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We welcome you to the College of Nanoscale Science and Engineering (CNSE) of the University at Albany - State University of New

York. Nanotechnology is rapidly changing the face of our world, broadening our view via unprecedented access to information, unique opportunities to influence our environment, and an evergrowing ability to engineer materials for novel and previously unimaginable applications. At CNSE, we combine world-class academic pursuits in the areas of nanoscience, nanoengineering and nanobioscience with a focus on rapid transfer of novel concepts and ideas into industrial use. To this end, we have established a unique industry-university-government partnership model that provides access to state-of-the-art 300mm wafer processing capabilities required for rapid insertion of such concepts into the mainstream manufacturing menu. CNSE provides an environment that bridges the gap between university research opportunities and manufacturing implementation. Nanoscience refers to the observation, identification, description, discovery, experimental investigation, and theoretical interpretation of nanoscale phenomena. Nanoengineering is the application of nanoscience principles to practical ends, such as the design, manufacture, and operation of efficient and functional structures, machines, processes, and systems on the atomic scale. Nanoeconomics is the formulation, study, and analysis of the economic and business principles underlying the development and deployment of nanoscale know how, products, and systems. Nanobioscience refers to the application of nanoscale scientific concepts and principles to the study of biological and biomedical structures and systems. In addition, nanobioscience encompasses CNSE's NanoHealth initiative, which is aimed at developing novel nanotechnology applications in nanomedicine, including nanotoxicology and environmental and public health. Michael Liehr CNSE Vice President for Research

TABLE OF CONTENTS
The Nanoscience Constellation
Ion Beam Laboratory ............................................................................................ 6 Hassaram Bakhru, Ph.D., Professor and Head, Nanoscience Constellation Mengbing Huang, Ph.D., Associate Professor of Nanoscience EUV Research Projects ...................................................................................... 10 Robert Brainard, Ph.D., Professor of Nanoscience Metrology ............................................................................................................ 15 Alain Diebold, Ph.D., Empire Innovation Professor of Nanoscale Science, Executive Director Center for Nanoscale Metrology Defects and Microstructural Engineering ............................................................ 19 Kathleen Dunn, Ph.D., Associate Professor of Nanoscience Materials Fabrication and Integration .................................................................. 25 Eric Eisenbraun, Ph.D., Associate Professor of Nanoscience Nanoelectronics for CMOS and Post-CMOS ...................................................... 27 Robert Geer, Ph.D., Professor of Nanoscale Science, Vice President for Academic Affairs and Chief Academic Officer E-Beam Lithography Research ........................................................................... 34 Timothy Groves, Ph.D., Empire Innovation Professor of Nanoscale Science and Associate Head, Nanoscience Constellation Spin-Transfer Graphene Research ..................................................................... 40 Vincent LaBella, Ph.D., Associate Professor of Nanoscience Microanalysis and Image Analysis ...................................................................... 43 Eric Lifshin, Ph.D., Professor of Nanoscience Reliability Science and Engineering .................................................................... 46 James Lloyd, Ph.D., Senior Research Scientist X-ray Scattering .................................................................................................. 50 Richard Matyi, Ph.D., Professor of Nanoscience Compound Semiconductor Research ................................................................. 52 Serge Oktyabrsky, Ph.D., Professor of Nanoscience

Surface Science .................................................................................................. 56 Carl Ventrice, Ph.D., Associate Professor of Nanoscience

The Nanoengineering Constellation


Plasmonic Based Chemical Sensors .................................................................. 59 Michael Carpenter, Ph.D., Associate Professor of Nanoengineering E-beam Lithography and Mask Writing ............................................................... 61 John Hartley, Ph.D., Professor and Head, Nanoengineering Constellation Device Physics.................................................................................................... 64 Ji Ung Lee, Ph.D., Empire Innovation Professor of Nanoscale Engineering Static and Dynamic Photoresist Shrinkage Effects in EUV Photoresists ............ 66 Warren Montgomery, Assistant Vice President, Advanced Technology Business Development EUV Technology Team ....................................................................................... 68 Warren Montgomery, Assistant Vice President, Advanced Technology Business Development Nanoelectronics .................................................................................................. 69 Bin Yu, Ph.D., Professor of Nanoengineering

The Nanoeconomics Constellation


Economics of High Technology Industries .......................................................... 73 Unnikrishnan Pillai, Ph.D., Assistant Professor of Nanoeconomics Nanotechnology Economic Impact Report .......................................................... 77 Laura Schultz, Ph.D., Assistant Professor of Nanoeconomics

The Nanobioscience Constellation


Sensors, Components, and Models of Stress and Damage Signaling ................ 80 Thomas Begley, Ph.D., Assistant Professor of Nanobioscience

Substrate-selective Patterning; Virus-based Nanoparticles for Cancer Therapy ................................................................................................. 84 Magnus Bergkvist, Ph.D., Assistant Professor of Nanobioscience Occupational and Environmental Health and Safety of Nanomaterials ............... 87 Sara Brenner, M.D., M.P.H., Assistant Professor of Nanobioscience and Assistant Vice President for NanoHealth Initiatives Nano-enabled Biotechnology .............................................................................. 93 Nathaniel Cady, Ph.D., Assistant Professor of Nanobioscience Development of CMOS-compatible Resistive Memory Devices ......................... 99 Nathaniel Cady, Ph.D., Assistant Professor of Nanobioscience Wafer Processing and Nanobioscience Research ............................................ 101 James Castracane, Ph.D., Professor and Head, Nanobioscience Constellation Cancer Cell Metastasis and Nanoscale Topography ........................................ 105 Nadine Hempel, Ph.D., Assistant Professor of Nanobioscience Development of Nano-based Therapeutics to Limit Cancer, Aging, and Infectious Disease Processes .......................................................................... 110 J. Andres Melendez, Ph.D., Professor of Nanobioscience and Associate Head, Nanobioscience Constellation Stem Cell Biology and Bio-NEMS/MEMS ......................................................... 114 Janet Paluh, Ph.D., Associate Professor of Nanobioscience Mammalian and Microbial Cell Bioprocessing .................................................. 117 Susan Sharfstein, Ph.D., Associate Professor of Nanobioscience Gene Expression .............................................................................................. 121 Scott Tenenbaum, Ph.D., Associate Professor of Nanobioscience Nanobioengineering Stem Cell Technology ...................................................... 125 Yubing Xie, Ph.D., Assistant Professor of Nanobioscience

Nanoscience Constellation

Nanoscience refers to the observation, identification, description, discovery, experimental investigation, and theoretical interpretation of nanoscale phenomena.

The Nanoscience Constellation

Ion Beam Laboratory (H. Bakhru and M. Huang)


Scope: Ion beam characterization (RBS, NRA, PIXE, High-Res RBS, microbeam) and fabrication (ion implantation) Goal: Fabrication and characterization of nanoscale and microscale devices and structures for electronic and photonic applications 2011 Accomplishments TOPIC 1: Fabrication of Embedded Ag Nanoparticles in Silicon for Photovoltaic Applications Fabrication of Ag nanoparticles using ion implantation, thermal deposition, and annealing has been achieved with the Extrion 400kV implanter and Dynamitron 2MeV implanter. RBS data indicates large amounts of Ag gettered to cavity regions that can be placed at a desired depth by tailoring the implantation energy.

Figure 1.

The Nanoscience Constellation


N. Kadakia, M. Huang, and H. Bakhru. Embedded Silver Nanoparticle Fabrication for Surface Plasmon-enhanced Silicon Photovoltaics. SPIE Conf. Proc., 8111 (2011), DOI:10.1117/12.891638. N. Kadakia, M. Huang and H. Bakhru. Fabrication of Subsurface Metallic Nanoparticles for Enhanced Carrier Generation in Silicon-based Photovoltaics. MRS Conf. Proc., 1322, mrss111322-b06-07 (2011), DOI:10.1557/opl.2011.1104.

TOPIC 2: LASER Annealing of Semiconductors-Dopant Diffusion and Activation of Boron in Silicon. Depth profiling of Boron in Silicon was achieved using Boron Nuclear reaction analysis combined with thin film sectioning. A depth resolution of less than 5 was achieved using these techniques. Laser annealed samples with junction depth less than 10 nm was characterized using this method. Defect characterization of LASER annealed samples showed increased amount of defects near the surface. The concentration profile can be calculated from:
C[ Z n ] = Bn 1 Bn Tn

where C[Zn] is the concentration of boron at depth Zn, Bn-1 is the Boron concentration before ozone oxidation, Bn is the Boron concentration after HF etching, and Tn is the thickness of the silicon layer removed using thin film sectioning. This experiment can be repeated continuously until we profile the concentration of boron to the desired depth as shown in Figure 2.

Figure 2. Lakshmanan Vanamurthy, Mengbing Huang, Hassaram Bakhru, High Resolution Depth Profiling of Boron Ultra Shallow Junctions. To be submitted to the Journal of Vacuum Science and Technology A.

The Nanoscience Constellation TOPIC 3: Fabrication of Freestanding LiNbO3 Thin Films Via He Implantation and Femtosecond Laser Ablation A combination of ion-implantation exfoliation and femtosecond laser Ablation was used to fabricate thin micrometers-thick single-crystal lms of a complex oxide, LiNbO3. The process physics for the method is bounded by the threshold for ablation and the onset of laser thermal out-diffusion of the implanted He used in exfoliation selective etching In this work we have demonstrated ablative lateral patterning of implanted LNO, followed by HF-mediated exfoliation, and shown that precisely formed shapes can be obtained at useful patterning rates. In particular, we have demonstrated that trenches up to the implantation depth could be ablated in implanted samples and that patterned lms could then be exfoliated from their parent crystal. Our results show that this ablative writing method has a clear laser power process window: Low power reduces process rate, while a relatively high power level drives off implanted He, thus preventing subsequent HF selective etching for exfoliation.

Figure 3.

Figure 4.

Avishai Ofan, Ophir Gaathon, Lihua Zhang, Kenneth Evans-Lutterodt, Sasha Bakhru, Hassaram Bakhru, Yimei Zhu, David Welch, and Richard M. Osgood, Jr. Twinning and dislocation pileups in heavily implanted LiNbO3 Phys. Rev. B 83, 064104 (2011) Ophir Gaathon, Avishai Ofan, Jerry I. Dadap, Lakshmanan Vanamurthy, Sasha , Bakhru, Hassaram Bakhru, and Richard M. Osgood Fabrication of freestanding LiNbO3 thin films via He implantation and femtosecond laser ablation. J. Vac. Sci. Technol. A 28, 462 (2010); M. Lilienblum, A. Ofan, . Hoffmann, O. Gaathon, L. Vanamurthy, S. Bakhru, H. Bakhru, R. M. Osgood, and E. Soergel Low-voltage nanodomain writing in He-implanted lithium niobate crystals, Appl. Phys. Lett. 96, 082902 (2010)

The Nanoscience Constellation TOPIC 4: Fabrication and Analysis of Embedded Nickel Nanoparticles in Silicon for Spintronic Applications Cavities were created by Hydrogen implantation and annealing inside a silicon substrate which were then decorated by implanted Nickel. This has been achieved using the Extrion 400KV implanter and the Dynamitron 2MeV implanter.

Figure 6 Figure 5.

Figure 6.

Moment (emu) vs Magnetic Field (Oe) Figure 7. Figure 8.

The Nanoscience Constellation

EUV Research Projects (Brainard Group)


Scope: EUV Photoresist Fundamental Research Goal: To determine the root-cause of the degradation of LER in EUV resist thin films and to evaluate new nanoparticle ligands for improved EUV lithographic properties 2011 Accomplishments TOPIC 1: LER Limitations of EUV Thin Film Resists: Mechanistic Studies into Root Causes (Funded by Sematech; Published at EUV Symposium (11/11) and SPIE Advanced Lithography (2/12)) As EUV lithography advances toward better and better resolution, the thickness of resist films must decrease to minimize pattern collapse. Unfortunately, as the resists get thinner, their LER performance degrades (Figure 1). Our primary objective in this program is to determine the root-cause of the degradation of LER in EUV resist thin films. In this project, we lithographically evaluated resist LER performance as a function of resist optical density, Tg and substrate. To explore optical density, we designed a series of polymers with fluorine content in the range from 3 to 50 weight percent. Similarly, to explore glass transition (Tg), we designed a series of polymers with Tgs in the range from 80-140oC. For each of these sets of polymers, we evaluated the LER performance as a function of film thickness from 20-90 nm. Lastly, we studied the lithographic properties of an open source and commercial EUV resist as a function of substrate. All LER vs. thickness curves have been evaluated using a single mathematical model.

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The Nanoscience Constellation

(A)

(B)
Film Thickness

120 nm

60 nm

30 nm

Figure 1: Lithographic performance of four resists as a function of film thickness.

TOPIC 2: Advanced Ligands for HfO2 Nanoparticle Resists (Funded by Sematech; Published at EUV Symposium (11/11) and SPIE Advanced Lithography (2/12)) As EUV prints features with increasingly smaller CDs, the thickness of the resist films will need to decrease. Unfortunately, however, traditional organic resists will be unable to provide the necessary etch resistance in these thin films. In response, our collaborators at Cornell University have developed EUV photoresists based on Hafnium Oxide nanoparticles resist capable of resolving 40-nm lines with 6 mJ/cm2 sensitivity. In this project, we conducted three studies aimed at providing new nanoparticle ligands for improved EUV lithographic properties (Figure 2). We conducted thermodynamic studies that determined the relative ligand binding energies of several ligand types. We designed and synthesized strongly-bound ligands capable of participating in free-radical imaging reactions and are capable of providing Nanoparticle films that are aqueous developable.
OH OH F3C O P HO O HO O O O P HO O HO S O O HO CF3 OH

S O O HO

Figure 2: New ligands for Hafnium Oxide Nanoparticle Resist.

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The Nanoscience Constellation TOPIC 3: Confidential EUV Resist Projects. Stable Acid Amplifiers for EUV Lithography (Confidential, Funded by an Industrial Partner). The microelectronics industry is capable of printing images in photoresists with 2022 nm resolution with good sensitivity and low Line Edge Roughness (LER). In 2016, this industry will need to be able to print images with 11 nm resolution. However, the materials properties of the photoresists, and the diffusion length of photoelectrons and secondary electrons generated in these photoresists will need to reach higher control. Most EUV photoresists image using mechanisms based on acid catalysis. This catalytic acid is produced in these resists when Photoacid Generators (PAGs) interact with photons and electrons. This research project is aimed at producing advanced PAGs for use in EUV lithography. One challenge facing the developers of EUV resists is the need to simultaneously improve resolution, line-edge roughness (LER), and sensitivity. However, these characteristics are inversely related, a relationship commonly referred to as the RLS trade-off. EUV resists are composed primarily of organic polymers and photoacid generators (PAGs). During exposure to extreme ultraviolet (EUV, 13.5 nm) light, the PAGs produce strong, fluorinated acids. Acid amplifiers are compounds that detect an acid signal (from PAG) and produce additional acid. This can be helpful in a photoresist by creating more acid in exposed regions thereby creating faster resists. This paper is focused on the development of stable acid amplifiers (AA) and PAGs that produce lithographically useful strong, fluorinated acids. It has been shown that fluorinated sulfonic acids give improved lithographic performance due to more efficient catalysis with decreased diffusion. This, ultimately, allows the photoresist to have improved sensitivity and better resolution. Central to the design of new acid amplifiers for EUV lithography, is the need to control three properties:
Acid Strength: Catalytic acids should be as strong as possible, which is best done by incorporating fluorine atoms into sulfonic acids. Acid Diffusion: Generated acids should diffuse as little as possible, which can be done through covalent linkage to polymer molecules. Stability: Acid amplifiers should be as stable as possible in the absence of catalytic acid, and be thermally unstable in the presence of acid.

Unfortunately, acid amplifiers are significantly less stable as the strength of the acid generated by them increases. Figure 3 shows twelve first-order thermal decomposition

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The Nanoscience Constellation rate constants as a function of acid strength as predicted pKa's and acid-amplifier body type. Figure 4 shows a plot of log decomposition rate vs. pKa of the acid generated by the AA. For the twelve compounds shown in Figure 3, the log-log plot is linear with R2 all greater than 0.98. We have developed a new type of AA that provides 4-5 orders of magnitude greater stability when the acid generated is pentafluorosulfonic acid, and can produce a stable AA that produces one of the strongest acids knowntriflic acid. The design and structures of several additional AAs will be presented along with their lithographic performance.
Predicted pKa ( 0.5) Sulfonic Acid
SO3H

O OSO2R

OH OSO2R

O OSO2R

OH OSO2R

-1.1
CF3
SO3H F3C

16 21
F F F

3.6 5.1 73

1.6 2.4 37

1.2 1.7 33

-1.2 -2.2

SO3H F F

240

Figure 3: First-order dissolution rates of acid amplifiers as a function of body, trigger, and acid precursor.

3 2

O
OH

A
OSO2R

Log(Decomposition Rate)

1 0 -1 -2 -3 -4

B
OSO2R

4-5 Order of Magnitude Improvement in Stability


OH
Body A Body B Body C Body D Body E

OSO2R

New AA body-type that will be disclosed during SPIE presentation and manuscript

D
OSO2R

-4

-3.5

-3

-2.5

-2

-1.5

-1

pKa

Figure 4: A new AA body/trigger combination provides 10,000 to 100,000 times greater stability than the previously published acid amplifiers (A-D).

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The Nanoscience Constellation


Confidential EUV Resist Projects. Photoacid Generators for EUV Lithography (Confidential, Funded by an Industrial Partner). Confidential EUV Resist Projects. EUV Photoresists Capable of 11-nm Resolution (Confidential, Funded by an Industrial Partner).

TOPIC 4: Material Development for Biological Applications Effect of extracellular scaffold elasticity on salivary gland acinar cells (Funded by NIH). Our group is collaborating with Professor Melinda Larsen in the department of Biological Sciences at the University at Albany. The very long-term goal of our collaboration is to build three-dimensional polymer matrices that will enable the growth differentiation of epithelial cells so that functioning, artificial salivary glands can be grown and implanted into patients. It will take many years of research before this dream can become a reality. However, the research proposed here can provide critical first steps toward completing our overarching goal. Synthesis of multifunctional PEG polymers. Our synthetic approach will allow us to control the composition of the polymer and, by extension, the properties of the hydrogel. We will prepare PEG polymers as random terpolymers from ethylene oxide (EO) monomers containing two important functionalities: methacrylate groups (OMMA) for cross-linking and alkynes (POMO) for attachment of IKVAV cell binding sites (Figure 5a). The resulting PEG backbone will be used to generate all hydrogel variants.
O EO

O 5% POMO

O 10% OMMA

(a)

Polymerize
10% Crosslinkable Groups O O O O O O O O OH

O O HO O

PEG Backbone

5% IKVAV Attachment Sites Using Click Chemistry Med-High IKVAV High IKVAV 5 Levels of X-Linkers

(b) (c)

No IKVAV

Low IKVAV

Med. IKVAV

Figure 5: Strategy for synthesis of PEG hydrogels to systematically explore 25 combinations of IKVAV and cross-linker levels.

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The Nanoscience Constellation

Metrology (Diebold Group)


Scope: All areas of metrology including materials characterization and in-line measurements Goal: Provide R&D materials/structures 2011 Accomplishments TOPIC 1: Advanced Semiconductor Materials Characterization of Structure vs Function {Optical (Ellipsometry, Photoreflectance, & Second Harmonic Generation), X-Ray Diffraction and Reflectivity, XPS, and Microscopy} X-Ray Characterization has shown clear differences in the phase and ordering of polycrystalline films fabricated using ALD processing. The texture (ordering) of high-k was found to depend on both thickness and deposition method: Post Deposition Anneal vs. Deposit/Anneal cycles. The crystal phase matters because the static dielectric constant for the amorphous, monoclinic, and tetragonal phases are about 20, 15, and 27, respectively. This information allows Tokyo Electron Technology Center USA (TEL) to develop a new ALD process for future high-k materials. for metrology of nanoscale electronic and other

Figure 1: Grazing Incidence XRD and Texture Analysis using Pole Figure-Data Taken at Brookhaven NL.

