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7 Emerging Areas: New Opportunities at the Nanoscale and at the Interface Between Biology and the Physical and Engineering Sciences INTRODUCTION Generating the base of fundamental knowledge needed for the development of technologies that would allow NASA to accomplish more with fewer resources and learning how reduced gravity affects human health in space are central to NASA's programs. Much of NASA's past work has focused on finding solutions to the challenges at the macroscopic and micron scales, some of which is summarized in previous chapters. Novel nanoanalytical techniques and methods for engineering materials at the nanoscale are opening new frontiers with the potential to have a major impact on NASA's technologies, including technologies for remote and miniaturized sensing, and smaller, faster and integrated devices and systems. The Physical Sciences Division (PSD), which has already begun to invest in research in fields such as nanomaterials, biomolecular physics and chemistry, and tissue engineering, is in a good position to make significant contributions to exploiting the nanoscale if its limited resources are used well. Many agencies, including the National Science Foundation (NSF), the National Institutes of Health (NIH), the Department of Energy (DOE), the Department of Defense (DOD), and the Defense Advanced Research Projects Agency (DARPA), as well as other NASA divisions, are rapidly increasing their investments in nanotechnology. The PSD can make unique contributions to these emerging fields by applying the expertise and tools of the physical science community to (1) address certain challenges faced by the biomolecular sciences, (2) develop a pipeline of (initially) ground-based experiments that probe how stress-mediated subcellular processes are affected by microgravity, and (3) develop a knowl- edge base on how to store and convert energy using emerging technologies. In accordance with the committee's earlier recommendation set forth in its phase I report (NRC, 2001, p. 2), the PSD should invest in a given topic in an emerging field only if both of the following criteria are met: 1. [The topic] directly addressees] challenges at the interface between the physical sciences, engi- neering, and biology in support of NASA's mission, preferentially capitalizing on existing expertise or infrastructure in the Physical Sciences Division, and 62

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EMERGING AREAS 2. [The topic] supports research either not typically funded by other agencies or to be conducted in close partnership with other agencies. 63 Based on these criteria, the committee assessed in which areas nanoscale science at the convergence of the physical sciences, biology, and engineering is most likely to have a major impact on NASA's space programs. After selectively reviewing in this chapter the current state of the art in a number of disciplines, including a far larger number of areas than the PSD could possibly fund, the committee suggests how the PSD could optimize its impact in select areas by either leveraging investments made by other agencies or taking a leading role itself. Among those areas recommended for research, summarized in Chapter 8, the highest priority is given to areas where the potential exists for the PSD to assume a leadership role. A unifying theme of the research discussed in this chapter is that new frontiers are opening at the nanoscale whose technological exploitation requires systems integration at different length scales. The scientific and technological potential and the social and ethical impacts of nanotechnology were ex- plored recently in a series of workshops and reports that are now available to the public, among them the reports of the Interagency Working Group on Nanoscience, Engineering, and Technology (WTEC, 1999; NSTC/CT/IWGN, 2000~; the report of the NSET workshop "Societal and Ethical Implications of Nanoscale Science and Nanotechnology" (NSTC, 2001~; and the report of the NIH workshop "Nanoscience and Nanotechnology: Shaping Biomedical Research" (NIH, 2000~; as well as a report by DOE, "Biomolecular Materials" (DOE, 2002~. The NRC recently concluded a review of the National Nanotechnology Initiative, which resulted in the report entitled Small Wonders, Endless Frontiers (NRC, 2002~. According to yet another report issued by the National Science and Technology Council of the Executive Office of the President of the United States (NSTC, 2000), "Nanoscale science and engineering promises to become a strategic, dominant technology in the next 10-20 years, because control of matter at the nanoscale underpins innovation and progress in most industries, in the economy, in health and environmental management, in quality of life, and in national security." Hundreds of experts in academia and industry have made significant contributions to the above-mentioned reports, the content of which is highly relevant to the PSD, and U.S. funding agencies are well prepared to make major investments in these emerging technologies. Because the PSD is expected to have limited resources to invest in these emerging areas, clearly it must invest in research that will have a maximum impact on NASA's future flight technologies. Re- search in emerging areas focused on NASA applications is unlikely to have the requirement for low gravity that characterizes most areas of current PSD research. Thus most, but not all, of the recom- mended research is likely to be ground-based. The PSD must strive to find unique technical niches in support of NASA's core missions. For example, novel insights into nanoscale phenomena and the availability of an increasing number of nanoanalytical tools could have a major impact on NASA's ability to generate and store power in space, manufacture lightweight materials on the ground and in space, design materials with integrated sensory functions, and develop new sensor technologies. The confluence of the biological. physicals and engineering sciences at the nanoscale is an ideal Point at ~ , ~ ~ , ~ ~ ~ Waco NA5A couIct leverage the investments made by NSF, NIH, DOE, DOD, DARPA and others to enhance its own missions. The committee believes that, in addition to the programs the PSD develops in synchrony with other agencies and other NASA programs, there are select topics in the emerging areas that provide promising opportunities for the PSD to assume leadership with limited financial resources. The PSD needs to ensure, however, that it takes an integrative approach such that the new knowledge it develops is consistent with overarching larger programs that target particular needs of

