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Advanced Functional Materials

A key objective of scientists is to incorporate functional properties of biological materials into new materials and devices. The properties sought include molecular recognition, sensitivity and specificity of response, energy storage and conversion, force dynamics of elasticity, adhesive and other mechanical properties, and optical filtering and detection. In this chapter, key advances, opportunities, and challenges are reviewed in creating biomolecular materials with these specific functional attributes. To organize this chapter, important socioeconomic areas are described where applied biomolecular functional materials are having a strong impact: alternative and renewable energy, health and medicine, and national security. In each of these areas, exemplars of fundamental discoveries and challenges are explored. Finally, the efforts under way to exploit the functional properties of new bioderived, bioinspired, and biomimetic materials are discussed.

Advances in functionalizing biomolecular materials will have enormous impact on U.S. society. To date, there has been demonstrable progress harnessing the functional power of biomolecular materials, especially in alternative and renewable energy, health and medicine, and national security, as described in this chapter. The interest in fuels derived from plants is largely based on a greater understanding of energy conversion processes in these materials as well as a greater understanding of how to manipulate the plant genome. The significant role medical diagnostics play in everyday life (for example, the new generation of glucose testing for diabetics) is a direct result of the understanding of biomolecular recognition events and the ability to manipulate them in useful, easy-to-use devices. Approaches based on bioinformatics and synthetic biology are currently being vigorously pursued, with



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3 Advanced Functional Materials A key objective of scientists is to incorporate functional properties of biological materials into new materials and devices. The properties sought include molecular recognition, sensitivity and specificity of response, energy storage and conversion, force dynamics of elasticity, adhesive and other mechanical properties, and optical filtering and detection. In this chapter, key advances, opportunities, and challenges are reviewed in creating biomolecular materials with these specific functional attri- butes. To organize this chapter, important socioeconomic areas are described where applied biomolecular functional materials are having a strong impact: alternative and renewable energy, health and medicine, and national security. In each of these areas, exemplars of fundamental discoveries and challenges are explored. Finally, the efforts under way to exploit the functional properties of new bioderived, bio- inspired, and biomimetic materials are discussed. Advances in functionalizing biomolecular materials will have enormous impact on U.S. society. To date, there has been demonstrable progress harnessing the functional power of biomolecular materials, especially in alternative and renewable energy, health and medicine, and national security, as described in this chapter. The interest in fuels derived from plants is largely based on a greater understanding of energy conversion processes in these materials as well as a greater understanding of how to manipulate the plant genome. The significant role medical diagnostics play in everyday life (for example, the new generation of glucose testing for diabetics) is a direct result of the understanding of biomolecular recognition events and the ability to manipulate them in useful, easy-to-use devices. Approaches based on bioinformatics and synthetic biology are currently being vigorously pursued, with 

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insPired biology  by the goal of making cells produce products of societal and economic value. Most of the focus today is on products of interest to the pharmaceutical industry. Related approaches may also be of value for the synthesis of new biomolecular materials. While significant progress has been made, the potential future impact of under- standing and utilizing functional biomolecular materials is enormous. Imagine that one could . . . • Engineer biological enzymes to convert organic matter to usable fuels with very high efficiency in order to substantially reduce dependence on foreign sources of fuel. • Manipulate biomolecular recognition events to create a biosensor with no false alarms that responds with sensitivity and specificity, mitigating threats before people or other key assets are exposed. • Create new arrays of medical diagnostic assays that can predict susceptibil- ity to and progression of disease. • Deploy new materials that will protect people and material assets from chemical and biological contamination. • Design and fabricate new materials that capture the superlative properties of adhesion in a gecko foot or the elegant strength in design of a diatom or mollusk shell. These seemingly futuristic touchstones represent some of the future impact that could be realized through the understanding and exploitation of functional properties of biomolecular materials. Following discussion of certain areas of research, specific challenges and opportunities are outlined at the end of this chapter. ALTERNATIvE AND RENEWABLE ENERgY FROM BIOMOLECULAR MATERIALS AND PROCESSES Life requires energy and the continual conversion of energy from one form to another. Biological systems have adopted diverse means by which to convert between different forms of energy in order to compete and survive. These unique, adaptive, energy-converting properties of biomolecules have inspired biomate- rial scientists. There have been great advances in the understanding of functional biomolecular processes that efficiently convert energy in biological systems. These include the chemical conversion of high-energy-containing materials such as poly- saccharides (one of which is cellulose) into fuels, the production of electrical energy with enzymes for fuel cell or battery applications, the conversion of light energy into chemical energy in photosynthesis, and the conversion of chemical to mechanical energy by biological motor proteins.