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The Nanoscience Constellation


Structural Characteristics of Electrically Scaled ALD HfO2 from Cyclical Deposition and Annealing Scheme, S. Consiglio, R. D. Clark, E. Bersch, J. D. LaRose, I. Wells, K. Tapily, G. J. Leusink, and A. C. Diebold, ECS Transactions 41, (2011) 89-108. http://www.ecsdl.org/getabs/servlet/GetabsServlet?prog=normal&id=ECSTF80000410000020000 89000001&idtype=cvips&gifs=yes&ref=no

TOPIC 2: 3D IC TSM Metrology, Scanning Acoustic, IR, & X-Ray Microscopy (XRM) Void Detection & FEM Fabrication of through-silicon vias (TSVs) is challenging and often hampered by the presence of voids inside the TSVs. Stress-assisted void growth in throughsilicon vias (TSV) was studied by finite element stress modeling and X-ray computed tomography (XCT). Because physical cross sectioning of TSVs is not required for X-ray imaging, the same TSV can be imaged before and after annealing. Imaging of TSV by laboratory based X-Ray microscopy is discussed. Voids that nucleate (form) during copper electroplating are observed in as-deposited samples. Research with SEMATECH and the Fraunhofer Institute (IZFP), Dresden, compared simulated results with experimental data to show that void growth in TSVs is stress-assisted. Vacancies diffuse and coalesce at the void as a result of the hydrostatic stress gradient. This work proved that conformal plating is prone to voiding making bottoms p plating more reliable.

Figure 2: A. X-Ray microscopy image of an array of Cu TSVs. The picture is a single view of tomographic image allowing 3D visualization of voids in TSV structures. B. Contour plot of simulated hydrostatic stress gradients at a void in a TSV after annealing. Applying X-ray Microscopy and Finite Element Modeling to Identify The Mechanism of StressAssisted Void Growth In Through Silicon Via (TSV), L.W. Kong, J. Lloyd, K. B Yeap, E. Zschech, A. Rudack, and A.C. Diebold, J. Appl. Phys. 110, (2011), 053502 1-7.

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The Nanoscience Constellation TOPIC 3: Physics of Optical Processes Optical Metrology requires knowledge of the complex refractive index (or equivalently dielectric function). Recent attempts to measure the thickness of ET-SOI has shown that use the refractive index of bulk silicon results in a 20% error in thickness for 2 nm thick SOI. These ET SOI materials as also referred to as crystalline silicon quantum wells (c-Si QW). Until recently dielectric function of all nanoscale crystalline semiconductor materials was understood in terms of the effects of quantum confinement (QC). For instance, the experimentally measured blue shift (increase in energy) in the direct gap absorption or critical point (CP) of indirect band gap semiconductors (like silicon) with increased dimensional confinement seemed to be explained by the particle in a box analogy. Recently, we provided experimental evidence of the effect of change in phonon dispersion on the dielectric function of ET-SOI. HfO2 covered c-Si QWs show redshifts in the E1 CP energy and thus quantum confinement does not play a dominant role. Our paper presents a temperature dependent study of the dielectric function of c-Si QWs, which shows that electron-phonon interactions also play a key role in the optical properties of semiconductor nanostructures. We further demonstrate that the dielectric function will change with different phonon dispersions using c-Si QWs with three different surface layers: native oxide, thick silicon dioxide, and hafnium oxide. This work explains the unexpected challenges in determining the complex refractive index of FinFET fins when using scatterometry to measure critical dimensions.

Figure 3: A. Second derivative of the imaginary part of the dielectric function of c-Si QW below a HfO2 (~9 nm) surface layer at 300 K. Inset: (a) Energy and (b) lifetime broadening () of the E1 CP extracted using direct space analysis. B. Imaginary part of the dielectric function of ET-SOi (c-Si QWs) (~ 5 nm) with native oxide, 20 nm SiO2, and 10 nm HfO2 with a SiO2 interfacial layer. Note the clear shift in the energy of the E1 CP and the changes in lifetime broadening.

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The Nanoscience Constellation


Electron-phonon interaction effects on the direct gap transitions of nanoscale Si films, V.K. Kamineni and A.C. Diebold, Appl. Phys. Lett. 99, (2011), 151903.

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The Nanoscience Constellation

Defects and Microstructural Engineering (Dunn Group)


Scope: Using charged particle beams to uncover the relationships between crystalline defects and chemical inhomogeneities in advanced materials Goal: Manipulate microstructure defects to improve performance and achieve new functionalities 2011 Accomplishments TOPIC 1: Cryogenically Assisted Deposition of Metallic Nanostructures Using Focused Electron Beam Induced Deposition Electron Beam Induced Deposition (EBID) has been used to develop nanoscale structures for plasmonics, nanoscale templating, field emitters and contacts to nanoscale objects. However, the primary disadvantages of EBID are poor growth rates, low target purity and little ability to tailor deposit structure. Using a custom-built cryogenic stage for EBID, we demonstrated the growth is reaction-rate limited, yielding growth rates 4-5 orders of magnitude higher than conventional EBID. In addition, we showed that in this growth regime, the morphology of the structure can be tailored based on the electron fluence delivered to each pixel. The development of these structures was described by accounting for incomplete conversion of the precursor and diffusion of non-volatile reaction products during thermal cycling.
(a)

(a) Figure 1: Volumetric growth rate as a function of flux for cryo-EBID (red circles) and room-temperature EBID (black squares). Cryo-EBID is reaction-rate limited and has volumetric growth rates up to 4-5 orders of magnitude faster than RT-EBID.

(b)

(b) Figure 2: SEM image of cryo-EBID deposits showing change in morphology as a function of accumulated fluence (discrete changes in fluence indicated by white overlay).

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The Nanoscience Constellation


M. Bresin, B.L. Thiel, K.A. Dunn and M. Toth, Focused Electron Beam-Induced Deposition at Cryogenic Temperatures, J. Mater. Res. 26 (3), 357-364 (2011). M. Bresin, K.A. Dunn, and M. Toth, Investigation of Inter-diffusion between Layers in Cryogenic th Enhanced Electron Beam-Induced-Deposition oral presentation at The 55 International Conference on Electron, Ion and Photon Beam Technology and Nanofabrication (Las Vegas, NV, May 31-June 3, 2011).

TOPIC 2: Microstructure and Ordering in Quantum Dot Materials To enhance p-type doping in ZnSe/ZnTe, we have attempted to modify the quantum dot (QD) bandgap by incorporating sub-monolayer quantities of Mg along with Te, to form ZnMgTe, instead of pure ZnTe QDs. Strong vertical ordering but only weak lateral order of the QDs was found. Small scale oscillations in Secondary Ion Mass Spectrometry (SIMS) Mg signal throughout the multiple QD structure layers suggest strong confinement of Mg to the QD layer, with superlattice modeling of the high resolution x-ray diffraction (HRXRD) spectra suggesting 32% of the Mg confined to the ZnMgTe QDs themselves. Transmission Electron Microscopy (TEM) demonstrated the average period of the superlattice increased with the number of periods deposited and identified regions where vertical ordering of the layers broke down entirely.

Figure 3: SIMS profiles for (a) sample A consisting of 100 periods, and (b) sample B consisting of 200 periods (b) showing periodic variations in Mg signal.

Figure 4: TEM images for (c) sample A consisting of 100 periods of average thickness 3.93 0.04 nm, and (d) sample B consisting of 200 periods, of average thickness 4.82 0.02 nm.

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The Nanoscience Constellation


U. Manna, I. C. Noyan, Q. Zhang, I. F. Salakhutdinov, K. A. Dunn, S. W. Novak, R. Moug, M. C. Tamargo, G. F. Neumark, and I. L. Kuskovsky, Structural properties and spatial ordering of multilayer ZnMgTe/ZnSe quantum dots, accepted for publication in J. Appl. Phys.

TOPIC 3: Impurity Incorporation and Redistribution in Copper for Advanced Interconnects For very narrow, high-aspect-ratio features, it is difficult to achieve a desired bamboo grain structure for optimal line resistivity and reliability. The exact cause of this problem is not known; conventional wisdom suggests grain boundaries in the copper are pinned by additives from the plating bath (or fragments thereof) which become incorporated into the copper during plating. To examine this, we used a custom-built 5syringe injection plating system to seamlessly modulate the composition of the electroplating bath during deposition. These bath modulations translated into distinct composition gradients within the electroplated copper, as determined by SIMS. The microstructure, however, did not show striations corresponding to the regions of low/high impurity concentrations. Subsequent annealing at 250C allowed both grain growth and impurity redistribution, but room temperature annealing led to grain growth with little to no redistribution of the impurities. This result is contrary to the conventional wisdom. In fact, it strongly suggests that impurity motion and structural transformation are actually decoupled.

No additives (low impurities) All additives (high impurities)

Si

1 m

Figure 5: (above) cartoon of 10-layer structure produced with syringe (left) and microstructure immediately after deposition (right). No striations in the microstructure are visible. Figure 6: (below) SIMS spectra and microstructure for the room temperature annealed (left) and 250C annealed samples. The microstructure transforms, whether or not the impurities diffuse, contrary to expectations. Room T recrystallization Concentration (cm-3) 250C Anneal 1 hour

1.E+23 Concentration (cm-3) 1.E+22 1.E+21 1.E+20 1.E+19 1.E+18 1.E+17 1.E+16 0

1.E+23 1.E+22 1.E+21 1.E+20 1.E+19 1.E+18 1.E+17 1.E+16 0

COSCl500 Depth 1000

COSCl500 Depth (nm) 1000

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M. Rizzolo, H. Parvaneh, S. Novak, E. Lifshin and K.A.Dunn, Impurity Incorporation and Microstructural Evolution of Electrochemically Deposited Copper, oral presentation, 2011 Spring Meeting of the Materials Research Society (San Francisco, CA: April 25-29, 2011). M. Rizzolo, Development of an Acid-Compatible, Microfluidic Electrochemical Deposition System, research report submitted in partial fulfillment of the requirements for the degree of Master of Science (CNSE, Albany NY: August 2011).

The Nanoscience Constellation

TOPIC 4: Driving Forces for Copper Recrystallization in Ultrafine Structures The spontaneous structural transformation of electroplated copper, even at room temperature, is driven by the reduction in free energy. The two main contributors to this are the reduction in surface/interface energy, and the reduction in strain energy. Because of the highly anisotropic mechanical properties of copper, the reduction of strain energy favors the development of 200 texture, while the reduction in surface energy favors 111 texture during recrystallization. Thus texture can be used as a forensic test for driving force identification. However, the development of texture is complicated by the native texture of the copper prior to transformation, which is largely influenced by the texture of the underlying seed layer. For example, 111 texture has been shown to transform more slowly than untextured copper, even though the driving force is quite high. In patterned samples the field regions are known to the 111-textured but little is known about the texture of the IPVD seed on the sidewall of narrow trenches. We developed a protocol for protecting the sidewall surface and extracting longitudinal TEM specimens. Diffraction analysis showed no preferred texture along the sidewall, suggesting that pre-emptive nucleation in the trenches prevents the penetration of bamboo grains from the overburden.

e Beam

Figure 7: (above) Perspective drawings showing protocol for longitudinal sectioning of a trench. TEM observation is a projection of the structure viewed side-on, which is ensured by tilted to the 110-zone axis of the Si substrate.

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The Nanoscience Constellation


Figure 8: (below) Montage TEM image of the longitudinal images, showing distinct grains on the sidewall of the trench. Selected area diffraction patterns were taken from the sidewall only, along the entire length (~8 m) of the specimen (example, inset). No reflections were absent, suggesting no preferred orientation in the seed. Protective Pt Sharpie

Field Sidewall Bottom

TOPIC 5: Additive Screening Methodologies for ElectroChemical Deposition of Copper To reduce time-to-knowledge and costs associated with wafer scale processing, a laboratory scale copper electrochemical deposition system was developed for screening new organic additives which promote bottom-up fill in interconnect trenches and vias. The main objective of the research is to test two previously published models describing copper fill inside the trenches by bridging the gap between fundamental electrochemical measurements and wafer scale plating results. It was therefore necessary to ensure that this coupon-plating system mimics the dynamic conditions found inside the wafer scale plating tool. In particular, the laboratory setup includes a rotating disk electrode, hot entry waveform, forced circulation of the electrolyte, and a diffuser/shield to reduce terminal and edge effects. Qualification of this setup included reliability and repeatability testing, including corroboration with the 300-mm wafer plating tool in the cleanroom. This new setup enables working process conditions and functionality trends to be identified for open source and proprietary suppressors and levelers at leading edge feature sizes (sub-50 nm). Models of additive interactions based on electrochemical measurements are currently being tested for generalizability from open source chemistries as well as proprietary chemicals in development by Atotech.

Figure 9: Cross-sectional SEM images of 50 nm trenches plated in (a) beaker setup. (b) 300 mm plating tool (after CMP). The voids in the beaker-plated sample indicate that further improvements are needed; however, the fill in 60 nm trenches and larger was identical.

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The Nanoscience Constellation

Figure 10: Cross-sectional SEM images of 90100 nm trenches demonstrating overburden mounding as a function of concentration of leveler LK0816. Dotted line added as a guide to the eye. (a) 0.01 mL/L (b) 0.1 mL/L (c) 1 mL/L. Mounding decreases with increasing concentration. K. Ryan, K. Dunn, and J. van Eisden, Development of Electrochemical Copper Deposition Screening Methodologies for Next Generation Additive Selection, poster, 2011 Spring Meeting of the Materials Research Society (San Francisco, CA, April 25-29, 2011). K. Ryan, K. A. Dunn, and J. van Eisden, Development of Electrochemical Copper Deposition Screening Methodologies for Next Generation Additive Selection, Microelectron. Eng. (2011), doi:10.1016/j.mee.2011.04.051

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The Nanoscience Constellation

Materials Fabrication and Integration (Eisenbraun Group)


Scope: Functionality of directly platable diffusion barriers, new etch chemistries for on chip interconnect and 3D TSV applications, nanoscale processes for fuel cell and battery applications, and novel interconnects Goal: Research and development of materials and processes for advanced IC fabrication, renewable energy, MAMS, and related applications 2011 Accomplishments TOPIC 1: Development of Atomic Layer Deposition (ALD)-Based Processes for the Growth of Multicomponent Direct-Plate liners and copper seed layers Benchmark performance and extendibility metrics have been developed for ALDbased RuTaN and RuCo direct plate barriers. Both material systems possess direct copper platability and diffusion barrier functionality to thicknesses of 2-3nm, thus making both candidates for use in sub-28 nm interconnect technologies. In addition, as these systems represent examples of multiphase (RuTaN) and single phase (RuCo) compounds, this research offers insight into the fundamental mechanisms of how directly platable diffusion barriers function. Likewise, ALD copper seed layers have been developed employing a novel and enabling room-temperature process. Processing below 100 C is crucial for copper seed layers so as to avoid the natural tendency of copper thin layers to agglomerate on many liner surfaces. This novel process has resulted in the scaling limit of copper seed layers to be reduced to ~10nm, which not only enhances the extendibility of copper seed layers, but also offers a potential route to complete filling of sub-28nm damascene interconnects without the need for a plated copper layer to be used. Topic 2: Development and Benchmarking of Novel and Enabling Replacement Etch Chemistries for On-Chip Interconnect and 3D TSV Applications Alternative etch gases to replace high global warming potential (GWP) etch gases such as C4F8 have been developed for use in on-chip and 3D TSV applications. These gases, including C6F6, enable an improved etch profile and etch rate while representing a class of environmentally friendly high performance gases. These etch processes, developed on commercial etch hardware, are targeting both leading edge IC and TSV manufacturers as well as MEMS manufacturers.

25

The Nanoscience Constellation TOPIC 3: Development of Nanoscale Processes for the Growth of Metal OxideBased Supports and Low Platinum-Loading Catalysts for Emerging Fuel Cell and Battery Applications Highly conductive metal oxide (TiOx)-based support structures have been fabricated on silicon nanowire (SiNW) and anodic aluminum oxide (AAO) substrates. These conductive oxide layers have been demonstrated to retain their electrical conductivity even after exposure to high temperature oxidizing ambient, which makes these materials strong candidates for emerging fuel cell and battery applications. Likewise, ALD has been used in a combinatorial chemistry approach to develop low-PT loading and no-Pt loading multicomponent catalysts for fuel cells. In particular, NiCo(Pt) layers have been developed and tested electrochemically, and have been shown to provide catalytic performance equivalent to that of pure Pt catalysts. This represents a potential huge benefit for fuel cell marketability and applicability, as the use of large loadings of Pt in conventional fuel cells represents a cost-prohibitive roadblock to the wide use of such systems for high performance renewable energy uses. TOPIC 4: Development of Ultra-Low Electron Scattering Planar Metallics for Future Interconnects Ultra-thin Ag/Cu bilayers have been utilized as candidate structures to demonstrate increased electrical performance of future metal interconnects via the modulated reduction of electron-phonon coupling in nanoscale interconnects. This represents a possible route for the development of planar metallic layers that exhibit ultra-low scattering, thus reducing the resistivity of sub-28nm damascene interconnects, which offers a pathway to increased IC performance. The fabrication of these bilayers has been coupled with cryogenic testing and electron beam lithography (EBL)-based electrically testable structures.

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The Nanoscience Constellation

Nanoelectronics for CMOS and Post-CMOS (Geer Group)


Scope: Thermo-Mechanical Metrology and modeling of stress in Si; highfrequency TSV structures; post-CMOS materials including graphene and NiSi; nanomaterials for energy applications Goals: Stress mapping to eliminate substantial stress between TSVs in linear TSV arrays; studying graphene pn junctions for post-CMOS applications; evaluation of NiSi nanowires to limit power dissipation in devices; developing a new method to grow carbon nanotubes 2011 Accomplishments TOPIC 1: Thermo-Mechanical Metrology and Modeling of Stress in 3D ICs Structures (w/ Sematech) Top-down and cross-sectional Raman microscopy and finite element modeling were used to create 3D maps of stress induced in Si by isolated Cu through-silicon-vias (TSVs) and Cu TSV arrays for 3D integrated circuits. Isolated TSVs can induce substantial stress in Cu (approaching 100 MPa). Top-down Raman and stress maps are shown below.
Si-Si Raman (cm-1) Shift of TSV (post Cu CMP)
2D Stress Map of 5 m Round TSV (post Cu CMP)
<110> direction
-90 -78 -66 -54 -42 -30 -18 -6.0 6.0 18
15 20 25 30 35 35 30 25 20 15

Cu TSV
35

-0.064 -0.038 -0.011

Y Position (m)

30

0.042 0.068 0.094 0.121

25

20

15

Si
15 20

0.147 0.174

Y Position (m)

0.015

X Position (m)

25

30

35

0.200

30

X Position (m) Compressive stress (green/blue)

Tensile stress (yellow/red)

Figure 1: (left) 2D Si Raman shift map near an isolated 5 x 25 um TSV (wafer B). The inset denotes relative crystal orientation of the wafer. (right) Corresponding 2D stress map assuming biaxial symmetric stress. Note transition from tensile stress in Si far from the TSV to compressive stress near the TSV.

Stress mapping of TSV arrays reveals significant tensile stress superposition. Our work has shown that optimizing process consumables (and liner technology) can reduce this superposition to eliminate substantial stress between TSVs in linear TSV arrays.

