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6

Reducing Logistics Requirements

The Army continues to be interested in increasing the “tooth-to-tail” ratio, that is, increasing combat effectiveness and reducing logistics support requirements. Reductions in the logistics burden are especially important at the level of the individual soldier in the field. This chapter discusses trends and developments in biotechnology that could reduce logistics requirements.

Logistics is at the heart of military operations and is a significant factor in success or failure in battle. A major aspect of logistics is providing adequate quantities of fuel, ammunition, food, water, and other consumables to support an operation. Logistics also includes transporting soldiers and equipment, repairing battlefield systems, and providing medical services. Reducing the Logistics Burden for the Army After Next, an NRC report published in 1997, recommended that the Army focus on technologies that contribute to reductions in the weight and volume of systems and materials. The same study suggested that reductions could also be achieved by increasing combat effectiveness and that lightening the load soldiers must carry would, in fact, do both. Even a single improvement, such as simplifying a system, changing a process, even altering the dimensions of a cargo bed, can ripple into reductions and savings of major significance.

The biotechnological evolution of sensor technologies discussed in Chapter 3 could enable the Army to chart a course toward the miniaturization of multifunctional systems, such as the laboratory-on-a-chip, which would reduce the logistic burden. Similarly, agricultural biotechnology for creating edible, digestible, nourishing food from raw materials that might be foraged on the battlefield would reduce, or even eliminate, the need to transport food to foreign ports. Water generation and purification using locally supplies is equally important. Finding ways to satisfy energy needs locally would reduce logistics requirements for fuel, as well as help reduce the numbers of batteries needed to power soldier-portable electronics.

The Army currently is engaged in a transformation process to make its organizations and systems capable of responding more rapidly to contingencies anywhere in the world with smaller, lighter forces (Gourley, 2000). The trend toward smaller and lighter underscores the importance of soldiers being able to operate independently and in small units with minimal direct logistics support.

The particular applications that can make a difference in logistics may depend on geography. Sending seeds to Siberia may be worthless, but putting nutrients into candy bars could elevate body temperature. Coatings for the skin could provide insulation from the cold, and “gray-day” photovoltaics could harvest solar energy when there is no sun.

Army priorities for taking advantage of biotechnology will depend on the Army’s interpretation of its role in the future. In general, however, anything smaller and lighter will reduce the logistic burden, will further the Army’s transformation, and will be in keeping with trends and developments in biotechnology, such as small-scale biological devices, functional foods, biological photovoltaics, and renewable resources.

MINIATURIZATION OF BIOLOGICAL DEVICES

The miniaturization of systems and components would reduce logistics support requirements by making things smaller, lighter, and more portable and by reducing requirements for fuel and power. Small-scale systems may also be easier to repair or replace. The incorporation of biological components into MEMS (bio-MEMS) will help to make nanoscale technologies feasible. Indeed, miniaturization will not only have an impact on Army logistics, but will also make many battlefield concepts that depend upon miniature devices feasible. The development of bio-MEMS is being driven by the commercial market for sensor instrumentation and is likely to lead to near-term breakthroughs in design and manufacturing.



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Page 46 6 Reducing Logistics Requirements The Army continues to be interested in increasing the “tooth-to-tail” ratio, that is, increasing combat effectiveness and reducing logistics support requirements. Reductions in the logistics burden are especially important at the level of the individual soldier in the field. This chapter discusses trends and developments in biotechnology that could reduce logistics requirements. Logistics is at the heart of military operations and is a significant factor in success or failure in battle. A major aspect of logistics is providing adequate quantities of fuel, ammunition, food, water, and other consumables to support an operation. Logistics also includes transporting soldiers and equipment, repairing battlefield systems, and providing medical services. Reducing the Logistics Burden for the Army After Next, an NRC report published in 1997, recommended that the Army focus on technologies that contribute to reductions in the weight and volume of systems and materials. The same study suggested that reductions could also be achieved by increasing combat effectiveness and that lightening the load soldiers must carry would, in fact, do both. Even a single improvement, such as simplifying a system, changing a process, even altering the dimensions of a cargo bed, can ripple into reductions and savings of major significance. The biotechnological evolution of sensor technologies discussed in Chapter 3 could enable the Army to chart a course toward the miniaturization of multifunctional systems, such as the laboratory-on-a-chip, which would reduce the logistic burden. Similarly, agricultural biotechnology for creating edible, digestible, nourishing food from raw materials that might be foraged on the battlefield would reduce, or even eliminate, the need to transport food to foreign ports. Water generation and purification using locally supplies is equally important. Finding ways to satisfy energy needs locally would reduce logistics requirements for fuel, as well as help reduce the numbers of batteries needed to power soldier-portable electronics. The Army currently is engaged in a transformation process to make its organizations and systems capable of responding more rapidly to contingencies anywhere in the world with smaller, lighter forces (Gourley, 2000). The trend toward smaller and lighter underscores the importance of soldiers being able to operate independently and in small units with minimal direct logistics support. The particular applications that can make a difference in logistics may depend on geography. Sending seeds to Siberia may be worthless, but putting nutrients into candy bars could elevate body temperature. Coatings for the skin could provide insulation from the cold, and “gray-day” photovoltaics could harvest solar energy when there is no sun. Army priorities for taking advantage of biotechnology will depend on the Army’s interpretation of its role in the future. In general, however, anything smaller and lighter will reduce the logistic burden, will further the Army’s transformation, and will be in keeping with trends and developments in biotechnology, such as small-scale biological devices, functional foods, biological photovoltaics, and renewable resources. MINIATURIZATION OF BIOLOGICAL DEVICES The miniaturization of systems and components would reduce logistics support requirements by making things smaller, lighter, and more portable and by reducing requirements for fuel and power. Small-scale systems may also be easier to repair or replace. The incorporation of biological components into MEMS (bio-MEMS) will help to make nanoscale technologies feasible. Indeed, miniaturization will not only have an impact on Army logistics, but will also make many battlefield concepts that depend upon miniature devices feasible. The development of bio-MEMS is being driven by the commercial market for sensor instrumentation and is likely to lead to near-term breakthroughs in design and manufacturing.