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a d va n c e d f u n c t i o n a l m at e r i a l s  Biofuels and Processes Rudolph Diesel contemplated that the engine named in his honor would be powered by vegetable oils. However, the widespread availability of inexpensive petroleum during the twentieth century altered that vision. Twenty-first century realities have rekindled interest in Diesel’s original thinking. Cellulose is the world’s most abundant biological polymer. Studies demonstrate that with technological advances, biofuels, such as ethanol from cellulose, could supply a significant fraction of the world’s demand for transportation fuels in a way that is carbon dioxide neutral and does not compete with land for food production. The key to achieving these advances is research in plant genetics, biotechnology, process chemistry, and engineering that will lead to new manufacturing concepts for converting renewable biomass to valuable fuels and products. For certain practical applications, biologically based feedstocks are already having an impact. These include solvents, plastics, lubricants, and fragrances. For example, poly(lactic acid) is a hydrolytically degradable plastic that is currently manufactured on a million-kilogram scale in the United States and on a smaller scale in Europe and Japan. The route to the final product ferments corn dextrose for the production of lactic acid, which is then dimerized and polymerized. The final product is used in food packaging and the clothing industry. Substrate utilization remains a key challenge in the use of biological feedstocks for meeting energy needs. The abundant products of photosynthesis are primar- ily renewable cellulose, hemicellulose, and lignin. Although energy-rich, these abundant products are not easily transformed into usable fuels. This challenge, along with process methods that treat these substrates as chemical engineering feedstocks, will be the focus of much of the effort in this area of research. Figure 3.1 summarizes the key global biomass resources from agricultural residues, wood, and herbaceous energy crops. Polysaccharides and lignin are separated and processed to make feedstocks for materials and fuels. Current methods for separating the constituent biomolecular components rely on thermochemical processing; they are relatively harsh and energy-intensive. The development of more benign and economical processing steps is clearly a challenge. In principle, enzymes could be brought to bear, but doing so in a cost-effective manner remains problematic. The science of genomics, supported by new tools such as proteomics, metabolomics, and imaging in con- junction with the genomic databases, could give us insight into how microorgan- isms utilize untreated biomass to produce metabolic energy. The logical companion to bioinspired renewable energy production is the utilization of that energy. This is the focus of research in microbial fuel cells. Microbial fuel cells are electrochemical cells that convert chemical energy into electrical energy by using bacteria as a catalyst to convert substrate materials into

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insPired biology  by FIGURE 3.1 Key biomass resources: agricultural residues, wood, and herbaceous energy crops. SOURCE: A.J. Ragauskas, C.K. Williams, B.H. Davison, G. Britovsek, J. Cairney, C.A. Eckert, W.J. Frederick, Jr., J.P. Hallett, D.J. Leak, C.L. Liotta, J.R. Mielenz, R. Murphy, R. Templer, and T. Tschaplinski, “The path forward for biofuels and biomaterials,” Science 311:484-489 (2006). available electrons. The principle of operation of a microbial fuel cell is illustrated in Figure 3.2. Organic substrates (e.g., glucose) are oxidized to carbon dioxide in the anode compartment. Electrons from the substrates are transferred to the anode. The pathway by which this transfer is achieved is another topic of current research. Several options include soluble electron relays that shuttle between microbe and electrode, direct membrane contact, or nanowires that are produced by the bac- teria themselves. In principle, a broad spectrum of substrates can be utilized as fuel. The geometry of the cell is such that electrons are forced to flow through an external circuit and load resistor to the cathode compartment. Simultaneously, a proton-conducting membrane that separates the anode and cathode compartments is needed to maintain electroneutrality. Among the science and engineering chal- lenges associated with this research are the molecular mechanisms for transporting

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a d va n c e d f u n c t i o n a l m at e r i a l s  FIGURE 3.2 The microbial fuel cell and its operating principles. SOURCE: B.E. Logan, B. Hamelers, R. Rozendal, U. Schröder, J. Keller, S. Freguia, P. Aelterman, W. Verstraete, and K. Rabaey, “Microbial fuel cells: Methodology and technology,” Environmental Science and Technology 40:5181-5192 (2006). Copyright 2006 American Chemical Society. reducing equivalents to the anode, internal resistance of the device, efficiency, the range of organic substrates, and the selection of microorganisms. These problems lie at the intersection of physics, chemistry, biology, and bioengineering. Figure 3.3 illustrates the overall concept of the fully integrated agro biofuel, material, power cycle for sustainable technologies. There is growing interest in finding alternative biological materials from which to make fuel. While biofuels still represent a small fraction (less than 15 percent) of the world’s overall energy, the yearly growth rate of 15-20 percent contrasts significantly with the rate of 1-2 percent for fossil fuels. Today, established biofuel

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insPired biology  by FIGURE 3.3 The fully integrated agro-biofuel-biomaterial-biopower cycle for sustainable technologies. SOURCE: A.J. Ragauskas, C.K. Williams, B.H. Davison, G. Britovsek, J. Cairney, C.A. Eckert, W.J. Frederick, Jr., J.P. Hallett, D.J. Leak, C.L. Liotta, J.R. Mielenz, R. Murphy, R. Templer, and T. Tschaplinski, “The path forward for biofuels and biomaterials,” Science 311:484-489 (2006). industries are a reality in countries like Brazil and Germany. The production and processes to efficiently produce fuels are being pursued for palm oil, cottonseed, peanut oil, castor oil, sunflower, and cattle fat. Success in this industry will require focused research to understand and utilize plant genetics, chemical processing methods to recover useful materials from the crops, and means to efficiently pro- duce carbon-rich fuels from these biomaterials. Biomimetic Photosynthesis Photosynthesis, the conversion of solar energy into stored chemical energy, is a key biological process that sustains life on Earth. The energy-rich molecules produced by photosynthesis are primarily reduced carbon compounds such as cellulose, hemicellulose, and lignin, which are difficult to convert into chemical fuels. Other photosynthetically produced carbon compounds such as glucose are directly fermentable to ethanol.