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The Nanoscience Constellation


(a) (b)

POR

Figure 2: (a) Raman profile of 14 TSV (5m diameter) array (Sematech) processed in using Cu plating solution 1. (b) Raman profile of isolated TSV processed using Cu plating solution 2. The tensile stress regions in the Si are absent in the TSV array fabricated using plating solution 2. Benjamin Backes, Colin McDonough, Larry Smith;Wei Wang, Robert E. Geer, Effects of Copper Plasticity on the Induction of Stress in Silicon from Copper Through-Silicon Vias (TSVs) for 3D Integrated Circuits Journal of Electronic Testing: Theory and Applications, DOI 10.1007/s10836011-5242-7 (2011). Colin McDonough, Benjamin Backes, Larry Smith, Wei Wang, and Robert E. Geer, Thermal and Spatial Profiling of TSV-induced Stress in Si for 3D Integrated Circuits Transactions on Device and Materials Reliability (in press).

TOPIC 2: High-Frequency TSV Structures for High-BW Core-Core Interconnects (SRC/DARPA/NSF) Many core processor designs demand increasing levels of core-core BW, especially for 3D network-on-chip (NoC) topologies where the core-core wiring mesh is non-planar. In response to this need we have designed, fabricated, and analyzed radiofrequency (RF) TSV-based via chain structures for 3D ICs. A signal+multi-ground TSV has been combined with a coplanar waveguide for a 3D core-core link test structure (Fig. 3 below).

TSV

TSV

TSV

TSV

28

TSV

TSV

TSV

TSV

The Nanoscience Constellation


1S2G/Diff 1S4G 1S6G

Topside metal (M1)

1S2G RF TSV Bottomside CPW

10:1 TSVs

Bottomside metal (M2)

Handle wafer

Figure 3: (Upper left) Top-down layout for 1S2G+CPW and 1S4G+CPW RF via link test structures. (Bottom left) 3D schematic of 1S2G+CPW RF link structure. (Upper right) Optical micrograph of 1S6G+CPW structure. (Lower left) cross-section of TSVs.

High frequency transmission measurements on the test structures shown above are plotted in Fig. 2. The one-signal/two ground TSV array combined with an in-plane coplanar wave guide yielded a transmission (S21) of -0.8 dB at 50 GHz (shown at left in Fig. 4). This is dramatically higher than the simple plug TSV (1S) version (shown at right in Fig. 4). Measured results agree well with simulations. Current work focuses on high-f crosstalk in such structures.
1S2G+CPW RF TSV Via Chain 1S4G+CPW RF TSV Via Chain 1S Plug-TSV Via Chain

Figure 4: (left) Measured and simulated transmission (S21) of 1S2G+CPW RF via link; (Center) Measured and simulated transmission (S21) of 1S4G+CPW RF via link; (right) Measured and simulated transmission (S21) of 1S plug-TSV via link. Le Yu; Haigang Yang; Jing, T.T.; Min Xu; Geer, R.; Wei Wang; , "Electrical characterization of RF TSV for 3D multi-core and heterogeneous ICs," Computer-Aided Design (ICCAD), pp.686-693, 711 doi: 10.1109/ICCAD.2010.5654244 (2011)

TOPIC 3: Post-CMOS Devices and Interconnects: Electrostatic Doping Mapping in Graphene pn Junctions (SRC/NRI/DARPA) Carriers in single-layer graphene have been predicted to exhibit optical behavior due to their photon-like linear dispersion relation. This opens the possibility of using pn

29

The Nanoscience Constellation junctions in graphene to optically redirect carriers similar to light confined in a waveguide. The width of the pn junction doping profile in graphene is the key parameter in determining this behavior. We have modified a scanning Kelvin-Probe system to measure these profiles in exfoliate and CVD graphene. Figure 5, below, shows direct imaging of reconfigurable electrostatic doping profiles in exfoliate graphene deposited on a split-gate electrode.
P-N Junction Profiles: Pristine Graphene
SiO2 BLG SLG SLG SiO2 BLG

+5V -5V No Bias


p-regions n-regions

+5V

-5V
p-regions n-regions

Figure 5: (upper left) KPFM images of graphene exfoliates on a split gate test structure. (Lower left) 3D KPFM images of graphene Fermi level in different bias configurations. (Upper right) Surface potential curves across switchable graphene pn junction.

The measured graphene pn junction doping profile shown in Fig. 5 was compared to FEA simulations (Fig. 6). The agreement between model and measurement is excellent. These measurements are being expanded to graphene+BN systems to directly predict electron reflection at the pn junction interface.

Surface Potential (mV)

100 75
0

G1=+10V; G2=-10V Measured (Erf profile) Modeled (Step potential)

50 0
0

25
0

1.8

2.0

2.2

Figure 6: (left) Simulation geometry of KPFM profiling on graphene pn junction. (right) Measured and simulated graphene pn junction surface potential profiles. Yunfei Wang, Ji Ung Lee, and Robert E. Geer, Direct Profiling of Electrostatic Doping in a Switchable Graphene PN Junction Nano Letters (submitted).

Position (m)

30

The Nanoscience Constellation TOPIC 4: NiSi Nanowires for On-Chip Local Interconnects (SRC/DARPA) On-chip Cu interconnects suffer from electron scattering as the line width decreases below 50 nm. This is expected to have significant consequences in terms of power dissipation and performance for line widths below 20 nm. Possible alternatives include NiSi. Although exhibiting bulk resistances 5X that of Cu, the relatively small electron scattering length in NiSi (5 nm) makes it a potentially attractive replacement for Cu at line widths < 10 nm. A modified SOI process flow has been used to construct NiSi nanowire interconnects on a 300m test wafer. Figure 7 shows 4-pt resistivity measurements for NiSi lines approximately 50 nm in length. The large resistivity is attributed to LER.

50nm 14nm 50 m NiSi line

Figure 7: (left) Resistivity for 50nm wide NiSi nanowires patterned on an SOI substrate. (right) SEM micrographs of 4pt test structure.

Figure 8 shows similar 4-pt resistivity data for NiSi on-chip nanowires < 25 nm in width. Although some wires exhibit large resistivity (attributed to large LER) several wire structures displayed resistivity at or below that of thicker wires, consistent with scaling for a material with a short electron scattering length. Current work is focusing on substantial reduction of LER to probe intrinsic electron scattering in NiSi nanowires.

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The Nanoscience Constellation


Pre-trim width: 60 nm

23.2 nm

18.5 nm 100 nm

24.4 nm

Large variability in measured resistivity in sub 30-nm lines LER and Stress-induction Effects Significant
Figure 8: (left) Resistivity for 50nm wide NiSi nanowires patterned on an SOI substrate. (right) SEM micrographs of 4pt test structure.

TOPIC 5: Nanomaterials for Energy Applications: Hierarchical Nanostructures Based on SiNWs and CNTs (SRC/DARPA/NREL) Nanoengineered materials offer important new opportunities for device technologies requiring extremely high surface/volume ratios and/or surface chemical activity. Hierarchical nanostructures are an important class of materials for filling this role for energy applications including new battery and fuel cell technologies. Our group has developed a novel method to grow carbon nanotubes directly on silicon nanowires (SiNWs) using a carbon-rich nickel plasma-enhanced ALD process. Equally important, this process creates an intrinsically conductive SiNW template through NiSi formation. Figure 9 below shows various SEM and TEM images which show the hierarchical NT/SiNW structure.
Figure 9: (a) Silicon substrate and (b) SiNWs coated with PEALD Ni. MWNT growth was observed at both surfaces (c, d) after RTA processing. (e) Representative TEM micrograph of the MWCNTs on a trunk silicon nanowire surface. (f) Ni particle captured inside a multi-wall nanotube grown from a SiNW trunk. TEM indexing showed the particle is Ni with 0.206 nm of spacing with (111).

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The Nanoscience Constellation The innovation central to this process is a carbon-rich Ni layer (PEALD) and the direct silicidation of the SiNW. The mechanism for CNT growth at a SiNW surface using this approach is shown in Fig. 10 below.

Figure 10: Schematic illustration of MWNT growth on SiNWs: (a) PEALD of carbon-containing Ni on Si; (b) Thermal annealing which induced nickel silicide formation, increased local carbon concentration and drove carbon diffusion and segregation; (c) MWNT growth resulting from carbon segregation at surface. J H Lee, I N Lund, E T Eisenbraun and R E Geer, Silicide-induced Multi-wall Carbon Nanotube Growth on Silicon Nanowires Nanotechnology 22, 085603 (2011).

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The Nanoscience Constellation

E-Beam Lithography Research (Timothy R. Groves)


Scope: E-beam lithography as well as applications for nanoscale biology Goals: (1) Directing (with Prof. John Hartley) the use of the VB300 e-beam lithography tool at CNSE to fabricate novel structures for research; (2) Extending and improving the state-of-the-art of e-beam lithography through innovation; (3) Investigating the use of e-beam lithography for nanoscale biology; (4) Directing the ARDEC Nanosensor Stagegate Accelerator program as Principal Investigator; (5) Serve International SEMATECH in an advisory role for lithography, and as CNSE representative on the Executive Steering Council, and as a CNSE representative on the PVMC ETAB; (6) Develop a book: Introduction to the Optics of Charged Particle Beams, by T.R. Groves 2011 Accomplishments TOPIC 1: Develop a Nanoscale Photoelectron Source for a Massively Parallel EBeam Array A light-concentrating wave guide was designed, simulated, and fabricated using the VB300 tool. This is shown in Figure 1 below. It makes use of surface electromagnetic waves on a structure of concentric rings to amplify the intensity of a 257 nm laser up to 185 times at the center of the structure. The amplified laser light illuminates a 10 nm diameter photoelectron emitter. A test system was constructed, and the first photoelectron emission current measured from bulk film. A custom photoemission electron microscope (PEEM) was designed and constructed to measure the electron optical properties of the source. It is presently being integrated into the test system.

180 nm

Figure 1: (left) Cross-section schematic of the light amplification wave guide structure, (a) quartz, (b) metal, (c) vacuum. The small white square represents the nanoparticle photoelectron source. The 257 nm laser light is incident from the left, and the photoemitted electron beam propagates to the right. (right) Simulated light intensity. (Courtesy of Heon Joon Choi, Ph.D. student, CNSE)

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The Nanoscience Constellation TOPIC 2: Study the Motility of Cancer Cells on Topographically Patterned Surfaces Human breast cancer cells were grown in vitro on a patterned silicon dioxide structure fabricated using the Vistec VB300 e-beam lithography tool at CNSE. This is shown in Figure 2 below. We observe that the cells extend invasapodia which align with the pattern features. Interestingly, normal cells of the same type of tissue do not exhibit this behavior. It is known that cancer cells metastasize throughout the body by first penetrating small gaps in the tumor tissue and blood vessel walls. It is also known that cancer cells differ morphologically from normal cells of the same tissue. This work shows early indication of the mechanisms underlying cancer cell metastasis. We have established an ongoing and active cancer metastasis working group at CNSE, including faculty members Nadine Hempel, Andre Melendez, Scott Tenenbaum, and Timothy Groves. The group also includes Dr. Thomas Goodman, a cofounder and partner of the Upstate Hematology and Oncology Clinic, located in Niskayuna, NY.

Figure 2: Human breast cancer cells grown in vitro on a patterned silicon dioxide surface. The cells spontaneously align with the pattern features. This provides early indication of the mechanisms underlying cancer cell metastasis. (Courtesy of William Stephenson, Ph.D. student, CNSE).

TOPIC 3: Develop a Book: Introduction to the Optics of Charged Particle Beams, by T.R. Groves This book has been in the making since 1998. The manuscript was submitted in 2011 for publication by Cambridge University Press, and is presently in the review process. A description follows.

35

The Nanoscience Constellation Charged particle beam instruments are widespread and indispensible in presentday research, development, and practical technology. The highly diverse applications include high resolution electron and ion microscopy, physical and chemical analysis of materials, fabrication of nanometer-scale structures, metrology and inspection for quality control in volume manufacturing, medical diagnosis and therapy, and probing the fundamental properties of matter at the sub-nuclear level, to name just a few. Recent achievements include extension of the resolution of transmission electron microscopes to 0.06 nm by correction of aberrations, introduction of ion sources with unprecedented high brightness, improvement of energy resolution to below 1 meV in analytical instruments, and increase of design beam energy to 7 TeV in the Large Hadron Collider at CERN. Production of charged particle instruments comprises an annual multibillion dollar industry, with investment in research and development in the hundreds of millions of dollars. As an example, scanning electron and ion beam microscopes were invented during (some of) our lifetimes. These instruments were subsequently commercialized and made available to the larger community on an impressive scale. They have proven to be indispensible for a wide range of applications in nanoscale fabrication, analysis, metrology, and end-user applications. An example of images routinely obtained is shown in Figure 3 below. This pair of images provides a striking demonstration of the differing contrast mechanisms for electron beams and ion beams.

Figure 3: Images obtained from a helium ion microscope (left), and scanning electron microscope (right). The focused ion beam more clearly resolves surface detail, because of the shorter range of fast ions in matter. (Courtesy of Carl Zeiss SMT, Inc.)

Enormous productivity has been enabled by extensive education. This consists primarily of training in the details of instrument construction and operation. In contrast to the extensive literature on light optics, only a few books are currently available which treat the physical and optical principles underlying charged particle instruments at the

36

The Nanoscience Constellation fundamental level. In particular, an urgent need exists for a graduate-level textbook, which presents a coherent theory of both geometrical and wave optics, together with the intimate connection between these two. This unique book proposes to satisfy that need. We begin with an introduction for the intelligent layperson. It is a survey of theory and experiment, presented in the simplest and most practical possible way. It contains a number of visual examples, and is intended to convey the enormous scope and impact of charged particle beam instruments, and their indispensible role in science and technology on the atomic scale. The intention is to motivate students of all fields of science, engineering, and technology to tackle the details of this subject. The main text then identifies the important optical concepts and derives each in mathematical terms from first principles of physics:
Only the important ideas are presented. This is not intended as a comprehensive reference, a general and rigorous mathematical treatment, nor as a review of current research. This makes the material suitable for a one-year introductory course at the graduate and advanced undergraduate levels. The material is presented as a logical progression, with each idea following from the previous one. This greatly facilitates understanding of the mathematical concepts. A reader who makes the effort to follow the logical progression will gain an exceptionally strong foundation. The theory is directly applicable to experiment and to real-world problems. The reader will be able to link theory with practical application in the laboratory. The mathematical progression is illustrated with many figures, examples, and problems to facilitate an intuitive feel for the subject.

The target audience consists of several distinct groups, including:


Students at the graduate and advanced undergraduate levels, who seek a basic understanding of the physical concepts of charged particle beams. Experimentalists, who are interested in explanations of fundamental concepts underlying their measurements. Scientists and engineers who develop useful instruments, and who seek a reference for basic principles.

This book comprises the main text of the course titled, Introduction to the Optics of Charged Particle Beams, which is an elective course, and part of the graduate curriculum at the College of Nanoscale Science and Engineering at the University at Albany, State University of New York. Details of the Approach Chapter One of the main subject begins with a review of relativistic classical mechanics, starting with Hamiltons principle of least action. This leads immediately to the equation of motion of a massive charged particle in an arbitrary magnetic and electric potential. We then consider the trajectory of a single particle, and the family of trajectories, infinitesimally separated from one another in phase space. This introduces the true optical nature of a beam, including brightness conservation and image formation. The ray equation is developed for a general curvilinear axis for the important

37

The Nanoscience Constellation special case where the potentials have no explicit time dependence. The case with axial symmetry is studied in considerable detail, including the primary aberrations and Coulomb scattering in beams. In Chapter 2 we review quantum mechanics, starting with the basic postulates leading to the wave equation. Energy eigenvalues and eigenfunctions are derived for unbound states. The solution for the wave function is then developed for a general electromagnetic potential using the path integral approach of Dirac and Feynman. A relativistically covariant solution is found which leads naturally to an accurate waveoptical description of charged particle motion, including aberrations. Scalar diffraction theory is then developed, starting from the wave equation and Huygenss principle. The intimate connection between diffraction and the Heisenberg uncertainty principle is shown. In both the classical and quantum mechanical descriptions, the action integral is stationary with respect to first order perturbations about the physical ray traced out by a single charged particle in a general four-vector electromagnetic potential. In the case where the potential depends explicitly on time, this is the time integral of the classical Lagrangian, evaluated between constant start and end times. In the case where the potential has no explicit time dependence, this reduces to the path integral of the canonical momentum component along the trajectory between constant start and end positions. In the quantum mechanical description, this action integral divided by forms the phase of the wave function in the quantum mechanical description. This phase is stationary with respect to first order perturbation about the physical trajectory. The canonical momentum vector is everywhere perpendicular to the surfaces of constant phase. The correspondence between the classical and quantum descriptions becomes strikingly transparent in this formulation. All relevant information about the single particle ray, including the geometrical aberrations, is thus contained in the action integral. This forms a central unifying and simplifying theme of this book. In Chapter Three, we separately derive two-particle scattering classically and quantum mechanically. Scattering is the mechanism underlying the interaction of particle beams with matter. This, in turn, forms the basis of most useful charged particle beam instruments. Derivation of the scattering cross section from first principles represents a beautiful example of elementary quantum mechanics in its own right, quite apart from its widespread applicability to charged particle instruments. Chapter Four derives the properties of electron emission from conductive materials. This is a strikingly simple example of Fermi-Dirac statistics, the Pauli exclusion principle, and Sommerfelds model of the electronic properties of metals. This forms the theoretical basis of many useful electron sources. This chapter again provides an instructive and practical application of quantum mechanics in its own right.

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The Nanoscience Constellation Several essential mathematical topics are discussed in the appendices. These are instrumental to derivations in the main body of the text. These topics are separated from the main body, in order that the intuitive flow of ideas not be interrupted by mathematical detail. Problems are given throughout the text. These are simple extensions of the material, as opposed to clever and arcane applications of the theory. As such, students are expected to solve the problems on their own, without consulting printed solutions. This also encourages self-testing along the way.

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The Nanoscience Constellation

Spin-Transfer Graphene Research (LaBella Group)


Scope: Exploring the fundamental physics of carrier transport across material interfaces and spin relaxation in graphene Goal: Extract elastic scattering lengths for electrons from nm thick metal films. Increase the spin relaxation time in graphene 2011 Accomplishments TOPIC 1: Role of Interface Band Structure upon Hot Electron Transport Interface band structure is the projection of the bulk three-dimensional band structure onto a specific two-dimensional face of the Brillouin zone. This, combined with conservation of parallel momentum, are fundamental aspects of carrier transport in a wide range of solid state electronic devices. Hot electron spectroscopy methods such as ballistic electron emission microscopy (BEEM) offer an ideal technique to study these effects since the injected electrons have a narrow energy and momentum distribution. To date, direct observation of interface band structure effects and parallel momentum conservation has been elusive for nonepitaxial metal semiconductor systems. In our recent work the interface band structure of silicon is shown to affect the Figure 1: Hot electron attenuation lengths for Ag transport of hot electrons across a non as a function of tip bias. Divergence at low bias epitaxial metal-semiconductor interface is due to differences in the interface band (Ag/Si). Samples consisted of nanometer structure between the Si(111) vs. Si(001) shown thick Ag films that were deposited on above. chemically cleaned Si(001) and Si(111) wafers and capped with 10 nm Au to prevent oxidation of the films. Attenuation lengths were extracted by measuring the BEEM current as a function of the metal layer thickness. The hot electron attenuation length of Ag is observed to increase sharply for energies approaching the Schottky barrier height when deposited upon Si(001) substrates, and decreases slightly when deposited upon Si(111) substrates as displayed in the figure. This is a result of differences between the interface band structure of the two silicon orientations and the conservation of parallel momentum of

40

The Nanoscience Constellation the electrons. This effect is observed for both hot-hole and hot-electron injection on ntype silicon substrates. At higher tip biases the attenuation lengths converge, allowing extraction of the inelastic and elastic scattering lengths in the silver. These results demonstrate that hot electron attenuation length measurements have the potential to map out the interface band structure of metal-semiconductor interfaces. This new understanding illuminates the role of the interface upon these measurements giving further confidence in the extraction of elastic and inelastic scattering lengths in the metal films. TOPIC 2: Electron Spin Transport in Graphene Grown on Silicon Carbide (0001) Graphene is an ideal candidate for the transport channel in future spintronic devices due to its long spin lifetimes at room temperature. The long lifetime arises due to the small intrinsic spin orbit coupling and low hyper-fine interaction of the electron spins with the carbon nuclei. Graphene based nonlocal Hanle measurement devices were fabricated on epitaxially grown graphene on SiC, provided by IBM. Spin injection and non-local detection were achieved in these devices using cobalt nano-magnets directly deposited on the graphene (Figure A) and with an HfO2 barrier between the Co and graphene (Figure B). Spin precession was observed and the spin lifetimes for the epitaxial graphene were extracted from the Hanle curves. The spin lifetimes for the direct Co contacts were found to be comparable to those found in an exfoliated multi-layer flake with direct contacts. Improved spin lifetimes were observed in the epitaxial graphene with an HfO2 (~0.7nm) barrier. The lifetime was found to be independent of contact separation. These improved lifetimes are a result of a reduction spin relaxation from the contacts. The reduced spin relaxation times measured in epitaxial graphene fabricated

Figure 2: A and B Spin precession in epitaxial graphene on SiC(0001).

