The panel received an overview presentation on Nanomanufacturing that summarized NIST’s nanotechnology strategy, its leadership in providing documentary standards in nanotechnology, several types of nanomanufacturing, and major needs and challenges. This overview was followed by presentations on nanocomposite manufacturing and nano environmental health and safety. The following detailed presentations and tours in the area of Nanomanufacturing were also given during the review:
1. Dimensional Metrology for Semiconductor Nanomanufacturing
2. CMOS Devices Metrology for the Continuation of Moore’s Law
3. Flexible Electronics
4. NEMS (nanoelectromechanical systems) Measurement Science
5. Nanoparticle Measurement Methods and Standards
6. Carbon Nanotube Metrology and Standard Reference Materials
7. Nanomechanics Cleanroom Facility
8. Carbon Nanostructure Growth Optimization
In the following section, the panel presents general comments on the overall Nanomanufacturing area. These comments are followed by discussions of the Nanomanufacturing activities in terms of their technical merit and scientific caliber, the efficacy of NIST’s engagement with outside stakeholders, and program coordination and cohesion across NIST. The same aspects of the Biomanufacturing program are then discussed. Finally, recommendations are offered.
The technical merit and scientific caliber of the work in the Nanomanufacturing area are impressive. Much of the work is among the best in the world, evidencing the unique skills and contributions of NIST. Some of the projects represent very significant examples of nanomanufacturing, and some are paradigm shifting. For example, one panel member called the “rice-sized” atomic clock developed at NIST the most significant example of nanomanufacturing that he had seen, noting that this is paradigm-shifting work which the automotive industry can use today if the clock can be manufactured cost-effectively.
The specialized facilities that are contained in the NIST nanotechnology laboratories represent a unique collection of advanced tools. One such facility that panel members toured was the nanomechanics measurement laboratory, in which the temperature is controlled to a few thousandths of a degree. This control is necessary in order to provide calibrated atomic force microscope (AFM) cantilevers. It is hoped that access to these tools will be maximized.
However, the panel noted that there was a significant challenge in reviewing the Nanomanufacturing area. Unlike the case with the other two manufacturing areas (Smart Manufacturing and Next-Generation Materials) addressed during this site visit, the overarching ownership of the Nanomanufacturing area did not seem to exist clearly under the authority of a
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2 Nanomanufacturing INTRODUCTION The panel received an overview presentation on Nanomanufacturing that summarized NIST's nanotechnology strategy, its leadership in providing documentary standards in nanotechnology, several types of nanomanufacturing, and major needs and challenges. This overview was followed by presentations on nanocomposite manufacturing and nano environmental health and safety. The following detailed presentations and tours in the area of Nanomanufacturing were also given during the review: 1. Dimensional Metrology for Semiconductor Nanomanufacturing 2. CMOS Devices Metrology for the Continuation of Moore's Law 3. Flexible Electronics 4. NEMS (nanoelectromechanical systems) Measurement Science 5. Nanoparticle Measurement Methods and Standards 6. Carbon Nanotube Metrology and Standard Reference Materials 7. Nanomechanics Cleanroom Facility 8. Carbon Nanostructure Growth Optimization In the following section, the panel presents general comments on the overall Nanomanufacturing area. These comments are followed by discussions of the Nanomanufacturing activities in terms of their technical merit and scientific caliber, the efficacy of NIST's engagement with outside stakeholders, and program coordination and cohesion across NIST. The same aspects of the Biomanufacturing program are then discussed. Finally, recommendations are offered. GENERAL COMMENTS The technical merit and scientific caliber of the work in the Nanomanufacturing area are impressive. Much of the work is among the best in the world, evidencing the unique skills and contributions of NIST. Some of the projects represent very significant examples of nanomanufacturing, and some are paradigm shifting. For example, one panel member called the "rice-sized" atomic clock developed at NIST the most significant example of nanomanufacturing that he had seen, noting that this is paradigm-shifting work which the automotive industry can use today if the clock can be manufactured cost-effectively. The specialized facilities that are contained in the NIST nanotechnology laboratories represent a unique collection of advanced tools. One such facility that panel members toured was the nanomechanics measurement laboratory, in which the temperature is controlled to a few thousandths of a degree. This control is necessary in order to provide calibrated atomic force microscope (AFM) cantilevers. It is hoped that access to these tools will be maximized. However, the panel noted that there was a significant challenge in reviewing the Nanomanufacturing area. Unlike the case with the other two manufacturing areas (Smart Manufacturing and Next-Generation Materials) addressed during this site visit, the overarching ownership of the Nanomanufacturing area did not seem to exist clearly under the authority of a 8