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a d va n c e d f u n c t i o n a l m at e r i a l s  One of the great scientific challenges of the twenty-first century for researchers inspired by naturally occurring photosynthesis is extracting and mimicking the essential solar-energy-conserving reactions. The general equation of photosynthe- sis guides the way: water + carbon dioxide + sunlight → oxygen + stored energy. Biomolecular and bioinspired energy transducers need not replicate all of photo- synthesis. Nonbiological photoreactions could in principle mimic the reactions of photosynthesis by producing small fuel molecules such as hydrogen, methane, or methanol. In all these reactions, molecular oxygen would be produced, since water is the source of electrons for the fuel molecules. For example, in the case of renewable hydrogen production by light-activated water oxidation, the reaction is 2H2O + sunlight → O2 + 2H2. Current research is focused on synthesizing efficient catalysts for molecular oxygen and fuel formation. Cutting-edge photosynthesis research is aimed at understanding the molecular mechanism of oxygen evolution, whereas cutting-edge solar fuel research is aimed at understanding the catalytic pathway for the production of the fuel molecules. Understanding light-activated oxygen evolution by plants and cyanobacteria is one of the great challenges in photosynthesis. Progress has been made in elucidating the structure of the photocatalytic oxygen-evolving center in natural photosynthe- sis. The oxygen-forming steps are mediated by an Mn4Ca-tyrosine catalytic center illustrated in Figure 3.4. The photocatalytic oxygen-evolving complex (OEC) is the starting point for bioinspired energy transduction research for biomimetic pho- tosynthetic fuel formation. Within the next 5 years the synthesis of this structure with proven oxygen-evolving capabilities should be complete. This work includes linkage to a photochemical reaction that drives the oxygen evolution reaction. Advanced computation, simulation, and modeling techniques—in addition to chemical synthesis— should be brought to bear on this problem, with the goal of understanding how this high-potential multielectron transfer reaction is achieved. Even with oxygen evolution fully understood, less than half the scientific challenge of bioinspired energy transducers for renewable energy production will have been overcome. The other part of the challenge focuses on the photocatalytic centers for fuel formation: the chemical fate of the electrons and protons in the reaction 2H2O + solar energy → O2 + 4H+ + 4e–. Biomolecular energy transducers are a rich area for basic research, with poten- tially important applications in the field of renewable fuels and chemicals pro- duction. The key challenge, following the example of natural photosynthesis, is the conversion of solar energy into stored chemical energy using electromagnetic energy contained in the visible portion of solar emission spectrum. A molecular- level understanding of the mechanisms of photosynthetic oxygen evolution must be achieved. This includes the de novo synthesis of photocatalytic oxygen-evolving complexes that are able to drive the light-activated oxidation of water. Understand- ing oxygen evolution at the molecular level, which is well under way, will permit the

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insPired biology  by FIGURE 3.4 Mechanistic model for the formation of photosynthetic oxygen. SOURCE: M. Haumann, P. Liebisch, C. Muller, M. Barra, M. Grabolle, and H. Dau, “Photosynthetic O2 formation tracked by time-resolved X-ray experiments,” Science 310:1019 (2005). synthesis of artificial oxygen-evolving structures without the need to synthesize or recreate an entire biological organism. The desired fuels will determine the catalysts and chemistry to be studied. For example, simple fuel molecules like hydrogen can be produced with well-known metallic catalysts or mimetic analogues of the enzyme hydrogenase. Drawing further inspiration from natural photosynthesis, light-induced charge separations of photosynthetic reaction centers occur across a membrane that separates oxidizing and reducing equivalents. Bioinspired pho- tosynthesis will build on this example by constructing artificial photosynthetic membranes that can photoproduce oxygen and fuel molecules on opposite sides of the membrane. A priority research goal should be the synthesis of artificial photosynthetic membranes that mimic the essential energy-conserving properties of natural photosynthesis with equal or greater energy conversion efficiency. Theo- retically, synthetic systems could be more efficient than natural systems for three reasons: (1) photosynthesis has evolved to maximize survivability, not efficiency; (2) in principle, a synthetic system, combined with suitable catalysts, should be able to produce small fuel molecules such as hydrogen, methane, and methanol, which are immediately useful, unlike cellulosic biomass; (3) synthetic chromophores