41

The Nanoscience Constellation with direct cobalt contacts and an exfoliated graphene flake with similar contacts are believed to be caused by an increased contact induced relaxation mechanism effectively removing spin from the channel.

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The Nanoscience Constellation

Microanalysis and Image Analysis (Lifshin Group)


Scope: Focused electron and ion beam techniques as well as the characterization of materials at the micron to nanometer scale Goal: The principal focus of my research is to both develop and apply focused electron and ion beam techniques to the characterization of materials at the micron to nanometer scale 2011 Accomplishments TOPIC 1: Understanding the Fate of Additives in Copper Plating Baths and Their Role in the Development of Desired Microstructures in ULSI Interconnects As microelectronic interconnects become progressively smaller, it is critical that the copper plated into Damascene trenches be as large grain as possible, preferably in a bamboo structure to minimize resistivity and also to reduce possible electromigration effects. As some trenches are now 40 nanometers and less in width, few techniques are available to do high spatial resolution chemical analysis to determine where the various plating additives are localized or even if they are localized. This knowledge is important because while these additives are essential to plating into such fine structures they may also be responsible for undesirable fine grain structures that are observed by both scanning and transmission electron microscopy. In the ongoing study sponsored by SRC (Task 1292.055) a variety of advanced analytical techniques including high resolution STEM/EDS, Auger analysis and time of flight secondary ion mass spectrometry have been applied to localizing additives in plated and annealed copper. Our major findings thus far suggest that chlorine (present in all copper plating) appears to be distributed throughout grains, but will cluster at boundaries if excess additives were present in the original plating solutions. The exact reason for this level of uniform distribution at the levels where chlorine can be detected by STEM/EDS of around 1 weight percent is unclear since chlorine should not be soluble in bulk copper at that concentration. Clustering of excess chlorine at boundaries is more consistent the larger the space available at such locations. It is speculated that chlorine is somehow trapped within the film as it is grown, but is more in pockets than in lattice vacancies or interstitial positions due to the relatively large size of chlorine atoms.

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The Nanoscience Constellation

Figure 1: These research findings and much more were presented at the annual CAIST Review for SRC held at CNSE in October 2011. They are now being prepared for journal publication.

TOPIC 2: Resolution Enhancement in Scanning Microscope Images The desire to improve the spatial resolution of images obtained with a variety of scanning microscope techniques is one of the major goals of many techniques including scanning electron microscopy (SEM), microbeam x-ray fluorescence microscopy, Auger microscopy, x-ray photoelectron microscopy and many others. Consequently, manufacturers have spent a great deal of effort on reducing the sizes of the probes used, as well minimizing the interaction volume from which signals are generated. Our approach, which is a collaborative effort with Professor Michael Stessin of the Department of Mathematics, is to recognize that the probe interaction area is a series of localized excitations of measured signals in which the sum is what is measured. We then take a series of conventionally obtained images under carefully defined conditions and separate out the signals that come from various parts within the probed area. To better understand this concept one must recognize that the purpose of decreasing probe size in most advances in this area is to limit the measured signal to just the area thats excited. The smaller the area the higher the resolution is. Our approach can get the same information using a larger probe that under normal conditions would give relatively blurry images, however multiple images are required and must be collected using conditions where we can very accurately position the probe at certain locations and obtain a series of images with different probe characteristics. Details of the method have been presented in a patent filed both in the U.S. and abroad. The method has successfully been applied to an x-ray microscope and to SEM images. Below is an example of before and after using the technique with SEM images.

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The Nanoscience Constellation

Figure 2: Metal spheres taken with large probe. Numbers refer to pixel coordinates.

Figure 3: Metal spheres after image enhancement software applied.

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The Nanoscience Constellation

Reliability Science and Engineering (Lloyd)


Scope: Reliability in nano-scaled electronics Goal: Provide R&D for reliability physics and practices for nanoelectronics 2011 Accomplishments TOPIC 1: TDDB (Time-Dependent Dielectric Breakdown) Modeling for Low-k and Ultra-Low-k Dielectrics A fundamental model for TDDB failure in low and ultra-low-k interlevel dielectrics was developed as an extension of the earlier Impact Damage model. The model is basically a lucky electron model where breakdown is a result of damage caused by impact with an electron passing through the dielectric. The probability that an electron would gain sufficient energy to cause damage given the mean free path, results in the expression for failure time (tf) t f = A(T ) exp E + E where T is temperature, and E is the applied electric field. Objections to the model were raised that the electron could never get enough momentum to kick out an atom and produce a trap that would lead to breakdown. It was shown that if the criterion for failure is not the energy of the collision, but the momentum exchange, there is sufficient momentum to kick out a hydrogen atom and then produce traps that will accumulate leading to a percolating path and dielectric breakdown. The implication is that root-E failure kinetics is only valid for dielectrics with hydrogen incorporated in the structure, such as in the low-k and ultra-low-k dielectrics used in contemporary nanoscale devices. If there is no hydrogen in the structure, the McPherson E model appears to be the most appropriate, as has been shown in SiO2 based dielectrics. A paper was presented at the International Reliability Physics Symposium. TOPIC 2: Constant Voltage Electromigration Testing Electromigration damage is caused by the momentum exchange between conducting electrons and diffusing metal atoms. Therefore electromigration damage is proportional to the current density in the metal conductor. Normally tests are performed by passing a constant direct current through a suitable conductor. In these tests, however, variations in the current density would be caused by variations in the metal cross section leading to a spread in the electromigration lifetime that is not really characteristic of the failure process. As conductor dimensions shrink to the sub 100nm level, variations from structure to structure become significant and the variation in lifetime correspondingly affected.

46

The Nanoscience Constellation Electromigration failures follow a lognormal distribution. The variations in geometry mentioned above can produce increases in the lognormal standard deviation, sigma, of the lifetimes that is not characteristic of the failure mechanism. A way to alleviate this is to perform electromigration tests at constant voltage. If all samples are the same length (variations in length would be negligible if not zero) then a constant voltage would produce a constant electric field (E) for each sample and therefore a constant current density (j) assuming constant resistivity. E=j Under these conditions, it is anticipated that the sigma of the failure distribution should be reduced compared to constant current testing and also be a more realistic value for the failure mechanism. Experiments were performed using samples with known misprocessing. A layer of interlevel dielectric was missing allowing short circuiting to underlying patterns and parallel conductors. The initial resistances of the testing structures varied by factors of 2 to 3 reflecting the parallel paths. In the constant voltage tests current is monitored and failure is defined as an abrupt decrease in the current.

Figure 1: Example of current vs time for CV testing of poor material.

At constant current, these samples expectedly exhibited very broad failure distributions with very high sigmas, whereas the same samples stressed at constant voltage showed comparable (almost identical) median times to failure, but sigmas less than half the value of those stressed at constant current. One interesting feature of stressing these misprocessed structures was the staircase pattern where different parallel paths (presumably at the same current density) had failed in succession. When samples with better geometrical control were tested, the effect was substantially smaller with sigmas being basically the same. Also note that the staircase behavior was absent indicating that the parallel paths were not present.

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The Nanoscience Constellation

Figure 2: Example of current vs time for CV testing of better material.

This behavior reflects the value of using constant voltage stressing for very fine line widths and for immature processes when the lithography is not yet well established. Intrinsic performance can be evaluated with less sensitivity to the geometrical issues characteristic of early development material. A paper was presented at the International Integrated Reliability Workshop. TOPIC 3: Effect of Thermal Stresses on Electromigration The criterion for metal failure due to electromigration is the attainment of a critical stress that produces delaminations that then grow to voids and open circuits. Electromigration in the presence of unavoidable flux divergences (contacts to Si) will produce a stress gradient opposite to the electromigration driving force. When the stress gets high enough to promote a delamination, a void will nucleate and eventually grow to failure. The stress that is required for failure could also be supplied by thermal stresses, i.e. those stresses generated by the differences in the thermal coefficient of expansion between the metal lines and the Si wafer and the dielectric coverings. These thermal stresses are known to cause failures even without passing current known commonly as Stress Voiding. Thus, thermal stresses can reduce the electromigration lifetime substantially. In addition, since the effect is temperature dependent, but not thermally activated, the effective activation energy as normally extracted will be affected producing lower values than expected and also should show significant curvature. Experiments were conducted using the constant voltage technique for electromigration samples over a very large temperature range to look for both early failure and curvature in the Arrhenius plot. Electromigration tests were carried out over the largest temperature range recorded, from 300C to 125C in 25C increments at relatively low, near use, current density (10 mA/square micron). Although early failure was observed (t50 of hundreds of hours at lowest stress) and a low activation energy

48

The Nanoscience Constellation was extracted (0.75 eV for Cu.normally 0.9 to 1 eV at higher temperature) the Arrhenius plot was remarkably straight.

Kinetics 1
9 8 y = 9095.2x - 15.213 R = 0.9778 7 6 5 4 3 2 1 0 0.0015 0.0017 0.0019

mu

0.0021 1/T

0.0023

0.0025

0.0027

Figure 3: Kinetics plot.

It is speculated that this result may indicate that the material used in the experiment (same material as used in the constant voltage test above), was of poor quality and may have already had a large number of pre-existing voids thus precluding any void nucleation which would produce the anticipated curvature in the Arrhenius plot. Experiments are continuing to confirm or deny this speculation. This work was presented at the SRC meeting and additional experiments are under way.

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The Nanoscience Constellation

X-ray Scattering (Matyi Group)


Scope: Basic science and applications of X-ray scattering methods for materials and nano-structure analyses Goal: Develop improved metrology methods for nanoscale electronics, materials and structures 2011 Accomplishments TOPIC 1: Development of Statistical Dynamical Diffraction Theory (SDDT) as a Novel Method for Partially Relaxed and Defective Heterostructures The dynamical theory of X-ray diffraction is extensively used to evaluate the structural characteristics of ideally perfect single crystals. Information such as layer thickness, chemical composition, and both strain and strain relaxation can be extracted from X-ray rocking curves recorded under high resolution diffraction conditions. Statistical dynamical diffraction theory (SDDT) provides the ability to model defectinduced structures in high resolution X-ray diffraction analyses by incorporating both coherent (dynamic) and incoherent (kinematic) scattering. We have developed an implementation of the SDDT that is relatively simple but permits the analyses of complex, highly defective structures such as fully relaxed SiGe on Si that are inaccessible by conventional dynamical diffraction analysis. We have investigated the viability of this approach by fitting experimental high resolution X-ray diffraction data from structurally defective and partially relaxed Si0.70Ge0.30 ion implanted heterostructures (Figure 1). This work has shown the capabilities of the SDDT theory for providing fully quantitative HRXRD analyses of highly defective materials
P.K. Shreeman and R.J. Matyi, Appli-cation of Statistical Dynamical Diffraction Theory to Highly Defective Ion Implanted SiGe Heterostructures Physica Status Solidi A, 208, 2533 (2011).

Figure 1: Comparison of analyses of ionimplanted SiGe/Si with both conventional dynamical diffraction theory (blue) and SDDT (red)

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The Nanoscience Constellation TOPIC 2: Sensitivity Perturbations of X-ray Reflectometry Analyses to Experimental

Specular high resolution X-ray reflectometry (XRR) (below, left) has numerous characteristics that make it a desirable tool for thin film materials characterization. It is non-destructive and provides thickness, density, and interface information in depth from even complex thin film stacks. In our studies of the fundamental limits of XRR metrology, the effects of common experimental perturbations on specular XRR analyses of polymer thin films on silicon substrates have been examined. Specifically, the impact (both individually and combined) of sample curvature, sample displacement, instrument function, and noise have been assessed by incorporating these factors into a calculation of a theoretical XRR profile from a model structure. Among other results, this work has shown that extrinsic parameters such as sample curvature (below, right) can have a major impact on the assumed accuracy of measurements of density as well as significantly increasing their statistical error.
C.S. Settens, C.D. Higgins, R.L. Brainard and R.J. Matyi, Experimental Sensitivity of Measurements of Density-in-Depth with Specular X-ray Reflectometry Journal of Applied Crystallography, submitted.

Figure 2: This XRR scan from a thin PMMA film on Si shows excellent agreement between the experimental data (blue circles) and the calculated pattern (red line).

Figure 3: Mass density measurements (density and density error) determined from specular XRR as a function of radius of curvature of the substrate.

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The Nanoscience Constellation

Compound Semiconductor Research (Oktyabrsky Group)


Scope: Group III-V/high-k oxide MOSFETs for high-speed low power integrated circuits Goal: Develop, demonstrate and research technologies of gate stacks for scalable MOSFETs with low interface trap density and superior channel transport using III/high-k oxide materials systems 2011 Accomplishments TOPIC 1: Provide Benchmarks for Electron Mobility in InGaAs MOSFET Channels and Determine Primary Interface-Related Scattering Mechanisms The Hall effect and resistivity at various temperatures in un-gated and gated InGaAs MOSFET structures with different high-k gate oxides and buried modulationdoped InAlAs/InGaAs/InP quantum well (QW) channels were studied. Data was obtained on mobility behavior as a function of top semiconductor barrier thickness, carrier concentration, nature of oxide, and annealing. Improvement of Hall mobility has been demonstrated with the increase of top barrier thickness. In the structures with 3nm-thick top barrier the Hall mobility of ~5500 cm2/Vs at room temperature was demonstrated with ALD oxides at sheet densities (1-2)x1012 cm-2. Degradation of mobility with reduction of screening at low carrier density and due to increased Coulomb scattering after thermal annealing is demonstrated. Gated Hall measurements allowed for our group to directly obtain mobility vs. carrier density characteristics, and also determine the interface trap density using CVs and Hall concentration data.

Figure 1: Room temperature Hall electron mobility in In0.77Ga0.23As QW channel as a function of top semiconductor barrier layer thickness and different high-k oxides. Electron sheet density is in 12 -2 the range of (1-2)x10 cm . The inset shows the design of the measured structures.

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The Nanoscience Constellation


S. Oktyabrsky, P. Nagaiah, V. Tokranov, M. Yakimov, R. Kambhampati, D. Veksler, G. Bersuker N. Goel, and S. Koveshnikov, Electron Scattering in Buried InGaAs/High- MOS Channels, Int. J. High Speed Electronics and Systems, 20(1), 95-103 (2011). S. Rumyantsev, W. Stillman, M. Shur, S. Koveshnikov, V. Tokranov, R. Kambhampati, and S. Oktyabrsky, Low frequency noise and interface density of traps in InGaAs MOSFETs with GdScO3 High-k dielectric, Int. J. High Speed Electronics and Systems, 20(1), 105-113( 2011). S. Oktyabrsky, D. Veksler, P. Nagaiah, T. Chidambaram, V. Tokranov, M. Yakimov, R. Kambhampati, Y.-T. Chen, G. Bersuker, N. Goel, and C. Hobbs, Electron Scattering in Buried InGaAs/High-k MOS Channels, ECS Transactions, 35(3), 385-395 (2011).

TOPIC 2: Improve/Optimize p-Channel Transport in Strained III-Sb Channels Grown on Metamorphic Buffers on GaAs Substrate Metamorphic Al0.7Ga0.3AsySb1-y buffers on GaAs substrates to reduce defect density in the strained GaSb QW p-channels were developed by employing superlattice (SL) consisting of alternating 10 nm-thick layers with different As-content. The maximum hole mobility of 1070 cm2/Vs was obtained in a sample with As-, Sb- valves toggled, and Al-, Ga- shutters constantly open. The p-channel hole mobility strongly depended on the As average composition in AlGaAsSb SL and the resulting strain in GaSb QW. InGaSb QWs have demonstrated maximum hole mobility of about 1000 cm2/Vs, and minimum sheet resistivity ~3.8 k/sq. Thinning down the QW to increase strain in the channel leads to drop in mobility likely due to high interface roughness and defect density in the AlGaSb barrier. The lowest interface trap density measured by conductance method with MBE Al2O3 gate oxide, showed mid-1013 eV-1cm-2 near the conduction band of GaSb. Maximum ON current of 11.6 mA/mm for 3 um MOSFET has been demonstrated.

(a)

(b)

Figure 2: (a) TEM images and of metamorphic superlattice (SL) buffer with 1 um GaSb epi-layer, and Al2O3 gate oxide, MBE grown on GaAs substrate. AFM image of the surface of high-k oxide 7 8 -2 deposited on GaSb/GaAs structure. Dislocation density in GaSb is reduced to high 10 - 10 cm . Cross-hatch surface roughness is ~1nm. (b) Hole mobility in InGaSb quantum wells on GaSb- like metamorphic substrate as a function of strain.

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The Nanoscience Constellation


V. Tokranov, P.Nagaiah , M.Yakimov, R.J.Matyi,,S.Oktyabrsky, AlGaAsSb superlattice buffer layer for p-channel GaSb quantum well on GaAs substrate, J. Cryst. Growth, 323, 35-38 (2011). L. Xia, V. Tokranov, S. Oktyabrsky, and Jesus A. del Alamo, Experimental Study of <110> Uniaxial Stress Effects on P-channel GaAs Quantum-Well FETs, IEEE Trans. Electron Dev. 58(8), 25972603 (2011).

TOPIC 3: Improvement of Interface Properties in the (In)GaSb/high-k Gate Stack An interface with atomic layer deposited (ALD) Al2O3 oxide was improved by a thin (2nm) interface layer of InAs which was treated with HCl or (NH4)2S immediately prior to ALD process (Fig.3). Optimized annealing of the ALD oxide in forming gas at 350oC further improved the C-V frequency dispersion, stretch-out, reduced interface trap density down to 1012 cm-2eV-1 and p-MOSFET sub-threshold slope down to 200 mV/dec., increased dielectric breakdown and reduced leakage current. Increasing annealing temperature to and above 450oC drastically degraded C-V characteristics, which corresponded to low thermal budget of antimonides. Very fast minority carrier (electron) response up to 5MHz at RT was observed on p-type GaSb/InAs capacitors contrary to the in-situ structures. This effect could not be completely suppressed at 77K and is attributed to fast electron generation/recombination through a high density of bulk traps in these structures.

(a)

(b)

Figure 3: (a) TEM image of n-GaSb/InAs/Al2O3 MOS structure with EDX depth profile. (b)C-V characteristics and interface trap density (Dit) extracted using Low-High frequency method with and without InAs interface passivation. P. Nagaiah, V. Tokranov, M. Yakimov, S. Novak, H. Bakhru, and S. Oktyabrsky, In Situ Deposited HfO2 with a-Si Passivation as a Potential Gate Stack for High Mobility (In)GaSbBased p-MOSFETs, 220 ECS Meeting, Tech Digest, E4-12180. P . Nagaiah, V. Tokranov, M. Yakimov, S. Madisetti, A. Greene, S. Novak, R. Moore, H. Bakhru and S. Oktyabrsky, In-situ Deposited HfO2 with Amorphous-Si Passivation as a Potential Gate Stack for High Mobility (In)GaSb- Based P-MOSFETs, ECS Trans. 41 (3), 223 (2011);

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The Nanoscience Constellation


A. Greene, M. Yakimov, P. Nagaiah, S. Madisetti, V. Tokranov, R. Moore, and S. Oktyabrsky, Improvement of the GaSb/Al2O3 Interface Using a Thin InAs Surface Layer, ISDRS 2011, Technical Digest. Andrew Greene, Shailesh Madisetti, Padmaja Nagaiah, Michael Yakimov, Vadim Tokranov, Richard Moore and Serge Oktyabrsky Improvement of the GaSb/Al2O3 Interface Using a Thin InAs Surface Layer, Solid State Electronics, 2012 (submitted).