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laboratory director. Unlike the presentations given on the topics of Smart Manufacturing and Next-Generation Materials, the overall area report on Nanomanufacturing did not adequately convey the area's self-assessment of strength and weakness in the field or a focus direction. For example, there did not seem to be a consensus in the area as to which of the following descriptions best fits the objectives of the activities in the Nanomanufacturing area: Making small features on large objects, Making nanosized objects, Making nanoscale objects to obtain special properties, Incorporating nanoscale objects in larger objects, and Using nanotechnology to manufacture other things. In his overview presentation, the Director of the Center for Nanoscale Science and Technology (CNST) indicated that this area is trying to do work related to all of the above definitions of nanomanufacturing. Since resources, time, and funds must be limited in any scenario, it would be preferable for NIST to make clear choices about which aspects of nanomanufacturing best fit the NIST mission. Note that this selection process must also include what not to do. Similarly, there was a lack of clarity about the formal or informal organization of Nanomanufacturing-related activities within NIST. Some possible ways of looking at such structure range from a minimalist to an expansionist viewpoint. Nanomanufacturing could thus be viewed in various ways: 1. One possible view would have Nanomanufacturing existing in the five mission- specific laboratories. The work of these laboratories extends by natural progression down the relevant length scales. As problems of scale are encountered, they are solved in the laboratory setting, sometimes with the involvement of the CNST in a role as an enabler. 2. A second possible view of NIST's Nanomanufacturing organization would expand on the first viewpoint by adding two crosscutting program organizations--the Nanocomposite Manufacturing program and the Nano Environmental, Health and Safety (Nano-EHS) program. These crosscutting programs address two specific issues and are National Nanotechnology Initiative (NNI) Nanomanufacturing Signature Initiatives. 3. A third possible view would extend the Nanomanufacturing effort to include selected programs from the mission-specific laboratories. These selected programs would expand the Nanomanufacturing portfolio. 4. A fourth view, and the most expansive, would include all of the NIST programs that contain elements involving nanofabrication techniques. In this view there is a "shared vision" of what nanomanufacturing means, and common crosscutting problems and issues would be drawn out for special attention. Adopting a particular organizational view has significant consequences for programmatic review. If the most minimalist (first) view were adopted, the Nanomanufacturing effort would not need to be reviewed at all; rather, a detailed review of the CNST would suffice. If the second view were adopted, the merit of the Nanomanufacturing effort would be based entirely on the review of the two crosscutting NNI programs. If the third view were adopted, the portfolio of the Nanomanufacturing effort would increase, but it would be essential to understand how the 9
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various programmatic elements were chosen or not chosen for inclusion in the Nanomanufacturing initiative. Finally, if the most expansive view of the organizational structure were taken, a "shared vision" and management structure would have to be clearly articulated to allow for such an enterprise to thrive. It is clear that NIST is taking the first steps toward articulating its vision for nanomanufacturing technology by drawing together some programmatic elements that contain strong nanomanufacturing components. However, NIST is encouraged to continue to define its vision further. Photovoltaics (PV) is one area in the Nanomanufacturing activities in which NIST has research, testing, standards, and standards to support PV manufacturing. There should be a coupling between NIST and the two PV manufacturing centers in the country funded by the Department of Energy (DOE) under the DOE Sunshot Manufacturing Initiative)--one is the PV Manufacturing Center (PVMC) under SEMATECH at Albany, New York, and the other is the Bay Area Photovoltaics Consortium (BAPVC) run from Stanford University--because NIST could add value (e.g., technology roadmapping, manufacturing support, etc.), and smart manufacturing is very much needed by the PV industry. (In the PV area, because the industry is heavily driven by end-product pricing--unlike, just to give one example, precision machine tools--resulting from intense cost pressures from offshore competition, the need for smart manufacturing in the United States has become especially critical.) Since the PVMC and the BAPVC are specifically funded for PV manufacturing, and since they are just getting started, NIST (which leverages much other electrooptical activity in addition to its PV nanomanufacturing focus) could bring value to these two national efforts. These centers have