IEEE PULSE presents

How Nanomaterials Are Reshaping Biomedical Technology

Feature March/April 2014

Three leading figures in the world of nanotechnology research, commercialization, and policy were invited by IEEE Pulse to discuss how this rapidly emerging area has been shaping biomedical technology in recent years, as well as its most promising applications in years to come. The panel consists of Eric Keller, CEO of Nano Terra Inc., a company devoted to bridging the gap between laboratory research in nanomaterials and coatings and scalable, marketable products; Art Coury, an organic chemist with decades of experience in research for various companies including several years at Genzyme; and Tarek Fadel, a staff scientist with the National Nanotechnology Coordination Office, a central coordinating body for federal research in nanotechnology. (See “More About Our Roundtable Participants” to read more about them.)
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Left to right: Eric Kelly, Tarek Fadel, Art Coury
Left to right: Eric Kelly, Tarek Fadel, Art Coury

Eric Keller received his A.B. degree from Harvard College and his J.D. degree from Boston College. He is the chief executive officer at Nano Terra, Inc., which he cofounded with Harvard professor George Whitesides. Previously, he worked in several technology start-ups, venture funds, and Fortune 100 companies. He was a vice president of America Online and played a major role in its business development. He began his career as an attorney, representing both venture funds and venture-backed companies at Testa, Hurwitz, and Thibeault and later at Piper and Marbury.
Tarek Fadel received his B.Sc. degree in chemical engineering from Oregon State University and his Ph.D. degree from Yale University. Later, at Yale, he worked on developing nanoscale biomaterials for cancer immunotherapy and acquired business and entrepreneurial experience at the Yale School of Management. He is a staff scientist at the National Nanotechnology Coordination Office and executive secretary for the Nanoscale Science, Engineering, and Technology (NSET) Subcommittee within the National Nanotechnology Initiative (NNI). He previously held engineering positions at Hewlett Packard Corp.
Art Coury received his B.S. degree in chemistry from the University of Delaware, his Ph.D. degree in organic chemistry, and his M.B.A. degree from the University of Minnesota. He is an independent medical device consultant at Coury Consulting. He was vice president for biomaterials research at Genzyme Corp. for eight years and previously held the positions of vice president for research and chief scientific officer at Focal, Inc., senior research chemist at General Mills, Inc., and director of polymer technology and research fellow at Medtronic, Inc. His career focus has been polymeric biomaterials for medical products such as implantable electronic devices, hydrogel-based devices, and drug delivery systems. He holds more than 50 patents.
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IEEE Pulse: Could you begin by describing your sense of the impact various areas of nanomaterials research have had on biological and medical research over the last several years, and where the field stands today?
Coury: Let me begin by going back. “Nanomaterials” has only been a buzzword for the last 20 years or so, and that word has been a great source of funding. And with new technologies, new techniques, and new compositions, nanomaterials have been shown to have great promise. But you know, 100 years or more ago, we were already using colloids—in essence, we were using nanoparticles in medicine. For example, colloidal silver and colloidal gold have been used therapeutically for a very long time.
Twenty years ago I was working on a hydrogel, and it was made by first forming micelles in an aqueous medium and then polymerizing these micelles so that you went from a liquid to a hydrogel. The micelles were about 1–10 nm in size. So this field has been important for many years.
Nanomaterials include many things; they can be nanoparticles that are in separate form, for example. These nanoparticles then can be in a matrix of some sort, such as in a silicone polymer, to toughen up the polymer. And nanoscale surfaces are just as important as separated particles. So nanotextured surfaces can have a major effect—almost independent of their compositions—if the composition is stable. It could be a polymer or a metal, and cells, for example, react to the structure, rather than the composition. Also, nanoscale can also be nanoscale porosity. There are valuable applications for all of these compositions.
Until recently, most nanoparticles have been based on minerals or metallic compositions. We have developed the ability to make nanoparticles of polymers over the last 20–30 years or so. Today, there are over a thousand commercial products that are nanomaterials, and I think cosmetics are ahead of medical devices and drug delivery.
Keller: The concept of nanotechnology itself is a bit of a misnomer. People talk about it in terms of nanomaterials and nanoparticles and the like. But my typical answer when people ask me “What is the meaning of nanotechnology?” is, “very little.”