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The Nanoscience Constellation

Surface Science (Ventrice Group)


Scope: Processes for the growth of graphene films Goal: To identify and characterize the growth of graphene films to produce films with a lower defect density 2011 Accomplishments TOPIC 1: Substrate Grain Size and Orientation of Cu and Cu-Ni Foils Used for the Growth of Graphene Films Graphene growth on Cu foils by catalytic decomposition of methane forms predominantly single-layer graphene films due to the low solubility of carbon in Cu. On the other hand, graphene growth on Cu-Ni foils can result in the controlled growth of few-layer graphene films because of the higher solubility of carbon in Ni. One of the key issues for the use of graphene grown by chemical vapor deposition for device applications is the influence of defects on the transport properties of the graphene. For instance, growth on metal foil substrates is expected to result in multi-domain graphene growth because of the presence of grains within the foil that exhibit a variety of surface terminations. Therefore, the size and orientation of the grains within the metal foil should influence the defect density of the graphene. For this reason, we have studied the effect of total anneal time and temperature on the orientation and size of grains within Cu foils and Cu-Ni alloy foils with a nominal concentration of 90/10 by weight. TOPIC 2: Characterization of Graphene Films Grown on Cu(111) As mentioned above, monolayer graphene films can be grown on Cu substrates

Figure 1: EBSD images of (a) the unannealed Cu foil (1.4 mm x 1.1 mm), (b) the Cu foil after anneal at 1035C for 30 min in 40 mTorr H2 followed by 5 min in 145 mTorr CH4 (2.5 mm x 1.9 mm), and (c) the EBSD legend. Corresponding inverse pole figures for (d) the unannealed Cu foil, (e) the Cu foil after graphene growth, and (f) the color map of the relative areas.

56

The Nanoscience Constellation by the catalytic decomposition of various carbon containing molecules. Typically, the substrates are poly-crystalline Cu foils, which have a tendency to recrystallize with a (100) texture during the graphene growth procedure. Since graphene crystallizes in a hexagonal lattice and the (100) surface of a Cu has a square symmetry, this is expected to result in multi-domain graphene growth. Because the Cu(111) surface has hexagonal symmetry and a lattice mismatch of 3.7% with graphene, growth on this surface termination has potential for producing films with a lower defect density. There have been relatively few studies of graphene growth on single crystal Cu substrates, owing to the fact that pressures of at least a few millitorr are needed for most hydrocarbon molecules, which is incompatible with most UHV systems. In this study, graphene films were grown on Cu(111) substrates by first preparing the clean surface in UHV by sputtering with inert gas ions followed by annealing. The sample was then transferred to a conventional tube furnace where the graphene film was grown by annealing in forming gas to reduce the surface oxide, followed by annealing in ethylene to produce the graphene film.

Figure 2: a) AFM image and b) line scan of graphene film grown on Cu(111). Growth results in flat regions with well ordered graphene and raised regions with ~100 nm topography. c) STM image of a flat region showing a Moir interference pattern that results from the slight mismatch between the graphene overlay and the Cu(111) substrate lattices. Facilities available for surface science studies at CNSE include UHV based analysis systems in Prof. Ventrices laboratory (NFE 1906) that have LEED, TPD, STM, and EELS capabilities and central use instrumentation (XPS, AFM, EBSD, and SEM) available in the Nanoscale Metrology and Imaging Center. In addition, the Ventrice group has active collaborations with groups at the National Synchrotron Light Source (beamline U13UB) at Brookhaven National Laboratory and the Center for Nanophase Materials Sciences at Oak Ridge National Laboratory.

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Nanoengineering Constellation

Nanoengineering is the application of nanoscience principles to practical ends, such as the design, manufacture, and operation of efficient and functional structures, machines, processes, and systems on the atomic scale.

The Nanoengineering Constellation

Plasmonic Based Chemical Sensors (Carpenter Group)


Scope: Study of the optical properties of nanocomposite materials comprised of gold nanoparticles in metal oxides as a function of temperature and gas exposure Goal: Develop and understand the optical properties of Au-metal oxide nanocomposites for use in harsh environment conditions for development of novel chemical sensor techniques 2011 Accomplishments TOPIC 1: Selective Plasmonic Gas Sensing: H2, NO2, and CO Discrimination by Au-YSZ, Au-TiO2 and Au-CeO2 Nanocomposite Films, Kinetic studies of hydrogen dissociative adsorption on yttria stabilized zirconia, Combined Raman and plasmonic studies of interfacial chemical reactions on metal oxide nanocomposite materials under harsh environment conditions A Au-CeO2 nanocomposite film has been investigated as a potential sensing element for high-temperature plasmonic sensing of H2, CO, and NO2 in an oxygen containing environment. The CeO2 thin film was deposited by molecular beam epitaxy (MBE) and Au was implanted into the as-grown film at an elevated temperature followed by high temperature annealing to form well-defined Au nanoclusters. The Au-CeO2 nanocomposite film was characterized by x-ray diffraction (XRD) and Rutherford backscattering spectrometry (RBS). For the gas sensing experiments, separate exposures to varying concentrations of H2, CO, and NO2 were performed at a temperature of 500C in oxygen backgrounds of 5.0, 10, and ~21% O2. Changes in the localized surface plasmon resonance (LSPR) absorption peak were monitored during gas exposures and are believed to be the result of oxidation-reduction processes that fill or create oxygen vacancies in the CeO2. This process affects the LSPR peak position either by charge exchange with the Au nanoparticles or by changes in the dielectric constant surrounding the particles. Multivariate analysis was used to gauge the inherent selectivity of the film between the separate analytes. From principal component analysis (PCA), unique and identifiable responses were seen for each of the analytes. Linear discriminant analysis (LDA) was also used and showed separation between analytes as well as trends in gas concentration. Results indicate that the Au-CeO2 thin film is selective to O2, H2, CO, and NO2 in separate exposures. Combined with the observed stability over long exposure periods, the Au-CeO2 film shows good potential as an optical sensing element for harsh environmental conditions.

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The Nanoengineering Constellation Kinetic studies have also been performed which studied the hydrogen dissociative adsorption properties on yttria stabilized zirconia (YSZ) at temperatures between 100 and 500oC and its corresponding effects on the plasmonic properties of embedded gold nanoparticles.
Figure 1: The square of the LSPR peak position during exposures at 500C. a) Analyte on-off cycles with the concentrations shown using air as the carrier gas. N. A. Joy, C. M. Settens, R. J. Matyi, M. A. Carpenter, Plasmonic Based Kinetic Analysis of Hydrogen Reactions within Au-YSZ Nanocomposites Journal of Physical Chemistry C, 115, 6283 (2011) Nicholas A. Joy, Manjula I. Nandasiri, Phillip H. Rogers, Weilin Jiang, Tamas Varga, Satyanarayana V N T Kuchibhatla, Suntharampillai Thevuthasan, and Michael A. Carpenter Selective Plasmonic Gas Sensing: H2, NO2, and CO Discrimination by a Single Au-CeO2 Nanocomposite Film, Submitted to Analytical Chemistry Metal Oxide Nanomaterials for Chemical Sensing Applications, Ed. M. A. Carpenter, S. Mathur, A. Kolmakov, Springer (to be published 2012) http://www.albany.edu/wwwres/sensors/

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The Nanoengineering Constellation

E-beam Lithography and Mask Writing (Hartley Group)


Scope: Exploring E-beam lithography, mask patterning and throughput Goal: To extend potential commercial applications for E-beam lithography 2011 Accomplishments
TOPIC 1: Electron Beam Lithography

The Hartley Group operates and maintains two electron beam lithography systems. The VB300, manufactured by Vistec Lithography Inc., is located in the CSR cleanroom in Nanofab 300 North. This system uses 50 or 100kV electrons to pattern a full spectrum of substrate types from pieces as small as 10x10mm to full 300mm wafers as well as a variety of standard mask formats. With a theoretical minimum probe size under 3nm, the system supports a wide variety of experiments at the nanoscale. The second system is reserved for E-beam technology development. TOPIC 2: Exploring Resolution Limits

Figure 1: VB300.

One of the primary objectives of the group is to develop the necessary tools to consistently and reliably pattern complex patterns below 10nm minimum feature size. While small isolated features have been patterned since the early history of electron beams, a number of new problems arise when arbitrary, large area complex structures are considered. We are currently investigating issues related to electron scattering, resist contrast, dose and exposure conditions and non-standard resist processes.
Figure 2: High resolution patterning testing limits.

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The Nanoengineering Constellation TOPIC 3: 300mm Patterning The ability to pattern on 300mm wafers provides the advantage of access to state of the art metrology and process equipment. 300mm automated CDSEMs provide an unprecedented level of detail on the performance of the E-beam system and process. One example of a 300mm project undertaken by the group is the fabrication of intentional defect array (IDA) wafers for the evaluation of next Figure 3: Sample IDA SRAM cells patterned on 300mm wafers. generation inspection tools. In order to be useful for an IDA application, it is essential to maintain a high degree of pattern fidelity across multiple chips. TOPIC 4: Mask patterning One of the most important commercial applications of E-beam lithography is mask patterning. While the throughput for mask applications of the VB300 is not competitive with commercial shaped beam mask writers, the high resolution and brightness enables a number of applications both unique and mundane.

Lacking access to mask etch capability, the group has used wet etching to fabricate binary chrome on glass masks down to 0.1m. For EUV applications, the group has developed a high resolution lift-off process for an additive absorber deposition step, as opposed to the more traditional subtractive etch.

Figure 4: EUV test mask patterned by the Hartley group.

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The Nanoengineering Constellation TOPIC 5: Throughput Throughput has always been the main limitation to widespread adoption of ebeam lithography in manufacturing. Together with Vistec, the Hartley group has designed and implemented a series of improvements to the VB300 to reduce the writing time. Some of these improvements are process driven we have implemented resist platforms that enable speed resolution tradeoffs so that flexibility is available to always use the fastest material that will deliver the required resolution. In a similar fashion, multiple tool databases are maintained that optimize tool parameters for the applications requirements. On a hardware level, a high speed blanker 600X faster than the one currently installed on the system was designed Figure 5: High Speed Blanker assembly. and built for a future integration.
Current and former graduate students: Ananthan Raghunathan, Ravi Bonam, and Adam Lyons, Junru Ruan PhD

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The Nanoengineering Constellation

Device Physics (Lee Group)


Scope: Characterization of CMOS devices Goal: Provide R&D support for device characterizations 2011 Accomplishments TOPIC 1: Our group focused on understanding the physics of highly scaled planar and non-planar CMOS devices. We carefully performed pulsed I-V, DC I-V and C-V curves on individual devices to provide a unified extraction of channel length and parasitic terms. This in turn was used to determine fundamental device properties, including mobility and threshold voltage. To accomplish this, we have established sub femto Amp and sub femto Farad measurement capabilities with temperature control from 500 to 10K Measuring intrinsic C-V curve of sub 100nm p-MOSFETs. Measuring the true channel C-V curve of highly scaled MOSFETs is critical for determining intrinsic device properties, including threshold voltage and mobility. In highly scaled devices, however, parasitic terms dominate, and to determine the intrinsic device properties requires the removal of the parasitic components. We have recently performed C-V curves on devices with varying gate length. These devices were fabricated with exaggerated overlap capacitances. The devices had gate lengths that varied from 100 to 175nm for a fixed width of 10m. By extracting the length-dependent parameters, we were able to determine the true channel C-V curve. This was then used to extract the gate bias dependent parasitic capacitance. These C-V curves are summarized in Figure 1. The details of our work can be found in the reference listed below.

Figure 1: Extracted channel and parasitic capacitances for Lmask = 100nm device. The intrinsic C-V curve was determined by examining devices of varying length. The parasitic C is the difference between the measured and intrinsic capacitance.

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The Nanoengineering Constellation TOPIC 2: Additional Topical Areas Include Graphene and Carbon Nanotube Electronics Our group has pioneered the use of buried split-gates to fabricate p-n junctions along individual nanotubes and on monolayer graphene films. Both materials are promising for future nanoelectronic applications, and we are developing both new devices for post-CMOS applications and the fundamental understanding of electronic transport properties of these devices.
Parasitic Capacitance Removal of sub-100 nm p-MOSFETs Using CapacitanceVoltage Measurements, Daniel R. Steinke, Joseph Piccirillo, Steven C. Gausepohl, Saikumar Vivekand, Martin P. Rodgers, Ji Ung Lee, Solid-State Electronics, , Available online 16 November 2011. Observation of the Urbach Tail in the Effective Density of States in Carbon Nanotubes, David A. Jones and Ji Ung Lee, Nano Lett. 11, 4176 (2011);

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The Nanoengineering Constellation

Static and Dynamic Photoresist Shrinkage Effects in EUV Photoresists (EUV Technology Team)
Scope: EUV resist materials development (A joint project with SEMATECH Metrology and Lithography) Goal: Determine if there is a difference in the SEM induced line sliming seen as a function of the polymer used in the photoresist 2011 Accomplishments TOPIC 1: Determine the static and dynamic photoresist shrinkage effects in EUV photoresists (during various imaging times in an SEM) using a polyhydroxystyrene (PHOST) based polymer and a methacrylate based polymer. This error source will be a key factor in CD-SEM metrology on these polymer materials as the industry moves to EUV lithography. Learning to work around this issue will continue to be necessary Two methacrylate polymer based photoresist compositions, from two different suppliers, have been imaged and compared to a PHOST formulation. At this point the materials show similar behavior, though the PHOST system seems to be much more sensitive to the SEM shrinkage effects (it shrinks more rapidly). The plots below show how the CD changes over time using 193nm exposure; the team is currently duplicating this work at EUV for a PHOST resist system and two KrF systems.
Normalized Shrinkage wrt 0, CDwidest

0 -1 -2 -3 -4
CD [nm]

CDw idest1_CD150

20nm 30nm 40nm 50nm


100n m 150nm
0 5 10 15
20 25

CDw idest2_CD100 CDw idest3_CD80 CDw idest4_CD70 CDw idest5_CD65 CDw idest6_CD60 CDw idest7_CD55 CDw idest8_CD50 CDw idest9_CD45 CDw idest10_CD40 CDw idest11_CD35 CDw idest12_CD30 CDw idest13_CD25 CDw idest14_CD20

-5 -6 -7 -8

Figure 1: Static CD shrinkage of targets of different initial bottom CD values on iArF line targets, plotted as a function of the number of measurements (doses) and with respect to original CD from before exposure to electron beam.

-9 -10 -11 -12

Dose

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The Nanoengineering Constellation

Figure 2: Dynamic shrinkage results showing how 1 shrink (defined as the difference between st nd st nd the 1 and 2 SEM measurements) varies as a function of time between the 1 and 2 measurements. Results are plotted on a logarithmic time scale. Bunday, Benjamin., Montgomery, Cecilia., Montgomery, Warren, & Cordes, Aaron. Static and dynamic photoresist shrinkage effects in EUV photoresists. Proceedings of SPIE Metrology, Inspection, and Process Control for Microlithography 2012, v8324, 8324-48 (2012).

st

*Advanced Materials Research Center, AMRC, International SEMATECH Manufacturing Initiative, and ISMI are servicemarks of SEMATECH, Inc. SEMATECH, and the SEMATECH logo are registered servicemarks of SEMATECH, Inc. All other servicemarks and trademarks are the property of their respective owners.

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The Nanoengineering Constellation

Advances in EUV Technology (Montgomery Group)


Scope: EUV resist materials development (A joint project with DOW Electronic Materials) Goal: Jointly develop a low diffusion EUV resist for line width roughness (LWR) and pattern collapse reduction on various semiconductor focused substrates 2011 Accomplishments TOPIC 1: Advanced Photoresist Materials Characterization on Primed Si, on Both Organic and Silicon Containing Resist Underlayers When using Si underlayers, we see good overexposure performance for 28nm hp patterns and very little line collapse down to 20nm critical features (CDs). When using organic underlayers, we also see collapse at 20nm. However, when using the primed Si, we see dramatic resist mottling and poor LWR. Having completed the initial characterization of the various substrates, measurement of key surface parameters such as water contact angle and coefficients of thermal expansion will be related to the relative pattern collapse margin and also the contribution to LWR.

Figure 1: Low Diffusion CA Resist resolves 20nm hp using EUV lithography.

a. Si-UL

b. organic UL

c. Si

Figure 2: Pattern dependence on substrate.

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The Nanoengineering Constellation

Nanoelectronics (Bin Yu Group)


Scope: 1. Development of hybrid and stacked multilayer graphene interconnects; 2. Nonvolatile memory devices Goal: 1. To solve fundamental limits of conduction and breakdown reliability in graphene; 2. To demonstrate a new class of functionality for memory and logic applications 2011 Accomplishments TOPIC 1: Graphene Electronics: Devices, Circuits, and Interconnects We demonstrated graphene field-effect transistors (GFETs), logic gates, and interconnects. GFETs and complementary-doping based inverters were demonstrated using CVD-assembled graphene on boron nitride substrate. The impacts of substrate material and device scaling on multiple key device performance metrics (e.g., smallsignal transconductance, carrier mobility) were explored. Carrier mobility up to ~16,000 cm2/V-s @ 2x1012cm-2 was measured in a graphene monolayer on boron nitride. On passive components, hybrid and stacked multilayer graphene (sMLG) interconnects were proposed and demonstrated to address the fundamental limits of conduction and breakdown reliability in a graphene monolayer. We show that sMLG could deliver ~35x current-capacity at ~1/30 wire thickness as compared with that of Cu-based interconnect, yielding an overall improvement of current-carrying density by three orders of magnitude.
200 nm Graphene

eCu depletion

Figure 1.

Figure 2.

Figure 1: Fabricated graphene field-effect transistor on boron nitride. Figure 2: Interfacial diffusion of Cu atoms in graphene/Cu hybrid interconnect.

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The Nanoengineering Constellation


E. Kim, T. Yu, E. S. Song, and B. Yu, Chemical Vapor Deposition-Assembled Graphene FieldEffect Transistor on Hexagonal Boron Nitride, Applied Physics Letters, 98, 262103 (2011). E. Kim, N. Jain, Y. Xu, Y. Han, and B. Yu, CVD-Graphene Complementary Logic on Ultra-Thin Multi-Layer Hexagonal Boron Nitride, Proc. Material Research Society Symposium, in press (2012). T. Yu, E. Kim, N. Jain, and B. Yu, Carbon-Based Interconnect: Performance, Scaling and Reliability of 3D Stacked Multilayer Graphene System, Tech. Dig. IEEE International Electron Devices Meeting, 159-162 (2011).

TOPIC 2: Emerging ReRAM and PRAM Devices We explored nonvolatile memory devices based on two different families metal oxide based resistive switching ReRAM and phase-change nanowire PRAM. Resistive switching cells were fabricated based on several different metal oxide systems. We discovered that resistive variation in HfO2-based resistive switching device can be effectively controlled by employing material- and operation-oriented methodologies to meet different design requirements. A model of retention failure behavior was established in bipolar oxide-based ReRAM. Multilevel non-volatile data storage was demonstrated on HfO2-based RRAM. In addition, we are currently demonstrating a new class of functionality - utilizing oxide-based memristive cell for both memory and logic applications. On phase-change memory side, we chemically synthesized several types of binary and ternary chalcogenide nanowires via metal-catalytic CVD method. PRAM memory devices were fabricated using beam-based technique and basic function characterized.

