4

Physical Infrastructure for Nanotechnology

One of the key areas in which the National Nanotechnology Initiative (NNI) has provided, and should continue to provide, value is through creating and maintaining publically accessible infrastructure for nanoscale science, engineering, and technology research and development. This infrastructure (see Figure 4.1) comprises both physical and computational tools: characterization and fabrication facilities and online simulation and education resources. The existence and quality of these infrastructure resources are key factors in reducing barriers to research discovery and technological innovation, and in developing and retaining the U.S. science, technology, engineering, and mathematics talent pool. This chapter addresses the first element of part B of the committee’s statement of task relating to the physical infrastructure required for nanotechnology research, development, and commercialization.

Over the 15-year history of the NNI, the strongest agency participation in nanotechnology infrastructure development has come from the Department of Energy (DOE), National Institute of Standards and Technology (NIST), and the National Science Foundation (NSF), each of which has established and maintained extensive user facilities. In addition, the Nanotechnology Characterization Laboratory (NCL) was founded jointly by the National Cancer Institute (NCI), NIST and the Food and Drug Administration (FDA), to address the growing need for development and testing of nanomaterials for cancer diagnosis and treatment. Other NNI partner agencies, including the Department of Defense, maintain nanotechnology facilities for internal agency use in nanoscience research and devel-

opment. Descriptions of the available nanotechnology centers, both user and other facilities, is described below.¹

NANOSCIENCE USER FACILITIES

The network of nanoscience user facilities is geographically broad (see Figure 4.1) and sizable in scope (see Figure 4.2), with more than 11,000 researchers served at the NSF, DOE, and NIST user facilities alone. It should be noted that the rate of growth of the user base at all the facilities is limited to varying degrees by budget constraints. In 2014, more than 13,000 individual users were accommodated at the NSF, DOE, and NIST user facilities. The dip in total user numbers for 2015 is primarily due to difficulties in meeting user demand during the transition at NSF from the National Nanotechnology Infrastructure Network (NNIN) to the National Nanotechnology Coordinated Infrastructure (NNCI) program.

National Nanotechnology Infrastructure Network/National Nanotechnology Coordinated Infrastructure (NSF)

In 2004, NSF initiated NNIN as a successor to the preceding National Nanofabrication User Network. The NNIN was an integrated partnership among 14 user

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¹ More detail can be found at National Nanotechnology Initiative, “NNI R&D Centers & Networks,” http://www.nano.gov/centers-networks, accessed September 12, 2015.

facilities that provided unparalleled opportunities for nanoscience and nanotechnology research. The network provided extensive support in nanoscale fabrication, synthesis, characterization, modeling, design, computation, and hands-on training in an open environment available to all qualified users. In 2013, the NNIN trained more than 2,000 new users, serving a total base of more than 6,000 researchers² at 14 sites nationwide. The user population distribution has been roughly constant over time, at 82 to 85 percent academic, 15 to 17 percent industrial, and 1 to 2 percent government.

In 2015, after soliciting community input via individual and workshop formats,^3,4 NSF replaced the NNIN program with the NNCI program. The sites (shown on Figure 4.1) were announced in September 2015. Georgia Institute of Technology was selected in 2016 as the host site for the coordination office for the

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² Dan Ralph, Principal Investigator, and Roger Howe, Network Director, 2013, National Nanotechnology Infrastructure Network-NNIN Annual Report Year 10 (partial); new users in Figure 21; total users on page 9.

³ National Science Foundation, 2014, “Dear Colleague Letter: Community Input On Future NSF Nanotechnology Infrastructure Support Program,” NSF 14-068, https://www.nsf.gov/pubs/2014/nsf14068/nsf14068.jsp.

⁴Report to the National Science Foundation on the Workshop for a Future Nanotechnology Infrastructure Support Program, held August 18-19, 2014, in Arlington, Va., available at https://www.src.org/newsroom/src-in-the-news/2014/656/.