It’s a scale, it’s not a technology. Much of what we end up doing at Nano Terra is not nano. Some of it is: the things that are nano are nano because they have to be, but it’s really about applying the right forces, applying the right materials at the right scale, to achieve the desired function.
The basis of what we do is around surface science and materials. We start with a process that is inherently scalable, with materials that are well known and whose properties are well known and interactions well known. You’re using paper or cellulose or elastomers—common well-understood materials. You’re using components and chemistries that are compatible with the end-use applications. So you start with materials that are biocompatible—that are environmentally compatible—processes or materials that are compatible with the end use. So then you’re significantly improving the likelihood that the end product is compatible.
For example, Surface Logics, a company we acquired, developed a technology to improve the efficacy of known small molecule active ingredients. You start with a known active ingredient, something that’s already been proven to be nontoxic and efficacious, either as a drug or as an agricultural ingredient, but a biologically active ingredient. By making nanostructural changes to the surface, you can then have a large effect on the function of that known compound.
You can use chemical groups to modify the response to microenvironments, to improve the pharmacokinetic or pharmacodynamic profiles. You can prevent undesired interactions and enhance desired interactions. You can improve solubility and absorption. So you can create new functions in some cases—in some cases better functions, improved efficacy, reduced ­toxicity—by modifying the surface interactions without changing the properties of the underlying known active ingredient.
Fadel: Over the last ten years, there have been many commercial opportunities in nanotechnology. In my research at Yale, we worked on the development of novel nanoparticles for vaccine delivery, for example. One of the interesting areas of research has been in drug delivery, where nanomaterials have been shown to improve the solubility and bioavailability of some cancer drugs, some hydrophobic drugs or protein vectors, and to reduce toxicity, enable targeting, and allow for interesting modes of action such as controlled delivery, combinatorial therapy, “hitchhiking,” and so on.
There are also applications in regenerative medicine, where nanomaterials have been shown to have a large impact. A lot of my research has involved how the topography of the surface can influence cell growth and proliferation. Nanomaterials can also provide delivery of crucial biomolecules that can influence growth, differentiation, and cell signaling within a cell scaffold.
There are applications in diagnostics, where they can enable you to use smaller and smaller amounts of blood or other biofluids, for example, for a test. They could not only allow you to work with a small volume but also monitor accurately the kinetics of reactions between biomolecules, which I think is really important.
And finally, there are uses in imaging, where nanomaterials have been used as contrast agents or as vehicles for contrast agents, and have been targeted to particular tissues or to tumors to provide images with much higher specificity and resolution. In some cases, these nanoenabled imaging systems can be irradiated for therapeutic purposes and destroy surrounding target cells, making it a combination of diagnostics and therapy.
IEEE Pulse: What are some of the specific advantages that nanomaterials can provide to medical diagnostic or therapeutic devices or processes? Why is this an important area?
Keller: One major advantage is the ability of surfaces at the nanoscale to mediate all sorts of interesting properties. The surface can mediate wettability, adhesion, electronic properties, thermal transport, optical properties—you name it. We could go on and on, as all sorts of interesting stuff happens at the surface. And by controlling it, you can create new functions. But because you’re only modifying the surface, the amount of material that you’re affecting can asymptotically approach zero. And by modifying the surface only, you are not significantly affecting the cost of raw materials, and you’re not changing the compatibility of that raw material.
One example we’re working on is a bioinert coating that mediates the cell adhesion—the interaction between the cell and whatever substrate you’re on—by controlling the surface chemistry, that is, the surface properties. As a start, it could be used for tissue culture ware, where you want to make the underlying substrate—whether it’s glass or polystyrene—not change the environment that the cell sees. We’ve developed a coating that is biologically inert but can be functionalized, so you can pattern chemistries to allow the cell to see what you want it to see.
By starting with known materials and manipulating the surfaces we can achieve what we call minimal manipulation, where the cell is minimally influenced by the medium—the substrate that you’re using. The cell fate is controlled by many things. And some are understood and many are not understood. If you can influence cell fate by the introduction of small molecules that affect particular pathways, the proteins that the cell sees can affect cell fate. So we started on the basis of whether or not we can make the surfaces invisible to the cells. That’s the most easily understood factor. But we did this in such a way that we now have tools to control the surface, so we can use it as a way to influence the cell fate.