a mission in concert with the PV area of the NIST effort, and they would benefit from the NIST PV nanomanufacturing expertise. The suggested coupling could allow the rather extraordinary level of effort and concentration of expertise at NIST to enhance and assist the DOE manufacturing effort, as well as increasing the exposure and potential for expansion of work at NIST into other technologies. An important issue for consideration in NIST Nanomanufacturing activities is "bankability." Many new technologies suffer because the emphasis is placed only on demonstrating them at some performance levels. However, if they are too expensive to manufacture, they cannot be commercialized. It would be good for NIST to avoid projects that may provide exciting research opportunities but are weak in manufacturability and/or commercialization potential (e.g., they are too expensive, or there is insufficient market size). Bankability was the issue with Solyndra, for example. NIST can play an important role here in many ways--by providing, for example, methodologies, databases, reference materials, and modeling to the manufacturing community (especially new entrants) so as to enable them to evaluate their approaches independently. Within the Nanomanufacturing area, it is important to note the excellent and unique capabilities that NIST has built and operates in its shared facilities. The Nanomechanics Cleanroom Facility is an excellent example of how NIST is making important contributions with unique facilities. Particularly impressive (shown during one of the tours) was the millikelvin controlled room used to provide AFM tips standards. TECHNICAL MERIT AND SCIENTIFIC CALIBER The technical merit and caliber of the work performed in the Nanomanufacturing area are generally very impressive. All of the groups are either world leaders in their chosen area or making strong strides toward a leadership position. This is particularly evident in the CMOS 10
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(complementary metal-oxide semiconductor) device metrology laboratory. The semiconductor industry is the largest nanotechnology industry in the United States, and NIST has strongly contributed to a technology roadmap addressing key issues using advances in measurement. Issues addressed at NIST include mobility degradation, the role of series resistance, and low- voltage reliability. As a result, numerous measurement advances have been made, including the ability to make an advanced reliability measurement on 3,000 devices simultaneously. The technical diversity evident in the research groups is also impressive. For example, the Flexible Electronics program is a leading and visible program supporting the organic PV industry through a wide range of measurement and process research capabilities. The program's researchers are a young, engaged, knowledgeable, and enthusiastic group of scientists and engineers and a well- assembled group of chemists, materials scientists, and, notably, a device physicist/engineer. NEMS Measurement Science appears to be a promising new area of research, but it is not far enough along at this point for evaluation. The impact that NIST has made on the semiconductor industry, which plays a critical role in the U.S. economy, is particularly impressive. NIST has done an outstanding job in identifying important problems that the semiconductor industry has overlooked or is not in a position to investigate. NIST has addressed several major current issues in semiconductor technology, such as mobility degradation, the role of series resistance, and low-voltage reliability. NIST also has identified some emerging issues of importance, such as single-defect control and random telegraph noise. It is recommended that, in addition to the focus on the current CMOS technologies, NIST should work with industry to develop the metrics for benchmarking the new, potential CMOS replacement technologies. Flexible Electronics is an important emerging area, particularly as it relates to the photovoltaic industry. One challenge in this area is deciding which problems to focus on solving. The industrial participants themselves are in the throes of figuring out what to measure, what to monitor, and what standard(s) to adopt. It appears that NIST is taking the approach of pulling together the key industry players and, in some sense, facilitating cooperation to help elucidate some solutions to these questions. Two potential issues have been identified: (1) Critical mass: Is the size of this group sufficient to meet the needs of the program goals? With growing capabilities in the processing support, is there enough technical coverage for different technical approaches--for example, single-junction, tandem, small-molecule, large-molecule, and other technology approaches? (2) Leveraging: It is unclear how the group interacts and interfaces with the other PV activities at NIST (although this obviously must exist). The Carbon Nanotube (CNT) Metrology and Standard Reference Materials activity (involving the production of standards and reference materials, and measurement techniques and methodologies) is an important area for NIST to pursue. It fits squarely within NIST's charge. This program leads the world. The method for selectivity for sorting of single-wall CNTs using deoxyribonucleic acid (DNA) is innovative. There seems to be interest