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64 ASSESSMENT OF DIRECTIONS IN MICROGRAVITY AND PHYSICAL SCIENCES RESEARCH AT NASA NASA. For example, a coordinated multidisciplinary effort could quickly result in compact biosensors and medical diagnostic devices, both of real use to NASA's human exploration efforts. NANOSCALE MATERIALS Recent technological advances have made it possible to engineer materials on the nanometer length scale by exploiting self-assembly processes. Materials engineered at the nanoscale exhibit unique structural and functional phenomena not achievable with conventional materials. For example, materi- als are envisioned that can sense emerging internal defects in materials and alert the user in a timely fashion, before there is a catastrophic failure. Other materials might sense environmental cues and respond to them by, for example, delivering drugs, healing defects, undergoing mechanical motion, or altering an optical or magnetic response. Simultaneously, modern biology, with its new genetic and analytical tools, is providing insights into how nature synthesizes and processes materials. Cellular processes such as light harvesting, energy conversion, data storage and processing, self-replication, and locomotion occur at the nanoscale. Nature has devised sophisticated solutions by evolving complex molecules and molecular assemblies to perform these tasks. By emulating nature, researchers have begun to develop new processing strategies for the fabrication of synthetic materials and the integration of biological systems into artificial materials. Merging the biological and the synthetic world at the nanoscale promises revolutionary technological developments, particularly for sensors and diagnostics. Nanoscale materials, a rapidly expanding field involving many different disciplines, is being sup- ported by a number of different government agencies. As with many areas discussed in this chapter, the committee concluded that any investment that the PSD might make in nanomaterials should focus on research that will have the greatest impact on NASA's missions and that is consistent with the criteria cited at the beginning of this chapter. This requires that the PSD identify the questions that are relevant to NASA before soliciting solutions from the community through peer-review processes. The examples below illustrate how such an approach could provide NASA with enabling technology to meet its goals. For each of the topics, the significance to NASA is given and the background, state of the art, and any research recommendations are discussed. Nanoparticles New materials with tailored properties are important to achieving NASA' s goals of low-cost space- flight and establishment of a permanent human presence in space. A promising approach production of such materials involves the assembly of nanoparticles or the hybridization of nanoparticles with organic and/or inorganic matrices. This approach extends the novel materials properties derived from nanoscale phenomena to larger scales and tailors them to the requirements of macroscopic appli- cations. These tailored nanomaterials can exhibit unique sets of complementary structural, magnetic, optical, thermal, chemical, and electric properties. One impediment to converting these research find- ings into products is the difficulty of synthesizing most nanoparticles in large quantities. Precise control of their size (and their quantum phenomena), their stabilization over extended time periods, and control of assembly processes are also critical issues. Significant progress has been made in growing inorganic and organic nanoparticles and in assem- bling certain nanomaterials and giving them temporal stability. A particle's size and shape strongly influence its properties, and scaling up the synthesis of nanoparticles to large quantities is of interest. Researchers have made much progress in growing monodisperse nanoparticles of metallic and semicon- ductor materials, including gold, silver, and magnetic nanoparticles. To exploit nanoscale phenomena to the

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EMERGING AREAS 65 for technological applications, future experimental and theoretical work will focus increasingly on the mechanisms for growing nanoparticles with more complex shapes (Manna et al., 2000) and on the use of complex shapes to fine-tune properties (Li et al., 2001; Hu et al., 2002~. Indeed, the periodic table leaves much room for the synthesis of more nanoparticles with unique shapes and properties from other combinations of elements. Far-from-equilibrium processing of nanostructured materials is another emerging area of scientific interest and potentially great technological importance. For example, the superplastic formability of a nanocomposite ceramic having three constituent nanophases with comparable volume fractions has been demonstrated (Liao et al., 1997, 1998; Colaizzi et al., 2001~. The key to this application has been the ability to produce metastable powders by a rapid melt-quenching process, followed by controlled decomposition into the final stable, three-phase nanocomposite structure. Possible applications include the superplastic forming of rocket engine and space vehicle components, where there is a need for light weight and resistance to heat, radiation, and erosion. Magnetic nanocomposites that result from the decreased size of the domains or grains within the material are also of significance to NASA. These include composites having enhanced magnetocaloric effects, which enable both high- and low-temperature magnetic refrigeration; higher-density recording media; and giant magnetoresistance materials that provide large changes in resistance for a given magnetic field. Ferromagnetic materials of small diameter promise to further enhance the giant magne- toresistance effect (Xiao et al., 1993~. Hard magnetic materials are used in a wide range of applications such as motors. Nanocomposites consisting of materials with hard magnetic domains within a nonmag- netic phase, such as those produced in Nd-Fe-B alloys (for a review, see Buschow, 1988), are particu- larly promising routes to enhanced coercivity. Nanocomposites involving the coupling between atomic spins over atomic length scales promise to greatly enhance magnetocaloric efficiencies and, in particu- lar, to enable efficient magnetorefrigeration at close to room temperature. Because magnetic refriger- ants are widely used in a host of NASA missions, from satellites to refrigerators on the ISS, enhanced magnetocaloric properties could have a major impact. Perhaps no nanoparticle has received more attention than the single-wall carbon nanotube (SWNT), with a predicted Young's modulus of about 1 terapascal (TP) and excellent electrical conductivity. Applications ranging from ultralight high-performance SWNT structural composites to molecular-scale electronics are being actively investigated, often with NASA support.~ With NASA already heavily engaged in this rapidly emerging area, the committee felt that additional investment in nanotubes by PSD would be unwarranted. Nanoparticles in isolation will have limited use instead they should be seen as building blocks with which to fabricate materials and devices tailored to NASA's needs. The PSD should set its priorities carefully when considering what it might contribute to this area. The fields of molecular electronics and magnetic nanosystems, for example, are likely to be rapidly dominated by other agencies and industry. Functionalized Nanoparticles For many classes of material, it is essential to develop methods for stabilizing the surfaces of 1For example, NASA has teamed with recent Nobel Prize winner Richard Smalley of Rice University in a multiyear program to develop cost-effective nanotubes for space applications. The Johnson Space Center is working extensively on nanotube-reinforced composite materials, while NASA Ames is a leader in nanotube-enabled electronics. Other divisions of NASA are also major players in nanotube R&D (see NASA Web site for details).

