Proceedings from the Workshop on Biomedical Materials at the Edge: Challenges in the Convergence of Technologies (2006)

Crystal M. Cunanan

ReVision Optics

Bonnie A. Scarborough

National Research Council

Rapid developments in biomedical materials are being enabled by continuous advances in other areas of science, such as genomics and proteomics, cell-processing techniques, supramolecular chemistry, permutational chemistry, bioinformatics, and information technology. The need for interdisciplinary research in biomedical materials is therefore increasing, with the most exciting potential for new therapies lying at the point where a number of research disciplines converge. For example, promising new therapies can be created through combination products, miniaturization of biosensors, gene-based therapies, and the generation of engineered tissues to restore functional organs. Emerging biomedical materials hold out the promise of new therapies for the treatment of many currently untreatable medical conditions.

However, this convergence of technologies, while presenting new opportunities, also presents new challenges. Although scientific discoveries are being achieved at an ever faster pace in the life and physical sciences, these advances are not being translated as rapidly into medical innovation. Improved medical technologies are therefore not reaching patients at a rate that matches the rate of scientific advances. Because these scientific advances create an awareness of the tremendous complexity of the systems being studied, it can be argued that they may be slowing technology transfer by raising questions that are difficult, if not impossible, to answer. The emerging field of systems biology promises to synthesize this basic science into more usable formats. However, it will be many years before this promise can be fulfilled.

To explore the opportunities and challenges being created in the development and application of new biomedical materials and to discuss possible pathways to overcoming the challenges, the workshop “Biomedical Materials at the Edge: Challenges in the Convergence of Technologies” was held by the National Research Council’s Roundtable on Biomedical Engineering Materials and Applications (BEMA) on September 30 and October 1,

2004, in Washington, D.C. The workshop consisted of four sessions: setting the context for new biomedical materials; stem cells as biomaterials of the future; biomolecular materials composites; and supramolecular biomaterials engineering and design (nanotechnology) (see Appendix A for the agenda).

To understand the context in which new biomedical materials are evolving and the challenges and opportunities faced in creating innovative medical therapies from these emerging materials, it is important to understand current policy, regulatory, and economic conditions. In this session, presentations were given by Susan Bartlett Foote, Division of Health Services Research and Policy, University of Minnesota; Larry G. Kessler, Center for Devices and Radiological Health, U.S. Food and Drug Administration (FDA); Annabelle R. Hett, Swiss Re; and Stephen N. Oesterle, Medtronic, Inc.

Susan Foote presented her views on the role of public policy in medical technology innovation. Current public policy does not match the innovative advances occurring in science and technology. This is largely because the process of creating public policy is reactive rather than adaptive. Policy is constrained to develop within the limits of authorizing legislation, and while the law provides the authority to regulate, it also limits the extent to which that regulation can change. Instead of considering the overall landscape, the policy-making process normally focuses on making individual distinctions and incremental decisions with regard to smaller issues. Strategies for public policy could be developed, however, that would enable the design of more flexible and adaptable systems. The disciplines that will most likely have a substantial impact on the medical community include the biological sciences, information technology, and materials science. Out of these disciplines, new technology fields are being created: telemedicine, bioinformatics, microelectromechanical systems, tissue engineering, nanotechnology, and gene therapy, to name a few. In addition, the combination of biological materials with medical devices to repair, replace, restore, and regenerate tissues and organs promises to be an important new area of medicine.

When considering the role of public policy in medical technology innovation, it is difficult to generalize, because different device technologies will face different hurdles for development and commercialization. In addition, not all hurdles are policy-related. Markets, territory, costs, alternative technologies, and other intangibles also create barriers to the development of innovative technologies. For example, to understand the impact of the medical marketplace, one must consider the variety of customers, including providers, hospitals, physicians, and government and private

payers. Other factors that affect the development process are intellectual property, public perception, costs, and liability. Ms. Foote ended by saying that public policy is often in a state of flux, affected by the politics of the current environment, and this makes it difficult for policy to be as flexible and innovative as the basic sciences and technology can be.

