The evolution of biomaterials - interview

The evolution of biomaterials - interview

4 nature materials | VOL 8 | JUNE 2009 | interview

How did you become interested in ■■ working with biomedical materials? In 1974, I had just begun a postdoctoral position with Judah Folkman at Children’s Hospital and Harvard Medical School, and I needed to solve a problem: to isolate what would be the first angiogenesis [growth of blood vessels] inhibitor. To do this, I wanted to develop a corneal assay for stopping blood vessel growth in a rabbit; part of this involved the creation of a polymer system that could be embedded in the cornea to continuously release macromolecules that were angiogenesis inhibitors for many months. In 1976, we published this research in Science1 and since then the area of angiogenesis inhibitors has become an enormous field. Over 1 million people use such inhibitors every year to treat cancer or macular degeneration, a leading cause of blindness.

What are your principal research ■■ interests in the biomaterials area at the moment? We continue to work in drug delivery and controlled release. Some of the newer things we are doing in drug delivery include creating nanoparticles that are targeted to specific cells in the body, and the delivery of new molecules, such as siRNA [small interfering RNA], that can be used to turn genes off. We are also creating specifically designed nanoparticles containing DNA to allow gene therapy on many different cell types. Finally, we are carrying out work on tissue engineering — combining materials and cells to create new tissues and organs in the body. This work is leading to the creation of new skin and other tissues.

What work are you most proud of from ■■ your time working on biomaterials? There are many areas I’m proud of. One of these is our early discovery in 1976 of how polymers could be used to continuously release macromolecules2. Another area is the synthesis of new materials that have led to new treatments for brain cancer and other diseases. A third one is tissue engineering. In 1983, Jay Vacanti and I had an idea that if we designed polymer fibres in the right way, cells might be able to organize themselves on the fibres to create organs and tissues — and that turned out to be true. We’re proud of this work because these studies showed that you could make three-dimensional polymer scaffolds and use them in such a way to help organize cells to make tissues. This approach has been widely used in academia and industry as a cornerstone of regenerative medicine. I believe our 1993 Science paper on this topic has been cited over 2,0 times3.

Some tissues, clinically based on this concept, are already available — such as skin — but there are still many others that would be good to make, for example spinal cords, livers, pancreases and hearts. So we continue to work on all of the aspects that are required: cell biology, immunology and materials. The more complex organs — heart, liver, and kidney — are a bigger challenge. Increased complexity often means more cell types, which increases the difficulty of making the tissues or organs.

How do you approach the challenge of ■■ achieving this complexity? Materials are just one part of it. One might want to have a vascular supply, so one could use microfabrication as a manufacturing technique to build in microvessels. You may want to synthesize highly elastic, strong biomaterials because some tissues, such as the heart, require elasticity. Recently,

Lisa Freed, I and our colleagues showed that this approach could be useful in tissue engineering4 by making an accordion like polymer structure seeded with heart cells that could create new heart tissue (Fig. 1).

What has been the most impressive ■■ development in tissue engineering in the past five years? The whole area of stem-cell biology is one of the most exciting developments: trying to understand how to control stem-cell behaviour, and how you can convert regular cells into stem cells — such as the IPS [induced pluripotent stem] cells. These kinds of areas are very important. Though researchers have achieved a lot, the way they have achieved this is generally by using viral vectors [to deliver genetic material into cells]. I hope the work that we and others are doing will enable a way to do these steps with non-viral vectors.

We have been collaborating with

Rudy Jaenisch at the Massachusetts Institute of Technology, and he is a pioneer with IPS cells, although he started with viral vectors the same as everyone else. We have created materials that are very potent at gene therapy and so we hope we will be able to use these materials to replace viral vectors and this, of course, would be safer. In particular, Dan Anderson and others in our lab are synthesizing new polymers that can deliver genes very effectively and yet are still quite safe.

What important factors do you keep in ■■ mind when designing biomaterials? There are several factors. The materials themselves can be an inspiration — you might get an idea from what the tissue is like; what the strength and elasticity should be; what the degradation should be; whether you want a more complex microstructure because you might be using multiple cell types. One example that requires a more complex microstructure is the liver, which has five cell types plus a complex network of blood vessels. To work on this, we have been collaborating with Jeff Borenstein at Draper Labs using microfabrication technologies to create a microvasculature structure.

The evolution of biomaterials

Robert Langer has spent more than 30 years working with biomaterials and has seen their development from simple implants to complex multifunctional interfaces with the body. He shares his vision of the field’s origins and what the future holds with Nature Materials.