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66 ASSESSMENT OF DIRECTIONS IN MICROGRAVITY AND PHYSICAL SCIENCES RESEARCH AT NASA inorganic nanoparticles against atomic restructuring or unintended chemical reactions. For example, in highly luminescent semiconducting nanoparticles, ZnS shells have been used to stabilize the CdSe core, whose quantized electronic states give rise to narrow emission bands that can be continuously tuned by changing the particle diameters (Dabbousi et al., 1997~. Engineering that uses nanoparticles as building blocks will require unique ligands that specifically recognize each class of material. Furthermore, the ligands will have to bind selectively to particular crystal faces. Selective binding enables the control of nanoparticle self-assembly into hybrid materials or onto designated surface areas within devices. Thiol chemistry has been broadly employed to functionalize gold particles, and silica coatings have been introduced to conjugate nanoparticles to biomolecules in an attempt to render them biocompatible (Gerion et al., 2001; Michalet et al., 2001; Chan et al., 2002~. In the search for alternative chemistries that bind specifically to nanoparticles of interest, phage display technology has been recently demon- strated that can select, out of a random library, peptides that selectively bind semiconductors, even exhibiting selectivity for particular crystallographic faces (Whaley et al., 2000~. Much work is needed to identify high-affinity ligands for a wider range of technologically important materials and to allow their coassembly into hybrid materials. If the PSD is to develop nanotechnology along the lines of interest to NASA, it will have to ensure the development of a nucleus of investigators with expertise in the foregoing foundation technologies for the chemical modification of nanoparticle surfaces. Special attention should be paid on the one hand to the search for novel chemistries and biochemistries that specifically enable binding to materials of interest to NASA and on the other hand to the search for heterofunctional linker molecules that enable the assembly of nanoparticles of dissimilar materials with complementary properties. However, since the chemical modification of nanoparticles is at the core of much ongoing nanotechnology work, the committee suggests that the PSD support topics in functionalized nanoparticles indirectly, either by funding only the technology applications and encouraging investigators to look elsewhere for funding specific to these foundation technologies, or by forming close alliances with other NASA divisions or outside agencies2 to support research into foundation technologies for which there is a particular NASA need. Hybrid Materials with Multiple Functions Meeting its technology challenges will require that NASA have access to future materials and devices that incorporate nanosystems with complementary properties and functions. Examples range from materials with high strength and low weight to materials with integrated sensory functions. The challenges of producing such materials are many. Self-assembly could potentially be combined with templating technologies or with micro and nanofabrication to produce these complex structures. For example, use of proteins, DNA, and other biomolecular processes could open new routes to the nano- .. ~ . . . ~ ... . . . . . ,, - . . . ~ ~ ~AAA~ ~ .. .. . . . assemoly o~ nlgn-per~ormance, slllcon-nasecl materials (~;na et al., lYYY, ZUUU). U1~A ano olomolecular ligands (Whaley et al., 2000; Seeman and Beecher, 2002) could be used to connect, and control the self- assembly of, nanoparticles (Mirkin et al., 1996; Storhoff and Mirkin, 1999), nanowires (Huang et al., 2001; Hu et al., 1999; Wilson et al., 2003; Sapp et al., 1999), viruses (Lee et al., 2002), and devices (Yen et al., 2002; Nam et al., 2002~. 2For example, NASA has collaborated with the National Cancer Institute to solicit proposals for basic research on technol- ogy development related to biosensors.

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EMERGING AREAS 67 Since the properties of materials depend on the ordering of the building blocks at different length scales, technologies that induce or impose a long-range hierarchical ordering of the blocks will be pivotal (Whitesides and Gryzbowski, 2002~. The long-range ordering of liquid crystals, for example, has been used to serve as a template for mesoporous molecular sieves (Kresge et al., 1992; Ryoo et al., 1999) and inorganic solids (Braun et al., l999~. Colloids have been used to impose hierarchical order on sol-gel ceramics (Shin et al., 2001b). Crystal-imprinted polymers have been used to direct the nucle- ation of biominerals (D'Souza et al., 1999~. And ordered cellular structures in wood tissues have been mineralized using a surfactant-templated sol-gel process (Shin et al., 2001b). Finally, micromolding, combined with polystyrene sphere templating and the cooperative assembly of inorganic sol-gel species with amphiphilic triblock copolymers, has been used to pattern porous silica, niobia, and titania with three-dimensional structures over multiple length scales. The resulting materials show hierarchical ordering over several discrete and tunable length scales, from 10 nanometers to several micrometers (Yang et al., 1998~. The committee's recommendation to the PSD in the preceding section, "Functionalized Nano- particles," applies equally to future PSD research on the fabrication of nanomaterials. Namely, the development of integrated nanomaterials should take advantage of expertise developed in already exist- ing programs such as those described above, and build naturally on the PSD program's expertise in surface chemistry and interracial phenomena. For example, NASA's work in colloidal condensation and surfactant chemistry is relevant to advancing the sophistication of hybrid materials using self- assembly strategies. Nanoscale Systems for Energy Conversion and Defect Repair Research into technologies to fabricate hybrid materials must be complemented by research into nanoscale systems for signal transduction, so that sensory functions and readout capabilities can be integrated into artificial materials, or biological molecules can be manipulated on demand by external signals. Areas on the verge of being emphasized by several agencies (including DOE, DOD, DARPA, and others) are nanoscale systems that interconvert chemical, electrical, optical, thermal, mechanical, or magnetic signals. Many different avenues are currently being explored to transduce signals in manmade systems at the nanoscale. For example, the conductance of single molecules can be altered through conformational changes in the molecule (Donhauser et al.,2001~. Electronically programmable memory devices can use molecular self-assembled monolayers (Reed et al., 2001~. Elastic protein-based poly- mers have been developed that convert environmental stimuli into shape changes (Urry, 1997~. Mate- rials with continuously adjustable pore size have been made by templating silicates (McGrath et al., 1997~. Temperature-sensitive hydrogels have been utilized for various sensing applications, including thermally switchable diffractive arrays (Weissman et al., 1996) and thermosensitive clay nanocomposites (Liang et al., 2000~. Furthermore, ligand binding to proteins has been environmentally controlled using polymer-protein conjugates (Ding et al., 2001), and drug release from porous channels has been con- trolled using hybrid nanogels (Shin et al., 2001a). While these are important first steps, biology has evolved the most sophisticated nanoscale systems for the conversion of energy from one form into another. Examples include motor proteins, which convert chemical into mechanical energy. Photosyn- thetic membranes in chloroplasts harvest light to pump protons across membranes, thereby establishing an energy source for plants. The energy sources of aerobic cells are mitochondria, which use the metabolic oxidation of nutrients to pump protons across their active membranes to power other meta- bolic processes. Insights into the mechanisms by which these biological systems work provide inspirations for new