Fadel: Nanomaterials offer the opportunity to detect functional changes at the molecular or cellular levels, and that enables the possibility for early diagnosis and improved prognosis. It is an exciting step ahead, but also a shift in the way we do conventional medicine. Usual treatment methods focus on remediation when symptoms are already expressed. With these new methods, we could focus on doing something before the symptoms appear.
Another opportunity nanomaterials can offer is the possibility to facilitate the shift from conventional medicine to personalized medicine by allowing modulation of treatment to particular targets within the human body. These treatments would not only ensure targeted delivery, but optimal delivery for a specific patient.
Coury: The distinctive thing about nanoparticles is the ability to bind to a molecule and get into the cells, if it’s a therapeutic. If it’s a diagnostic, it’s the ability to circulate for long periods of time without getting caught in capillaries or organs—unless you want it to, and then you attach an antibody or peptide that will attach to certain tissues.
IEEE Pulse: Are there particular regulatory challenges or safety issues that apply to the use of nanomaterials that are different from those that apply to conventional materials?
Fadel: Nanoparticle-based therapies a priori don’t invoke harsher requirements than conventional medical treatments (since you need to demonstrate safety and efficacy in either case), but nanoenabled therapeutic systems are more complex than the drug alone, and that’s what makes it difficult. They require additional proof of effectiveness. And, for example, if a nanoparticle therapy is supposed to be targeted to the liver, you have to show that as well.
One thing that’s important to recognize is that this is an emerging technology and there is a lot of excitement, but it’s important to be aware of its limitations. There are economic, but also therapeutic, limitations. For example, particles in a particular size range, say 50–100 nm, will be diffused into certain tissues, but not into other tissues. Many applications are going to be limited by that.
Coury: I’ve been through this because I’ve tried to develop them, in this case, cosmeceuticals (combined cosmetics and pharmaceutical agents). You can’t do animal research on cosmetics or cosmeceuticals if you want to have a marketable product. You have to do this either by doing cell cultures or by doing human studies. So in a lot of ways there is a medical aspect to cosmetics. I think there are more cosmetics with a medical aspect than there are medical devices based on nanoparticles at this time.
The fact is that nanomaterials, depending on the scale and composition, have the ability to pass through skin, the ability to enter cells, they have the ability to pass through capillaries. If the particles stay separated and they’re fewer than 5 microns or so in size, they can just keep circulating in the bloodstream, in the lymphatic system, they can move about in the extracellular fluid if they get there. Once you start doing that kind of thing, then, effects really matter.
DNA alone is not going to penetrate the cell and get to the nucleus. But if you put it on a charged nanoparticle and it forms a spherical shape, then it can get right through. But once you get into a cell, you don’t want it to do damage, you don’t want it to stay around so long, so they’re developing resorbable compositions for nanomaterials for different applications.
Sometimes, with surface texture, it doesn’t matter what the composition is, but sometimes it does. If a particle of iron oxide gets in to your cell, that’s not as toxic as copper oxide. Copper is one of the worst things to get into a cell.
Then there’s also the issue of environmental safety. We don’t think you should be releasing a lot of industrial nanoparticles into the waste stream. I think you’re going to find a lot of environmental issues. There was a case using nanoparticles that were intended for use in electronic circuits, and they started flying around and shorting out the circuits. This just illustrates that you do have to keep control of those particles.
Keller: Well, there are both real issues with the materials, and there are perceptual issues. There’s a lot of mythology that’s out there. Our approach to it is that if we work with known material—materials whose properties are understood—and are dealing only with nanostructuring at the surface, then we will to a large extent avoid those regulatory issues, that is, those out-of-the-mainstream regulatory issues, not the regulatory issues that are inherent in any material.
There’s this sense that nanomaterials are a new class of materials that we don’t understand. In fact, nanomaterials exist in nature; they have been part of our interactions with natural materials forever, so there’s nothing about nano by itself that should raise new flags.
IEEE Pulse: What about on the economic side? Are there issues faced by companies wanting to pursue the use of nanomaterials in biomedical applications that are different than those that apply to other technologies?
Keller: Innovation is very hard to do at the corporate level. Quarterly pressures dominate. Large companies typically have more to lose than to gain. It’s very hard to build the right sort of unencumbered innovation environment and team, which is why you don’t see a lot of nanomaterials innovations coming out of large companies.