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Page 47 This section discusses trends toward miniaturization via MEMS and microfluidics to produce systems that are more supportable in the field (i.e., smaller, lighter, faster, and more power-efficient). These trends will have a significant effect on the development of biosensors and biochips. The discussion does not include basic evolutionary changes in microtechnologies that are expected to occur as a matter of course and some systems-engineering trends. For example, incremental improvements, such as microscopes in laboratory instruments or systems, are not included. In general, the microtechnology scale ranges from 1 × 10−6 to 100 × 10−6 meters; the nanotechnology scale ranges from 1 × 10−9 to 1,000 × 10−9 meters (i.e., from barely visible with the naked eye to visible only with special microscopes). Typically, microscale and nanoscale devices are manufactured with photolithographic techniques similar to those used for manufacturing silicon computer chips. Manufacturing methods for producing microscale and nanoscale devices out of other materials, such as plastic, usually involve a molding technique. In most cases, microcomponents and nanocomponents of miniaturized systems must interface to larger systems, perhaps in the millimeter scale or centimeter scale. This requirement must be taken into consideration when comparing the benefits and costs of a device a few millimeters in size to one a few centimeters (hand-held) in size. In some cases, only the micro/nanoscale device can perform the required function. Examples include in vivo devices, such as sensors placed in the human body, and catheters, tools that work inside blood vessels. The laboratory-on-a-chip illustrates how a multifunctional microsystem can eliminate the need for support personnel. If a complex sequence of operations that are currently performed in a laboratory by skilled technicians or scientists can be performed by a package the size of a sugar cube, two benefits will accrue. First, one less person must travel to the field; therefore, one less person must be supplied with food, water, and so forth. Second, miniaturization will save energy in two ways: (1) less weight would have to be transported, and (2) less energy and less reagent would be required for smaller devices. Microtechnology In Chapter 3, wristwatch-size sensing and analytical devices were described. To defend against chemical and biological agents, a collection of many highly parallel arrays of miniaturized sensors carried by multiple vehicles and soldiers would be necessary to detect or measure a targeted analyte. Other sensors could be used to monitor the human body, either in vivo or on the body surface. The Army could even leverage technologies developed for a laboratory-on-a-chip to combine sensor, laboratory, and antidotal delivery systems on a single, perhaps implantable, biochip, the ultimate defense against chemical and biological agents. Micro/nanosystems may be ideal for performing these sensory and analytical tasks. The development of easily portable sensor systems capable of reliably detecting and identifying chemical or biological species at trace levels outside a laboratory environment has proven to be a daunting task because of complexity, power consumption, and size and weight issues. The development of operational field units has been hampered by the lack of a commercial demand and the lack of a well-defined requirement by DOD. Even a practical, hand-held system will require a significant engineering effort. DOD and other government agencies have funded the conversion of some laboratory units to field use. Lawrence Livermore National Laboratory and Cepheid have developed a series of field-portable, briefcase-sized or hand-held, battery-operated, nucleic-acid analyzers for detecting bioagents via PCR (polymerase chain reaction) with real-time, fluorescent detection (Woolley et al., 1996). Multifunctional systems contain one or more key components that provide energy, interface with the environment, transduce signals, process samples, generate information, and communicate with the user. In biotechnological applications of miniature systems, all of these functions must operate in the context of obtaining a biological sample (e.g., fluid), interfacing with the user (e.g., a human), or processing the sample. To improve efficiency and portability, these systems will require miniature components. Component technologies important to miniaturizing biotechnology include fluid-handling devices (e.g., pumps, valves, sampling devices); reaction chambers (e.g., enzyme reactions, ligand binding, synthesis); detectors, (e.g., for target analyte, a physiological condition); and instrumentation (e.g., for information output, feedback, and utilization). Methods and devices will have to be robust, easy to use, and easy to interpret. Work to date has been focused on the development of miniaturized biochemical sensor systems based on MEMS, advances in microfluidics, and microoptomechanical (MOMS) technologies. Microfluidic Pumping Methods and Actuators Fluids normally flow in microstructures by laminar flow without turbulence. As a result, layers of fluids containing different components flow together and mix by diffusion only. The mixing resulting from this laminar flow is very rapid. For example, mass and heat transport is 100 times faster when a system is 10-fold smaller, which reduces processing times and enables higher throughput capacities (Bruno et al., 1998). A variety of mechanical and nonmechanical pumping methods have been used in chips. The most troublesome issues for pumping in microfluidic structures are the avoidance of cavities where fluid cannot flow and bubble formation, which creates back pressure and can inhibit (or even reverse) fluid flow. The fluid pumps in chips work by