Larry Kessler presented data showing that while advances in basic research have generated exciting new discoveries in, for example, genomics and nanotechnology, there has been a steady decline in the number of applications to the FDA for the approval of new drugs and biologics. In contrast, there has been an increase in applications for approval of new medical devices over the past 10 years. These medical devices are increasingly complex and are designed to address more serious diseases. FDA recognizes that it plays a key role in regulating the translation of medical discoveries into new therapies, especially in the final stages of clinical testing and market release. FDA does not want to be a barrier to that flow of new products, yet it recognizes that it may not have the organizational structure to assess these new technology submissions.

To avoid roadblocks in the translation of new ideas into new products, the U.S. Department of Health and Human Services (HHS), which oversees the Centers for Disease Control and Prevention (CDC), the Centers for Medicare and Medicaid Services (CMS), the FDA, and the National Institutes of Health (NIH), has developed a number of center-specific initiatives to keep these organizations abreast of scientific advances. NIH spearheaded this effort with its Roadmap Initiative,¹ which has three main themes: new pathways to discovery, research teams of the future, and reengineering the clinical research enterprise. FDA launched its Critical Path Initiative² to ensure that breakthroughs in medical science are demonstrated to be safe and effective for patients as quickly and inexpensively as possible. In addition, programs to advance clinical research are supported by the Agency for Healthcare Research and Quality (AHRQ) with the Translating Research into Practice (TRIP-II) Initiative.³ This effort focuses on the techniques and factors associated with successfully translating original research into routine clinical practice. Also at AHRQ, the Centers for Research on Therapeutics⁴ (CERTs) conduct research and provide education to advance the optimal use of drugs, medical devices, and biological products. Taken together, these programs and the Medicare Modernization Act of 2003 are examples of government efforts to ensure that systems keep pace with technology advances.

In May 2004, HHS formed an internal task force to encourage innovation in health care and to speed the development of effective new medical technologies, such as drug and biological products and medical devices. The Medical Innovation Task Force involved the CDC, CMS, FDA, and NIH. In recognition of the fact that a new technology must often clear hurdles in different parts of HHS before it can reach consumers, the task force was asked to make recommendations on how this process can be better coordinated across HHS. Dr. Kessler invited workshop participants to submit suggestions to the HHS task force. The task force submitted a report to the Secretary of HHS in January 2005 outlining opportunities for synergy and collaboration both within and between HHS and other government and private organizations.⁵

The successful development of an innovative medical technology will depend on economic as well as policy and regulatory conditions. Annabelle Hett explained that an emerging biomedical material may face additional economic hurdles because it is difficult to define the risks associated with it. If the risks cannot be defined, then global reinsurance companies cannot underwrite the companies seeking to develop applications for that technology. This can delay the introduction of new biomedical products into the marketplace for medical therapies.

Global reinsurance companies such as Swiss Re are the foundation that allows investment in emerging technologies. They identify, evaluate, underwrite, and diversify risk in order to minimize the total capital cost of carrying such risk. The ability to insure a risk depends on a number of factors, including the ability to assess and quantify the risk and its true randomness of occurrence. In addition, the exposed parties must be willing to join together to build a risk community to share and diversify risk, and it must be economically feasible to charge a premium commensurate with the risk. Finally, it must be possible to prove a causal relationship between an action or omission and the resulting damage or loss to cover liability costs associated with a newly developed product. Without these key elements, the industry cannot insure risk.

Underwriting for new products that use emerging technologies poses special difficulties. For example, nanotechnology is an area where the insurance industry does not have a clear risk profile. One reason is that although nanomaterials are expected to be ubiquitous in industrial production, their effects on living organisms are largely unknown. Because nanoparticles are relatively new, little is known about how they interact with living organisms, whether or not they are biodegradable, and how they behave. Nanomaterials exhibit properties different from their bulk properties.

In addition, it is difficult to assess the environmental impacts of nanotechnologies. Federal regulatory agencies do not have an adequate framework to assess whether a material’s properties on the nanoscale are different from that material’s properties on the macroscale or whether any such differences might affect public health. Finally, public perception is an unknown variable in evaluating technology risk. In summary, more accurate terminology, an improved ability to assess risk and severity, and improved regulatory guidelines are needed for insurance companies to develop appropriate models to support new technologies such as nanotechnology. To move forward with these technologies, Dr. Hett recommends starting a risk dialogue among regulators, businesses, scientific institutions, the insurance industry, and the general public.