Figure 3.

Figure 4.

Figure 3: Multi-state data storage in metal oxide based ReRAM. Figure 4: Binary chalcogenide phase-change nanowire memory. B. Yu, B. Nagabhirava, J. Liu, A. P. Manjeri, Phase-change GeTe Nanowire: Synthesis, Material Scalability, and Key Properties, Material Research Society Spring Meeting, San Francisco, CA, April 2529, 2011.

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The Nanoengineering Constellation


J. Liu, B. Yu, and M. P. Anantram, Scaling Analysis of Nanowire Phase-Change Memory, IEEE Electron Device Letters, vol. 32, no. 10, 1340-1342 (2011).

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Nanoeconomics Constellation

Nanoeconomics is the formulation, study, and analysis of the economic and business principles underlying the development and deployment of nanoscale know-how, products, and systems.

The Nanoeconomics Constellation

Economics of High Technology Industries (Unni Pillai)


Scope: The analysis and study of high technology industries Goal: Create economic models predicting the long run equilibrium market structure of the photovoltaic industry and other alternative energies based on technological advances and market environments to compare against competing energy sources 2011 Accomplishments TOPIC 1: Grid Parity of Solar Electricity The cost of generating electricity using solar photovoltaics (PV) has decreased rapidly in the last few decades. Solar electricity generation is, however, much more expensive than generation using coal or natural gas. The Sunshot initiative announced by Department of Energy has set the goal of reducing the installed cost of solar systems to $1/watt by 2020 (from the current $4/watt). Current models that predict the future cost of solar generated power simply extrapolate from the past trends observed in the price/watt of solar PV systems. A key missing element in these models is how market structure and competition among firms affects the rate of decrease in the cost of solar electricity generation. We develop economic models that predict the long run equilibrium market structure of the industry from its technology parameters. Such models provide a better estimate of the time at which solar electricity will achieve parity with conventional generation sources.

Figure 1.

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The Nanoeconomics Constellation TOPIC 2: International Pattern of Production and Trade in Solar Photovoltaics The international pattern of production and trade has changed dramatically over the lifetime of the solar industry. While U.S was the pre-eminent leader in solar PV production at the beginning of the industry, it was quickly replaced by Japan in the early part of the last decade and then by Germany. The last few years, however, have been marked by the dramatic rise of China as a producer and exporter of solar cells and modules. We look at the factors that have driven this changing pattern of production and trade, and examine the consequences of government policies like tariffs and subsidies on the pattern of trade and production, and on national welfare.

Figure 2.

TOPIC 3: Investment in Electric Grid Infrastructure for Integration of Wind and Solar sources Integration of wind and solar generation into the electric grid poses many problems. The ideal locations for wind farms or solar power plants are often in remote places, where there is no existing transmission infrastructure in place to carry the electricity to load sites. Further, both wind and solar are intermittent sources and variability in generation often means that these might work well when used in conjunction with energy storage (like batteries) to smooth out the intermittency. Lack of investment in transmission and storage infrastructure is often cited as a big impediment to electricity generation with wind and solar.

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The Nanoeconomics Constellation Many studies have argued that a lack of consensus on who should bear the upfront cost of building the transmission lines, and how the cost should be shared across the different parties affected by the project, has been a deterrent delaying the construction of new transmission and storage. We study how differences in ownership structures of these grid assets affect the investment into these assets, and the differences in welfare that result under different ownership structures. TOPIC 4: Vertical Specialization in High Technology Industries Some high-technology industries like the computer industry and the semiconductor industry show increasing levels of vertical specialization over time. Firms engage in all activities along the production chain in the initial stages of the industry, but over time firms specialize in one or few of the stages. In the solar industry, in contrast, production has become vertically integrated over time, with firms starting at one stage of production and integrating both backward and forward into other stages. We study the determinants of the vertical structure of the industry, with an aim of predicting the long run vertical structure from underlying technology parameters. TOPIC 4.1: Role of Vertical Consortia in High Technology Industries In vertically specialized industries undergoing ongoing technological change, coordination of different stages of production and innovation becomes a difficult problem. Even when production is vertically integrated, final product firms need to coordinate their innovative activities with the suppliers of equipment and materials. We examine the coordination role that vertical consortia can play in such industries. The College of Nanoscale Science and Engineering is the home to two such consortia, SEMATECH in the semiconductor industry and the Photovoltaic Manufacturing Consortium (PVMC) in the solar industry. TOPIC 4.2: Vertical Specialization and Outsourcing of R&D Vertical specialization in high-technology industries has often been accompanied by increasing geographic dispersion in production. In the semiconductor industry, most previous manufacturers of chips have outsourced manufacturing to specialized firms (foundries), choosing to focus on R&D and design. A pertinent question is whether these upstream activities like R&D and design will follow manufacturing and tend to move closer to the manufacturing hubs in other countries. We study the incentives for R&D and design activities to locate closer or away from manufacturing hubs. TOPIC 5: Valuation of High-Technology Companies Many problems are confronted when valuing companies in high technology industries. There are numerous new companies in these industries that obtain negative profits for many years. New industries often got through "shake-out" faces in which many new entrants enter the industry and subsequently exit as the industry matures.

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The Nanoeconomics Constellation We build on our industry models of solar and rechargeable batteries developed in other projects to predict long run equilibrium profits in the industry and use that to value companies in these industries.

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The Nanoeconomics Constellation

Nanotechnology Economic Impact Report (Laura Schultz)


Scope: Identifying and Measuring the Impact of University-Industry Collaborative Research Centers and Promoting Entrepreneurship Goal: University-Industry collaborative research centers are popular policy tools designed to drive innovation and support high-tech cluster development in regional economies. The goal of my research is to develop metrics and methods that can be used to identify their impacts on emerging areas of technology and economic growth. In addition, I use this knowledge of emerging technologies and technology transfer to promote entrepreneurship in Tech Valley 2011 Accomplishments TOPIC 1: CNSE Economic Impact Report I worked with Professor Pillai to estimate the economic impact of the College of Nanoscale Science and Engineering on the Capital Region and New York State. The co-authored report consisted of four chapters:
The CNSE Model (September 2010) Estimating the economic impact of CNSE using multiplier analysis (December 2010) Identify and measuring the intangible economic impact of CNSE (March 2011) The growth of the Nanotechnology cluster in Upstate NY, (September 2011)

The report estimated that the CNSE contributed $1.8-$2.2 billion to the Capital Region economy. CNSE corporate partners likely receive an 18-28% return on their investment in R&D performed at CNSE. CNSE alumni will earn 12-33% more over their lifetime than their non-nanotechnology peers.
Product: A draft of the report was delivered to SVP/CEO Kaloyeros and Dean Fuleihan in September 2011.

TOPIC 2: Nanotechnology Research Centers The emergence of collaborative research centers as a policy tool coincided with the introduction of the National Nanotechnology Initiative in 2001. As a result, dozens of university-based collaborative nanotechnology research centers (NRCs) were established across the U.S. These centers are extremely heterogeneous with a wide range of missions, research foci, and management structures. The goal of this project is to assess the outcomes and impacts a decade after their formation of these NRCs to identify best practices. In 2011, I developed a dataset of 28 U.S. university-based nanotechnology research centers. I created data series to quantify the research inputs and outputs of each center and performed an initial comparison of these centers. In addition, particular attention was paid to the current state of nanotechnology research centers. A

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The Nanoeconomics Constellation comprehensive review was completed assessing the educational activities of research centers at the K-12, undergraduate, and graduate levels. Product: Assessing the level of collaboration within university-industry nanotechnology research centers, has been submitted to Science and Public Policy.
Educational and Workforce Development in Nanobiotechnology, D. White. Chapter in The Handbook of Nanobiotechnology, 2012

TOPIC 3: Metric and Method Development Research centers, such as CNSE, create value through the advancement of emerging technologies and their contribution to regional innovation infrastructures. These activities attract additional researchers, funding, and businesses seeking to commercialize advancements. The challenge is in identifying and quantifying the value created. In 2011, I created a method to measure collaboration using publicly available bibliometric datasets. These measures can be used to track the development of a regional innovative infrastructure. They can also be used to assess the level of technology transfer from the university to the local private sector. These datasets were also used to track the development of four emerging energy storage technologies.
Products: University-Industry-Government Research Centers for Economic Growth, Chapter forthcoming in Colleges and Universities as Economic Drivers, 2012 What patents and publications can tell us about the development of Energy Storage Technologies, to be submitted.

TOPIC 4: Entrepreneurship For technology to create economic value it must be commercialized. There are multiple challenges associated with the transfer of new technologies from the university laboratory to the market places. Innovators must find the right applications for their technology, understand their market and customer, navigate the venture financing process, and effectively communicate their ideas to investors, customers, partners, and other stakeholders. My goal is to use my expertise in technology transfer to help inventors overcome these challenges and become effective innovators. This is accomplished through tasks such as one-on-one mentoring of entrepreneurs and the development of entrepreneurship education programs. Outcomes:
Served as commercialization advisor to CNSE startup companies BESS Technologies and aPV in 2011. Named to the iCLEAN Advisory Board. Developed a curriculum on Nanotechnology Entrepreneurship for high school students. The curriculum is a six-session introduction to nanotechnology and the entrepreneurship culminating in a business plan competition. The program will be launched in 2012 at five area high schools in collaboration with Junior Achievement.

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Nanobioscience Constellation

Nanobioscience refers to the application of nanoscale scientific concepts and principles to the study of biological and biomedical structures and systems. In addition, nanobioscience encompasses CNSE's NanoHealth initiative which is aimed at developing novel nanotechnology applications in nanomedicine, including nanotoxicology and environmental and public health.

The Nanobioscience Constellation

Sensors, Components, and Models of Stress and Damage Signaling (Begley Group)
Scope: Cell signaling after stress, signaling mechanisms, cancer biology, environmental health, toxicology Goal: Identify and characterize novel cell signaling pathways for use as biomarkers of exposure and drug targets for cancer treatment 2011 Accomplishments TOPIC 1: Protein Specific Autophagy Autophagy-dependent regulation ribonucleotide reductase 1. of the DNA damage response protein

Protein synthesis and degradation are posttranscriptional pathways used by cells to regulate protein levels. We have developed a systems biology approach to identify targets of posttranscriptional regulation and we have employed this system in Saccharomyces cerevisiae to study the DNA damage response. We present evidence that 50% to 75% of the transcripts induced by alkylation damage are regulated posttranscriptionally.

Figure 1: RNR1-GFP form foci that localize to the vacuole after DNA damage. RNR1-GFP expressing cells were stained with FM4-64 to localize the vacuolar membrane; images for green fluorescence, red fluorescence, and bright field microscopy were merged as indicated. Fluorescence microscopy was used to image cells expressing GFP-tagged proteins.

Significantly, we demonstrate that two transcriptionally-induced DNA damage response genes, RNR1 and RNR4, fail to show soluble protein level increases after DNA damage. To determine one of the associated mechanisms of post-transcriptional regulation, we tracked ribonucleotide reductase 1 (RNR1) protein levels during the DNA

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The Nanobioscience Constellation damage response. We show that RNR1 is actively translated after damage and that a large fraction of the corresponding RNR1 protein is packaged into a membrane-bound structure and transported to the vacuole for degradation, with these last two steps dependent on autophagy proteins. We found that inhibition of target of rapamycin (TOR) signaling and subsequent induction of autophagy promoted an increase in targeting of Rnr1 to the vacuole and a decrease in soluble RNR1 protein levels. In addition, we demonstrate that defects in autophagy result in an increase in soluble Rnr1 protein levels and a DNA damage phenotype. Our results highlight roles for autophagy and TOR signaling in regulating a specific protein and demonstrate the importance of these pathways in optimizing the DNA damage response.
Dyavaiah, M., Rooney, J., and, Lin, Q., Chittur, S., and Begley T. J. 2011. Autophagy-Dependent Regulation of the DNA Damage Response Protein Ribonucleotide Reductase 1. Mol Cancer Res 9: 101-114 (Highlighted on the cover). http://www.ncbi.nlm.nih.gov/pubmed/21343333

TOPIC 2: High Throughput Toxicology and Functional Genomic Tools Cross-species Functionome analysis identifies proteins associated with DNA repair, translation and aerobic respiration as conserved modulators of UV-toxicity. Cellular responses to DNA damage can prevent mutations and death. In this study, we have used high throughput screens and developed a comparative genomic approach, termed Functionome mapping, to discover conserved responses to UVC-damage. Functionome mapping uses gene ontology (GO) information to link proteins with similar biological functions from different organisms, and we have used it to compare 303, 311 and 288 UVC-toxicity modulating proteins from Escherichia coli, Schizosaccharomyces pombe and Saccharomyces cerevisiae, respectively. We have demonstrated that all three organisms use DNA repair,

Figure 2: Functional interactome mapping identified multispecies nodes over-represented with UV-toxicity modulating proteins. (A) The Functionome was compiled using GO identifiers for biological processes specific to 3,120 E. coli and 4,271 S. cerevisiae proteins (small grey spheres). A total of 511 GO identifiers (large red spheres) and 18,254 functional links (orange lines) were used to compile the functional interactome. (B) The Functionome was computationally analyzed to identify nodes overrepresented with both E. coli (light green spheres, lower case protein names) and S. cerevisiae (dark green spheres, upper case protein names) UV-toxicity modulating proteins. One of the top scoring functional nodes was NER (p < 1012). Blue lines represent protein-protein interactions. (C) All functional nodes that were significantly overrepresented (p < 0.06) with UV-toxicity modulating proteins from both E. coli and S. cerevisiae were visualized using Cytoscape.

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The Nanobioscience Constellation translation and aerobic respiration associated processes to modulate the toxicity of UVC, with these last two categories highlighting the importance of ribosomal proteins and electron transport machinery. Our study has demonstrated that comparative genomic approaches can be used to identify conserved responses to damage, and suggest roles for translational machinery and components of energy metabolism in optimizing the DNA damage response.
Rooney, J., Patil, Joseph, F., Endres, L., Begley, U. A., Zappala, M. R, Cunningham, R. P., and Begley T. J. 2010. Functional Interactome Analysis Identifies DNA Repair, Translation and Aerobic Respiration as Conserved Responses to UV-induced Damage. Genomics 97: 133-147 (Highlighted on the cover). http://www.ncbi.nlm.nih.gov/pubmed/21195161

TOPIC 3: Computational Analysis of tRNA Methyltransferases, Predicted Human Stress Response Enzymes Transfer RNA Methytransferases and their Corresponding Modifications in Budding Yeast and Humans: Activities, Predications, and Potential Roles in Human Health. Throughout the kingdoms of life, transfer RNA (tRNA) undergoes over 100 enzyme-catalyzed, methyl-based modifications. Although a majority of the methylations are conserved from bacteria to mammals, the functions of a number of these modifications are unknown. Many of the proteins responsible for tRNA methylation, named tRNA methyltransferases (Trms), have been characterized in Saccharomyces cerevisiae. In contrast, only a few human Trms have been characterized. A BLAST search for human homologs of each S. cerevisiae Trm revealed a total of 34 human proteins matching our search criteria for an S. cerevisiae Trm homolog candidate. We have compiled a database cataloging basic information about each human and yeast Trm. Every S. cerevisiae Trm has at least one human homolog, while several Trms have multiple candidates. A search of cancer cell versus normal cell mRNA expression studies submitted to Oncomine found that 30 of the
Figure 3: The tRNA methyltransferase reaction. A-D): Each reaction diagram shows an example of a methylation reaction for adenine (A), cytosine (B), guanine (C) and uridine (D). In these examples, the methyl group is added to the 1-carbon position of the purine ring (A, C), the 5carbon position of the pyrimidine ring (B) and the 2-oxygen position of the ribose sugar (D).

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The Nanobioscience Constellation homolog genes display a significant change in mRNA expression levels in at least one data set. While 6 of the 34 human homolog candidates have confirmed tRNA methylation activity, the other candidates remain uncharacterized. We believe that our database will serve as a resource for investigating the role of human Trms in cellular stress signaling.
Towns, W. L. and Begley T. J. 2011 Transfer RNA Methytransferases and Their Corresponding Modifications in Budding Yeast and Humans: Activities, Predications, and Potential Roles in Human Health. DNA Cell Biol. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/22191691

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The Nanobioscience Constellation

Biomimetic Nanomaterials and Development of Site-Specific Surface Modification Chemistry (Bergkvist Group)
Scope: Surface Chemistries and Adhesives for 3D integration. Development of Bio-Based Nanomaterials Goal: Exploring the most effective substrate-selective chemical patterning process for wafer production and evaluating virus-based nanoparticles for more targeted delivery of cancer therapy 2011 Accomplishments TOPIC 1: Molecular Vapor-Phase Deposition (MVD) of Reactive Silanes for Substrate-Selective Patterning, Bottom-up Polymerization and Adhesion Bonding (Elipsometry, XPS, AFM) Low temperature bonding (< 300oC) is of interest for through-silicon-via (TSV) integration and other chip-packaging on wafer-wafer, die-wafer and die-die level in order to minimize stress and material damage. Copper-copper bonding is one suitable approach for TSV integration although repeated heating to 350-400o C increases the risk of thermal stress and interface oxidation. We are interested in orthogonal surface chemistries that selectively modify silicon over copper and allow hybrid bonding (adhesive + copper bonding) below 300 oC. Orthogonal chemistry, where thin (0.5-2 nm) monolayer films provide, 1) surface protection of copper, and 2) chemical groups for selective surface reactions on surrounding silicon, is of interest. We have studied low-temperature (25-100 oC) MVD conditions at ambient or slightly reduced pressure of various functional organosilanes. The surface stability (surface bond) and end group reactivity of such films upon heating to 250oC were studied. We found that at elevated temperatures, a monolayer of organosilane is firmly bound to the surface. However, if multilayer films are present, which likely are loosely associated with the interface, molecules tend to desorb at temperatures >150 oC. The stability of chemically reactive end-groups of selected organosilanes was investigated at elevated temperatures. Epoxy, amine and isocyanate groups appear stable at 250oC in inert atmosphere. Experiments to chemically titrate the epoxy-reactive groups with amines show that approximately 80% present of the groups are available for reaction after MVD. Although monolayers with Azo-groups can be deposited at 80oC, the reactive azide group is inactivated during the deposition.
Figure 1: Substrate selective patterning of copper and SiO2 through SAM and MVD.

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The Nanobioscience Constellation

Substrate-selective chemical patterning of coinage metals (copper, gold etc.) and silica substrates were demonstrated using a combined self-assembled monolayer (SAM) + MVD approach (figure 1). We demonstrated that alkanethiol self-assembled monolayers are capable of protecting copper surfaces from oxidation and promote CuCu bonding at < 250 oC [Lim, 2011, Tan, 2009]. This SAM layer also protect the metal from further modification in the MVD step. Thus exposed silicon areas can be modified in a straight-forward, two-step approach combining liquid self-assembly with molecular vapor deposition. This enables one chemistry on copper areas, and another on silicon (figure 2). Areas with MVD deposited amines can be modified through a bottom-up, gas-phase polymerization approach to give ~100 nm of an adhesive film that we successfully used for adhesive bonding at 110oC. These results show promise to be applicable to patterned bottom-up fabrication and hybrid wafer-bonding strategies.

Figure 2: XPS peaks from Cu/Si patterned substrates. Thiol-SAM protection of copper areas prevents deposition of Amine-silane (APTMS), allowing spatial chemical patterning.