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68 ASSESSMENT OF DIRECTIONS IN MICROGRAVITY AND PHYSICAL SCIENCES RESEARCH AT NASA design principles for converting energy forms more efficiently. For example, inspired by nature, researchers have designed a photocatalytic dendrimer reactor (Hecht and Frechet, 2001), and block copolymers have been designed that capture features of their natural protein counterparts to synthesize ordered silica structures (Cha et al., 2000~. An examination of biological systems may also suggest new solutions for integrating nanoscale machines into functional systems at different length scales, since biological materials display an exceptionally high degree of spatial and temporal organization. This effort could build on already existing expertise in the PSD program on self-assembly, interracial phe- nomena, nanotubes and nanowires, and protein-protein interactions. Challenges related to systems integration are discussed in the next section, "Integrated Nanoscale Devices." Considering the many possible approaches to converting signals at the nanoscale, any PSD invest- ments in this field should be driven by clearly defined technological challenges that would determine which molecules, systems, and processes would be investigated at the fundamental level. Finally, to protect human health in space and for extended flight missions, NASA has to find solutions to the problem of identifying incipient materials defects before they result in a catastrophic failure of materials and devices and repairing defects during spaceflight. This is a particularly relevant issue since aging of materials is considerably accelerated by radiation damage. While concepts of self- healing are absent in industrial materials, biological systems are remarkable in their ability to self-repair molecules such as DNA, to self-heal materials such as bone or the skin after injury, and to grow or reconfigure materials on demand. NASA could invest in developing new strategies that potentially would borrow design principles from nature to introduce attributes of self-healing and repair that would extend the lifetime of manmade materials and devices. First approaches to the engineering of self- healing or self-repairing materials have been explored. For example, encapsulated adhesive or prepolymer has been distributed throughout a composite material. At the damage site, the adhesive is locally released or the prepolymer is locally polymerized, leading to partial recovery of the material's strength. In contrast, the self-repair mechanisms of biological materials are far more elaborate, because they involve the rapid exchange and replacement of damaged building blocks by energy-driven pro- cesses. Accordingly, molecular motors have been integrated into synthetic materials to carry molecular- or nanoscale cargo to user-specified locations (Hess et al., 2001), opening the possibility of locally repairing defects. It might also be possible to integrate molecules and nanoscale particles that can act as reporters into structural materials to monitor the material's properties in real time. This would enable lighter and safer structural materials for space exploration, including astronaut suits, and would greatly benefit the quality of life on Earth and in space. INTEGRATED NANOSCALE DEVICES The novel phenomena, properties, tools, and processes provided by nanotechnology advances have much to offer when it comes to addressing the challenges of human space exploration over extended time periods. They could be applied in areas such as power generation and energy storage, advanced life-support systems, water purification, human waste management, management of accidents and haz- ardous conditions, human health monitoring and diagnosis, and integrated sensors for the detection of threats to human life, to name a few. The high launch and operating costs of current space systems are usually proportional to their weight or mass, which in turn is a determining factor in the amount of functionality of a particular system or subsystem. The integration of micro- and nanoscale technologies into selected spacecraft subsystems could increase functionality and reliability while simultaneously decreasing weight. To capitalize on emerging nanotechnologies for advancing space exploration, NASA should focus on integrating large numbers of nanoscale subsystems into devices, potentially covering

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EMERGING AREAS 69 many different length scales. This requires a multidisciplinary approach and cross-disciplinary exper- tise. Furthermore, scientists should collaborate with engineers early on to ensure the successful integra- tion of nanoscale systems into the operational systems of relevance to NASA's mission. Three areas of particular interest are energy storage and chemically driven nanosystems; microfluidics; and integrated microelectrochemical and nanoelectrochemical systems. Energy Storage and Power Generation What energy sources will power NASA's macroscopic and microscopic devices in the future? Advanced miniaturization and exploitation of nanotechnologies could play an important role in the development of next-generation batteries and fuel cells. For example, hierarchically structured elec- trodes and nanostructured electrolytes would have broad applicability to different types of electrochemi- cal devices and would have the potential to significantly improve their performance compared to that of existing technologies. Finding more efficient approaches to increasing energy density at minimal weight is critical to NASA's space missions. A number of other near-term potential applications of nanotechnology are also emerging, such as novel matrices for hydrogen storage, including metal hy- drides and nanotubes; ionic conducting membranes; efficient utilization of sunlight; and direct produc- tion of biological nutrients and their reconversion into energy. Batteries, fuel cells, and other electrochemical devices often involve complex mass and charge transfer mechanisms. The fuel cell electrode, for example, requires pathways for electrical conduction, gas flow, and ion conduction. Configuring these pathways for optimal performance involves complex structural hierarchies with design issues that span nanometer- to millimeter-length scales. Typically, part of the electrode fabrication process involves slurry coating the electrode surface, a technique that does not offer sufficient control to fabricate complex hierarchical structures. The recent application of templating methods (Lellig et al., 2002; Velev et al., 1998) has resulted in a highly porous three- dimensional network with enough surface area for efficient electrode mass transfer. Chemical printing techniques might be another way to fabricate hierarchical structures that could even accommodate compositional variations across the electrode surface. This would facilitate the interdigitation of differ- ent conduction pathways. Nanostructured electrodes, which are formed with two or more types of nanoparticles, can increase mechanical strength while decreasing the electrode thickness and increasing the electrode conductivity (Sate et al., 2000~. Nanostructured electrodes can be fabricated using a variety of techniques, from molecular beam epitaxy and chemical vapor deposition to traditional colloidal processing techniques. In addition, it has been demonstrated that nanoscale devices have an inherent capacity for storing energy (she et al., 1999; Gomez-Romero, 2001) and for efficient electrochemical energy conversion in micro fuel cells (Chen et al., 2001~. These findings suggest that the field of energy storage and power generation can be pushed beyond the capabilities of conventional technologies. As space missions become longer in duration and more demanding in terms of energy usage, these new technologies will become increasingly important. Solid-state electrical power generation, based on the Peltier effect, is achieved when a temperature difference is maintained across a thermoelectric material. These thermoelectric devices offer the advan- tage of being environmentally friendly and not requiring moving parts. However, for thermoelectric generation to become a competitive source of power, the energy conversion efficiency has to be signifi- cantly improved by engineering superior thermoelectric materials that are not available naturally in elemental form. Promising thermoelectric materials include semiconductors with a high Seebeck coef- ficient, tailored to exhibit high electrical conductivity and controlled heat flow with relatively low