and some preliminary planning for expansion into biological areas (for DNA and ribonucleic acid [RNA] research) using the team's progress with CNT reference development. However, the team does not seem to have committed to this expansion. This may be an excellent area for a contribution by NIST--and NIST may want to consider extending the expertise of this laboratory to engage this area of technology. The presentation for the review team in the area of carbon nanomaterial composites provided an excellent view of the development of a technique and capability that will enable in situ measurement of nanomaterial growth processes (using a state-of-the-art environmental transmission electron microscope). Raman spectroscopy is being incorporated into the microscope, and the system is currently being developed and qualified. The method for parallel 11
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design and development of the special nano-Raman capability is a creative and time-efficient approach, and it reflects the expertise and experience of this group. This is a unique capability with multiple program applications. The review team received an impressive demonstration of the observation of the in situ growth of CNTs. It is clear that the new microscope capability will provide an understanding of exactly how the growth conditions control the morphology and properties. NIST ENGAGEMENT WITH OUTSIDE STAKEHOLDERS Overall, the research groups in Nanomanufacturing are significantly engaged with their constituencies. NIST is engaged with the "right players" in industry, particularly in the emerging organic photovoltaic (OPV) field, and NIST has positioned itself well within this emerging industry. The most significant impacts to date include helping the OPV industry by elucidating parameters that should be measured in addition to what the industry was measuring. NIST, including the Material Measurement Laboratory (MML), the PML, and the CNST Energy Research Group, has established working relationships and interactions with U.S. manufacturers in this technology, as well as critical interactions with leading U.S. PV organic device research groups. NIST has helped establish a plan for certification testing. Addressing issues such as thickness uniformity and compositional uniformity is much needed, and the benefits of contactless measurement contributions can be significant. In addition, NIST is involved in organizing, leading, and participating in workshops and meetings involving both industry and research institutions. Industry scientists at various times have worked in the NIST laboratories. This should be encouraged and enhanced to ensure value and direct feedback into the NIST Flexible Electronics operations. The following are potential issues and questions: 1. How does the NIST staff measure and document its contributions to this fledgling OPV industry? Is the industry itself involved with developing such metrics? 2. Would an industry advisory board be useful to ensuring relevance--as well as serving as an important feedback mechanism to the technical community, the Congress, and to NIST itself as to whether the investments are paying dividends? 3. Can this effort be a "one-stop shop" for OPV manufacturing, measurements, or processing? What reference materials can be provided? In the CMOS area, NIST seems very engaged with the semiconductor industry in CMOS device metrology for the continuation of Moore's law; samples of devices are regularly sent to NIST from companies such as Intel. The NIST work in this area is addressing key issues using advances in measurement, many of which have been incorporated into various standard semiconductor measurement techniques. In addition, NIST has leadership roles in the International Technology Roadmap for Semiconductors. Clearly, this area has made and continues to make important contributions to national competitiveness. Since the large CMOS device market is dominated by companies with vast resources, NIST should make careful judgments about where it positions itself with respect to device metrology supporting continuation of semiconductor technology advances. The Carbon Nanotube Metrology and Standard Reference Materials activity serves the CNT community through standards and reference materials, especially the measurement techniques and procedures that this group provides to other groups. This is a very valuable effort. Other nanotechnology activities (e.g., multi-wall CNT [MWCNT]) were identified as being carried out at NIST's Boulder, Colorado, facility, with good reason--the techniques for 12
