Biomedicine

Ideas Are Like Children

They used to call him crazy. Now they call him smart. Chemical engineer Robert Langer crafts cures from plastic.

There was a time when medicine and chemical engineering hadn’t been properly introduced. Then Robert Langer crashed the party.

That was in 1974, when Langer, now Kenneth J. Germeshausen Professor of Chemical and Biomedical Engineering at MIT, signed on as a postdoc in Judah Folkman’s cancer lab at Boston’s Children’s Hospital. Mingling with the surgeons and scientists, the young chemical engineer was far afield. Far enough, in fact, to discover his uncommon calling: molding materials that turn biological discoveries into medical cures.

Synthetic polymers are Langer’s specialty. He crafts, from plastic, implantable dispensing machines for some of biotechnology’s most esoteric therapies, as well as safer delivery devices for more conventional medicines. Langer’s work is one of the pillars of the multibillion-dollar drug-delivery industry. But the pace of his progress is such (his name appears on more than 330 patents) that he has populated not one, but two new industries with ideas and students. Langer’s second sphere of innovation is tissue engineering, an emerging discipline in which his synthetic polymers are helping researchers grow replacement body parts in the laboratory.

In his award-cluttered MIT office, Langer spoke with Technology Review Associate Editor Antonio Regalado.

TR: Biomaterials are the common thread in your work. What are they, and why are they important?
LANGER: A biomaterial is any substance other than food or drugs contained in a therapeutic system that’s in contact with biological tissues or fluids. Biomaterials have been around for a while-more than 2,000 years in the case of dental fillings. Pound for pound, fillings are the most common biomaterial in use. Newer applications of biomaterials in drug delivery and tissue engineering are important because they have the potential to revolutionize certain medical treatments.

TR: How have doctors chosen which materials to use?
LANGER: There’s some interesting history there. Until the 1970s physicians tended to adapt off-the-shelf materials designed for consumer applications. For example, a polymer called polyether urethane used in artificial hearts was originally used to make women’s girdles. Dialysis tubing was originally sausage casing. And breast implants, one of them was actually a lubricant and the other was a mattress stuffing. They just used any material they could find that resembled the tissues they were trying to replace.

But the off-the-shelf approach has led to a number of problems. For instance, when blood hits the surface of an artificial heart, clots may form and the patient may suffer a stroke.

TR: Weren’t chemical engineers or materials scientists involved in choosing which materials to use?
LANGER: Well, not very much. So at the very beginning of my career, I proposed a different approach to designing biomaterials, which was to ask “What do you really want in a biomaterial from an engineering, chemistry and biological standpoint?” and then synthesize it from first principles.

TR: At the time, was there any precedent for taking that kind of approach?
LANGER: Not really. And I can tell you that when I started out, this was very odd work for a chemical engineer to be doing, since it wasn’t mathematical modeling or something to do with the oil or chemical industries.

TR: What types of problems can better biomaterials solve?
LANGER: There are many applications, from pacemakers to contact lenses, but I have worked mainly on solving problems related to drug delivery. The things you’d like to do are keep drug levels within a certain range, target drugs to a particular cell type or tissue, or help out with drugs that don’t last long in the body, like peptides or proteins. It’s an important area, since up to 100,000 deaths a year in the United States each year can be attributed to adverse drug events, such as an overdose. For instance, I have synthesized polymers shaped to trap or encapsulate drugs, then release them at a precise rate.

TR: What are the engineering challenges in using polymers for drug delivery?
LANGER: It starts with an engineering design approach. For example, in the area of degradable synthetic polymers we are remarkably limited in terms of what we can put in the human body. For many years, the only degradable materials available were some synthetic polyesters used in sutures. But these get spongy and ultimately fall apart. If you put a drug into that kind of polymer, that could lead to a burst of drug release. That could be fatal with a potent drug like insulin.

What you’d really like to do is design a system that would erode, in much the same way a bar of soap dissolves. Along with my students, I went through an entire engineering analysis to determine how one would do this, and came up with a family of polymers that we call polyanhydrides.

TR: So you solved the engineering question, but are there applications for these polymers?
LANGER: A surgeon at Johns Hopkins named Henry Brem came to me about using these polymers in a new brain cancer treatment. There were many scientists who doubted us. They said we wouldn’t be able to synthesize these polymers. When we did, they said that the polymer would be toxic and that it couldn’t be manufactured.

Today as a consequence of studies done by us and others, polyanhydride matrices are used to deliver a powerful chemotherapy called BCNU to treat brain cancer. Normally, BCNU is delivered through the blood, and it is very toxic to the liver, kidneys, and spleen. In this case, the surgeon removes as much of the tumor as possible, but also places up to eight small polymer-drug wafers at the tumor site. The drug is slowly released from the polymer for one month to kill remaining tumor cells and harmful side effects are minimized. One recent clinical trial showed that after two years, 31 percent of the treated patients were alive whereas only 6 percent in the control group survived. This was the first new brain cancer therapy approved by the Food and Drug Administration in more than 20 years.