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70 ASSESSMENT OF DIRECTIONS IN MICROGRAVITY AND PHYSICAL SCIENCES RESEARCH AT NASA thermal conductivity. For this purpose, multimaterial nanostructures can be engineered, using tech- niques that increase the resistance to heat flow in the lattice responsible for thermal transport. Promising approaches have recently been reported including superlattices (Venkatsubramanian et al., 2001) and nanostructured thermoelectric materials with quantum confinement of electrons and phonons (Hicks et al., 1996; Dresselhaus et al., 1999~. Superior thermoelectric properties can be achieved by confining semiconductors in the 5- to 100-nanometer-size range (Sun et al., 1999), including quantum confine- ment of electrons in nanowires, to tailor the electronic band structure. Thermal conductivity can also be reduced by enhancing boundary scattering in nanowires that influences the phonon spectra and lifetime (Dresselhaus and Eklund, 2000~. Thermoelectric properties may be further enhanced by tailoring nanowire array composites. Advances in nanotechnology also offer promising solutions for converting energy from one form into another for example, light into electrical, chemical, optical, magnetic, or mechanical energy, as discussed in the section "Nanoscale Systems for Energy Conversion" above. While conventional solar cells have rather low conversion efficiencies compared with those of biological systems, molecular photonics mimicking how nature harvests light offers more efficient avenues for light harvesting and charge separation (Schwarz et al., 2000~. The efficiency of bioinspired synthetic molecules de- signed to separate charges when light is adsorbed has increased significantly (Gust et al., 1998~. Many new designs, such as conjugated -electron systems or quantum dots incorporated into matrices to facilitate charge separation and storage, will benefit from advances in the tailoring of materials from block copolymers to dendrimers, and nanotubes to colloidal systems at the nanoscale. The advances described above will not be realized without the ability to successfully integrate multiple nanosystems, which in turn requires the knowledge to assemble and synchronize their func- tions. Synchronizing their functions, for example, requires that the rate constants of the systems feeding from each other are properly adjusted with respect to the local transport rates and relative spatial separations of the systems. The physical science expertise within the PSD program, particularly the expertise in fluids and transport, could be applied to solving this problem. For example, computational models could be developed to simulate coupled nanosystems, potentially operating in confined spaces, or the behavior at their interfaces with larger systems, for example, fuel reservoirs or other material sources. Microfluidics Control of fluid and transport processes is essential to the fabrication and operation of many submicron-scale devices, with applications that range from chip-based chemical assays through human health monitoring and diagnosis to transport in proton exchange membrane fuel cell microchannels. Microfluidic flows can be driven by pressure gradients, electric or magnetic fields, or themocapillary flows. For each of these mechanisms, the details of the flow and the degree to which it can be manipulated depend on geometric factors and on length scale roughness that is, the length scale of the roughness of the channels in which the fluid flows. The production of devices that use microfluidic processing, or the use of microfluidics as a delivery mechanism, poses significant challenges to the designers, builders, and users of such systems (Unger et al., 2000; Beebe et al., 2000) and would require, for example, microfabricated components such as valves and pumps (Quake and Scherer, 2000~. These emerging research areas might rely on some form of microfluidic components such as so-called micro- chip-based assays (Wang et al., 2002) for electrochemical detection and on microfluidic chips for clinical analysis (Verpoorte, 2002), both of which will be technologies important to an array of human and robotic spaceflight applications.

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EMERGING AREAS 7 The control of fluid flow and transport of components will also play an important role in the operation of microreactors and miniaturized analysis systems, where flow and transport conditions can be controlled through the introduction of local microstructures (Beebe et al., 2000~. Many processes will require the mixing of two or more fluids or the dispersion of one phase in a host "carrier" fluid. Some applications will require thorough mixing of two or more components in a short time. However, design constraints and the low Reynolds numbers obtained in these systems prohibit the use of tradi- tional mixing techniques, such as mechanical actuators or a reliance on turbulence. Even though some difficulties have been overcome in specific instances (Stroock et al., 2002), a further knowledge of microfluidics is required for the realization of useful microfluidic devices. While many micro- and nanofluidic investigations do not require a microgravity environment, for others it is essential, such as for flows whose behavior depends critically on the motion of the fluid-solid contact line (a subject currently under investigation in the PSD fluid physics program). In addition, for flows in integrated arrays of microfluidic devices, the presence or absence of gravity significantly affects the large-scale distribution of the liquid within the system, even though capillary or molecular forces dominate the local fluid motion. If cell-based microdevices emerge as an important element in future missions, then the interaction between cells and microfluidic processes in micro- and nano-engineered environments will become a significant research area. There is an opportunity for NASA to capitalize on the existing expertise in the PSD fluid physics program in such areas as capillary-dominated flow, and to have an impact in the field of microfluidics, fostering its development to benefit spaceflight technology. Integrated Microelectromechanical Systems and Nanoelectromechanical Systems Devices Microelectromechanical systems (MEMS) and nanoelectromechanical systems (NEMS) devices can sense, actuate, and control mechanical, physical, chemical, optical, and biological processes. Revo- lutionary advances promise to come from integrating MEMS and NEMS components into large struc- tures (NRC, 2002), which could then play an important role in space exploration. MEMS and NEMS applications of importance to NASA range from their use as multiple sensing devices, microreactors, and microfluidic systems for spaceship operation to their use as biosensors for crew health and auto- mated medical treatment. In many of these uses, they could simultaneously satisfy the technological and economic demands for smaller, faster, integrated space exploration systems. Examples of NEMS devices include nanoengineered and biomimetic sensors with advanced proper- ties and functions that would allow for in situ monitoring of humans in space. The development and application of sensors could be extended to allow the rapid treatment of diseases and injuries a capability that will be needed for long-term human space travel. Another example, noted in a previous section, is the development of near-room-temperature, direct-methanol protein exchange membrane fuel cells for efficient energy storage, safe operation, and on-demand power supply. Such fuel cells could produce anywhere from kilowatts to megawatts of electricity to power spacecraft or could be scaled down to milliwatts to power electronic or biological sensors. Advances in nanomaterial self-assembly or MEMS- and NEMS-based manufacturing will enable the fabrication of protein exchange membrane porous membranes and electrodes with tailored mechanical and electrochemical properties. However, the successful integration of the micro- and nanoscale devices means addressing the system-level integration concurrently, as well as using the emerging knowledge in areas such as microfluidic han- dling and control and two-phase flow separation at the micro- and nanoscale. Investments in integrated MEMS and NEMS devices are poised to lead to new multiple sensor technologies, power-generation systems, and smart materials with integrated functionalities, including