NNCIs. Of the 16 primary NNCI institutions announced, 8 are entirely new sites, and 8 are located at prior NNIN primary institution sites. This mix of sites strikes a balance between continuity in operations for sites with complex and demanding architectural and environmental requirements and flexibility in establishing facilities to address emerging technological needs. The legacy NNCI sites (Stanford University, Cornell University, Georgia Institute of Technology, University of Minnesota, Twin Cities, Arizona State University, Harvard University, University of Washington, and University of Texas, Austin) all have established nanoscience and technology facilities with proven track records in user facility operation. The new NNCI centers (University of Pennsylvania, University of Kentucky, Montana State University, Northwestern University, Virginia Polytechnic Institute and State University, North Carolina State University/Duke University/University of North Carolina, Chapel Hill, and University of Nebraska, Lincoln) capitalize on recent investments at the respective host institutions. For example, the Mid-Atlantic Nanotechnology Hub for Research, Education and Innovation at the University of Pennsylvania leverages the establishment of the Krishna P. Singh Nanotechnology Center that opened in 2013.

Center for Nanoscale Science and Technology (NIST)

The Center for Nanoscale Science and Technology (CNST) supports the U.S. nanotechnology enterprise from discovery to production by providing industry, academia, NIST, and other government agencies with access to world-class nanoscale measurement and fabrication methods and technology. Since the inception of the facility in 2007, the fraction of nongovernment users has steadily increased, reaching 55 percent academic, 16 percent industrial, and 30 percent government in 2015. The CNST’s shared-use NanoFab gives researchers economical access to and training on a commercial state-of-the-art tool set required for cutting-edge nanotechnology development. Looking beyond the current commercial state of the art, CNST’s NanoLab offers opportunities for researchers to collaborate on creating and using the next generation of nanoscale measurement instruments and methods. The CNST reached more than 2,100 users in 2014, representing 464 unique institutions, including 168 private companies.⁵ Because industry and academia need access to the latest generation of instrumentation as they try out new processes, procedures, and standards that might be incorporated into a manufacturing capability, NIST includes funds for instrument recapitalization in the CNST budget line.

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⁵ From report presented to committee by CNST Director Robert Cellotta.

Nanoscale Science Research Centers (DOE)

The Nanoscale Science Research Centers (NSRCs) offer a comprehensive approach to addressing nanotechnology challenges, including theory, synthesis, characterization, fabrication, and platform integration. Strategic plans for the 2015 to 2019 timeframe for these facilities are posted on the individual center webpages. Each center has identified science focus areas that include growth, processing, characterization, and theory and computation. The five DOE NSRC sites are all located within larger DOE laboratories: the Molecular Foundry at the Lawrence Berkeley National Laboratory; the Center for Integrated Nanotechnologies at Sandia and Los Alamos; the Center for Nanoscale Materials at Argonne National Laboratory; the Center for Nanophase Materials Sciences at Oak Ridge National Laboratory; and the Center for Functional Nanomaterials at Brookhaven National Laboratory. These DOE laboratories are home to major user facilities, such as X-ray and neutron sources. The combination of NSRC instrumentation, staff scientist expertise, and world-class light and neutron facilities comprise a unique asset for the nanoscience research community. Recently, DOE merged the electron beam microscopy centers with the NSRCs to further consolidate nanoscale characterization capabilities.

The annual user base served by the five DOE NSRCs exceeds 2,000, with nearly 2,800 in combined electron beam center and nanomaterial center users in 2014⁶ from the United States and 45 countries worldwide.⁷ In addition to access to the physical infrastructure, these user facilities provide online and in-person training for use of the available experimental tools. The combined annual user population of the NSRCs is on par with that of individual light source user facilities and represents approximately one-fifth of the 14,000 of total users at the DOE Office of Science facilities. The distribution of NSRC users in 2014 was approximately 60 percent academic, 5 percent industrial, and 35 percent government.⁸

Network for Computational Nanotechnology (NSF)

The Network for Computational Nanotechnology (NCN), established in 2002 by NSF as part of the NNI, focuses on the delivery of education, training, and research support through a web-based platform entitled nanoHUB.org. Through web access—even using smartphones, tablets, and other devices—more than 13,000

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⁶ Information derived from the NSRC annual reports that are available at Department of Energy, Office of Science, “Science User Facilities (SUF) Division,” http://science.energy.gov/bes/suf/, accessed September 6, 2016.