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Page 48pressure, electronics, or a combination of both. The three primary means of electronic pumping are electrophoresis, electro-osmotics, and electrohydrodynamics. The most successful pumping in microstructures uses capillary electrophoresis to provide the pumping and valving action that moves solutions, suspensions, or components in solution through microchannels. Both electro-osmotic flow and electrophoresis pumping rely on the conductive nature of the solutions in the channels. The application of voltage along the channel or at ends of the channel creates electrostatic forces on the fluid and components in the fluid, thereby creating electro-osmotic flow and electrophoretic separation, respectively. In the absence of microvalves, electrokinetic pumping has several advantages over pressure-driven flow, especially for analytical separation systems. For example, separation efficiencies are improved as a result of the “plug-like” flow profile of electro-osmotic pumping, back pressure is minimized, and multiple channels on a chip can be readily controlled with a few electrodes (therefore the system has no moving parts). Both electro-osmotic and electrophoretic pumping methods are well suited to biological assays because most reagents and solutions are aqueous. Many researchers have successfully demonstrated electrophoretic or electro-osmotic fluid management in chips for biological screening (DeWitt and Pfost, 1999; Duffy et al., 1998; Fan et al., 1997; McBride et al., 1998; Mourlas et al., 1998; Studt, 1999; Wallace, 1998). The third type of electronic pumping, electrohydro-dynamic flow, enables the movement of either conductive or nonconductive fluids by the induction of a pressure differential caused by an electric field applied directly in the analyte solution. Both aqueous and organic fluids can be pumped using this method (Boone and Hooper, 1998). This method of pumping, however, has not been optimized and will require additional development before it can be used for applications. Microreaction Technologies Not all physical processes can be scaled down. For example, as described above, fluid flow in small-dimension channels is restricted to laminar flow, which precludes mixing by turbulence. Therefore, mass transfer depends on diffusion alone, which can be rate limiting. Analytical sensitivity is also decreased by miniaturization because fewer target molecules are present in a smaller volume. By contrast, heat transfer is improved by miniaturization. Therefore, the development of microreactors for soldier health monitors and internal sensors is very promising. Many chemical reactions depend on well-controlled environments. For example, in bioreactors for enzyme-substrate reactions used in production of biochemicals, such as vaccines, the reaction parameters (e.g., temperature, pH) should ideally be held constant and should be uniform throughout the vessel. This becomes increasingly difficult as reactions are scaled up in volume. Eventually, it becomes impossible to control the reaction parameters, and as a result poor productivity or, even worse, side reactions occur that can contaminate the reaction mixture. In some cases, volatile or even explosive intermediates can be generated. A growing trend in the development of many parallel microreactions in microfabricated reaction chambers is to scale out rather than scale up parameter-sensitive production processes (Ehrfeld, 2000). Microreactors may have many other applications: uniforms with self-adjusting control mechanisms for such things as temperature, humidity, contamination exposure, energy harnessing, and camouflage harvesting of nutrients, energy, medications, and therapies medical devices for self-application of drugs embedded microsystems to improve the performance of or replace organs and tissues synthesis of chemicals and biochemicals biosensor detection mechanisms and biofeedback systems Microreactors coupled with miniaturized sampling, fluidics, detectors, sensors, and computers could enable biosystems capable of solving many key operational problems in the future. In addition, microreaction technologies could be leveraged to improve the performance and capabilities of systems that do not have biological components. MEMS-Based Microfluidic Systems A wide variety of microfluidic systems are being developed using MEMS technology. Microflow channels are commonly implemented down to a few microns in size using selective etching on silicon, glass, and plastics. Although many types of integrated microvalves and pumps have been explored to date, progress has been slow, and few if any are commercially available (Petersen, 2000). Magnetic actuators have been difficult to realize in MEMS because they require materials that are not used in most planar fabrication processes. Electrostatic actuators can develop significant forces only across very small gaps (1µ or less), and the charged surfaces tend to attract particulates, which can clog moving mechanisms. Piezoelectric devices also require nonstandard materials; these devices can produce high force or high throw, but they do not produce both together. Several thermally actuated microvalves have been reported, but operating power levels are generally high (a watt or more) and performance is modest (Barth et al., 1994; Jerman, 1991). For gas-handling, a device must produce significant force with displacement measured in tens of microns and operating power levels that are consistent with small, portable applications. Thermopneumatic devices, in

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Page 49which a solid-liquid or liquid-gas phase transition is used to generate pressure, are among the more promising candidates (Zdeblick et al., 1994). A recent thermopneumatic valve using a liquid-gas transition uses an integrated pressure sensor in the actuation cavity to allow closed-loop control and minimize power requirements. Optimized power levels are in the vicinity of 50mW per valve for a 2,000-torr pressure rise and 1s response time (Rich and Wise, 2000). An integrated microvalve reported for use in a DNA analysis system (laboratory-on-a-chip) is based on the solid-liquid phase transition of wax and generates displacements in the 2nm to 5µm range with high forces (Carlen and Mastrangelo, 1999). The device operates with 50mW to 200mW of power and shows a response time of 30ms. The development of sample injection and propulsion systems for microfluidic devices, such as DNA processors, is being vigorously pursued (Mastrangelo et al., 1998). To take advantage of the large capillary pressures present in these systems, hydrophobic patches are used to stop the solution flow in the input injector of a DNA processor, and a thermally expanding, electrolytically generated bubble cuts and subsequently propels individual sample droplets (Handique et al., 1997). The device has a sharp neck in the channel to create a surface-induced pressure barrier that stops the flow. Electrolytic bubble generation allows precise metering, and the power dissipation is three orders of magnitude lower than for a thermal drive, making these devices compatible with portable deployment in the field. The capillary pressure barrier that develops when the channel cross-section changes abruptly is in the range of 1kPa to 6kPa, and electrolytically generated oxygen bubbles can be produced with as little as 150µW of power (Man et al., 1998). A device developed by Burns et al. (1998) is an example of an attempt to reduce laboratory functions onto a chip using micromachining technology. This system has a mixture of micromachined parts and external instrumentation to provide functionality, including microfabricated fluidic channels, heaters, temperature sensors, and fluorescence detectors, to analyze nanoliter-sized DNA samples (see Figure 6-1). The tie-clasp-sized chip includes a nanoliter liquid injector, a sample mixing and positioning system, a temperature-controlled reaction chamber, an electrophoretic ~ enlarge ~ FIGURE 6-1 MEMS device for integrated DNA analysis. Source: Reprinted with permission from Burns et al., 1998. Copyright 1998, American Association for the Advancement of Science.