TOPIC 2: Virus-Based Nanoparticles for Photo-Dynamic Cancer Therapy Virus capsids offer a multi-functional platform for nanomaterial engineering. We have for instance developed the MS2 bacteriophage as a biotemplate to synthesize water soluble CdS nanoparticles [Cohen, 2009]. MS2 also offer advantages for nanomedicine applications. Challenges associated with cancer treatment using photodynamic therapy (PDT) include the packaging and site-specific delivery of therapeutic agents to the tissue of interest. We have explored encapsulation of PDT agents inside surface-modified virus capsids for site-specific targeting of cancer cells (figure 3). Figure 3: Schematic showing porphyrin penetration The icosahedral MS2 bacteriophage has a porous capsid with an exterior diameter of ~28 nm
through capsid pores and association with interior RNA (assembly packaging). Results show ~ 250 molecules load into each capsid and that they produce ROS.

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The Nanobioscience Constellation where the pores allow small molecules access to the capsid interior. Furthermore, MS2 presents several suitable group residues on the exterior capsid that allow conjugation of targeting ligands. We have successfully demonstrated that a PDT active heterocyclic compound (meso-tetrakis(para-N-trimethylanilinium)porphine, TMAP) can be loaded into the MS2 capsid. Upon photoactivation, the production of radical oxygen species (ROS) was shown to be equal or higher compared to TMAP in solution [Cohen, 2011]. ROS are key components in photodynamic therapy as they induce cell death at high concentration. Most recently we have modified the capsid exterior with an aptamer that targets MCF-7 cancer cells. We have demonstrated that we can deliver PDT-active MS2 constructs in site-specific manner and use low-intensity 635 nm light to eradicate cancer cells.
Cohen, B. A.; Kaloyeros, A. K.; Bergkvist, M. In MS2 Bacteriophage as a Biotemplate for Semiconductor Nanoparticle Synthesis, MRS Proceedings, Boston, MA, Nov 30 - Dec 4, 2009; Boston, MA, 2009; pp 1220-BB05-18. Cohen, B. A.; Kaloyeros, A. K.; Bergkvist, M., Nucleotide-driven packaging of a singlet oxygen generating porphyrin in an icosahedral virus. Journal of Porphyrins and Phtalocyanines 2011, 15, 1-8. Lim, D. F.; Goulet, S. K.; Bergkvist, M.; Wei, J.; Leong, K. C.; Tan, C. S., Enhancing Cu-Cu Diffusion Bonding at Low Temperature Via Application of Self-assembled Monolayer Passivation. Journal of The Electrochemical Society 2011, 158, (10), H1057-H1061. Tan, C. S.; Lim, D. F.; Singh, S. G.; Goulet, S. K.; Bergkvist, M., Cu-Cu diffusion bonding enhancement at low temperature by surface passivation using self-assembled monolayer of alkane-thiol. Applied Physics Letters 2009, 95, (19), 192108-3.

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The Nanobioscience Constellation

Occupational and Environmental Health and Safety of Nanomaterials (Brenner Group)


Scope: The integration of exposure science, industrial hygiene, metrology, and occupational medicine to enhance and accelerate health and safety research of nanomaterials Goal: To proactively and innovatively address the emerging needs of health and safety research for nanomaterials, seeking to develop in real-time the technology and methodology needed to assess, monitor, and safely accelerate nanotechnology R&D worldwide 2011 Accomplishments TOPIC 1: NanoHealth & Safety Center NanoHealth & Safety Research

Figure 1: From Stebounova, L, Morgan H, Grassian V, Brenner S. (2011). Occupational Health & Safety Implications of Exposure to Engineered Nanomaterials. WIREs Nanomedicine & Nanobiotechnology, in press.

NanoHealth & Safety Center


Proactive collaboration between semiconductor industry, academia, and government Public-private partnership between CNSE and SEMATECH-ISMI New $10M Center focusing on: Occupational health and safety Environmental health Resource utilization Education and training 100 new EHS jobs over the next 5 years

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The Nanobioscience Constellation Mission: Provide a collaborative public-private framework that promotes innovative health and safety advances related to the development, utilization, and environmental interaction of nanoscale products and materials. TOPIC 2: Nanoparticle Exposure Assessment During CMP Operations and Maintenance Qualitative exposure assessments determined workers and specific job tasks for inclusion in the air monitoring events and the detailed sampling strategy for each task. The qualitative assessments also identified tasks of interest, task duration and frequency, number of employees potentially exposed, representative exposure groups, controls specified, controls used, and characteristics of the nanomaterial (e.g. chemical composition based on slurry formulation, size range, physical form). Because traditional industrial hygiene sampling and analyses methods relying on mass-based approaches have limitations in assessing nanoparticles, experimental sampling approaches use a combination of parallel methods that also incorporate electron microscopy and directreading instruments (see figure 2 below).

Figure 2: Parallel sampling approaches.

Tasks/activities sampled included: 1) handling/mixing of nanoparticle formulations into slurries; 2) slurry delivery system drum changes, preventive maintenance, and slurry filter changes; 3) preventive maintenance, repairs, and changeout of consumables for the CMP tools and; 4) handling of process waste. Preliminary electron microscopy has been conducted and images appear below.

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The Nanobioscience Constellation

Figure 3: TEM image (Left): silica nanoparticle agglomerate captured from air (worker breathing zone sample, collected by Brenner research team with NIOSH Nanotechnology Field Research Team on-site, image provided by NIOSH microscopist). Figure 4: SEM image (Right): silica nanoparticles in CMP slurry (imaged at CNSE by Gary Roth, Brenner lab).

TOPIC 3: Identification and Determination of Fate of Sio2 Nanoparticles During Conventional Wastewater Treatment Engineered nanomaterials are under increased regulatory scrutiny due to growing environmental health and safety concerns about their potential release and fate in the environment. Nanoparticles including SiO2 and other metal oxides are an important component of many commercial CMP slurries and current research suggests that a significant fraction of the nanoparticles used or produced during wafer manufacturing may escape conventional wastewater treatment systems. The first phase of this project focused on the preliminary investigation of analytical techniques for the identification, characterization, and quantification of SiO2 in process effluent and treatment system consumables (e.g., filters). Continuation of this project will allow further development and validation of these analytical techniques as well as inclusion of additional nanoparticles of interest (Al2O3, CeO2) and expansion from R&D to select manufacturing sites. Validated analytical techniques are required to evaluate the effectiveness of treatment units for the removal of nanoparticles from process effluents and ultimately identify the environmental fate of industrial nanoparticles. Expansion to manufacturing sites will provide additional information to evaluate the effectiveness of conventional wastewater treatment processes in high through-put systems.

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The Nanobioscience Constellation

Figure 5: SEM Image (above, left): silica particles in effluent collected from the main wastewater tank before filtration steps (Imaged at CNSE by Gary Roth). Figure 6: SEM Image (above, right): silica particles in the effluent after the bag and cartridge filtration steps (Imaged at CNSE by Gary Roth).

TOPIC 4: Fundamental Investigation of Semiconductor Personal Protective Equipment And Cleanroom Attire This project investigated the current and best practice standards for personal protective equipment (PPE) worn by workers who handle engineered nanomaterials in the semiconductor industry. Sources of potential exposure to nanoparticles are of growing interest to both the public and private sectors. Semiconductor processes like CVD, Etch, and CMP could be potential sources of nanoparticles, which may then be accessible for human contact in the workplace. In the first year of this project we identified current best practices and standards for PPE in the semiconductor industry. We also developed a plan to test the efficacy of PPE and cleanroom gowns at preventing worker exposure to nanoparticles. Some preliminary electron microscopy data indicate there are pore sizes in cleanroom gloves, gowns, and booties that could potentially allow nanoparticles to pass through (images below). Additional research will investigate if and how far nanoparticles penetrate the PPE and gowns under experimental and real-world conditions.

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The Nanobioscience Constellation

Figure 7: SEM Image (above, Left): cleanroom gown; 1.27 m gap identified (imaged at CNSE by Bushra Alam). Figure 8: SEM Image (above, Right): gap in standard nitrile glove used in the cleanroom (imaged at CNSE by Bushra Alam). Figure 9: SEM Image (Left): 2-200 m gaps identified in cleanroom shoe covers (imaged at CNSE by Bushra Alam).

Stebounova, L, Morgan H, Grassian V, Brenner S. (2011). Occupational Health & Safety Implications of Exposure to Engineered Nanomaterials. WIREs Nanomedicine & Nanobiotechnology, in press.

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The Nanobioscience Constellation TOPIC 5: Nanomedicine MD-PhD Program in Medicine and Nanoscale Science or Engineering Worlds first combined-degree clinical scientist training program nanomedicine. in

Nasir, A, Brenner, S. Think Small: Nanotechnology for Plastic Surgeons. Annals of Plastic Surgery, in press. Brenner, S, Ling, J. Nanotechnology Applications in Orthopedic Surgery. ASME Journal of Nanotechnology in Engineering and Medicine, submitted.

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The Nanobioscience Constellation

Nano-enabled Biotechnology (Cady Group)


Scope: (1) Combatting fouling and biofilms; (2) nanoscale cell printing; (3) field effect transistors (FETs) for DNA applications; (4) Resistive Switching Devices (ReRAM/memristors) Goals: (1) Create methods to directly measure biofilm properties for biofilm remediation; (2) to pursue novel strategies to better understand how cells behave in microenvironments; (3) study FETs for sensitive detection and analysis of DNA hybridization and/or damage events; (4) incorporate memristors into neural-like networks 2011 Accomplishments TOPIC 1: Antifouling and Biofilm Remediation Microbial fouling of surfaces and subsequent formation of biofilms is a major problem in medicine, industrial processes, and infrastructure. To combat fouling and biofilm formation, we are pursuing methods to limit bacterial attachment to surfaces and interrupt biofilm formation (or disrupt established biofilms). We are currently developing 3D nanomanufacturing strategies to create nanoscale topographical features that can be used to limit the attachment of bacterial cells to stationary surfaces. Our work has shown that topography in the 0.5 1 micrometer size scale is effective in reducing bacterial adhesion to surfaces, and that larger scale topography can increase surface attachment (as compared to flat reference surfaces). We are also exploring the combined use of topography and surface chemistry to further limit cell attachment and subsequent biofilm formation. This includes the use of low surface energy materials (primarily polymers) and low energy surface coatings. Each of these experiments are performed in novel microfluidic flow systems that allow us to observe surfaces microscopically during the experiment (Figure 1). This real-time view of the experimental system allows us to have a unique understanding of the various phases of biofouling, including initial surface attachment, surface motility/rearrangement, growth, and propagation/biofilm formation.
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Figure 1: (top) Microfluidic system for evaluating bacterial surface attachment. (bottom) Examples of a bright field image (showing surface topography) and fluorescent image (showing fluorescently tagged bacteria) which are used to determine the degree of surface attachment by various bacteria to topographically distinct surfaces.

The Nanobioscience Constellation Our surface topography experiments will provide insight for the design of low-adhesion surfaces that could resist bacterial adhesion and colonization. We are also working with collaborators (including Prof. Rabi Musah, UAlbany Dept. of Chemistry and Prof. Alexander Rickard, UMichigan-School of Public Health) to develop molecular antagonists of biofilm formation and methods of delivering these antagonists for prophylactic or therapeutic treatment against biofilms. Our initial work in this area has focused on the inhibition of bacterial biofilm formation by a library of natural products inspired compounds. Prof. Musahs group has developed these compounds, which we have shown to have efficacy against Pseudomonas aeruginosa biofilm formation. Interestingly, we also showed that these compounds are effective in reducing cell signaling (quorum sensing) behavior of P. aeruginosa. Our hypothesis is that disruption of quorum sensing pathways in P. aeruginosa affects the expression of genes involved in biofilm formation. While we are continuing to investigate this system, we are also pursuing this approach for organisms involved in oral biofilm formation. With my collaborators, Musah and Rickard, I was able to obtain an NIH-NIDCR RO3 (Young Investigator) grant to support work on oral biofilms. To this end, Dr. Musahs group is synthesizing a new library of compounds with structures that mimic quorum sensing signal molecules found in many Gram positive oral biofilm formers (e.g. Streptococcus mutans, Streptococcus sanguinis, Actinomyces oralis). Our goal is to isolate compounds that reduce biofilm formation in these organisms and then develop strategies to use them prophylactically, or integrate them into dental devices for cavity prevention. As part of our biofilm/antifouling effort, my laboratory is currently working on methods to directly measure the biophysical properties of biofilms using atomic force microscopy (AFM). By coupling microfluidic fluid control with precision AFM measurement, we hope to better understand the dynamics of cell behavior under varying fluid shear conditions and during exposure to external chemical signals. This work is partially supported by the NSF Major Research Instrumentation Program, which allowed us to assemble a combined AFM confocal laser scanning microscopy (CLSM) system. Using this unique research instrument, we are able to correlate optical images with AFM-based force, adhesion, and topography measurements, for an unparalleled view of bacterial and biofilm properties (Figure 2 below). One of the unique aspects of this approach is that we use a modular microfluidic system to establish biofilms for imaging and AFM analysis. This system (Figure 2A/B) allows us to observe biofilm growth in real-time, and to make real-time dynamic measurements of biofilm mechanical properties. Our ultimate goal with this system is to incorporate biofilm disruptive or dispersive agents (such as the small molecular compounds developed in Prof. Musahs group) to study the mechanical dynamics of biofilm disruption. This information will allow us to create biophysical models of biofilm behavior which will inform best practices for biofilm remediation.

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Figure 2: A) Microfluidic system for growth and maintenance of bacterial biofilms. B) Crosssection of the microfluidic growth chamber during combined AFM/confocal microscopy. C) Integrated Leica SP5 confocal microscope and Bruker/Veeco Catalyst Bioscope Atomic Force Microscope (AFM).

2011 Publications:

A.P. Mosier, A.E. Kaloyeros, N.C. Cady. Determination of Bacterial Biofilm Elastic Properties using MicrofluidicAssisted AFM Analysis. Submitted manuscript to Journal of Microbiological Methods September 2011. N.C. Cady, J. Behnke, R. Kubec, K. McKean, and R.A. Musah. Inhibition of biofilm formation in Pseudomonas aeruginosa by natural products-inspired organosulfur compounds. Submitted manuscript to Antimicrobial Agents and ChemotherapySeptember 2011. N.C. Cady, *J.L. Behnke, A.D. Strickland. Copper-based nanostructured coatings on natural cellulose: Nanocomposites exhibiting rapid and efficient inhibition of a multi-drug resistant wound pathogen, A. baumannii, and mammalian cell biocompatibility in vitro. (2011) Advanced Functional Materials. 21(13): 25062514.

TOPIC 2: Cell Patterning and Printing To better understand how cells behave in complex microenvironments, my group has pursued novel patterning strategies to attach cells to surfaces in fixed geometric patterns. This has resulted in a novel direct cell printing technology. This cell printing technology grew out of collaboration with the company BioForce Nanosciences that developed a nanoscale printing instrument called the Nano eNabler. My group beta-tested this instrument and developed our own micro scale quill pen printing components for live, whole-cell printing. This approach to live cell printing is much different than technique such as ink-jet or laser-based cell printing, both of which impart high thermal and shear forces on cells during the printing process. Due to the low-stress quill-pen printing method, both bacterial and mammalian cells can survive the printing process, including embryonic stem cells.

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The Nanobioscience Constellation Our quill-pen printing device and method has been submitted as a US patent application and has been used by several of our collaborators for a wide range of cell types.

Figure 3: A) GFP-expressing S. typhimurium patterned on a printed array of antibodies. B) Live/Dead stained mouse embryonic stem cells growing in a printed droplet of 3D matrix material. C) Micro scale cell-signaling study using printed E. coli receiver colonies which express GFP in response to quorum sensing signal molecules.

We are currently using our cell printing methods to study innate cell signaling (e.g. bacterial quorum sensing), as well as metabolic cross-feeding in synthetic or evolved bacterial systems (with our collaborator, Prof. Christopher Marx at Harvard University Dept. of Organismic & Evolutionary Biology). An example of these experiments is shown in Figure 3. Figure 3A shows our original cell patterning method (indirect printing of antibodies for subsequent cell capture), while Figure 3B shows mouse embryonic stem cells which were printed and allowed to grow for 96 hours. Finally, Figure 3C shows an example of a cell signaling experiment, in which quorum sensing autoinducers were printed next to spots of E. coli receiver cells that expressed GFP in response to the autoinducer signal. We are leveraging this technology in our most recent collaborative effort with collaborators Chris Marx at Harvard University and Daniel Segre at Boston University Biology Dept., in a Department of Energy grant entitled Open source platform for microbial ecosystems. In this work, we will use our cell printing technique to understand the micro scale dynamics of single bacteria and single colony interactions with nutrient sources, mimicking environmental scenarios. These studies will feed into simulation software to predict the outcomes of complex bacterial networks. This work is also being applied to a collaborative effort with Prof. Michelle Lennartz (Albany Medical College) to pattern surfaces for the study of phagocytosis and cell movement. TOPIC 3: Biosensor Development My group is currently focusing on field effect transistors (FETs) for sensitive detection and analysis of DNA hybridization and/or DNA damage events. A major focus of this work is to
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The Nanobioscience Constellation develop unique DNA immobilization strategies that optimize device sensitivity while also retaining native DNA structure and function. This includes the study of DNA interactions on materials used in modern nanoscale electronics, including high-K dielectrics, metal oxides, and compound semiconductors, as well as fabrication and testing of FET-based DNA sensors. We focus on field effect transistor (FET) and high electron mobility transistors (HEMT) devices, which are highly sensitive to changes in electrical potential at their surface. These sensors are ideal for detection of electrically charged molecules, such as DNA. This work is performed in collaboration with semiconductor physicists and engineers at the College of Nanoscale Science & Engineering, including Prof. Serge Oktyabrsky and Prof. Shadi Shahedipour-Sandvik. These collaborators focus on device engineering, while my group focuses on the interactions of biomolecules with device materials. We have developed unique strategies for linking DNA to semiconductor materials, including direct, coordination based linkage of phosphate-terminated molecules with metal oxides and Group III-nitride materials. Interestingly, we have shown that it is the terminal phosphate moiety that is responsible for this interaction, as phosphorylated DNA readily attaches to the surface while non-phosphorylated DNA does not attach. This fundamental surface chemistry/characterization allows us to better understand interactions on our surfaces and to exploit these interactions for the development of more sensitive electrical biosensors. We are currently leveraging this surface modification technique to construct high sensitivity DNA detection devices that can be applied towards pathogen detection, as well as for detection of DNA damage events. This work will be part of a future application to the NIH-NIEHS for development of a portable environmental monitoring device for assessing exposure to DNA damaging agents (with Prof. Tom Begley, CNSE). 2011 Publications:
N.C. Cady, S. J. Stelick, and C. A. Batt. PCR-based detection of Bacillus anthracis using an integrated microfluidic platform. (2011) International Journal of Biomedical Nanoscience & Nanotechnology. 211(2): 152-166.

TOPIC 5: Resistive Switching Devices (Re-RAM / memristors) As a biologist, I am interested in the science of memory formation, as well as the complex logic and memory functions of the human neural system. Memristors are nanoscale embodiments of rudimentary memory elements, such as neural synapses. The history of applied current and voltage on these devices dictate their resistance state, similar to how synapses are formed after repeated stimulation events. Our work focuses on the fundamental development of memristor devices, with the longer-term goal of incorporating these devices into neural-like networks, or complex
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Figure 4: The hysteretic behavior of memristors allows for repeatable programming under specific current/voltage conditions.