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a d va n c e d f u n c t i o n a l m at e r i a l s  might be able to harvest a larger fraction of the solar emission spectrum than the chlorophyll molecules of green plants. Of course, development of a real-world system, including long-term operational stability, will be a key challenge after the basic science problems have been solved. Bacteriorhodopsin (BR) is a stable transmembrane protein of the bacterium Halobacterium halobium and thrives in salt marshes at high salt concentrations. Like photosynthesizing green plants, BR converts light energy into chemical energy. Whereas green plants convert light energy into chemical energy by photon-induced charge separation, BR is a photon-driven proton pump. In its native state, BR is a backup source of metabolic energy that is activated when available oxygen becomes too low for normal respiration, a transition that is accelerated by the poor solubil- ity of oxygen in concentrated salt solutions. Following photon absorption, protons are pumped out of the cell through the cell membrane at the rate of one proton per photon. The Gibbs energy of the hydrogen ion gradient that is formed by this process is converted into chemical energy in the form of adenosine triphosphate (ATP) molecules by ATP synthase enzymes. As illustrated in Figure 3.5, BR molecules are composed of seven α-helical sub- domains that form a hexagonally close-packed, oriented structure that assembles into large aggregated patches in the cell’s membrane. The structure of a single BR molecule is illustrated in Figure 3.6a, along with the movement of protons from the inside to the outside of the cell. Photon absorption triggers a series of spectroscopic changes that include a trans-1,3-cis transformation, rearrangement of electronic charge within the protein, protonation, deprotonation, and con- formational changes. As illustrated in Figure 3.6b, the spectroscopic states have characteristic lifetimes and absorption spectra that collectively are known as the BR photocycle. The creation of gradients is a recurring theme in the harvesting of light and its conversion to chemical energy in biomolecular systems. The physical and chemical principles of the action of BR have inspired research in the field of light-activated proton gradient production. For example, BR processes involving light-driven proton pumping and production of ATP catalyzed by F0F1-ATP synthase have been demonstrated in artificial liposome photosynthetic membrane and other systems. In all cases energy is conserved by the creation of proton gradients following pho- ton absorption that utilizes a suitably designed chromophore. The biomolecular principles for converting light energy into chemical energy are now understood to follow a conceptually simple plan that provides guidance for bioinspired research. Design principles drawn from naturally occurring biological systems can be used to form the basis of near-term (5 years) research. Nanoscale energy sources based on light-induced formation of gradients should be mastered in a range of synthetic systems to illustrate the themes and variations of this mode of energy transduction. In addition to light-energy harvesting, research in

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insPired biology 0 by FIGURE 3.5 Illustration of the seven α-helical domains that constitute BR molecules. SOURCE: J. Baudry, E. Tajkhorshid, F. Molnar, J. Phillips, and K. Schulten, “Molecular dynam- ics study of bacteriorhodopsin and the purple membrane,” Journal of Physical Chemistry B 105:905 (2001). Copyright 2001 American Chemical Society. Reprinted with permission. BR has taken on a life of its own in fields removed from the biological origin and energy-transducing function of the protein, including protein-based field-effect transistors, artificial retinas, spatial light modulators, three-dimensional volumet- ric memories, and optical holographic processors. These applications will require standardization of materials, components, and manufacturing methods in order to be successfully developed.

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a d va n c e d f u n c t i o n a l m at e r i a l s  FIGURE 3.6 BR structure and photocycle. (a) BR is an ion pump that results in the net transfer of a proton from the intracellular to the extracellular surface. Key residues are high- lighted, and the proton transfer channel is shown. (b) The main and branched photocycle in BR used for three-dimensional memory device applications. The branching reaction involves the O → P transition that is optimized using directed evolution. M and O state lifetimes and yields can also be optimized using directed evolution. SOURCE: Adapted from J.R. Hillebrecht, J.F. Koscielecki, K.J. Wise, D.L. Marcy, W. Tetley, R. Rangarajan, J. Sullivan, M. Brideau, M.P. Krebs, J.A. Stuart, and R.R. Birge, “Optimization of protein-based volumetric optical memories and associative processors using directed evolution,” Nanobiotechnology 1:141-152 (2005). Biomolecular Motors All active cellular movements, such as separation of the chromosomes and the two daughter cells during cell division, determination and modulation of cell shape, locomotion, and targeted transport of intracellular cargos, such as mem- brane bound vesicles containing neurotransmitters or waste products, involve the

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a d va n c e d f u n c t i o n a l m at e r i a l s  biological optical structures and processes have evolved that can compete with or even outperform the cutting-edge optical technology being developed by today’s scientists: multilayer reflectors, diffraction gratings, optical fibers, liquid crystals, and structures that scatter light—all of them devices that can be described using optical theory—are found in animals as well, based on a diversity of designs. Iri- descent sparkle and the blue color of a Morpho butterfly, which can be seen for hundreds of meters, are caused by a periodic photonic structure in scales cover- ing the wings (Figure 3.15). No dye is involved. Structural color appears to be a common strategy in nature: “Living opals” are reported to be present in peacocks, beetles, and marine organisms. FIGURE 3.15 Optical microscope photograph of scales on a Morpho wing. SOURCE: P. Vukusic, University of Exeter.