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72 ASSESSMENT OF DIRECTIONS IN MICROGRAVITY AND PHYSICAL SCIENCES RESEARCH AT NASA "intelligent" space suits for astronauts. Other applications of interest to NASA include biosensors and bioelectrodes for the detection and monitoring of chemicals and toxins; blood-glucose sensors; and detectors of bacterial or other toxic contamination. Bio-MEMS and microrobotics can be adapted for use in systems for noninvasive telesurgery and for other micromechanical machines with biomedical applications. Systems for sensing biomedical and inorganic substances in both aqueous and gaseous phases will be important to life-support systems. The use of nano- and microtechnology in radiation monitoring and dosimetry, and the development of methods for connecting biomedical microtechnology and biotelemetry equipment, would also clearly be of interest to NASA's bioastronautics program as well. To capitalize on emerging technologies such as those discussed in previous sections, NASA will have to be able to integrate them in order to produce innovative systems with application to advanced space technology. To ensure this successful integration into operational systems requires multidi- sciplinary expertise and scientists working closely with engineers. Modeling of fluid behavior in fluid- fluid and fluid-material systems is one key to understanding nanoscale phenomena, their interactions with macroscopic components, and their final integration into systems. Overcoming the challenges of such work will require computational modeling and simulation across several length scales when de- signing functional devices. Research on modeling nanodevices, nanosystems, and nanoarchitectures, as well as on the physics of nanoscale devices, is needed to develop reliable predictive capabilities for the design of integrated nanosystems for space exploration. Alliances with NIH, such as cooperative research agreements, on some of these topics would be an attractive way for NASA to further explore this frontier. MOLECULAR AND CELLULAR BIOPHYSICS One of the toughest challenges faced by NASA is maintaining human health and handling medical emergencies in space. While NIH invests heavily in point-of-care technology to diagnose and treat disease remotely, NASA is the only agency with a vested interest in learning how human health is affected by low gravity and how to maintain human health on extended flight missions. An example is the need to develop countermeasures for the rapid loss of bone mass and the muscle atrophy that occur in long-duration spaceflight. Although many low-gravity-related physiological phenomena and their medical implications are well documented, there is little insight into the underlying cellular and molecu- lar mechanisms. It is at those levels that these phenomena will have to be understood if there is to be significant progress in overcoming their deleterious effects. Further research is required into the role of mechanical forces (including shear, loading, and stretching) and low gravity in molecular recognition and cell signaling, and significant new insights are expected based on rapid advances in novel tools for nanoanalysis and biotechnology. Since there is a significant amount of U.S. research, including research in other NASA divisions, into the molecular basis of cell signaling and how the equilibrium structure of proteins relates to protein function, the PSD can have the most impact by focusing on the pertinent physical aspects of these processes. Discussed below are the specific topics where the committee believes PSD could have the greatest impact. o Protein Stabilization for In-Space Applications Long-term preservation of protein function is essential to using proteins in space in sensors, for diagnostics, and in bioreactors on extended flight missions. For instance, to be of the most utility in

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EMERGING AREAS 73 space, sensors assembled on the ground would be stored in spacecraft under ambient conditions and would be ready for use with no need for thawing, freezing, or other damaging preparatory operations. In addition, sensors worn by astronauts would have to operate, perhaps for extended periods, at physiologi- cal temperatures. Proteins, unless frozen, typically lose their function within days or weeks; this is well recognized in biotechnology and medicine. However, frozen proteins weigh more and require more storage space, nor are all the desired functions likely to be preserved in proteins stored for extended periods. Proteins can degrade by various mechanisms, including gradual thermal or interracially in- duced denaturation,3 enzymatic activity, and precipitation. Indeed, many proteins in the body, e.g., plasma proteins, have a natural half-life ranging from a few minutes (like tissue plasminogen activator) to several weeks (like albumin). On the ground, equipment-intensive procedures and single-use devices are often used to cope with the inherent instability of proteins. Once protein-containing materials or devices are brought into contact with water, their lifetime is reduced to a few days. For extended-flight applications, components or devices with such short lifetimes are completely inadequate. Although a number of methods have been explored for the stabilization of proteins used in materials applications or devices, most of the methods were based on biochemical approaches. For example, it has been shown by limited site-directed mutagenesis involving a few amino acid residues that protein stability can be altered without changing function significantly (McGuire et al., 1995~. Protein stability can also be increased by the addition of disulfide bonds, by cross-linking surface histidines by external tethers (Kellis et al., 1991), by directed evolution of the primary structure through random mutagenesis (Arnold et al., 2001), and by the use of chaperones and conjugates (Goes and Martin, 2001; Sheffield et al., 2001~. The use of artificial amino acids is also a promising new route for engineering novel properties into proteins or for preventing their enzymatic degradation. For example, protein stability can be increased by introducing fluorinated amino acid side chains, thereby enhancing hydrophobicity and stabilizing the conformation (Tang et al., 2001; Niemz and Tirrel, 2001~. Recently, the introduction of nonnatural amino acids into the primary sequence of proteins made possible the chemoselective modification of proteins at specific locations (Kiick et al., 2002; Lei et al., 2002b). Although physical approaches to protein stabilization, as opposed to the biochemical ones discussed above, appear to be feasible, they have received little attention to date. It is here that the NASA PSD program can make a valuable and unique contribution. One example of such physical approaches is to slow the gradual denaturation of proteins adsorbed to surfaces by embedding or surrounding the mol- ecules of interest in an otherwise nonadhesive surface coating. For example, antibodies have been stabilized for short-term use on the surface of polyethylene glycol, with obvious importance for immu- nochemical-based sensing. Also, recent experiments suggest that native protein structures may be stabilized if the proteins are immobilized in liposome (Corvo et al., 2002), polymer matrices (Schwendeman, 2002; Baran et al., 2002), peptide matrices (Battistuzzi et al., 2003), or nanoengineered environments, for example nanopores (Led et al., 2002a). Attempts have also been made to encapsulate proteins during sol-gel formation (Eggers and Valentine, 2001; Kato et al., 2002~. Finally, it has been shown that the topography of a protein surface and some aspects of its surface chemistry can be imprinted into nonbiological surfaces using templating technologies (Vlatakis et al., 1993; Plunkett and Arnold, 1995; Shi et al., 1999; Boal and Rotello, 2000; Liu et al., 2000~. Thus, it can be seen that several physical-science-based methods are beginning to emerge that can address the difficult challenge of how to preserve or mimic protein function. The PSD is ideally suited 3For example, proteins can degrade if they are adsorbed to a surface such that their hydrophobic moieties are exposed.