TR: What are the major technical trends in biomaterials for drug delivery?
LANGER: One area my lab is working in is designing polymer nanoparticles to deliver DNA efficiently in gene therapy. This is basically a tiny polymer sphere with DNA inside that you want to get into a cell. It’s very challenging, but the plus is that you may get some significant safety advantages over the gene-delivery systems that are now in clinical trials, which make use of viruses.

Further out, we’re thinking about things like “smart” systems that can deliver drugs in response to specific body signals. You could have an implantable biosensor that can detect glucose levels and tells a drug-delivery implant to release insulin when it is needed.

TR: What about permanent implants?
LANGER: A lot of people think the ultimate solution will be smart systems that behave a lot like the part of the body you are trying to replace. With artificial blood vessels, we are thinking now about approaches where you could attach molecules that might be desirable, say, something to attract endothelial cells [the cells that line normal blood vessels] and help create a natural lining. In a sense, I think what you want to do is get rid of materials-you want them to do their job and then disappear, or become invisible.

TR: You’re talking about combining synthetic materials with proteins or cells?
LANGER: Right. The merger of engineering and biology is very important today. There is a real revolution going on in the biological sciences, and the associated engineering opportunities are enormous. In a field like tissue engineering, it’s the integration of knowledge from cell biology, materials science and process science that you need to create a new tissue.

TR: You mentioned tissue engineering. Can you explain what this field is about?
LANGER: The approaches that we use start from the observation that if you take cells and inject them into the body at random, nothing happens. But if you take those same cells and line them up close enough together, they can form tissue structures. If you take mammary epithelial cells and line them up, they will organize and make milk.

The first engineered tissue was skin, which you can grow on a two-dimensional surface. But in 1986, along with Jay Vacanti [a pediatric surgeon at Massachusetts General Hospital], I decided that if you really wanted to make tissues-bone, cartilage, liver, you name it-you could use synthetic polymers and put them into three-dimensional structures. That provides a template for the cells to grow and allows them to reform structures.

TR: What kinds of tissues are you making in your lab?
LANGER: We are trying to make cartilage by growing cartilage cells on degradable polymer foams. We can design the foam in the shape of a human nose, for example, then place cells throughout the foam and grow it in a bioreactor. Over time, the cells produce extracellular matrix which provides strength, and the polymer dissolves. The result is pure cartilage in the shape of a human nose.

TR: Has this kind of work progressed outside of the lab?
LANGER: This field is growing pretty fast. Several tissue-engineered skins are approved by the FDA [for treating burns or wounds]. Cartilage is in clinical trials, and liver is in clinical trials [a device for liver-failure patients in which blood is passed outside the body through a cartridge filled with liver cells]. So there are a number of things that have moved out of the laboratory. And before that, in animals, there are probably about 20 tissues being worked on, including heart valves, blood vessels and intestine. All of these are grown on polymer scaffolds.

TR: Will we be able to regrow very complex organs, like hearts?
LANGER: I am sure with enough time, perhaps decades, all these things will be figured out. But right now, it’s very difficult. It really depends on the complexity of the tissue, and our understanding of the biology and engineering challenges, and also how perfect you need the system to be. Though the FDA has approved tissue-engineered skins, those are not absolutely perfect skins-they’re just better than anything else you can do. And there are cell types, like nerves, that have proven to be really complicated. We are just starting to learn things from biology that are enabling us to do a little bit better in this area.

TR: More than 50 companies have licensed your inventions in polymer chemistry. How does it feel to help create new industries?
LANGER: It feels good. My goal has always been not just to write the scientific paper or file a patent, but to really push some of these ideas to the point where they will affect people’s lives in a positive way. And it takes a long, long time for the most part. When you start doing these things, no one believes in them, nobody wants to fund them, and companies don’t want to do them. And you get criticized a lot.

The important thing to remember is it’s not going to be by the efforts of one person or one lab that these problems get solved. What makes these approaches work is ultimately having hundreds or thousands of people working on them. And that is what has happened in drug delivery, and that is what is starting to happen in tissue engineering and bioengineering in general.

TR: What does the future hold for you?
LANGER: The big thing for me is to keep coming up with these early-stage ideas, which people may call crazy as they called some of the other ideas crazy 10 or 15 years ago. For instance, we’re working on implantable microchips that can release specific drugs or vaccines into the body on demand by telemetry. One of my graduate students, John Santini, is building a drug-delivery chip with 1,400 reservoirs, in which you could put 1,400 different substances, or many doses of one drug. You’d probably put a little microprocessor on it and signal it from the outside. I want to move this far enough along so that, again, we’ll end up seeing a lot of people working on it. For me, ideas are like children growing up. I want to nurture them so they are stable and so they will happen.

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