FCC and the FDA,
00:29:15.24 and sometimes people think about tampering,
00:29:17.16 I mean... I doubt that that's going to be a problem,
00:29:21.05 and that should be the biggest problem we'd face,
00:29:22.25 but to that extent
00:29:24.26 we even can have a special computer code
00:29:27.23 that we built in
00:29:29.16 that only the patient or doctor could know,
00:29:31.07 if they want to change or administer the dose.
00:29:33.11 Also, what we have,
00:29:35.14 what we built in is in a bidirectional communications link
00:29:40.04 between the chip itself and the receiver.
00:29:42.09 The receiver, by the way, could be a cell phone,
00:29:45.06 it could be something like this,
00:29:46.25 and it can give you all kinds of information like, did you take the drug?
00:29:49.07 I have to admit, as I've gotten older,
00:29:50.25 that's something I sometimes forget about,
00:29:52.27 so, did you take the drug, the battery life, and so forth.
00:29:56.25 Okay, let me tell you about the clinical trial that we did.
00:29:59.01 We did 8 patients,
00:30:01.10 this was done in Denmark,
00:30:03.23 and thinking about what kind of trial we wanted to do,
00:30:06.20 one of the things that happened as we'd send our grants in
00:30:09.07 is people would keep telling us
00:30:11.09 why our approach wouldn't work,
00:30:12.26 and the biggest reason they told us it wouldn't work
00:30:14.16 is you'd get what's called fibrous encapsulation
00:30:16.24 around the chip and that would mean that molecules
00:30:18.29 couldn't diffuse through that fibrous capsule
00:30:22.00 and wouldn't get into the bloodstream.
00:30:23.23 So we felt, let's give ourselves a hard test
00:30:26.02 to really see if they're right.
00:30:27.24 Let's give us...
00:30:30.00 let's pick a large molecule,
00:30:31.23 and if that got through certainly
00:30:33.10 we'd expect smaller molecules to get through.
00:30:35.04 So, what we chose was parathyroid hormone,
00:30:37.06 which is a large peptide,
00:30:39.18 and it's used in osteoporosis,
00:30:42.17 and we also chose it because we felt
00:30:45.07 this is a place where someday, maybe,
00:30:47.04 we could even make an impact.
00:30:49.09 In the case of osteoporosis,
00:30:51.04 women are supposed to take parathyroid hormone
00:30:53.16 by injections once a day,
00:30:55.16 but one of the additional problems with this
00:30:58.04 is that the women don't do it.
00:31:01.14 There's actually a 77% dropout rate
00:31:05.10 of the women who have to take these shots.
00:31:07.16 And you can't take it continuously, either,
00:31:09.11 with the little microspheres.
00:31:11.04 Continuous is bad
00:31:13.02 because that'll actually cause bone resorption.
00:31:14.29 So, you really have to give an injection once a day apparently,
00:31:18.10 and that just has been fraught with problems.
00:31:21.22 So, what was done is the trial is a small office procedure
00:31:25.01 in the doctor's office to do the implant,
00:31:27.05 and the results were very positive.
00:31:28.28 The women preferred this to some of the other methods.
00:31:32.03 You got the same pharmacokinetics,
00:31:33.20 I'll go over what I mean by that
00:31:35.19 in a second and show you some of the data,
00:31:38.01 with less variability,
00:31:39.23 which may not be important in this case
00:31:41.17 but could be important in others,
00:31:43.10 and the three major measures
00:31:45.13 of whether you're treating this disease
00:31:49.01 are Ca, PINP, and CTX,
00:31:51.23 and they were the same as daily injections.
00:31:54.05 Just to show you the data, on the next to final slide,
00:31:58.20 the top curve is human data
00:32:02.04 where what you see is data
00:32:05.01 for the woman at day 60, 68, 76, and 84.
00:32:09.17 Notice how the points really are pretty much
00:32:11.26 superimposed on top of each other.
00:32:13.26 It's very reproducible.
00:32:15.06 On the bottom right,
00:32:17.06 what you see are pictures of the chip itself.
00:32:19.17 In this case what we did is we made these little chips
00:32:23.04 and in them we also put electrical components,
00:32:26.25 a battery, a power source,
00:32:31.26 and even a computer program.
00:32:33.18 What you can't see on these chips
00:32:35.12 is on the back end of it
00:32:38.10 we actually built in an antenna,
00:32:41.06 we imprinted an antenna right into the back end of the chip,
00:32:44.01 and that's how you can communicate with it.
00:32:45.27 You can communicate with it by, depending on your device,
00:32:48.20 it could be a cell phone,
00:32:50.11 it could be something like this, and so forth.
00:32:54.15 As you can also see from these pictures,
00:32:56.17 the amount of fibrous encapsulation...
00:32:58.15 it's not zero, we definitely get some,
00:33:00.10 but it's very small
00:33:02.17 and obviously it's small enough
00:33:05.13 so that it has no effect on the release rate of this large molecule
00:33:08.11 and it's also, I'd say maybe 1/20th of what a pacemaker gets.
00:33:12.06 We also did histology,
00:33:14.02 that's actually taking sections of the tissue
00:33:16.10 and seeing whether you got inflammatory cells.
00:33:20.02 And, in the panels on [the left]
00:33:22.02 we see that there are no inflammatory cells
00:33:24.07 over the implant.
00:33:27.02 So, it ended up being very safe,
00:33:30.00 and effective,
00:33:31.25 and now we're moving this project in at least three directions.
00:33:34.19 One is we're making a two-year device.
00:33:38.02 Two, we've been working with the Gates Foundation,
00:33:41.15 where they've been interested in a...
00:33:44.01 for family planning in the third world,
00:33:46.13 that you could have a contraceptive device
00:33:48.14 that you could turn on and off whenever...
00:33:50.07 a woman could turn on and off whenever she wanted.
00:33:51.27 That can't be done with conventional technology,
00:33:54.09 but with this you can,
00:33:56.07 so we're actually designing a 16-year device
00:33:58.20 that could be turned on and off
00:34:00.28 whenever the woman wanted it to.
00:34:03.05 And finally, what we're doing...
00:34:05.02 one of my colleagues, Michael Cima,
00:34:06.23 he's been putting little sensors in these chips,
00:34:08.21 and someday our hope is we'll be able
00:34:10.21 to sense signals in the human body
00:34:12.20 and then tell the chip how much to deliver
00:34:14.17 in response to those signals.
00:34:16.21 So, that's what I wanted to largely go over in this lecture.
00:34:19.24 Just to summarize where we are,
00:34:22.01 in the first lecture I've gone over
00:34:24.25 advances in controlled release technology
00:34:26.18 and gave an overview.
00:34:28.13 Here I've given some examples of both current and possibly future technology.
00:34:32.23 And, in my third lecture,
00:34:34.11 I'll go over biomaterials and biotechnology
00:34:36.20 and talk about how one might use...
00:34:38.22 create new biomaterials for drug delivery,
00:34:40.17 and also how one might use biomaterials
00:34:42.17 to help lay the foundation for tissue engineering.
00:34:45.16 Thank you.

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.