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Page 50separation system, and a fluorescence (photodiode) detector. A sample of DNA-containing solution is placed on one fluid entry port while a reagent-containing solution is placed over the other port. Capillary action draws each solution into the device, and the sample is stopped by hydrophobic patches just beyond the vent line in each input channel. Pressure is used to split off precise nanoliter drops, and the DNA and reagent solutions are mixed and moved into a thermal reaction region, where heaters and temperature sensors control the reaction. After the reaction is complete, the sample is moved forward by pressure to the start of a gel electrophoresis channel. The DNA is electrokinetically loaded onto the gel and size fractionated. As the fluorescently labeled DNA migrates through the gel, an external blue-light-emitting diode excites emission, allowing the photodiode to detect DNA concentrations down to 10ng/µl. Several problems have arisen in miniaturized systems with dimensions measured in microns and fluids in nanoliters: (1) surface tension is so high that fluids can only be moved by large forces; (2) air bubbles can completely block fluid flow; (3) the sample volume is so small that the concentration of the analyte must be very high (i.e., low sensitivity results); and (4) the small dimensions of the device make interfaces to the outside worlds of the sample input and user difficult. Unless these problems can be overcome, systems an order of magnitude bigger (i.e., hand-held systems) will be more useful for analyzing real-world volumes and samples. The chip mentioned above (Burns et al., 1998) requires an external power supply, a light source, and data analysis electronics. DNA amplification efficiency is limited, and much more development will be required. With significant efforts in packaging, such devices, roughly the size of a pocket calculator, could be available in the next 10 years. To meet its requirements, the Army may want to consider pulling academic work “over the wall” to more advanced prototypes and testing them in the field to accelerate development time. True integration of miniaturized devices remains a significant challenge with a high potential payoff for the Army. Woolley et al. (1996) showed the successful integration of miniaturized DNA amplification via PCR coupled to microchannel electrophoretic detection of a Salmonella-specific assay. The two microcomponents were successfully integrated, and the battery-operated amplification system was the size of a hand-held device. However, a laser-based, fluorescent, confocal microscope of significant size was needed for detection. This laser-based detection system was designed for high resolution, and miniaturization was not considered. With increasingly powerful light-emitting diodes and sensitive miniature photodetectors, DNA fragments can be excited and detected in microchannels. Researchers have detected labeled DNA and peptides in 50µ by 100µ channels; thus, it appears that miniature, low-power detection components are becoming available that are adequate for miniature systems. Basic research will be necessary to study the fundamental physics and chemistries of sample purification processes and possibly to develop universal sample processing methods. The research would probably have to be focused on different assay types (e.g., DNA test or immunoassay) and determine universal methods for each assay type (see Chapter 3 section on assay formats). Chip Architectures Advances in the computer industry have laid the foundation for the integration of fluids with microfabricated chips using silicon, glass, quartz, elastomers, and plastic materials (Hughes et al., 1998). Plastic microfluidic devices offer several advantages over glass or silicon structures, including lower processing temperatures, more options for surface treatment, lower cost, and extensions to multilayer device fabrication. Typically, the fluidic channels in microreactors are 10µ to 300µ in diameter (by comparison, a single strand of human hair is approximately 100µ in diameter). One significant difference between computer chips and fluidic chips, however, is the three-dimensional nature of fluidic chips. The computer industry typically uses single layers to create electrical networks. The creation of “pipes and valves” to contain and manipulate fluids requires two or more layers bonded or sealed together. More complex fluidic networks combining both horizontal and vertical fluid flows can be achieved in three-layer chips. However, until the advent of microfluidic chips, there was little need for multilayer chips. Development so far has been driven by the discovery research community, and unit costs have been high enough to preclude evaluation and implementation of new applications. These costs will probably come down when design and production approaches are adopted. A variety of chip architectures and associated pumping methods have been developed. In general, current chips are two-layer devices operated as linear or branched flow-through systems. The throughput needs of a biological screening program (e.g., 100,000 samples per week) using these chips could be met because of the significantly reduced assay times in the microfluidic environment (i.e., less than 15 s per assay) and using multiple chips in parallel. A design alternative to the flow-through chip developed by Orchid BioSystems is a multilayer device that can parallel process samples simultaneously, analogous to conventional plate-based screening (i.e., 96-well chip). Overall, however, implementation of chip architectures for biological assays has been limited. Cepheid has developed microfluidic structures that combine a variety of materials, such as micromachined silicon (with an SiO2 layer) embedded in a plastic cartridge (analogous to a microfluidic