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insPired biology  by In addition to the beauty and structural complexity of Venus’s flower-basket, there is now a scientific understanding of the efficient fiberoptical lamp in the base of its latticework (Figure 3.13). The optical features of these biological fibers are remarkably similar to those of their commercial counterparts, and their mechani- cal properties are better still. Another example of a cutting-edge technology found in nature is the array of optically optimized, single-crystalline calcitic microlenses formed by a brittle star. In this amazing, tunable optical structure, the lenses are compensated for birefringence and spherical aberration and are combined with a microfluidic system that transports pigment to regulate the intensity of light reaching the receptors. Recent studies mark the beginning of our appreciation for the complex optical structures found in biological specimens and open this field for future discoveries. Only now, when the physical and biological sciences are beginning to come together and new methods of nanoscale fabrication and characterization are developing, do these studies have a good chance of reaching fruition. It is noteworthy that only one optical device in animals has been taken through the manufacture stage: the fly-eye antireflector. Currently there are attempts to fabricate a functional microlens array combined with a microfluidic system, which mimics the features of brittle star optics. However, natural photonic and optical structures are often highly complex at the nanoscale, and mimicking their design may be beyond the ability of today’s engineers. This might justify the study of cellular and biomolecular mechanisms and processes. Can researchers also exploit the flawless processes of optical manu- facture employed by animals? Biological Inorganic Supermaterials Although polymers and organic materials have found their way into modern technology, inorganic materials will remain the basic elements in engineering. There is, however, a growing realization that the traditional methods of “heat and beat” will not be able to fulfill the requirements for future advanced materials, in particular the construction of higher-order architectures from the nanometer to the macroscale. New approaches that use molecular design and assembly should be developed. The ability to take inorganic building blocks and organize them into nanoscale, microscopic, or bulk materials is of importance in electronics, catalysis, magnetism, optics, sensors, and mechanical design. Again, the best guidance in the search for new inorganic materials and fabrica- tion strategies should come from the study of biological processes. The formation of inorganic materials in organisms, so-called biomineralization, results in exqui- site, finely tuned hybrid superstructures that possess exceptional mechanical, opti- cal, and magnetic properties. In addition to the well-known structural biominerals, such as calcium carbonates, calcium phosphates, and silica, a variety of unexpected

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a d va n c e d f u n c t i o n a l m at e r i a l s  inorganic materials (Fe, Sr, Ba, Cu, Ag, Au, sulfides, oxides, sulfates, and hydroxides) have recently been found in organisms. The organisms control the inorganic poly- morph, the location of nucleation, the size of the inorganic particles, their crystal- lographic orientation, and their intricate shapes and assembly, from the nanoscale to the macroscale. The importance of the study of the (bio)molecular processes that lead to these supermaterials and the relevance of biomineralization processes to modern technology were wonderfully depicted by Stephen Mann, one of the pioneers of biomimetic inorganic chemistry. He generalized that three biological principles are critical: (1) preorganization/assembly of (bio)organic molecules into structural and chemical scaffolds at the nanometer scale prior to mineral deposi- tion; (2) templating and molecular recognition at organic-inorganic interfaces that result in controlled, site-directed nucleation of oriented inorganic nanoclusters within preformed supramolecular assemblies; and (3) larger-scale cellular process- ing of the nanostructures into higher-order, functional architectures. The molecular details of these processes are largely unknown and require thorough investigation by cell biologists, structural chemists, materials scientists, molecular biologists, physicists, and engineers working in tandem. Recently it has been shown that even the most primitive use of these principles, when complex bio- logical matrices were replaced by synthetic self-assembled molecules that mimicked biological supramolecular architectures and surface micropatterning was used to template site-specific oriented nucleation, could lead to significant successes in controlling the orientation, polymorph, shapes, positioning, and nano/micropat- terns of synthetic inorganic crystals. “Currently we are only at the beginning of a biomimetic approach to inorganic materials, and there is a long way to go, but it is feasible that one day, the dusty, dirty world of minerals could be transformed by biological insights. A quiet revolution is underway.”1 Materials That Mimic Proteins and Membranes There are considerable efforts to mimic many of the functional properties of biomolecules and their assemblies. Most man-made polymeric materials used today serve structural purposes in plastics, fibers, paints, and rubbers. These polymers lack precise sequence specificity, and do not approach the functional sophistication of biomolecular materials. For example, proteins can catalyze chemical reactions, transport ions, convert energy to motion, repair other biopolymer molecules, and transduce signals and energy. Biomolecular functions can be linked together into complex, interacting and responsive systems that exhibit emergent, higher-level 1 S. Mann, D.D. Archibald, J.M. Didymus, T. Douglas, B.R. Heywood, F.C. Meldrum, and N.J. Reeves, , “Crystallization at inorganic-organic interfaces: Biominerals and biomimetic synthesis,” Science 261:1286-1292 (1993).

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insPired biology  by functionalities. These powerful functionalities are possible because, unlike current man-made polymers, biopolymers are informational as well as structural in nature: Their functions are encoded within distinct sequences of diverse monomer sets. An exciting research area that has emerged in the past decade involves the mimicry of these functions in new man-made polymeric materials that are informational and designed to have a wide range of sequence-structure-function relationships. For example, microbes are transfected with artificial genes with de novo- designed monomer sequences, allowing these biological cells to be harnessed for the production of nonnatural proteins. Researchers are synthesizing nonnatural amino acids that can still be polymerized by a microbe’s protein synthesis machin- ery, leading to proteins with novel properties. In other cases, simple oligopeptide sequences are patterned after Alzheimer’s disease peptides, both to study the aggre- gation process that underpins the disease and also to create new self-assembling materials. Other researchers are creating minimalist proteins—molecules that are simple enough that the sequence patterns can be designed without computers, often to test folding principles and create simple proteinlike functionalities. Folded peptides are being designed as cages, with gates that can be triggered to synchro- nize the release of dyes that allow complex biological and chemical events to be followed in real time. An important recent development in creating useful and functional new pro- teins that can mimic particular functions is directed evolution. In this approach, a gene is first randomly mutated to create a library of variants. The library is then screened to select mutant proteins having the desired properties. This method is now widely practiced in academia and being industrialized to produce new proteins that are more stable or enzymatically more active or that have different substrate specificities. Efforts are also under way to mimic the conformal activity of proteins in con- structs termed foldamers, which are chain molecules composed of nonbiological monomers that, in principle, can fold like proteins and possibly function like proteins. One example is a class of polymers called peptoids, which are sequence- specific heteropolymers based on chains of N-substituted glycines. Peptoid-based helical bundles have been made that fold cooperatively, have hydrophobic cores, and can bind zinc tightly and cooperatively, serving as a proof of principle that such polymers are proteinlike in important ways. A family of peptoid 9-mers with hydrophobic side chains was discovered to form a uniquely folded, highly stable threaded-loop structure in acetonitrile, held together by hydrogen bonding, which surprisingly has a polar core and a hydrophobic outer surface. Like mirror-image proteins, peptoids are not degraded by protease enzymes and so may be useful as therapeutics and biomimetics. Peptoids have been used to create novel lung sur- factant protein mimics, as well as bioavailable mimics of antimicrobial peptides. Excellent progress is being made as well in the design of protein-mimetic structures