⁷ See U.S. Department of Energy, “The NSRC User Community,” https://nsrcportal.sandia.gov/Home/Communities#map, accessed September 6, 2016.

⁸ George Maracas, DOE, “User Distribution,” e-mail communication, on September 2, 2015.

annual users run simulation tools that appear to be like smartphone apps but are powered by a powerful cloud-based computational infrastructure. These simulation tools are typically outcomes—from a computational Ph.D. thesis or from community codes—that have been adapted for delivery via a user friendly graphical interface. The interface allows these tools to be operated by experimentalists or to be adopted in formal classroom training and education. The median adoption time of these research tools into the classroom is less than 6 months.

NanoHUB user behavior analysis (see Figure 4.3) reveals that more than 24,600 students in more than 1,268 courses at 185 institutions globally have utilized simulation tools on nanoHUB in formal classroom settings over the past 10 years. About 50 percent of the simulation users reside in the United States.

Lectures, tutorials, and research seminars hosted by nanoHUB attract more than 300,000 users annually. More than 4,000 resources are hosted on nanoHUB, including over 100 complete courses in various aspects of nanotechnology. These lectures, and even complete courses, are utilized globally and integrated into new and modified curricula.

Nanotechnology Characterization Laboratory (NIH/NCI)

While not a user-facility per se, the NCL is yet another example of physical facilities that contribute significantly to progress in nanotechnology—in this case, nanomedicine. NCI’s investment in the NCL in Frederick, Maryland, has resulted in standardization of characterization protocols, the reformulation of a number of useful active pharmaceutical ingredients (APIs), and the creation of sensors, contrast agents, devices, and hybrid medical products for the treatment of cancer and other diseases.^9,10 The development of a large number of these new pharmaceutical entities was made possible and supported by the human and physical infrastructure provided by the NCL. This somewhat unique arrangement has arguably become a major catalyst in the submission to the FDA of standardized information on nanomedicines and devices on which the FDA may make evidence-based regulatory decisions throughout the life cycle of a product (e.g., preclinical–Phase IV).

Finding 4.1: The NNI agencies fund a substantial set of facilities that support experimental, computational, and educational activities and users from academia, industry, and government. While information about each facility or center is available on the NNI website, there is little evidence of coordination among the agencies to facilitate access and use by the community at large.

Recommendation 4.1: User facilities should strive to better serve the collective nanoscience research community by (1) sharing—perhaps via a central web-based portal—training materials and simulation and computational tools developed at the individual user facilities and (2) creating a common proposal form and process that facilitate users moving between facilities to access the more expensive or specialized instrumentation.

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⁹ V. Wagner, A. Dullaart, A.-K. Bock, and A. Zweck, 2006, The emerging nanomedicine landscape, Nature Biotechnology 24:1211-1217.

¹⁰ N.K. Mehra, K. Jain, and N.K. Jain, 2015, Design of multifunctional nanocarriers for delivery of anti-cancer therapy, Current Pharmaceutical Design, Epub ahead of print.

LEADING-EDGE CAPABILITIES AT RISK

In recognition that infrastructure needs to evolve over time, NNI agencies have arranged the funding and management of facilities and sites to consolidate functions, eliminate duplication, and achieve cost efficiencies. For instance, in 2013 DOE moved to incorporate the electron microscopy user facilities with the nanomaterials user facilities, which were previously managed separately. The DOE-led TEAM project,¹¹ and other DOE-funded developments in electron microscopy¹² enabled revolutionary advances in electron beam-based materials characterization through the development of aberration-correction technology, low-voltage operation, and new detector designs. The integration of these facilities, fully realized in 2015, brings leading-edge nanoscale characterization tools together. The merger has the potential for positive impact on the nanomaterials user community. Specifically, it enables researchers to submit a single comprehensive research proposal for fabrication and characterization, rather than individual proposals, to separate evaluation boards, thus lowering the burden to researchers and laboratory staff, as well as accelerating the pace of innovation.