New biomedical materials create challenges for traditional medical device companies as well. Stephen Oesterle described a new business model created by two health-care companies, Medtronic, Inc., and Genzyme Corporation, to address these challenges and take advantage of emerging opportunities. Medtronic partnered with Genzyme in the formation of MG Biotherapeutics, which is exploring, among other things, clinical applications of skeletal myocyte transplantation into the diseased hearts of congestive heart failure patients. The financial investments, technology contributions, and skilled expertise across a variety of disciplines associated with addressing this medical condition were estimated to be more than any one company could support. By partnering with Genzyme, Medtronic lowered its investment risk and thereby increased its probability of developing successful cell-based treatments. An interdisciplinary organization was created with skills in both traditional medical device technologies, which are essential for delivery of the new therapy, and autologous cell manufacturing techniques, a unique core competency of Genzyme. MG Biotherapeutics represents a new business model for the convergence of new technologies to make products with high potential; it combines contributions in basic research, development, engineering, intellectual property, regulatory affairs, clinical research, quality control, and marketing. MG Biotherapeutics plans to create a pipeline of new products to treat serious medical conditions such as neurodegenerative diseases, diabetes, and cardiovascular disease.

The first technical session of the workshop focused on stem cells as biomaterials of the future. Speakers were Philip H. Schwartz, director of the National Human Neural Stem Cell Resource at the Children’s Hospital of Orange County

(CHOC); Steven L. Stice, University of Georgia; Michael A. Laflamme, University of Washington; and Mark F. Pittenger, Osiris Therapeutics.

Many challenges are involved in using stem cells as a biomaterial, including funding issues,⁶ ethical considerations, and cell quality. In addition, stem cells are difficult to work with because they can spontaneously differentiate into different lineages. The precise culturing conditions needed to control cellular differentiation are poorly understood. Despite the belief that stem cells are immune-privileged, we know that stem cells from pooled sources or cell lines present safety concerns due to issues of immunogenicity and tumorgenicity. Nevertheless, interest in using stem cells as biomaterials or in combination with biomaterials remains high because they could allow the treatment of currently untreatable diseases. NIH has developed centers such as those at CHOC and the University of Georgia to train scientists and technicians in the specialized techniques required to properly isolate, propagate, and maintain these cells.

While embryos are one source of stem cells, the hematopoietic system is another source that is free of many of the ethical issues surrounding embryonic stem cells. Human mesenchymal stem cells also have differentiation capabilities, although they are more limited than those of embryonic stem cells. Because these cells present the potential for autologous therapies, numerous companies, including Osiris Therapeutics, are performing clinical trials of a variety of applications, including treatments for congestive heart failure. An emerging issue with hematopoietic stem cells is that, although they can be injected into healthy heart tissue, they do not appear to do as well when injected into diseased heart tissue. Thus the environment plays a role in influencing stem cell differentiation even in vivo.

The second technical session of the workshop focused on biomolecular materials composites, or the ability to manipulate biological molecules to create novel materials. Nadrian C. Seeman, New York University; Virgil Percec, University of Pennsylvania; and James L. Harden, the Johns Hopkins University, presented information on their research in this area.

Nadrian Seeman has used the unique repeating structure of deoxyribonucleic acid (DNA) to create materials that can be used for the design of various objects, lattices, and devices. Specifically, he has exploited the base pairing capabilities of DNA that allow structures to self-assemble in specific and reproducible ways. His research group has successfully created nanoelectronic components, polyhedral catenanes, and crystalline arrays with the intent of combining these biomolecular structures to create the desired nanomechanical devices. The inherent properties of DNA make it uniquely well suited to meet the requirements of lattice design components, which include predictable local product structure interactions and structural integrity.

Using self-assembled monolayers (SAMs), Virgil Percec has been able to create supramolecular structures that mimic porous transmembrane proteins. Modeling of these proteins has important therapeutic applications because transmembrane proteins are an important means of introducing molecules into cells. These proteins can be either selective or nonselective, and Dr. Percec focuses on the selective proteins as a means to control the introduction of molecules into cells. By taking advantage of the inherent properties of selective membrane proteins, his research group is trying to determine how to assemble the correct structure in order to create the desired function. Reversing chirality is one way to make a protein that can be both selective and permeable, and Dr. Percec’s group exploits solvent differences to create supramolecular helical hollow columns that self-assemble. One example of the group’s work is dendritic, dipeptide, hydrophobic, pore-protein transport molecules. Solvents such as cyclohexanes enable the use of phospholipids to create the supramolecular structures.