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a d va n c e d f u n c t i o n a l m at e r i a l s  based on β-peptides and chimeric α/β-peptides, including peptidomimetics that kill bacteria in the same manner as antimicrobial peptides and inhibit protein- protein binding interactions involved in viral fusion and the cell cycle. Mimicry and patterning of lipid bilayer membranes is an active area of research to create spatial domains at the micro- and/or nanoscale, potentially leading to nanowires, nanonetworks, and to the formation of nanoscale “corrals” in which different membrane proteins may be localized. These efforts have obvious appli- cations because many of the functional activities of biomolecules (for example, drugs) are manifest in lipid membranelike environments. Since 40 percent of the blockbuster drugs currently on the market act on membrane proteins, any new method that can successfully isolate, characterize, or utilize membrane proteins is an important advance. To advance the field of mimicry of functional materials, there are several chal- lenges that remain to be addressed: in synthetic chemistry, in the creation of new monomer types and new ligation strategies for linking them together with high efficiency, and to improve the yields of functional polymers. There are challenges in characterizing structural and physical properties of bioinspired or mimicked polymers that are created. And, there are substantial challenges in computational chemistry, to be able to design the sequences having targeted properties. Integration of Functional Biomolecular Materials Exciting progress is now being made, but a great deal of work remains, toward seamlessly integrating functional, nonbiological materials and devices with living, mobile biological systems, including cells and tissues. Such nonbiological materials must be stable for a tunable period of time and remain uninfected and ideally non- encapsulated when implanted in vivo. While certainly functional, today’s metallic replacements for missing bones and joints remain at a primitive state of integration with the recipients’ living tissue. An ideal compatibility of medical implants such as pacemakers and artificial hearts with the host site is clearly very important since these devices remain in place for 5-10 years. Outside the medical realm but in the area of biotechnology, a host of biomol- ecules and their assemblies (cells, enzymes, antibodies, light-harvesting complexes) could provide useful functional system elements if they could be stably interfaced with man-made systems, many of which tend to be metallic or plastic (electrodes, batteries, computers, etc.). Many of nature’s most useful proteins are embedded in lipid membranes, and learning to work with these types of proteins in artificial membranes will allow many important advances in biotechnology. Finally, a variety of machines could be designed to interface more intimately and effectively with their operators (for example, fighter jets, passenger vehicles, cranes and other heavy

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insPired biology 0 by equipment, surgical robots and lasers) if effective interfacing from the human mind and nerves to the machine could be created. A variety of polymeric materials have been used in the human body, but so far, none perform as fully required or desired. Most of the presently used materi- als were “found” or “discovered” rather than “designed” materials. For example, polymers and plastics not originally created for use as biomaterials were found to be serviceable in artificial hearts, valves, and so on. Clearly, these found materi- als have very limited biocompatibilities. All of the presently used biomaterials eventually fail in vivo, in part because of problems with uncontrolled nonspecific cell/protein binding or fouling and a propensity for infections to occur at the site. Virtually all of today’s biomaterials cause undesired clotting of blood; all patients implanted with cardiovascular materials require systemic anticoagulant therapy. All endotracheal tubes become infected after 5 days; 99 percent of systemically delivered nanoparticles or nanogels end up uselessly in the liver or spleen; 100 percent of small-diameter vascular grafts fail within 21 days in vivo; and virtually all implanted biosensors fail in vivo within 20 days. This highlights the tremendous work that remains to be done by engineers and scientists in understanding and controlling the interactions between abiotic and biotic interfaces. Today’s approach to integrating elastomeric or inorganic materials with living cells or tissue is to functionalize the surfaces with biocompatible and/or bioac- tive materials. Such tailored interfaces are now starting to make their way into clinical trials but still represent technology that is primarily academic and not yet commercialized. A significant amount of fundamental research has been done to discover the best ways of forming strong bonds between inorganic surfaces (such as gold, copper, silicon, silica, titania, and carbon surfaces) and tethered or bound polymers or biomolecules. Thiol moieties bind strongly to gold or copper, while reactive organosilanes can be used to modify silica or oxidized silicon. Some of the strongest bonding moieties yet discovered are inspired by natural systems, such as the modified L-DOPA amino acid that evolved to serve in the tethering elements of shellfish to allow them to adhere to shoreline rocks. When chemical approaches are taken, this is typically done using hydrophilic, uncharged oligomers or polymers, most commonly based on ethylene oxide. Polyethyleneglycol seems, at this time, to be the best polymer to reduce nonspecific binding of proteins and cellular material. On the other hand, some very physical approaches to modifying surfaces, including laser treatments, glow discharge plasma treatments, and supercritical fluid process- ing are showing significant promise as well in decreasing the nonspecific binding or fouling of abiotic interfaces with biomolecules. Second, for the best biological compatibility, the appropriate molecular signals, typically but not always proteins or their assemblies, must be presented on the engineered surfaces. Micropattern- ing of these surfaces appears to be a powerful way to control cellular behavior, as