A major challenge for the DOE NSRCs going forward is how to maintain the leading-edge level of service to the user community provided during the initial NNI 10-year period, as the present instrumentation approaches obsolescence. As NNI moves forward, funding for development of new instrumentation to fully realize three-dimensional atom-by-atom materials design, or other opportunities identified in the Future of Electron Scattering and Diffraction Workshop report,¹³ has not yet been identified. Nor is there a plan for recapitalizing the commercially acquired instruments, which become outdated over time.

NSRC operating budgets have remained roughly constant since 2010, with infrastructure funding for fabrication, characterization, and computational tools and upgrades limited to the discretionary funding within the individual center budgets. The relative size of the operating budgets compared to the cost of the core instruments (individual major tools are more than $2 million, or 10 percent of each center budget, and new nanoscience instrument development projects are approximately $5 million; 25 percent of a center operating budget) makes major upgrades prohibitively expensive without additional sources of funds.

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¹¹ P. Preuss, 2008, “Debut of TEAM 0.5, the World’s Best Microscope,” Berkeley Lab Research News, January 22, http://www2.lbl.gov/Science-Articles/Archive/MSD-NCEM-TEAM05.html.

¹² O.L. Krivanek, M.F. Chisholm, V. Nicolosi, T.J. Pennycook, G.J. Corbin, N. Dellby, M.F. Murfitt, et al., 2010, Atom-by-atom structural and chemical analysis by annular dark-field electron microscopy, Nature 464:571.

¹³ U.S. Department of Energy, 2014, Future of Electron Scattering and Diffraction, Report of the Basic Energy Sciences Workshop on the Future of Electron Scattering and Diffraction, February 25-26, 2014, http://science.energy.gov/~/media/bes/pdf/reports/files/Future_of_Electron_Scattering.pdf.

The challenges imposed by budget constraints are illustrated in the 2015-2019 Strategic Plan for the Center for Functional Nanomaterials, Resource Section:

Similar challenges are faced at each of the centers.

Tightening budgets are not limited to DOE; with the end of the NNIN and launch of the NNCI, NSF has moved to an integration and coordination approach to maximize the value of infrastructure dollars. In the NSF NNCI planning process, the community highlighted the conflict between the desire for state-of-the-art facilities and the realities of budget constraints. With a total budget of $81 million in 2016 dollars over 5 years for 16 selected sites, the annual award budgets range from $0.5 million to $1.6 million for the individual sites.¹⁵ In comparison the NNIN budget for its 14 sites in the period 2004-2014 was ~$180 million.¹⁶ The purchase of an individual tool for lithography at sub-20 nm resolution (>$1 million) or a single aberration-corrected electron microscope (>$2 million) for a given site is outside the budget scope. Thus, the planning report made strong recommendations that selection preference be given to sites with significant existing infrastructure and established user communities, geographically located for greatest local community impact, and specifically recommended against investment in aberration-corrected electron microscopes. This recommendation was based on the consensus that the level of funding available prevented NNCI from building new nanofabrication centers from the ground up. However, the NNCI funding can provide critical support to enable public access to diverse nanofabrication and characterization facilities that have been established through other funding mechanisms. Similar to the DOE centers, the NSF NNCI budgets do not have adequate monies for equipment recapitalization. NSF does have a Major Research Instrumentation program that is

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¹⁴ Brookhaven National Laboratory, “Five-Year Strategic Plan,” https://www.bnl.gov/cfn/strategicplan/resources.php, accessed August 22, 2016.