Also, connecting the innovation that’s happening in academic labs to real products in the market is hard to do, but it’s especially hard to do in materials science. In drug discovery, there’s a process for doing that, it’s not a very good one and it’s a hugely inefficient one, but people are used to doing it. But it doesn’t exist in the materials science area. There’s insufficient awareness of product needs and product requirements.
And what that leads you to is the well-known valley of death, where the amount of investment required to go from a lab-scale technology to a manufactured product is prohibitive. And very few companies get through that valley. You have to build manufacturing capability, you have to build broad infrastructure, you have to build all the trappings of a company, and it becomes very expensive to do. It’s the place where the venture capitalists play, and they play very effectively, but inefficiently.
To fund what’s required to get across that valley, you’ve got to have a really big market at the back end. And that’s why you have this industry that’s developed in the venture capital world of going after homeruns. And they succeed on very few homeruns. And it leaves a lot of the valuable technology unrealized.
Another issue is that scientists are undervalued in this whole process. [Nano Terra founder George] Whitesides said his best people were leaving to go to McKinsey, or Goldman Sachs, and not going into research, and that’s backwards. For this industry to thrive, it has to be on the basis of innovation. We have to overvalue scientists.
Fadel: Commercialization is a significant undertaking. In between the lab bench and the final product, there is a whole litany of challenges that must be tackled. The challenges include the ability to scale up processes for production. For scale-up to be viable, laboratory processes must be compatible with current manufacturing capabilities. Also, newer nanomedicines under development often include additional properties, such as for a “targeting” that is designed to promote the association of the nanoparticle with a particular cell type or tissue.
And there are economic issues, including looking at the magnitude of development cost when considering the extent of the resulting improvements in effectiveness. And understanding that nanoenabled therapeutic platforms, with all the excitement they’ve generated, are going to have some limitations.
IEEE Pulse: What do you see as the most promising new emerging areas for applications of nanomaterials in medicine and biomedical research?
Coury: One possible area is the use of quantum dots or other types of nanoparticles as imaging agents. They would be on some sort of a carrier—a solid carrier—but on the nanoscale. Currently, with imaging agents for an angiogram you squirt in a particulate material and it usually gives you about a second or two of imaging. But this certain nanoparticle systems give you a minute or two—it can image the whole vascular system. In therapeutics, nanoparticle-based drug delivery is coming to the fore.
And don’t forget surfaces as well as suspended particles. If you want to, say, improve the sensitivity of an electrode, you might want to nanotexture it, so you get the right kind of ingrowth of tissue into the surface. The use of engineering of surfaces is going to be big for nanotechnology.
Fadel: There is an opportunity to defy conventional medicine. One of the most promising things that nanoparticles offer is a chance to offer personalized treatment, the ability to get a personal understanding of your situation. It’s very enabling. It’s an opportunity to make a real change.
Keller: We think that the promise of cell biology and stem cell biology is enormous. Cell biology is still done on 50-year-old technology (of culture plates). So improving the interfaces, the tools, the methods for controlling cells in the research process, and eventually in the therapeutic process, and making the environments that you’re working with more in-vivo-like, has enormous promise.
Think of toxicology. Toxicology for a couple of generations has been done on cells grown on a two-dimensional tissue culture, where the cells have stress fibers because they develop in a stressed environment, so the toxicology results done on these cells that are already stressed is not necessarily particularly representative of their effects on cells in vivo. So I think there is huge potential in making the lab in vitro environment more correlated to the real in vivo cell biology.
Another area is simple tools: being able to do things on paper, on a chip, using simple, inexpensive microfluidic devices. If you can drastically reduce the cost of the device needed to do the diagnostic, it puts the value on the information. There is promise in developing faster, simpler, lower-cost, and ultimately, more accurate diagnostic tools. It’s starting to happen now. We’ll ultimately get to the point where the cost of the diagnosis is essentially free. But right now, these tools are being developed for near-term use. It can reduce the time to diagnosis, and allow more relevant decisions.
The need for innovation and the need for new products to come out of that innovation will continue to accelerate. We have problems that will require innovative solutions. As raw materials become more difficult to obtain, and in greater scarcity, the ability to use just the amount of material that you need, when you need it and where you need it, will become even more important and more relevant, including for medical and biological applications.
I think the area of nanomaterials has enormous promise and it’s at the cusp of being broadly applicable to a broad range of problems. If I were a young student today, this, to me, is an area of enormous application and I would think very seriously about becoming a materials scientist and working in this area.

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