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evaluation are in-house there. Overall, this activity is a true NIST resource, one that fits the NIST mission well. The cooperation and research exchanges between the Boulder team and this group are essential to ensuring the same success with the MWCNT reference activity. The new instrumentation in the recently established Carbon Nanocomposites project offers unique and important capabilities for providing information for the manufacturing industry. PROGRAM COORDINATION AND COHESION The evaluation of the Flexible Electronics program shows evidence of collaboration and coordination across several NIST laboratories and programs. Material measurements, device fabrication, and device characterization leverage resources from several groups. NIST understands the need for these various elements within this emerging field. In the area of CMOS devices metrology, the level of coordination of this effort with other Nanomanufacturing-related initiatives was not made clear. The group is urged to explore ways of expanding its silicon-centric efforts to other materials that have the potential to impact the semiconductor industry. The Carbon Nanotube Metrology and Standard Reference Materials team has a singular focus--the production of reference materials, standards, and measurement techniques and methodologies. It is not difficult to identify the success that this team has achieved. Clear goals were expressed at the beginning of the presentation to the panel--provide CNT reference materials and techniques and methodologies to measure and characterize carbon nanotubes. The team knows the major markets for its reference materials (now and in the near future). The main question is the following: In addition to the continuing refinement and development of these processes for standards, what areas is this team developing? (The MWCNT work seems to be in the scope of NIST's Boulder facility, although the Gaithersburg staff obviously will play some role in that.) The Carbon Nanomaterial Composites program and instrumentation are in their initial stages, but the investigators have designed the capability to meet new and special needs in order to advance knowledge that can advance manufacturing. Since the capability is not currently online, it is too soon to comment on the issues of coordination and cohesion. BIOMANUFACTURING The Biomanufacturing program at NIST is in its infancy; it was started earlier this year. The program will focus initially on the development of new or improved measurement science, standards, and reference data for more accurately and precisely determining the structures of biologic drugs. Since protein biologics and monoclonal antibodies are emerging as major economic drivers of new drug development and as new therapeutics for unmet medical needs, this focus is ideally suited to leveraging current internal protein science and cell biology programs at NIST. Three program goals are envisioned in the area of protein therapeutics: protein stability, protein structure, and production cell variability. Based on discussions with the Food and Drug Administration (FDA) and industry, NIST considers these as critical areas in which NIST measurement tools will provide useful data to underpin regulatory decisions scientifically, to support the development of biosimilars, and to increase the knowledge of biopharmaceuticals necessary for improving therapeutics and developing next-generation treatments. 13
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Technical Merit and Scientific Caliber Work on protein stability has taken advantage of soft-neutron technology at NIST, leading to the development of new tests for the efficacy of proteins stabilized by various glycerol formulations in collaboration with a major pharmaceutical company. The data are early but promising. Measurement methods are needed to analyze protein aggregation and stability in order to monitor product integrity during manufacturing, in bulk drugs, and for final-product release. Developing standard measurements for these complex formulations will provide important guidance to regulatory agencies. This work has considerable promise and future value. In the area of protein structure measurements, NIST has excellent resources available internally and through its 20-plus-year relationship with the University of Maryland's Institute for Bioscience and Biotechnology Research (IBBR), formerly the Center for Advanced Research in Biotechnology (CARB). New structural analysis methods will provide improved measurements, standards, and reference data in three specific areas: 1. Primary amino acid sequence and identification of low-abundance variants and unintentionally chemically modified variants. This is a solid focus of high importance. Low-abundance variants are problematic for the biopharmaceutical industry and new methods for their detection and quantitation. The results should be of broad significance and applicability. 2. Post-translational modifications (PTMs) of proteins, including glycosylation. The significance of PTMs in biological processes and in new protein biological therapeutics cannot be overstated. The precise determination of PTMs in biologics and their correlation to issues of efficacy and toxicities will be invaluable data for ensuring standards of composition and potency for manufactured therapeutics. 3. Three-dimensional (3-D) protein structure. The structural determination of biologics constitutes another useful parameter for assessing the impact of variants. The required work will likely rely on efforts at both NIST and IBBR. The goal is worthy, albeit loosely defined at this point. Future work should be directed to providing clarity to this goal. The goal of understanding parameters affecting production-cell variability also has high impact potential; however, the strategies are not clear. As noted by NIST, approximately 70 percent of therapeutic proteins are produced in Chinese hamster ovary (CHO) cells. Thus, NIST believes that developing new methods for understanding and quantifying these complex drug factories will enable the development of new strategies for engineering and controlling CHO cells so as to ensure efficient production and consistent quality of manufactured protein therapeutics. It remains to be seen what these new methods will be and how effectively they will compete against the vast array of molecular biological techniques already employed to reengineer cells and regulate their production profiles. The Biomanufacturing effort at NIST is early and a bit tentative. The focus in protein therapeutics makes good sense. Careful integration with other complementary NIST efforts will potentially lead to a robust and valuable initiative. 14