¹⁵ National Science Foundation, 2015, “$81 Million to Support New National Nanotechnology Coordinated Infrastructure,” Press Release 15-112, September 16, https://www.nsf.gov/news/archivereleases.jsp.

¹⁶ Information from Dr. Lawrence Goldberg, National Science Foundation.

designed to procure instruments in the range of $0.1 million to $4 million. However, a search of the awards made by this program since 2005 show that 75 out of 580 have had a nanoscience or engineering focus, with only one granted to a NNIN center.

Additional measures recommended in the NNCI planning workshop report¹⁷ in order to achieve maximum impact per grant dollar include the use of computation and simulations to model and predict processes, and close integration with the national laboratories for access to the unique, or more expensive characterization tools. These recommendations are in agreement with Recommendation 4.1 of this report. However, while the coordination with DOE user facilities can no doubt help cut down on expensive duplication or eliminate underutilized facilities—and given the lack of clear funding for recapitalization of the equipment, such as electron lithography and microscopy tools at the DOE facilities—there is a serious risk that no agency has the sufficient resources to maintain the level of advanced instrumentation provided during the past 10 years of the NNI.

Finding 4.2: There is a clear lack of identified funds for the development of new leading-edge instrumentation or recapitalization of commercial tools at NNI-sponsored user facilities, with the exception of CNST. As a result, there is a real risk of obsolescence of the physical and computation infrastructure available to the nanoscience and technology research enterprise, and a corresponding decrease in the user value.

Recommendation 4.2: The National Science Foundation and the Department of Energy, in concert with other NNI agencies with instrumentation programs, should identify funding mechanisms for acquiring and maintaining state-of-the-art equipment and computational resources to sustain leading-edge capabilities at their nanoscale science and engineering user facilities.

NANOMEDICINE AND NANOBIOTECHNOLOGY

There is growing recognition that investment is needed in areas of nanoscale science and technology beyond those of traditional micro- or nanoelectronics fabrication. For example, the range of science topics and technological capabilities of the new NSF-sponsored NNCI sites has expanded to include centers of expertise in two-dimensional materials, additive 3D manufacturing, hybrid hard-soft materials, nanoparticle-based photonics, environmental and geological nanoscience, and biological and medical nanotechnology. In particular, the NNCIs will provide

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¹⁷ See Report to the National Science Foundation on the Workshop for a Future Nanotechnology Infrastructure Support Program, held August 18-19, 2014, in Arlington, Va., available at https://www.src.org/newsroom/src-in-the-news/2014/656/.

much greater capabilities than the prior NNIN for soft, biological, and medical nanotechnologies.

As nanomaterials and nanotechnologies are increasingly developed for medical and other applications that involve contact with the body or the environment, there also will be an increasing need to establish manufacturing standards for nanomaterials and guidelines for assessing and managing environmental, health, and safety (EHS) impact in manufacturing and end use environments, as well as following disposal at the end of the product life cycle.

EHS research, tools, and standards are being addressed by various NNI agency efforts. The NCL plays an important role in facilitating the development of safe nanomaterials specifically for cancer diagnosis and treatment. NIST has developed protocols for nano-EHS research and testing.¹⁸ In 2015, the National Institute for Occupational Safety and Health (NIOSH) and the State University of New York Polytechnic Institute’s Colleges of Nanoscale Science and Engineering announced a joint Nano Health and Safety Consortium to advance research and guidance for occupational safety and health in nanotechnology-related industries. The National Institute of Environmental Health Sciences (NIEHS) established the Centers for Nanotechnology Health Implications Research (NCNHIR) Consortium. The NCNHIR Consortium seeks to coordinate research efforts among NIEHS grantees with the overarching goals of gaining fundamental understanding on how the physical and chemical properties of nanomaterials influence their interactions with biological systems and to develop computational models to better predict potential health risks associated with nanomaterial exposure.