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Page 51chip) to extract DNA from biological samples, including samples in the presence of blood plasma (Christel et al., 1998). These microfluidic cartridges have been able to extract infectious bacterial DNA (chlamydia and gonorrhea) from urine, lyse the cells, and reconcentrate, filter, and quantitate the organisms via PCR in less than 30 min (Pourahmadi et al., 2000). This pragmatic, nonmicroscale device is hand-held, fits into a portable, breadbox-sized instrument, and is designed to replace a large laboratory system, including several technicians. The relatively large scale is necessary for high sensitivity assays. Reducing this particular system to a truly microsized system may not be possible without sacrificing sensitivity, a significant barrier to miniaturization. Nanotechnology The term nanotechnology refers to man-made devices and structures with functionally defining elements or components with at least one dimension of 100nm or less. Following federal interagency activities that culminated in a report to the White House, nanotechnology has become a major component of the strategic new research portfolio of the United States (NSTC, 2001). Fundamental research areas in the field of nanotechnology include the science and technology of carbon nanotubes and buckyballs; the self-assembly of chemicals to form tightly controlled supramolecular films and structures; and the direct atom-by-atom assembly of nanostructures by way of manipulation through the tip of atomic-force microscopes. Theoretical models that may be applied in the nanotechnological domain include molecular dynamics and doublet mechanics (Ferrari et al., 1997). The nanofabrication methods listed above are bottom-up methods in the sense that they feature the construction of structures from atomic-level or single-molecule-level building blocks. Although this approach ensures the greatest latitude for the fabrication of useful constructs, it also encounters major difficulties in the transition from the prototype level to production scale. A different, and probably more scalable, approach involves top-down methods, such as those currently used in microchip processing. For instance, nanopores, which may prove to be instrumental in the development of instrumentation for ultrarapid sequencers, are obtained by a combination of photolithography and sacrificial-layer technologies. Improved sequencing methodologies may also result from a combination of nanotube and atomic-force resolution technologies (Wong et al., 1998). A very long list of Army-related breakthroughs could result from nanotechnology. Among these are the development of ultrasmall electronic devices, such as single-electron transistors, and nanostructured materials with superior properties. Trends and barriers in nanotechnology developments for bioapplications are described further in Chapter 7 in the section on improved technologies for drug delivery. Direct Readout of DNA at the Atomic Level Imagine being able to detect a threat and then obtaining a direct readout of the genetic information (DNA) associated with the threat. Such a technology could not only interrogate microscale particles or molecules to determine friend or foe but could also make an exact identification. This would require the amplification of DNA on a microscale, as well as the sequencing of the DNA once it was available. Many challenges remain to the direct readout of DNA, including extraction and preparation of the DNA sample and producing overall structures robust enough for use in the field. But direct readout of DNA strands in field-compatible, wristwatch-sized microinstruments is possible in a 20-year time horizon. The PCR-based process of DNA amplification, separation, and electronic readout has been implemented on a single chip (Burns et al., 1998). In the future, nanotechnology could be used to allow the direct readout/analysis of single strands of DNA at the atomic level at even higher speed (Quate, 2000). There are several important steps in the development of such devices, and several milestones along this path have already been reached. The first step was the development of scanning surface probes during the 1980s, when it was demonstrated that a sharp tip, brought very close (within < 1nm) to a surface, could allow atomic profiling of that surface through the measurement of tunneling currents or atomic forces between the tip and the sample. The resulting scanning microscopes have revolutionized surface science and are widely used laboratory instruments. Scanning microscopes are also being developed for many applications involving the manipulation of atoms (e.g., in ultrahigh-density data storage systems). These probes are based on micromachined cantilevers with dimensions of a few microns and are fabricated using MEMS technology. A sharp stylus integrated near the tip of the cantilever is used to profile the surface in either contact or noncontact modes. In the case of force measurements, readout is normally done using some form of optical interferometry. An example of a tip and cantilever designed for separately positioned fiber-optic readout is shown in Figure 6-2 (Kong et al., 1993). A more advanced structure is shown in Figure 6-3. Here, cantilever deflection is measured with respect to an integrated, interdigitated reference plate, allowing very sensitive (0.1Å) determination of cantilever/stylus position. Arrays of these cantilevers can potentially be positioned adjacent to a solid-state imaging array (e.g., a charge-coupled display) and used to read out many points simultaneously. In Korea, cantilever arrays of 780 × 1,000 devices have been realized. The IBM Zurich Laboratory is developing cantilever arrays as a basis for an artificial nose, in which different cantilevers are coated with different materials; the beam bending/stress induced by the adsorption of different molecules is used to identify different gases in the

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Page 52 ~ enlarge ~ FIGURE 6-2 A micromachined cantilever and tip-mounted stylus designed for readout using a separately positioned fiber-optic reference. Source: Reprinted with permission from Kong et al., 1993. Copyright 1993, Journal of Vacuum Science and Technology. ambient air (Lang et al., 1999). Cantilever bending by oligonucleotide hybridization has also been demonstrated. A second milestone in the development of atomic-scale DNA chips is the ability to detect extremely small amounts of charge. Snow and Campbell (1995) have shown that very thin titanium films can be selectively oxidized using a scanning probe to create tunneling junctions, and K. Matsumoto et al. (1996) of the Electrotechnical Laboratory, Tsukuba, Japan, has used this technique to form single-electron transistors (the most sensitive electrometers), as illustrated in Figure 6-4. When fabricated with dimensions of 10nm, these devices can operate at room temperature. It is, ~ enlarge ~ FIGURE 6-3 An interdigitated cantilever and fixed-reference plate forming a scanning surface probe. The cantilever position can be measured with great accuracy using diffraction. Source: Quate, 2000.

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Page 53 ~ enlarge ~ FIGURE 6-4 Schematic drawing and structure of a single-electron transistor for measuring electronic charge. Source: Quate, 2000. therefore, possible to think in terms of integrating single-electron electrometers with scanning cantilevers to measure the charge on single DNA strands as they are lowered past the tip (e.g., pulling them through 1.5–2nm holes, such as has recently been demonstrated in silicon nitride membranes). The use of single-wall carbon nanotubes has been proposed for the integration of single-electron transistors directly into the stylus tip of the probe. (Nanotubes are perfect quantum conductors in which adjacent molecular interactions effect conductivity.) Key Recommendation The Army should support basic research in microfluidics and nanotechnology that will facilitate the miniaturization of sensing capabilities for both internal (in vivo) and external (in vitro) applications. In addition to supporting the development of new Army systems and reducing logistics, micro/ nanotechnologies could potentially benefit other Army systems that will perform a wide range of missions. FUNCTIONAL FOODS Functional foods are foods or ingredients with components that influence metabolism or physiology beyond ordinary nutrition. Functional foods can contain nutraceuticals, which are both nutrients (vitamins) and physiologically active compounds, and/or phytochemicals, which act as health protectants. Phytochemicals are plant-derived compounds purported to afford specific health benefits (Watkins, 2001). A critical barrier to the development of functional foods may be the public perception that genetically modified organisms are undesirable. The development of crops with higher levels of natural pesticides reduces the need for chemical pesticides. Although public resistance in the United States has been relatively minimal, resistance in Europe has been widespread due in part to the incidence of prion diseases, such as mad-cow disease, which have been traced to alterations in the beef processing chain in Great Britain. Other barriers to the development of functional foods include maintaining palatability and cooking characteristics while introducing the new functions. Crops with enhanced levels of nutritional components, built-in vaccines, or edible factors that impart resistance to spoilage are in the offing. The benefits to the Army of functional foods are numerous, and some foods could be developed to meet specific Army needs. Foods that could reduce the incidence of dysentery, for example, could significantly increase the readiness of Army personnel. Rations could be formulated to contain edible enzymes that are natural, tasteless, and nontoxic, to aid digestion. More efficiently digested foods would mean that more calories could be transported to troops for the same amount of weight. Foods with built-in, naturally occurring, antimicrobial factors could inhibit the pathogenic microorganisms soldiers might be exposed to in the field. Anti-infective properties might be based on edible proteins or peptides. Foods could also be optimized for safety and storage (Linton, 2001). If the need for refrigeration of some types of fresh fruits and vegetables could be reduced or eliminated, it would reduce the need to transport and power refrigeration equipment.