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a d va n c e d f u n c t i o n a l m at e r i a l s  well as the integration of microscale technologies with the use of biocompatible polymers and hydrogels. Understanding the mechanisms of cell adhesion at the molecular level will be very important. Reengineered enzymes, more stable than natural proteins, may be critical for the tasks of interface engineering. Strategies for the synthesis and derivatization of nanoparticles such as cross-linked copolymer micelles and dendrimers are maturing rapidly, and these types of particles may soon find their way into clinical use. In general, the primary challenges faced today involve fool- ing biological molecules, which are very potent sensors of their environment, into believing that abiotic, human-made functional elements are not there. Using engi- neered biomaterials, artfully applied, researchers may succeed in putting realistic sheep’s clothing on inorganic materials that are normally seen by living systems as the wolf. OPPORTUNITIES AND CHALLENgES The wide range of biological functions and advances in the understanding of their properties present enormous opportunities for further science and techno- logical advances. In this chapter, selected topics were reviewed in the discovery and application of these functional properties, including alternative and renewable energy, health and medicine, and biomaterials for national security needs. Particu- lar functional properties of biological systems were also reviewed, and superior functional properties that have not yet been fully appreciated or exploited were described. Finally, issues in mimicry, synthesis, and integration of functional bio- molecular materials were discussed as important underpinnings to the science and technology of functional biomolecular materials. Some challenges to the scientific understanding of advanced functional materials are enumerated below where new understanding is beginning to emerge (first-level bullets). They are followed by opportunities that might arise if researchers develop enough of an understanding to address the challenges. Alternative and Renewable Energy There have been considerable advances in the understanding of energy stor- age and conversion properties of biomolecular materials and greater interest in engineering new properties that extend these important functional attributes. Efforts to create new functional biomaterials in plants, based on engineering the plant genome, that can be efficiently converted to usable, high-energy-containing materials are largely motivated by the promise of new sources of biofuel. Biomi- metic photosynthesis is gaining momentum as researchers unlock the mechanisms involved when light is used to fix carbon.

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insPired biology  by • Challenges to scientific understanding: Expanded use of biofuels from plant and animal biomaterials —Opportunity: Improved conversion efficiency and utilization of substrates —Opportunity: Robust and controlled genetic engineering of new syn- thesis in plants • Challenges to scientific understanding: Research and development of arti- ficial photosynthetic and other proton gradient systems —Opportunity: Efficient conversion of light to useful products —Opportunity: Expanded selection of new biomolecules for energy con- version and storage —Opportunity: Integration of photosynthetic complexes into artificial matrices • Challenges to scientific understanding: Discovery of the structural and functional dynamics of biological motors in situ —Opportunity: Assembly and integration of linear and rotary biologi- cal motors into useful nanomachines or devices that realize biomotor performance —Opportunity: Stability and robustness of biological motor complexes Health and Medicine The use of biomolecular materials in health and medical devices is widespread and has already had a significant socioeconomic impact on society. The engineering of new biomolecules for increased functions such as sensitivity or specificity is an active area of research and has shown early payoff in the design of new tools such as diagnostic assays. Nanotechnology efforts have found new ways to manipulate the delivery of drugs to specific sites in the body and to enhance the delivery of new therapeutic compounds. Finally, the area of neuroprosthetics, which combines innovation across a number of disciplines, including neuroscience, materials sci- ence, microelectronics, and engineering, is moving rapidly. • Challenges to scientific understanding: New functional biomolecular mate- rials for diagnostic array detection with desired sensitivity and specificity —Opportunity: Sample preparative and other methods to enhance signal detection and reduce background noise in a diagnostic platform —Opportunity: Computational analysis of multiplexed, large diagnostic and profiling datasets for prognostic medicine • Challenges to scientific understanding: Improved delivery of drugs using functionalized and controlled-size biomolecular materials