Other health and environmental aspects of nanomaterials are subject to study at various sites, including two centers for the environmental implications of nanotechnology jointly funded by NSF and the Environmental Protection Agency (EPA)—at Duke University and the University of California, Los Angeles. Other environmental implication studies are funded, however in an uncoordinated fashion.

Infrastructure gaps pose important barriers to success in the development of nanomedicines. Some lessons and ideas for nanomedicine infrastructure support can be drawn from the development of ultrahigh-purity chemistries by the electronics industry.¹⁹ In addition, the organization MOSIS (which originally stood for Metal Oxide Semiconductor Implementation Service) is an example of a service supported by industry and academic researchers that has reduced development and prototyping costs by allowing multiple integrated circuit designs to be fabri-

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¹⁸ National Institute of Standards and Technology, “Protocols for Nano-EHS,” last updated June 30, 2015, http://www.nist.gov/mml/nanoehs-protocols.cfm.

¹⁹ See Honeywell, “Electronic Chemicals,” https://www.electronicmaterials.com/semiconductor/electronic-chemicals/, accessed August 22, 2016.

cated on a single silicon wafer.²⁰ Researchers are able to fabricate and test research designs that otherwise would be too costly to manufacture using commercial-scale services. This process offers flexibility and efficiency through the multiplexing of large numbers of high-fidelity small-scale processes in a pooled batch or lot. Such sharing of infrastructure and collaboration should be supported for a broad spectrum of soft nano-bio materials.

NCI’s NCL, with support from NIST and the FDA, has been successful in developing tiered analyses and providing data that help in the assessment, by both developers and the FDA, of the safety of nanoparticles for cancer therapeutics and diagnostics. This demonstrated approach could be expanded to address nanomaterials for other medical applications. NCL also could be expanded or replicated to develop standard analyses and provide information at an early stage of development of nanomaterials in general, for assessment of potential risks to humans and the environment. Along these lines, the FDA National Center for Toxicological Research (NCTR) in Jefferson, Arkansas, is the site of a new nanotechnology core facility. The facility serves the needs of NCTR by supporting nanotechnology toxicity studies, developing analytical tools to quantify nanomaterials in complex matrices, and developing procedures for characterizing nanomaterials in FDA-regulated products. Unlike the NCL, these facilities are not accessible to commercial developers. In addition, the 2017 NNI budget includes Consumer Product Safety Commission funding for a new nanotechnology center at NIEHS to conduct research in exposure and risk assessment of engineered nanomaterials in consumer products. Access by commercial developers to this center has not been established.

Finding 4.3: NCL serves as a trusted source of information on the safety of nanomaterials being developed for cancer and has facilitated FDA assessment. However, there is a lack of centralized facilities for addressing other areas of nanomedicine and nanobiotechnology.

Recommendation 4.3a: The National Institutes of Health (NIH) should assess what emerging medical applications, in addition to cancer diagnostics and treatment, rely on engineered nanomaterials. NIH should expand the Nanotechnology Characterization Laboratory to address nanomaterials being developed for those other medical applications.

Recommendation 4.3b: The National Institute for Occupational Safety and Health, the National Institute of Standards and Technology, and the Envi-

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²⁰ The MOSIS Service, “About Us”, https://www.mosis.com/what-is-mosis, accessed August 22, 2016.

ronmental Protection Agency should join with the Consumer Product Safety Commission and the National Institute of Environmental Health Sciences to support development of centralized nanobiotechnological characterization facilities, at the Nanotechnology Characterization Laboratory or elsewhere, to serve as a trusted source of information on potential environmental, health, and safety implications of nanomaterials.

In addition to the need for physical infrastructures to support development of nanomedicines and related medical devices, there is also a need for better understanding of and tools for integration of nanotechnology into existing technological platforms. In general, most successful nanotechnologies are adopted in the commercial sector by integration into existing products (e.g., in composites and as coatings, rather than in isolated nanoparticle form). Thus, a physical infrastructure to serve these integration needs will need to be developed at current and future user facilities.