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Page 54 More efficient and complete digestion might also reduce the amount of food a soldier must carry because less food would be providing the same amount of energy. NASA-sponsored research for human space flight suggests that significant reductions may be possible (Dunbar, 2000). Providing a means of identifying people as friend or foe is critical to battlefield and peacekeeping functions; in combat, combat identification should be possible at great distances, perhaps with remote sensing. The presence of particular biological organisms or attributes could be used to help identify, trace, or track individuals. Biological tagging of soldiers could also be accomplished by feeding soldiers foods containing biomarkers, thus distinguishing friendly soldiers from the enemy. Being able to distinguish among friendly forces and units could also significantly improve command and control. Agriculture will be an essential component of the emerging biotechnology industry, both as an end user of technological advances and as a supplier of the carbohydrates and other biological materials. Agricultural biotechnology can also play a direct role in reducing the logistics burden. Rapidly growing plants could provide in-theater sources of food, fuel, or energy. Perhaps infrared or radar-absorbing properties common to vegetation in the field could be used to grow new materials that would make troops undetectable by enemy sensors. In effect, these would provide a native camouflage. Genetically Engineered Foods Genetically modified seeds have had a great impact on agriculture. Corn and cotton modified by Bacillus thuringiensis (B.t. corn and B.t. cotton) for example, have greatly reduced the amount of pesticides that are required during growth cycles. Genetically modified soybean seeds resistant to herbicides have also been introduced. Monsanto and other companies have made significant investments in the development of these foods. Although most of these agricultural developments are not appropriate for Army investment, the impact of these developments should be carefully monitored, particularly for the availability of biomaterials, like food and fuel, that the Army might be able to use. The genetics of plants and animals have been manipulated for centuries for the purpose of amplifying positive characteristics ranging from robustness of the organisms when faced with a range of environmental conditions to enhancement of the ratio of edible to nonedible portions. The commercial potential of genetic manipulation using recombinant methods has only recently begun to be realized; at the same time significant public resistance has arisen to genetically modified organisms. Nevertheless, research continues, and foods with amplified functions are being developed. Some new foods are being developed that are only achievable using genetic engineering techniques. Research by and for the U.S. space program has provided insight into many potential applications (Kohlmann et al., 1996; Mitchell et al., 1995; Velayudhan et al., 1995). In the future, plant converters could take energy from sunlight and carbon dioxide from air and convert them into required materials in days rather than weeks. A pocketful of seeds could become the slow-motion equivalent of a Star Trek type “replicator.” Edible Vaccines Edible vaccines are a very good example of functional foods that could greatly simplify the logistics of vaccinating soldiers. The purpose of a vaccine is to prepare the immune system to destroy specific disease-causing microorganisms before they multiply sufficiently to cause symptoms. Priming the immune system against possible invaders is typically achieved by presenting whole viruses or bacteria that have been killed or weakened to the immune system. This causes an acute response followed by the establishment of memory cells that remain on alert to mobilize the immune system if a real pathogen enters the body. Some vaccines provide life-long protection. Others must be readministered periodically. Some vaccines pose a slight risk of propagating and causing the diseases they are meant to forestall. Subunit vaccines avoid this risk because they consist of antigenic proteins separated from the parent cell’s genes and the parent cell itself. A subunit vaccine does not form the pathogenic organism from which the protein is derived. Charles Arntzen is credited with the concept of genetically engineering foods to be like subunit vaccines when the food is eaten; that is, the protein that induces immunity is separated from the pathogenic organism from which it is derived (Langridge, 2000). See Appendix D for detailed discussion of subunit vaccines. Edible vaccines in foods seem especially appropriate for combating diarrhea. The causes of this affliction include the Norwalk virus, rotavirus, Vibrio cholerae (the cause of cholera), and enterotoxigenic Escherichia coli (a toxin-producing source of “traveler’s diarrhea”). Mucosal membranes that line the digestive tract, the first line of defense against these pathogens, generate proteins (referred to as secretory antibodies) that are secreted into the cavities lined by the membranes and that play a role in neutralizing pathogens. A systemic response to a pathogen adds to this protection by circulating cells that destroy pathogens that may have passed through the membrane. Because edible vaccines would contact the lining of the digestive tract, in theory, they could activate both mucosal and systemic immunity. Challenges being addressed by ongoing research include engineering plants so that their edible part carries genes that express specific proteins when the plant is grown; packaging proteins in food so that they are not destroyed by the digestive system; and identifying and confirming that the proteins generate an effective response. Edible vaccines would be attractive, easy to administer, and, presumably, would elimi-