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74 ASSESSMENT OF DIRECTIONS IN MICROGRAVITY AND PHYSICAL SCIENCES RESEARCH AT NASA to assume leadership of research on these methods based on its expertise in such physical sciences areas as the microscale physics at the interracial zone. In addition, new approaches to these problems are required, and they should be encouraged and fostered by studying the underlying mechanisms of protein structure stabilization by physical constraints. Such studies would require interdisciplinary teams bringing together the frontiers of nanotechnology and molecular biology. The topic of protein stabilization could be expanded to include the stabilization of RNA that has been shown to exhibit catalytic activity. Similarly, biologically or synthetically produced oligonucle- otides might provide an alternative route to biorecognition in a nonbiological environment. The area of biomolecule stabilization would benefit enormously from a more focused effort, such as could be mounted by NASA, with an emphasis on physical interactions such as capillary effects and diffusive transport processes. It is relevant to note that some of the expertise to address this challenge already exists in NASA' s protein crystallization community, which is concerned with protein structure and protein-protein interactions. Long-Term Stabilization of Cell Cultures The sensing, diagnosis, and remote treatment of disease will be a key element of a successful human presence in space. Many attractive approaches to these critical capabilities involve the use of cells as active biosensors or bioreactors to sense or synthesize the many molecules critical for human survival during extended flight missions. Cells cultured ex vivo often lose their phenotype after short time periods. This limits their applications in bioreactors and their integration into material scaffolds (tissue- engineered constructs), sensors, and other devices. Moreover, although cells can be stored frozen for extended periods at cryogenic temperatures, this approach again carries a weight and volume penalty. In addition, it is clear that cells should be available that remain stable indefinitely under the conditions in which they normally function. Our understanding of the fundamental biology of cell interactions with their natural environment and how cell behavior can be regulated by engineered environments is still in its infancy. Again, as in the protein stabilization work, research at the most fundamental level is needed to make progress and ultimately to learn how to preserve cell structure and function over extended time periods. Some applications allow. one to circumvent mammalian cell instability ex vivo by exploiting less 1 1 ~ ~ 1 0 . .. . . .. . . .. .. .. . complex cells for example, yeast or plant cells rather than mammalian cells for sensor applications. Ow.inp to its smaller penome compared with that of mammalian cells, yeast has been a preferred O 0 1 ~ 1 . . . . . . . . . . . . . . . .. . platform for many microbiologists trying to Identity regulatory mechanisms and metabolic pathways. Of most interest to NASA, however, is the fact that yeast can be frozen and stored for extended time periods. Only minutes after contact with nutrients, the yeast cells recover fully and function normally. The first attempts to use yeast cells for sensor applications are under way. With financial support from the PSD program, one start-up company (LifeSensors) is developing a microfabricated platform to use the saliva of astronauts to test for early stages of diseases in space. Applications that require the use of mammalian cells will depend on advanced insights into how to engineer micro- and nanoenvironments for mammalian cells that allow controlling and regulating cell function and preventing cell death. Fundamental in this connection is an understanding of the physical and chemical cues that allow cells to function properly. Our knowledge of cell interactions with nonbiological systems has been expanded considerably in recent years by bringing modern cell biology together with chemical and engineering technologies. Biophysical methods used to modulate cell function include sequestration in three-dimensional matrices that incorporate or release regulatory molecules (e.g., growth factors and enzymes) at controlled rates,

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EMERGING AREAS 75 ~ - 7 7 I - 7 7 Thus, success in exploiting cells that are integrated into materials and devices is dependent on a considerable extension of our knowledge of how the cell cycle, cell proliferation, differentiation, and, finally, apoptosis relate to the physical and chemical properties of the matrix that serves as the host for the cell, and on the nanoscale transport of nutrients to the cell and of cellular products away from it. The PSD research community has both expertise and novel technology to offer and could make meaningful contributions to understanding how physical cues complement the much better understood biochemical cues in regulating cell function. For example, the PSD biotechnology program has already made investments in the past to better understand how mechanical stresses (e.g., gravity) acting on the cell and cell matrix affect the cell cycle, cell proliferation, and apoptosis (NRC, 2000~. The PSD could capitalize on its existing expertise in biotechnology particularly its programs in cell science, surface chemistry, materials science, and fluid physics, all of which are essential topics, for example, in engineering cell surface interactions and controlling the nutrient flow.

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76 ASSESSMENT OF DIRECTIONS IN MICROGRAVITY AND PHYSICAL SCIENCES RESEARCH AT NASA Developing a scientific basis for the parameters that are essential to stabilizing and controlling cell phenotypes over extended time periods will revolutionize our knowledge of how cells can be exploited for use as sensors, for the cleanup of waste, and for the production and recycling of nutrients, enzymes, and hormones in space. In addition, learning how to stabilize cell cultures will undoubtedly have an impact on the research in tissue engineering being funded by other agencies, notably NIH. While the committee does not recommend that NASA launch a broad research program in tissue engineering, the much more focused objectives discussed above are of great relevance to NASA's manned spaceflight programs and will ultimately have an important impact on many other fields, including biotechnology and regenerative medicine. Cellular Responses to Gravity-Mediated Tissue Stresses A large body of data has been accumulated clearly indicating that the microgravity environment causes significant physiological problems for astronauts. For example, significant and continuous bone loss is intimately linked to the prolonged exposure of astronauts to a microgravity environment, but the underlying causes of this loss are not well understood. While much has been done to study the physiological effect of low gravity on organisms, organs, and cells, the underlying mechanisms by which gravity (or the lack of it) regulates cell signaling thereby triggering larger systemic responses- remain unknown. The loading on various elements of the human anatomy is changed or eliminated as gravity is reduced. Even on Earth, many pathologies including osteoporosis, hypertension-related cardiovascu- lar disease, atherosclerosis, and pulmonary hypertension are thought to be associated with or even caused by increased or reduced levels of mechanical strain (Pelouch et al., 1993; Maniotis et al., 1997; Chaqour et al., 1999; Prajapati et al., 2000~. Mechanical forces are also known to play an important regulatory role in tissue development and have been demonstrated to regulate gene expression (Owen et al., 1997; Goldspink et al., 2002; Mourgeon et al., 2000; Li and Xu, 2000; MacKenna et al., 2000; Geng et al., 2001~. At the cellular and particularly the molecular levels, little is known about how mechanical forces affect cell signaling and gene expression, despite the fact that several of the molecular players in mechanically regulated signaling pathways have been identified (Shyy and Chien, 1997; Chicurel et al., 1998; Li and Xu, 2000; Carson and Wei, 2000~. Much of the gap in our understanding of how nature uses mechanical forces in synchrony with chemical cues has been due to the lack of appropriate tools for studying protein structure and mechanical properties under nonequilibrium conditions. This has been changing in the last few years as a result of emerging nanotechnologies, including optical tweezers, atomic force microscopy, and advances in optical spectroscopy (Block et al., 2003; Galbraith et al., 2002; Oberhauser et al., 2002; Benoit and Gaub, 2002~. Preliminary experimental and computational data suggest that mechanical forces regulate the functional states of some proteins by stretching them into nonequilibrium states (Vogel et al., 2001; Baneyx et al., 2002; Thomas et al., 2002; Onoa et al., 2003; Oberhauser et al., 2002~. Furthermore, external mechanical stretching may change the mass transport and induce shear stresses on cells that could directly affect the cytoskeletal organization (Ingber, 1999; Bhadriraju and Hansen, 2002; Pommerenke et al., 2002; Balaban et al., 2001; Karlon et al., 1999; Galbraith et al., 1998; Satcher et al., 1997), and the transport of growth factors and nutrients could be altered under mechanical stimulation. These stresses are a direct function of the applied load on the biological entity. NASA should support research aimed at developing a mechanistic understanding of how applied loads and stresses affect cellular processes, including the underlying molecular processes. New insights from molecular biology, combined with the development of novel nanoanalytical tools, promise to