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NIST Engagement with Outside Stakeholders The three program goals (protein stability, protein structure, and production-cell variability) are based on discussions with the FDA and industry and have been determined to be critical areas in which NIST measurement tools will provide useful data. As stated above, work on protein stability in collaboration with a major pharmaceutical company has taken advantage of the NIST NCNR to develop new tests for the efficacy of proteins stabilized by various glycerol formulations. Also as noted above, in the area of protein structure, NIST has excellent resources available internally and through its 20-plus-year relationship with the University of Maryland's IBBR. Work on production-cell variability is the least-developed program goal. The manufacturing of biologic drugs in living cells, such as CHO cells, is a critical process in the pharmaceutical industry, and controlling product consistency is a significant challenge. Thus, identifying new measurement methods and tools for quantifying and controlling cellular machinery is an admirable NIST goal. There is little doubt that NIST technologies could be invaluable here. What remains is to develop a clear strategy to execute, which will engage the appropriate external stakeholders. This strategy should be forthcoming. Program Coordination and Cohesion Overall, the Biomanufacturing initiatives are appropriately focused in the short term on protein therapeutics, consistent with the strengths of the Material Measurement Laboratory. The Biomanufacturing group is encouraged to explore and foster crosscutting initiatives with other manufacturing groups, especially Nanomanufacturing. For instance, nanofabrication of engineered therapeutics is an area of emerging importance. Recent breakthroughs using materials specifically designed for imprint or soft lithography have enabled flexible methods for the direct fabrication and harvesting of monodispersed, shape-specific nanobiomaterials. These nanoparticles can be fabricated into numerous shapes and sizes, including nanocylinders, nanorods, or long, filamentous, "worm-like" nanoparticles. The unique control over size and shape leads to a variety of nanomaterials that can accumulate in specific tissues or diseased sites. This area could constitute an important crosscutting effort. Careful integration with other complementary NIST efforts will potentially lead to a robust and valuable program. RECOMMENDATIONS The recommendations for the Nanomanufacturing area, including Biomanufacturing, are the following: 1. NIST should continue to define its vision for its Nanomanufacturing program, making clear choices about what nanomanufacturing should be on the basis of the NIST mission. To have more impact, NIST should focus on the following definitions or aspects of nanomanufacturing: Making nanoscale objects to obtain special properties, and Using nanotechnology to manufacture other things. 15
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2. In addition to the focus in the Nanomanufacturing program on the current CMOS technologies, NIST should work with industry to develop the metrics for benchmarking the new, potential CMOS replacement technologies. 3. There should be a coupling between NIST and the two DOE-supported centers for photovoltaics (the PV Manufacturing Center [PVMC] under SEMATECH at Albany and the Bay Area Photovoltaics Consortium [BAPVC] run from Stanford University). NIST should add value through technology roadmapping or manufacturing support for this area of renewable energy and manufacturing, a priority for the current administration. 4. To play an important role with respect to the issue of bankability of new technologies, NIST should consider providing methodologies, databases, reference materials, and modeling so as to provide those in the manufacturing community (especially new entrants) with a way to evaluate their approaches independently and objectively. 5. In the large CMOS device market, which is dominated by companies with vast resources, NIST should make careful judgments about where it positions itself with respect to device metrology supporting continuation of semiconductor technology advances. 6. Scientists from the flexible electronics industry at various times have worked in the NIST laboratories, and this should be encouraged and enhanced to ensure value and direct feedback into the NIST Flexible Electronics operations. 7. Since the structural determination of biologics may constitute a useful measurement tool for assessing the impact of modified variants on Biomanufacturing, future work should focus on developing clear goals that will test the robustness of the approach for specific protein therapeutics. 16