James Harden engineers proteins for specific biomaterials applications using modular protein polymers, much like synthetic block copolymers, for biomimetic designs. Proteins make a suitable starting point for such bioengineered materials because of their tremendous sequence diversity as polymers. In addition, the ability to modify and create artificial amino acids provides a wide variety of basic building blocks. For example, design-directed protein synthesis can be used to control important molecular properties such as sequence length and molecular weight, secondary and tertiary structure, and inter- and intramolecular attractions. This, in turn, allows one to create self-assembled reversible hydrogels with specific structural and mechanical properties that mimic functional motifs from a variety of natural structural materials such as collagen, elastic, and silk. By mimicking these designs, Dr. Harden is able to create structures that have great biomechanical strength but no enzymatic degradation cleavage sites. These qualities make the materials both strong and biostable, giving them potential applications in the creation of vascular grafts, for example, where each layer of the trilaminate construct could be specifically designed to have

the properties desired (e.g., strength, elasticity, cell binding matrix). Currently, protein-based biomolecular materials tend to be either soft hydrogels or somewhat glassy brittle materials. The biocompatibility of these materials must be better understood, however, as proteins can trigger rejection when recognized as foreign by the immune system.

The final technical session of the workshop focused on the creation of new biomaterials using nanotechnology—in other words, supramolecular biomaterials engineering and design. Three speakers addressed the context in which nanotechnologies are developing in the United States today: James Murday, Naval Research Laboratories; Edward K. Moran, Deloitte & Touche; and Nik Rokop, Chicago Microtechnology and Nanotechnology Community. Three other speakers described potential environmental and public health issues related to nanotechnology and described research focused on manufacturing nanostructures for biological and medical applications: Vicki L. Colvin, Rice University; Charles R. Martin, University of Florida; and Jennifer L. West, Rice University.

To understand the context in which nanotechnology is developing in the United States, James Murday described the National Nanotechnology Initiative (NNI),⁷ an innovative federal program created by Congress that committed over $1 billion in 2005 toward the development of nanotechnology capabilities in the United States. Many believe that nanotechnology is tremendously important to the future of materials and that nanomaterials will someday be as ubiquitous as polymers are today. The goals of the NNI are therefore to strengthen and maintain U.S. leadership in nanotechnology.

The NNI represents a new paradigm in federally funded research, with the activities of a number of federal agencies and laboratories being coordinated across agency lines in order to build on the expertise of each group. Federal agencies involved in the NNI include NIH, NSF, FDA, the U.S. Environmental Protection Agency, the National Aeronautics and Space Administration, the Department of Defense, the Department of Energy, and the National Institute of Standards and Technology. These agencies would not normally have the opportunity to participate in the early stage development of such a technology. By involving so many agencies early on, however, each agency may begin to develop competency in nanotechnology,

thereby promoting an understanding of the impact of this technology on its mission. In addition, NNI provides research funding for many universities and small businesses focused on understanding the basic chemistry and physics of nanostructures; developing methods for earlier detection and treatment of diseases; improving implants; and enabling better delivery of therapeutic agents through nanostructures that have enhanced solubility properties, that contain specific targeting mechanisms, and that can provide localized delivery without systemic side effects.

While early signs of success do exist for some nanotechnologies, Edward Moran said, nanotechnology is still too new for most venture capital firms to invest in nanotechnology companies. Venture capitalists are reluctant to invest in a high-technology field that they do not understand well, perhaps as a result of their experiences with dot com and biotechnology companies. When venture capitalists consider an investment strategy, they evaluate technical risk, market risk, and team risk. Technical risk includes the probability that the technology will work, that intellectual property positions can be secured and maintained, and that regulatory agencies will approve the product. Market risk includes customer acceptance, potential revenue streams, the impact of competition and competitive technologies, and technology roadmaps for continuous evolution of the base technology. Team risk includes an evaluation of the management and technical team members, including their track record and prior associations, which determines whether or not the team will be able to deliver on its promises.