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nature materials | VOL 8 | JUNE 2009 | 445 interview

What do you think have been the pivotal ■■ moments and products that have shaped the biomedical industry? The artificial kidney was important as an early biomaterial-based implant. Heart valves have also been very important. But there are a lot of areas; biomaterials have a central role in almost any aspect of any implant. They have had a key role in medical devices, drug delivery systems and many other implants.

Moving towards degradable implants has been an attractive research direction because many of the problems that might evolve with non-degradable materials would go away. In tissue engineering, we use a temporary biodegradable scaffold and ultimately you generate natural tissue and no synthetic polymer.

Have there been any major set-backs in ■■ the industry? The biggest set-backs have been legal ones. I don’t think they were justified, and they were not decided on by people who really understand the field. Certainly, Dow Corning going bankrupt in the nineties because of lawsuits against breast implants had a bad effect. And Dupont had to give over millions of dollars in legal expenses because they supplied the materials for another company that was making an artificial jaw; that company went out of business, and lawsuits were made against Dupont even though they did nothing wrong.

Issues like these have stopped companies from becoming involved with biomaterials because of liability. This happens particularly in the US, probably more than other countries. For example, the National Research Council publication ‘Rising above the gathering storm’ states that more money is spent on tort litigation in the US than on all research and development. I doubt that could be said for any other country in the world.

Which therapeutic areas have been ■■ helped most? Heart valves and artificial dialysis are certainly among them. Biomaterials are everywhere. They help in controlled release systems in the pharmaceutical area, an enormously broad field that has a huge influence. Biomaterials affect hundreds of millions of people who use devices, diagnostics and drug-delivery systems. Examples are stents and pacemakers in terms of devices, blood tests for diagnostics, and injectable microcapsules and transdermal systems for drug delivery. Biomaterials are a central component of all of these systems.

What are the short-term goals of the ■■ biomaterials industry? I don’t think there is a single goal: there are a variety of goals. Creating materials that can solve different problems — it could be a better bioprosthesis, it could be stronger materials — there are all kinds of challenges, and each area has its own.

For instance, in the treatment of cancer and heart disease, one of the challenges is coming up with a way to do targeted drug delivery, to target drugs right to the cells of interest. In many areas you’re also looking for materials that are highly biocompatible and non-inflammatory. Finding a material that is extremely biocompatible is a real challenge.

Moving into the longer term, I think by 2020 we will see new drug delivery systems with nanoparticles that can be targeted to specific cells or tissues.

some biomaterials are now beginning ■■ to come through clinical trials, appear on the market and even be used in therapies. Which products are you most excited to see being used? There are a few. One set of products is degradable stents — these are tubular constructs inserted in veins and arteries to provide support and keep them open — composed of lactic/glycolic acid copolymers, certain polycarbonates or other materials. A second one is nanoparticles for targeted drug delivery, composed of block copolymers, cyclodextrins or other materials. And even though a little further off — I would expect clinical trials to start in a year or two — there are implantable silicon microchips with arrays of glucose sensors to enable long-term glucose measurement. All of these systems could initiate fundamental changes in medical therapies.

Based on what we’re seeing today, what ■■ biomaterial products do you think we can expect to see coming to the market and being used in the next two to three years? I think we could see degradable stents used in human therapies in this time frame. Targeted nanoparticles will also be used, but may be a little further off. We could also see lipid-based systems for siRNA delivery.

How do you feel rewarded by working in ■■ this field? It’s very rewarding to see that the research we are doing is helping people’s lives. As I work at a hospital as well, I am sometimes able to see those effects first-hand. I feel biomaterials is a very important area that has helped and can help an enormous number of people.

References 1. Langer, R., Brem, H., Falterman, K., Klein, M. & Folkman, J.

Science 193, 70–72 (1976). 2. Langer, R. & Folkman, J. Nature 263, 797–800 (1976). 3. Langer, R. & Vacanti, J. P. Science 260, 920–926 (1993). 4. Engelmayr, G. et al. Nature Mater. 7, 1003–1010 (2008).

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Figure 1 | accordion-like honeycomb scaffolds yield anisotropic mechanical properties similar to native myocardium. a, Schematic diagram of the honeycomb design. Scale bar 1 m. b, Realization of the structuring in polymeric scaffold. Scale bar 200 μm. c, Preferentially aligned heart cells grown on the scaffold in vitro.