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a d va n c e d f u n c t i o n a l m at e r i a l s  —Opportunity: Prediction and control of in vivo response to implanted materials —Opportunity: Synthesis and characterization of controlled nanoparticles, polymers, and dendrimers with functionalized properties —Opportunity: Targeted delivery to specific sites • Challenges to scientific understanding: New neuroprosthetics with dynamic function for artificial limbs and sensors —Opportunity: Development of reliable interfaces with long-term function —Opportunity: Integration of recorded signals with response in closed- loop function —Opportunity: Understanding information coding from neuronal ensembles National Security Global threats from the environment and in the context of military and home- land defense present unique opportunities for the application of functional materi- als. The most mature application may be biosensors, where the hope of developing detect-to-warn systems continues to drive this field across a variety of interested government customers (Department of Energy, Department of Defense, Depart- ment of Homeland Security, and Environmental Protection Agency). Biosensor performance has improved, but needed advances in reducing false alarm rates and integrating samples from different sources are still a challenge. Decontamination materials that can detect and protect, degrade, and perhaps regenerate are under investigation by a number of agencies and provide good application platforms to integrate advanced functional materials. • Challenges to scientific understanding: Biosensors that reliably detect threats in time to prevent exposure and consequences of environmental threats (detect to warn) —Opportunity: Reduction of false-alarm rates —Opportunity: Sample processing and handling for optimal performance • Challenges to scientific understanding: New decontamination and protec- tive materials that incorporate functional biomolecules —Opportunity: Methods of incorporation that optimize biomolecular function —Opportunity: Cooperative functions that derive from multifunctional materials —Opportunity: Demonstration in real-world conditions with reliable measures of determining safety after cleanup

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insPired biology  by Next-generation Bioinspired Materials • Challenges to scientific understanding: Wide selection of biological mul- tifunctional systems to drive inspiration of new designs with advanced materials properties (e.g., strength, adhesion, optics, hierarchy, assembly) —Opportunity: Enriching and harvesting underlying principles and pro- cesses to drive engineering activities in a productive way —Opportunity: Fabrication and assembly of inspired materials • Challenges to scientific understanding: Biomimicry of biomolecules with directed conformation and information content —Opportunity: Defining desired properties and designing controlled synthesis —Opportunity: Characterization and implementation of new materials • Challenges to scientific understanding: Seamless integration of functional- ized biomolecular materials in the body and in devices —Opportunity: Preventing fouling and foreign-body reaction from func- tionalized biomaterials —Opportunity: Controlling reactions at the surface to optimize desired integration of material —Opportunity: Longevity and robustness SUggESTED READINg Department of Energy, Basic Research Needs for Solar Energy Utilization, Washington, D.C., 2005. Available online at http://www.sc.doe.gov/bes/reports/files/SEU_rpt.pdf. Last accessed March 26, 2008. Gellman, S.H. “Foldamers: A manifesto,” Accounts of Chemical Research 31:173-180 (1998). Humayun, M.S., J.D. Weiland, G. Chader, and E. Greenbaum (editors), Artificial Sight: Basic Research, Biomedical Engineering, and Clinical Advances, New York, N.Y., Springer, 2007. Jung, C.C., E.W. Saaski, D.A. McCrae, B.M. Lingerfelt, and G.P. Anderson, “RAPTOR: A fluoroimmunoassay-based fiber optic sensor for detection of biological threats,” Sensors Journal, IEEE 3(4):352-360 (2003). Langer, R. “Drug delivery: Drugs on target,” Science 293:58-59 (2001). Langer, R., and N.A. Peppas, “Advances in biomaterials, drug delivery, and bionanotechnology,” American Institute of Chemical Engineers Journal 49(12):2990-3006 (2003). Mann, S., Biomineralization: Principles and Concepts, Oxford University Press, 2001. National Research Council, The New Science of Metagenomics: Revealing the Secrets of Our Microbial Planet, Wash- ington, D.C., The National Academies Press, 2007. National Research Council, Polymer Science and Engineering: The Shifting Research Frontiers, Washington, D.C., National Academy Press, 1994. Pollard, T.D., W.C. Earnshaw, and J. Lippincott-Schwartz, Cell Biology, 2nd Ed., Saunders, 2007, Chapters 36-39. Raber, E., A. Jin, K. Noonan, R. McGuire, and R.D. Kirvel, “Decontamination issues for chemical and bio- logical warfare agents: How clean is clean enough?” International Journal of Environmental Health Research 11(2):128-148 (2001). Ragauskas, A.J., C.K. Williams, B.H. Davison, G. Britovsek, J. Cairney, C.A. Eckert, W.J. Frederick, Jr., J.P. Hal- lett, D.J. Leak, C.L. Liotta, J.R. Mielenz, R. Murphy, R. Templer, and T. Tschaplinski, “The path forward for biofuels and biomaterials,” Science 311:484-489 (2006).

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a d va n c e d f u n c t i o n a l m at e r i a l s  Russell, A.J., J.A. Berberich, G.F. Drevon, and R.R. Koepsel, “Biomaterials for mediation of chemical and biological warfare agents,” Annual Review of Biomedical Engineering 5:1-27 (2003). Vogel, P.D., “Nature’s design of nanomotors,” European Journal of Pharmaceuticals and Biopharmaceuticals 60(2):267-277 (2005). Vukusic, P., and J.R. Sambles, “Photonic structures in biology,” Nature 424:852-855 (2003). Wainwright, S.A., W.D. Biggs, J.D. Currey, and J.M. Gosline, Mechanical Design in Organisms, New York, N.Y., John Wiley and Sons, 1976. Wang, L., J. Xie, and P.G. Schultz, “Expanding the genetic code,” Annual Review of Biophysics and Biomolecular Structure 35:225-249 (2006). Weiland, J.D., W. Liu, and M.S. Humayun, “Retinal prosthesis,” Annual Review of Biomedical Engineering 7:361- 401 (2005).