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EMERGING AREAS 77 rapidly advance our understanding of the underlying physical mechanisms by which the loss of gravity ultimately affects human health. NASA has already contributed to this field for instance, by develop- ing rotating bioreactors and studying three-dimensional cell cultures in space. Further research is now needed to understand the mechanisms by which gravity affects cell signaling and gene expression at the molecular level. Since mechanical forces are typically induced or transmitted by the supporting matrix, fluid shear, or hydrostatic pressure, contributions to understanding these mechanisms are likely to come from the fields of cell biology, nanotechnology, fluid dynamics, materials science, chemistry, and physics. Many of these are areas in which the PSD has developed significant expertise. Major efforts are under way at NIH to understand how cells function as systems the field of proteom~cs. Neverthe- less, since NIH often focuses on the molecular level, the mechanoregulation of integrated molecular systems falls largely between the seams at the institutes even though an understanding of this process is critical for both health and disease. The process evokes even less interest at NSF and DARPA. The PSD might contribute to such work by bringing its experience in developing programs that bridge the interface between biology and the physical sciences to bear on how applied loads and stresses affect cellular and molecular processes, perhaps ultimately learning how low-gravity conditions affect proteomics and cellular metabolomics. NASA can also leverage its investments in microtechnologies, m~cromechanics, nanoparticles, and bioreactors to assist this effort. REFERENCES Arnold, F.H., Wintrode, P.L., Miyazaki, K., and Gershenson, A. 2001. How enzymes adapt: Lessons from directed evolution. Trends Biochem. Sci. 26~2~: 100-106. Balaban, N.Q., Schwarz, U.S., Riveline, D., Goichberg, P., Tzur, G., Sabanay, I., Mahalu, D., Safran, S., Bershadsky, A., Addadi, L., and Geiger, B. 2001. Force and focal adhesion assembly: A close relationship studied using elastic micropatterned substrates. Nature Cell Biol. 3~5~: 466-472. Baneyx, G., Baugh, L., and Vogel, V. 2002. Fibronectin extension and unfolding within cell matrix fibrils controlled by cyto skeletal tension. Proc. Natl. Acad. Sci. U.S.A. 99: 5139-5143. Baran, E.T., Ozer, N., Hasirci, V. 2002. Polythydroxybutyrate-co-hydroxyvalerate) nanocapsules as enzyme carriers for cancer therapy: An in vitro study. J. Microencapsulation 19: 363-376. Battistuzzi, G., Borsari, M., Cowan, J.A., Ranieri, A., and Sola, M. 2003. Control of cytochrome c redox potential: Axial ligation and protein environment effects. J. Am. Chem. Soc., in press. Beebe, D.J., Moore, J.S., Yu, Q., Liu, R.H., Kraft, M.L., Jo, B.-H., and Devadoss, C. 2000. Microfluidic tectonics: A compre- hensive construction platform for microfluidic systems. Proc. Natl. Acad. Sci. U.S.A. 97: 13488-13493. Benoit, M., and Gaub, H.E. 2002. Measuring cell adhesion forces with the atomic force microscope at the molecular level. Cells Tissues Organs 172~3~: 174-189. Bhadriraju, K., and Hansen, L.K. 2002. Extracellular matrix- and cytoskeleton-dependent changes in cell shape and stiffness. Exp. Cell Res. 278~1~: 92-100. Block, S.M., Asbury, C.L., Shaevitz, J.W., and Lang, M.J. 2003. Probing the kinesin reaction cycle with a 2D optical force clamp. Proc. Natl. Acad. Sci. U.S.A.100~5~: 2351-2356. Boal, A.K., and Rotello, V.M. 2000. Fabrication and self-optimization of multivalent receptors on nanoparticle scaffolds. J. Am. Chem. Soc. 122: 734-735. Boxer, S.G., and Kam, L. 2001. Cell adhesion to protein-micropatterned-supported lipid bilayer membranes. J. Biomed. Mater. Res. 55: 487-495. Braun, P.V., Osenar, P., Tohver, V., Kennedy, S.B., and Stupp, S.I. 1999. Nanostructure templating in inorganic solids with organic lyotropic liquid crystals. J. Am. Chem. Soc. 121: 7302-7309. Brown, R.A., Prajapati, R., McGrouther, D.A., Yannas, I.V., and Eastwood, M. 1998. Tensional homeostasis in dermal fibroblasts: Mechanical responses to mechanical loading in three-dimensional substrates. J. Cell. Physiol. 175: 323-332. Buschow, K.H.J. 1988. Permanent magnet materials based on 3a-rich ternary compounds. P. 1 in Handbook of Magnetic Materials, Volume 4 (E.P. Wohlfarth and K.H.J. Buschow, eds.~. Elsevier, North-Holland, The Netherlands, and New York.

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