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Page 55 nate the need for the refrigeration and delivery through injection of current vaccines. The Army should consider a number of logistical questions, such as if rations intended to prevent different diseases would have to be kept separate from other foods and how to keep track of which members of a unit had been vaccinated. Commercial challenges will also have to be overcome. As of 2000, no one had produced an edible vaccine for sale (Langridge, 2000). Key Recommendations Agricultural biotechnologies can be beneficial for the Army beyond improving nutrition. Engineered foods, edible vaccines, and biological tagging are all near-term technologies that could increase soldier effectiveness, improve command and control, and reduce logistics support requirements. The Army should build on developments and research at its Natick Research, Development and Engineering Center and should take the lead in developing new and innovative functional foods that provide high nutrition, are lighter, can be stored longer, and incorporate therapeutic or prophylactic properties. The Army should monitor developments in the field of plant biotechnology, because significant private and government sector investments will result in enhanced (transgenic) crops, functional foods, and plant-derived biomaterials. The Army may be able to leverage these investments by industry by taking advantage of new developments once they have been field-tested and received public acceptance. BIOLOGICAL PHOTOVOLTAICS Almost all of the energy the Army uses today comes from fossil fuels and batteries that must be transported to and distributed on the battlefield through the logistics system. As military forces become smaller and lighter, and as fuel sources for society as a whole change, a high proportion of the Army’s future energy needs may be satisfied by renewable resources. Biological photovoltaics may also help to meet energy requirements for individual soldier electronics in the field. Plants and algae convert sunlight into energy with a quantum efficiency of about 98 percent. Mimicking plant energy-conversion processes could provide a basis for solar-derived power for use on the battlefield at operational efficiencies competitive with semiconductor solar cells. Although not enough research has been done on biological photovoltaics to provide useful data on operational efficiencies, when the quantum efficiency approaches unity, the best solar cells can theoretically approach a maximum of 50-percent operational efficiency (with the system matched at maximum power point). Because system-coupling losses limit the operational efficiencies, semiconductor photovoltaic converter systems typically operate in the range of 10 to 15 percent. Biological photovoltaics may provide optimal coupling to the radiation field. Natural selection has already optimized plant and bacterial light-harvesting systems to couple efficiently with the solar spectrum so that many of these systems operate with quantum efficiencies approaching unity. Thus, it is not unrealistic to hope that these systems could be harnessed to produce devices with operational efficiencies approaching 40 to 50 percent. In addition, if biological photovoltaic devices can be made to mimic the responsivity of plants in both the infrared and visible regimes, the probability of enemy detection of large solar converters would be minimized. Photosynthesis Photosynthesis is the process by which green plants use the energy of sunlight to manufacture carbohydrates from carbon dioxide and water in the presence of chlorophyll. The initial electron-transfer (charge-separation) reaction in the photosynthetic reaction center sets into motion a series of reduction-oxidation reactions, passing the electron along a chain of cofactors and filling up the “electron hole” on the chlorophyll (the so-called bucket brigade). All photosynthetic organisms that produce oxygen have two types of reaction centers, photosystem II and photosystem I (PSII and PSI, for short), both of which are pigment-protein complexes located in specialized membranes called thylakoids. In eukaryotes (plants and algae), these thylakoids are located in chloroplasts (organelles in plant cells) and are often found in membrane stacks (grana). Prokaryotes (bacteria) do not have chloroplasts or other organelles, and photosynthetic pigment-protein complexes are either in the membrane around the cytoplasm, in invaginations thereof (for example, in purple bacteria), or are in thylakoid membranes that form much more complex structures within the cell (most cyano-bacteria). Photosynthesis, in general, is the reverse of respiration, a process of breaking down carbohydrates to release energy. Biomolecular Diodes Photosynthesis in plants is initiated by the absorption of light by the two specialized reaction centers, PSI and PSII. The absorption of a photon triggers rapid charge separation and the conversion of light energy into an electric voltage across the reaction centers. These complex protein systems are about 6nm in size and can be isolated and incorporated into devices to generate biomolecular diodes. This research, being carried out Oak Ridge National Laboratory, is summarized in Figure 6-5 (Lee et al., 1997). The value of biomolecular devices is in their potential, rather than their current realizations. Through genetic

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Page 56 ~ enlarge ~ FIGURE 6-5 The photosynthetic apparatus of plants converts light into energy with high efficiency. The isolated Photosystem I can be used as a biomolecular diode, as shown in the lower inset. Source: Reprinted with permission from Lee et al., 1997. Copyright 1997, American Physical Society. engineering, the voltage-response characteristics could be adjusted. Considering that PSI and PSII operate at efficiencies of 70 percent or more and are tuned to intercept solar radiation with optimal absorptivity, further engineering might produce the ultimate photovoltaic converter. These hybrid systems, which currently have operating lifetimes measured in days instead of years, will have to be stabilized. Isolating the photosystems and using their ability to convert light into an electron gradient as a photovoltaic device is not a simple task. These pigment systems were not designed just to convert light into electron translocation, but rather to use light for electron transfer simultaneously with the conversion of water to oxygen plus a proton (PSII) or to convert a light-induced electron gradient to convert the electron acceptor NADP (nicotinamide adenine dinucleotide phosphate) (PSI). Any photovoltaic system must either provide a superstructure to make these reactions possible or mimic their behavior to maintain functionality. The U.S. government’s investment of more than $1.5 billion in the past 25 years, combined with more than $3 billion invested by the private sector, has resulted in only a small improvement in the efficiency of semiconductor-based photovoltaics. Multijunction cells based on GaInP/GaAs have achieved efficiencies as high as 30 percent, but these cells are very costly. Cost-effective amorphous silicon is still below 15 percent in efficiency. Relatively little funding has been directed toward photovoltaics based on biomolecular systems.