Today’s business environment is a new world, and partnering often makes sense when bringing capital-intensive new technologies to market. Venture capitalists do not fund science for the sake of science, and there is a high failure rate among early-stage companies that are unable to cross the chasm from concept to commercial reality. In addition, the complexity of competition has increased across several dimensions, including competition from other nations that may have advantages over the United States because of concerted support from their governments or a cheap labor force and other economic factors. Some environmental issues—potential liability and regulatory constraints—can constrain technology development. Because of the small proportion of nanotechnology funding from venture capitalists, federal funding remains important for the early support and development of this technology.

To support and educate the growing nanotechnology business community, the Chicago Microtechnology and Nanotechnology Community trade organization holds public educational seminars and special events. The organization serves as a convergence point for midwestern micro- and nanotechnology companies seeking knowledge and resources and participates in an international technology exchange that showcases technologies from organizations around the world. Nik Rokop brought the first part of this

session to a close by stating that one should not look at nanotechnology in the United States alone but should consider it instead in a global sense and promote the growth of nanotechnology research and companies internationally as well as domestically.

Having a better understanding of nanostructures is important, as it is increasingly apparent that these materials have unique properties as a result of their size. Nanocrystals, for example, are highly crystalline with large surface areas and therefore offer potential for surface interactions in a biological system. Vicki Colvin, director of the Center for Biological and Environmental Nanotechnology at Rice University, presented her research on issues of biocompatibility for nanostructures.

In the past, incidental exposures to nanomaterials such as asbestos caused significant harm to public health. There is currently some negative public perception of nanotechnology materials as having potentially adverse environmental and health impacts. Dr. Colvin is working to understand the interactions of a variety of engineered nanomaterials with cells and biological systems. She hopes that by working proactively, it will be possible to understand potential safety issues early in the development of the technology. Dr. Colvin is exploring the risk to humans from direct exposure to nanomaterials and is characterizing the environmental impact of nanoparticles, which could indirectly affect human health.

While there are unknowns surrounding supramolecular materials in terms of public health and environmental safety, these materials clearly offer significant promise in the treatment of human diseases as well as protection against bioterrorism. Charles Martin and Jennifer West presented their research on the diagnostic and therapeutic applications of nanotechnology. Through proper design and functionalization, carbon nanotubes, for example, could be capable of detecting single molecules. They could therefore be used as ultrasensitive sensors, with applications in the detection of biological weapons.

Nanotechnology has also enabled an important new advance in cancer treatment that could one day be used therapeutically. Metal nanospheres can be fabricated that absorb energy at specific levels due to their metallic composition. When such nanospheres are functionalized with antibodies that target cancer cells, they bind specifically to the cancer cells and become internalized through the normal mechanisms of endophagocytosis. If the tumor area is then irradiated with energy specifically absorbed by the nanoshell, the heat absorbed by the nanosphere is enough to kill the cancer cells, thereby providing an effective, nonsurgical means of destroying the tumor in a specific and targeted way.

Another potential application of nanoshells is their use as optical imaging contrast agents for early detection of tumors. When nanoshells are targeted to breast carcinoma cells using conjugated antibodies, tumor

detection improves twofold compared to imaging without the nanoshells. Within this context, it may be possible to combine the imaging capability of nanoshells with the therapeutic capability of the nanospheres, thereby advancing the state of cancer therapy.

The workshop presentations and discussions raised six new and important questions for further consideration:

• What is the best business model for developing complex new biomedical materials, such as cell-based therapies?

• Is new policy necessary to ensure that the U.S. regulatory process can match the pace of science and technology innovation and development?

• What role will public perception play in the adoption of radically new technologies? How will it affect the further development and use of these technologies?

• Can new technologies ever be safe enough for widespread use when we don’t know what we don’t know yet? Should the development of new technologies be slowed in order to try to better understand their real risks?

• How does the convergence of new technologies affect the education system? Can we teach interdisciplinary teamwork in today’s academic system, which is typically structured around individual departments?

• How can the process from good idea to actual product be strengthened, particularly to narrow the gap between academia, where many good ideas originate, and product commercialization?