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Page 57 In light of the potential payoff, and despite the problems discussed above, it would seem prudent for the Army to investigate the potential of bioelectronics for photovoltaic conversion. If photovoltaic conversion were combined with camouflage, it could provide as much as 20mA at 12V from the surface of a protein-based photovoltaic coating on a Kevlar helmet. Full sunlight is not required, and gray-day photovoltaic converters could be combined with energy-storage mechanisms in regions where sufficient sunlight is not available. The power could then be used directly or used to recharge batteries in the field, thereby increasing the range of an operation and decreasing the soldier’s load. Advances in self-assembly techniques suggest that biomolecular photovoltaic paints could be developed to provide inexpensive, rapidly deployable, photovoltaic power for Army systems in the field using photosynthetic principles. It is unlikely that such technologies will be investigated without sponsorship from the Army. The high potential of biological photovoltaics provides ample rationale for Army research on making the photosynthetic apparatus of plants or bacteria compatible with current electronic storage systems. Key Recommendation Biological photovoltaics is a promising technology that could satisfy Army power requirements in the field, but usable products are at least 15 years away. Photovoltaic converters with superior efficiency are based on bioelectronics devices, such as hybrid diodes and transistors. The voltage-response characteristics in these devices may be adjustable by genetic engineering. The long-term potentials, therefore, will depend on intervening advances in genetic engineering and photovoltaics research. The Army should monitor the progress of research in genetic engineering and photovoltaics for new developments that could meet the energy requirements of soldiers in the field. RENEWABLE RESOURCES In 1998, a vision was articulated through a study led by the Office of Industrial Technology of the U.S. Department of Energy “to provide continued economic growth, healthy standards of living, and strong national security through plant/crop-based renewable resources that are a viable alternative to the current dependence on nonrenewable, diminishing fossil resources.” This vision responds to the rapid increase in total resource consumption and sets a goal of deriving at least 10 percent of basic chemical building blocks from plant-derived renewable resources by 2020 (DOE, 1999). The Army may be able to benefit from the research efforts expended in pursuit of this vision. For example, biologically derived fuels may provide practical alternatives to gasoline and diesel. Also, plant-derived indigenous materials might be used to satisfy requirements for food, fuel, or other high-volume consumables during extended operations. Renewable Fuels The primary motivation for investigating renewable resources as a replacement for oil is that the United States now imports over 50 percent of its oil. Continuing research is also attributable to environmental regulations for clean air and transportation fuels, renewed concern about the security of petroleum supplies, and continuing government subsidies. The tailoring of plants to give specific products is now possible due to the advances in transgenic plants. Biodiesel is a fuel derived from soybean (or other plant) oil that has been demonstrated to replace effectively petroleum-based diesel fuel. The Army uses both gasoline and diesel on the battlefield. Various blends of fuel, including those containing as much as 85 percent ethanol, have also been shown to be effective replacements for gasoline. The benefits of alternative fuels, which are currently very expensive, are simpler methods of processing and availability wherever there is vegetation. Small grains, grasses, even agricultural residues, can be converted to ethanol via fermentation, and oil seeds can be extracted to obtain lubricant oil. The effective yield of fuel alcohol would vary depending on crop yield and the type of crop, but the committee estimates that the yield would range from 100 to 400gal per acre. Biofuels could provide the Army a measure of independence from extended fuel supply lines. However, to take advantage of this capability, the Army must keep abreast of developments in conversion technologies, prepare conversion units, and test them to ensure that military engines can use both traditional and alternative fuels. The Army could also develop expertise in conversion bioprocesses so that the production of alternative fuels could be quickly initiated, as needed. As the potential for biologically based production grows, so will the requirement for engineering. Bioprocess engineering (the discipline that deals with the development, design, and operation of biologically based processes) will play a major role in the development of bioprocesses for transforming renewable resources into useful chemicals and products. Progress is being made in pretreatment and enzyme hydrolysis, as well as in obtaining genetically engineered microorganisms that can convert both pentoses and hexoses to ethanol; however, conversion processes used in these technologies will require major improvements to become economically viable (Gulati et al., 1996). Specialty Products The emergence of a cellulose-based biofuel industry in the United States would open the way for the production of

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Page 58many other types of oxygenated chemicals with potential Army applications. Concerns about pollution and global warming have driven the development of fuels and chemicals that are less likely to cause buildups of carbon dioxide or ozone-depleting substances in the atmosphere. Renewable resources that contain cellulose or starch are promising because the products derived from them are eventually broken down into carbon dioxide (e.g., combusting a fuel), which is recycled back into the plant via the Calvin cycle. The conversion requires sunlight as its source of energy. Waste cellulose materials, such as grasses, agricultural residues, wood chips, surplus grains, spoiled surplus food, and food wrappers, could be used as sources of sugars. These sugars could be fermented to chemicals that contain oxygen and could be used as building blocks for plastics and fabrics. In theory, these materials could be produced in the field (if the theater of operation were in a temperate zone) and used as fuels. The mass production of genetically engineered plants by modern agriculture in the United States could accelerate the development of specialty polymers or materials for soldiers’ uniforms. Materials from genetically engineered plants could be readily processed into fabrics, either directly or indirectly. Natural polymers could combine the best characteristics of cotton and artificial fibers to perform specialized functions to protect soldiers from the environment. Some products from renewable manufacturing sources will certainly be available before 2025, driven largely by consumer environmental concerns, international conventions on global warming, and the attractiveness of “natural” manufacturing processes that decrease the use of chemicals perceived to be undesirable because of their toxicity or other handling characteristics. Life-Support Applications Perhaps the ultimate application of biotechnology will be to control ecological life-support systems in an alien environment, such as space, or in the confined environments that may be encountered by soldier operators of future Army combat systems. Biological life support will also be necessary for long-term space travel and, particularly, for the colonization of Mars. Food will have to be generated and wastes recycled to support life (Westgate et al., 1992). Controlled, bioregenerative, life-support systems would mimic Earth’s ecosystem, recycling carbon, hydrogen, oxygen, and nitrogen through a complex, interconnecting series of biological and biochemical transformations (Averner et al., 1984). The technologies that result from research and development in these areas can be applied directly to the support of military operations for prolonged periods of time in remote locations. They will also add to our understanding of Earth’s ecosystem and provide solutions to environmental issues, such as pollution control and remediation. The Army is responsible for controlled destruction of chemical munitions and could benefit greatly from research in this area, especially bioremediation, the biological conversion of toxic wastes to nontoxic materials. Key Recommendations As biologically derived alternatives (surrogates) for gasoline and diesel fuels become available, they could provide increased flexibility for future Army operations. The Army should monitor the development of bioprocesses for alternative liquid fuels. Simultaneously, the Army should prepare to test and adapt military engines so that they can operate with either traditional or alternative fuels. Biological methods of recycling air, food, and water could improve Army systems that require soldiers to work in confined spaces for extended periods of time and could decrease the logistical support requirements of soldiers in the field. Many such methods are already under development in response to commercial and NASA requirements. The Army should identify conditions specific to its needs for operating future combat systems and monitor developments in biological life cycle support applications.