The Nanobioscience Constellation computational systems. My expertise in both biology and nanoscale device fabrication give me a unique perspective on these projects. My AFRL supported research on resistive switching focuses on development of memristors/Re-RAM for advanced computing and encryption applications, including neuromorphic computing. These projects leverage the advanced 300mm wafer processing facilities at the CNSE Center for Semiconductor Research (CSR), and fundamental nanomaterials processing and development with our academic collaborators. Our initial project focused on the development of nanomaterials for extremely small, high density memristor devices. This work has resulted in the development of nanomaterial synthesis and assembly strategies, as well as unique electrical testing approaches, such as conductive atomic force microscopy (C-AFM). As a follow-on to this project, I began collaborating with fellow CNSE faculty member, Prof. Wei Wang, an expert in computer architecture and circuit design. Together with Prof. Wang, I started two additional memristor programs with the AFRL. The first program focuses on the development of crossbar memristor devices (similar to the crossbar device shown in Figure 5 (top). This program was unique at CNSE and required close work with the CSR for device fabrication. The second program focuses on the use of memristors for combined transistormemristor logic and memory for advanced encryption applications. Prof. Wang has been responsible for the circuit architecture components of this work, while my group has focused on device fabrication and materials development. The materials aspect component of the work has led to fundamental insights into memristive device behavior, most notably when using copper-based electrodes. While developing metal oxide/metal combinations for individual memristive devices, we are also focusing on the mechanisms behind the resistive switching behavior that we are observing. These studies will pave the way for future efforts to create high density arrays of transistor-memristor hybrids which can be used for the long-term neuromorphic computing applications that are possible with these devices. 2011 Publications and Patents:
S.M. Bishop, H. Bakhru, S.W. Novak, B.D. Briggs, R.J. Matyi, and N.C. Cady. Ion Implantation Synthesized Copper Oxide-based Resistive Memory Devices. (2011) Applied Physics Letters. 99, 202102. B.D. Briggs, S.M. Bishop, K.D. Leedy, B. Butcher, R. L. Moore, S. W. Novak, and N.C. Cady. Influence of Copper on the Switching Properties of Hafnium Oxide-Based Resistive Memory. (2011) Proceedings of the Materials Research Society, San Francisco, CA. Ion Bombardment Synthesis of Transition Metal Oxide-Based Memory Devices. Submitted for US Provisional Patent, August 2011.

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Development of CMOS-compatible Resistive Memory Devices (Cady Group)


Scope: Resistive Memory Devices (RMDs) and novel processes to avoid interfacial voiding occurring in copper oxidation Goals: Produce resistive memory devices on a 300 mm-scale platform 2011 Accomplishments TOPIC 1: (1) Fabricate resistive memory crossbar arrays; (2) Fabricate CMOSReRAM hybrid devices for encryption circuitry The Cady group has worked closely with the Center for Semiconductor Research (CSR) during 2011 on the projects titled above to produce resistive memory devices (RMDs) on a 300 mm-scale platform. RMDs have a metal-insulator-metal structure and controllable change between resistance states by applying voltage/current. Two oxide materials were investigated to produce back-end-of-line (BEOL) compatible RMDs: HfOx and CuxO. Devices fabricated from these oxides have shown promising results. HfOx-based RMDs exhibited consistent on- and off-voltages from 10 m to 48 nm, as shown in the figure below (left).Using sweep-mode current-voltage measurements, endurance values of ~4000 cycles have been achieved for the HfOx devices. Working with the engineers of the CSR, our research has shown that oxidizing copper produces CuxO device layers that are not suitable for use in RMDs. To avoid the interfacial voiding that occurs in copper oxidation, the Cady group has invented a novel oxygen implantation process to synthesize copper oxide. RMDs fabricated from implantation-synthesized copper oxide switch down to diameters of 48 nm, as shown in the figure below (right).

Al SiOx CuxO

Cu

Cu

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Figure 1: Device scaling results for Ni/HfOx/Cu (left) RMDs and current-voltage behavior for a 48 nm Al/CuxO/Cu RMD (right).

2011 Presentations Include:


Challenges in the Fabrication of Copper Oxide Resistive Memory Devices, Spring Materials Research Society Meeting, San Francisco, CA, April 2011. Influence of Copper on the Switching Properties of Hafnium Oxide-Based Resistive Memory, Spring Materials Research Society Meeting, San Francisco, CA, April 2011. A Survey of Metal Oxides and Top Electrodes for Resistive Memory Devices, Spring Materials Research Society Meeting, San Francisco, CA, April 2011. Characterization of the Interfacial CuxO Layer in HfOx/Cu Resistive Memory Physical Electronics Conference, Albany, NY, June 2011. Properties and Challenges of Scaled Resistive Memory, Accepted for Oral Presentation at the International Semiconductor Device Research Symposium, Baltimore, MD, Dec. 2011 Analysis of Nonpolar Resistive Switching Exhibited by Al/CuxO/Cu Memristive Devices Created via Room Temperature Plasma Oxidation, International Semiconductor Device Research Symposium, Baltimore, MD, Dec. 2011. Comparison of HfOx-Based Resistive Memory Devices with Crystalline and Amorphous Active Layers, Accepted for Oral Presentation at the International Semiconductor Device Research Symposium, Baltimore, MD, Dec. 2011.

2011 Journal Articles:

Ion Implantation Synthesized Copper Oxide-Based Resistive Memory Devices, Appl. Phys. Lett. 99, 202102 (2011). Ion Bombardment Synthesis of Transition Metal Oxide-Based Memory Devices, Filed on 8/23/2011 (Serial No. 61/526537).

2011 Patent Applications:

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Wafer Processing and Nanobioscience Research (Castracane Group)


Scope: 3D interconnect nanobioscience research bonding materials/technology development and

Goal: Provide R&D in support of wafer integration activities 2011 Accomplishments TOPIC 1: Development of New Materials, Processes and Instrumentation to Advance Wafer to Wafer and Die to Wafer Integration Experiments were carried out in support of the Sematech 3D integration program. New bonder metrology instrumentation was developed along with bond strength tests and introduction/characterization of a set of novel materials for temporary bonding.

Figure 1: Multichannel Piezoelectric Array for Monitoring Bonder Uniformity.

Figure 2: Chevron Bond Strength Tester and Initial Cu-Cu Chevron Bond.

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Figure 3: Temporary Bond Materials Characterization Table.

Gracias, N. Tokranova, J. Castracane, A. Rudack, and R. Edgeworth, Evaluating the Chevron Test as a Potential New Mechanical Testing Technique for Comparing Wafer Bonds for 3D Integration, ECTC Conference, (2011). Gracias, N. Tokranova, B. C. M. Thelen and J. Castracane, Influence of Diamond Nanoparticles on the Thermal Properties of BCB, Phys. Status Solidi A, 208, 684-690, (2011)

TOPIC 2: Development of a GHz SAW Device for Lithography Mask Particle Removal Goal: Study the basic physics interaction between high frequency acoustic waves and surface contaminants for eventual application to mask cleaning. This work focused on the initial development of a customized Surface Acoustic Wave (SAW) device to study the physical interaction between high frequency acoustic waves and nanometer-scale particles. Prototype SAW devices were fabricated using Lithium Niobate and Lithium Tantalate substrates with micropatterned electrode arrays on their surfaces and tested. In addition, wave particle interactions have been studied using the COMSOL modeling package.

Figure 4: Prototype Focusing SAW Device.

Figure 5: Focusing SAW Electrodes (3 microns wide).

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Dry Focused IDT

Resonant Frequency

Figure 6: Experimental Resonant Frequency and COMSOL Simulation of Focusing Electrode SAW.

TOPIC 3: Development of The NANIVID for Cancer Cell Migration Studies Goal: Create an Implantable Device to Collect Migrating Cancer Cells as They Leave Primary Tumor Sites This work focused on the development and deployment of the NANo IntraVItal Device (NANIVID) in support of the cancer cell metastasis studies. The device successfully completed in vitro tests and began in vivo studies using a rat model.

Figure 7: in vivo NANIVID (5 mm long) and first example of cancer cells (green) captured in the device. M. Padgen, J. K. Williams, Y. Wang, F. Gertler, J. Condeelis and J. Castracane, Probing the Tumor Microenvironment: Collection and Induction, to be published, Microfluidics, BioMEMS and Medical Microsystems-SPIE, (2012). J. K. Williams, M. Padgen, Y. Wang, F. Gertler, J. Condeelis and J. Castracane, NANIVID: A New Technology to Analyze Shallow Gradient Chemotaxis in Vitro and in Vivo, Proceedings of the American Society of Cell Biology Annual Meeting, (2011). W. Raja, B. Glogorijevic, J. Wyckoff, J. Condeelis and J. Castracane, A New Chemotaxis Device for Cell Migration Studies, Invited Paper, Integrative Biology, Vol. 2, no. 11-12, pp. 696-706, (2010).

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TOPIC 4: Micro/Nano-Patterned Substrates for Salivary Gland Replacement Goal: Create Biocompatible Scaffolds for Effective Cell Growth and Re-generation. This work focused on the development of a nanofiber-based mesh which can be functionalized to assist in salivary cell gland growth and gland formation. The use of a micropatterned substrate overgrown with nanofibers drove cell growth and differentiation.

Figure 8: (Top) Micropatterned substrate with nanofiber mesh; (Bottom) ICC stained cells showing increased cell width on curved substrates. S. I. Cantera, R. Jean-Gilles, S. Sequeira, D. Soscia, J. Castracane and M. Larsen, Functionalizing PLGA Nanofiber Scaffolds to Regulate Salivary Gland Cell Behavior, to be published, Proceedings of the AADR Annual Meeting, (2012). S. Sequeira, D. Soscia, B. Oztan, R. Jean-Gilles, A. Gadre, B. Yener, J. Castracane, and M. Larsen, Nanofiber Artificial Scaffolds Regulate Salivary Gland Epithelial Cell Morphology and Focal Adhesion Complex Formation, to be published, Biomaterials, (2011). R. Jean-Gilles, D. Soscia, S. Sequeira, M. Melfi, A. Gadre, J. Castracane and M. Larsen, Novel Modeling Approach to Generate a Polymeric Nanofiber Scaffold for Salivary Gland Cells, Invited Paper, Journal of Nanotechnology in Engineering & Medicine, Vol 1, Iss. 3, pp. 1-9, (2011).

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Cancer Cell Metastasis and Nanoscale Topography (Hempel Group)


Scope: Using Nanobiotechnology in the field of Cancer Cell Biology, with specific interests in tumor metastasis, signal transduction and reactive oxygen species Goal: To understand the molecular and cellular mechanisms that drive tumor metastasis and to develop nano-scale topography for diagnostic and analytical applications in this context 2011 Accomplishments TOPIC 1: Development of Nanotopography Arrays for Metastatic Cancer Cell Characterization and Diagnosis

Figure 1: A. SEM images of 65nm nanotopography utilized in B & C. B. Anisotropy of 253J-BV cells on 65nm lines (right), unpatterned surface on left. Arrow indicates line direction. Angle of cellular protrusions in relation to direction of lines was quantified in pie charts C. 253J-BV migration is driven in direction of 65nm lines in a wound-healing assay.

There is a growing need for the development of novel platforms to study the metastatic phenotype of cancer cells. The ability of a tumor cell to metastasize begins with migration and invasion through the extracellular matrix (ECM). It is becoming apparent that physical cues have a prominent role in determining a cells ability to

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The Nanobioscience Constellation circumnavigate its environment and that this interaction regulates cellular signaling events. Physical features of the ECM are typically of the nano scale, below 100nm. We show that interactions with 65nm line topography are enhanced in bladder tumor cells that have acquired a metastatic phenotype (253J-BV) and that these cells display enhanced anisotropy compared to related non-metastatic cells (253J). Interactions with nanotopography that simulate the size and structure of ECM fibrils appears to be able to uniquely distinguish metastatic from non-metastatic cells, based on cell morphology, anisotropy, and differential pro-migratory signaling. Since joining the Faculty at CNSE in the fall semester of 2011, I have actively pursued the hypothesis that a nanotopographical feature array, which mimics the ECM, will serve as a precise and powerful diagnostic device for the identification and characterization of metastatic tumor cells, leading to the following applications: 1) High through-put screening tool for the identification of metastatic tumor cells. 2) Analytical platform to study migration of tumor cells in response to physical and chemical stimuli. 3) Molecular biological tool to study pro-metastatic signaling pathways that are driven by physical interactions and for the identification of novel metastatic tumor cell markers. 4) Screening device for multi drug resistance (MDR) and antimetastatic therapies. This project is being conducted in collaboration with Drs. Timothy Groves and Scott Tennenbaum and is the basis for a R01 NIH/NCI funding application.

Figure 2: A nanatopographical obstacle course will enable better characterization of the metastatic phenotype by uniquely discriminating between metastatic from non-metastatic tumor cells, allowing for analysis of the mechanisms that regulate tumor cell migration in response to physical cues.

TOPIC 2: Role of Reactive Oxygen Species on Pro-Migratory Signaling Events Reactive Oxygen Species (ROS) have an emerging role in regulating cellular signaling and have recently been implicated in metastatic progression. Our data show that subtle pico-molar increases in endogenous H2O2 are necessary and sufficient in regulating the migratory and invasive phenotype of metastatic cancer cells. We have shown that this redox-dependent regulation of migration occurs primarily at the level of the signaling adaptor protein p130cas, rather than previously reported redox control of Focal Adhesion Kinase.

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The Nanobioscience Constellation Compared to a non-metastatic parental cell line, intracellular increases in H2O2 levels strongly enhance p130cas phosphorylation and membrane recruitment, association with Crk, actin cytoskeletal reorganization and Rac1 activation within metastatic bladder cancer cells; events that are effectively abrogated following H2O2 removal by catalase. Mechanistically, redox-control of p130cas is driven by oxidative inactivation of its primary phosphatase PTPN12. The increased intracellular redox environment of metastatic tumor cells also leads to enhanced oxidation of the antimigratory phosphatase PTEN and we show that PTEN oxidation also leads to dissociation of PTEN from the plasma membrane, a major site of its action. These data introduce a new paradigm whereby ROS can reciprocally regulate the cellular localization of pro- and anti-migratory signaling molecules; and whereby subtle changes in the intracellular ROS environment can have profound effects on prometastatic signaling pathways.
Figure 3: Enhanced p130cas phosphorylation (as observed by immunofluorescent staining) regulates the metastatic phenotype of 253JBV cells. Higher oxidation profile and inactivation of phosphatases PTPN12 and PTEN underlies this change in prometastatic signaling.

Hempel N, Ye H, Abessi B, Mian B, Melendez JA (2009) Altered redox status accompanies progression to metastatic human bladder cancer. Free Radical Biology & Medicine, 46(1):42-50. PMCID: 2630461 Hempel N, Mian B, Melendez JA (2011) Intracellular redox-control of the metastatic phenotype through reciprocal regulation of pro- and anti-migratory signaling. Molecular and Cellular Biology, in submission. Project is funded by the NIH/NCI Transition to Independence grant K99CA143229 and is in collaboration with Dr. J. Andres Melendez.

TOPIC 3: Role of Antioxidant Enzymes and the Mitochondria on Metastasis Manganese superoxide dismutase (Sod2) has emerged as a key enzyme with a dual role in tumorigenic progression. Early studies were primarily directed at defining

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The Nanobioscience Constellation the tumor suppressive function of Sod2 based on its low level expression in many tumor types. It is now commonly held that loss of Sod2 expression is likely an early event in tumor progression allowing for further propagation of the tumorigenic phenotype resulting from steady state increases in free radical production. Increases in free radical load have also been linked to defects in mitochondrial function and metastatic disease progression. It was initially believed that Sod2 loss may propagate metastatic disease progression, in reality both epidemiologic and experimental evidence indicate that Sod2 levels increase in many tumor types as they progress from early stage non-invasive disease to late stage metastatic disease. Sod2 overexpression in many instances enhances the metastatic phenotype that is reversed by efficient H2O2 scavenging. In 2011 we prepared a review article that evaluates the many sequelae associated with increases in Sod2 that impinge on the metastatic phenotype. The ability to use Sod2 to modulate the cellular redox-environment has allowed for the identification of redoxresponsive signaling events that drive malignancy, such as invasion, migration and prolonged tumor cell survival. Further studies of these redox-driven events will help in the development of targeted therapeutic strategies to efficiently restrict redoxFigure 4: Changes in Sod2 mRNA levels are associated with signaling essential for Grade, Metastatic Progression and Survival of Breat (A & C) and malignant progression. We Brain Cancers (B & D). Data was obtained from oncomine.org are interested in further and expressed as box and whisker plots using GraphPadPrism this Statistical software. (*p<0.05, **p<0.01 *** p<0.001; A, B & C, t- understanding dichotomous role of Sod2 test; C, ANOVA, Tukeys Post test) and another antioxidant enzyme, Catalase, during cancer development and are actively studying the role of these enzymes in a number of cancer types including ovarian and bladder cancer cell lines. We are also interested in utilizing Nanoscale therapeutic delivery methods to specifically target these antioxidant enzymes at tumor sites.

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Conner K, Hempel N, Nelson KK, Dabiri G, Gamarra A, Van De Water L, Mian B, Melendez JA (2007) Manganese Superoxide Dismutase enhances the invasive and migratory activity of tumor cells. Cancer Research, 67(21):10260-7 Hempel N, Carrico PM, Melendez JA (2011) Manganese Superoxide Dismutase (Sod2) and Redox-Control of Signaling Events that Drive Metastasis Anti-Cancer Agents in Medicinal Chemistry, 11(2):191-201

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Development of Nano-based Therapeutics to Limit Cancer, Aging, and Infectious Disease Processes (Melendez Group)
Scope: Evaluate the role of reactive oxygen and nitrogen species in the control of cancer aging and infectious disease Goal: Provide R&D for the development of targeted antioxidant basted therapies for the treatment of metastatic cancer, aging and infection 2011 Accomplishments TOPIC 1: Identify the Redox-Regulated Molecular Events that Control Age Associated Matrix Destruction Mediated Through the Production of Senescence Associated Factors We have identified potent therapeutics that block age-associated matrix metalloproteinase (MMP) expression. Aberrant production of these matrix metalloproteinases (MMPs) is in large part responsible for joint destruction associated with arthritis, the invasive nature of malignant tumors, atherosclerotic plaque rupture, breakdown of the blood brain barrier associated with stroke injury and emphysema induced fibrosis.
DAPI DsRED-IL-1 Merge

We have also identified another trait that is associated with the aging process that is in large part responsible Young for the inflammatory properties of senescent tissue. Senescent cells which no longer divide secrete factors that drive inflammation and tissue destruction and tumor infiltration. We have established Old that the nuclear localization of the Figure 1. inflammatory cytokine interleukin-1 is key to this process. Studies are underway to define the molecular details surrounding this event and we are now in the process of developing nanoparticles that will allow for selective release of antioxidants at these sites of senescence.

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Relative MMP-1 cDNA units

**

** *** ***
Mix

PS

Sen Didox PomX Cat APE

Figure 2. Senescence associated H2O2 promotes the nuclear localization of IL-1 during cellular senescence. Confocal microscopy of a DsRED-IL-1 construct 16h post-transient transfected into young and old primary human fetal lung fibroblasts. Donald McCarthy, Nadine Hempel, Sita th Subbaram, and J. Andres Melendez, 18 Annual SFRBM Meeting, Atlanta, GA November 16-20, 2011. Redox-control of senescence associated IL-1 expression , nuclear localization and the inflammatory phenotype. DA McCarthy, A Ranganathan, S Subbaram, N Hempel and JA Melendez. Manuscript in Review, Aging Cell Natural compounds have the ability to reduce senescence associated increases in MMP-1. Combination treatment represents treatment with didox, pomegranate extract, and apple peel extract in equal parts. RT-PCR data error bars represent S.E., n=3. * represents p < 0.05, ** th represents p < 0.005. Nilay Patel, Donald McCarthy, and J. Andres Melendez, 18 Annual SFRBM Meeting, Atlanta, GA November 16-20, 2011.

TOPIC 2: Redox-Control of Metastatic Bladder Cancer Progression Bladder cancer incidence is commonly associated with tobacco use and exposure to environmental toxicants both of which lead to the production of biologically reactive oxygen and nitrogen species. We have identified redox-responsive gene signatures that regulate the development of metastatic bladder cancer and control their tissue invasiveness. One key attribute of the malignant lesions is a chronic increase in mitochondrial oxidant production which alters their migratory and invasive behavior. We continue to explore the molecular details that control the metastatic behavior of these tumor cells through ongoing collaborations with the nanobioscience group. Treatment for metastatic bladder cancer has not been forthcoming and these studies suggest that targeted-antioxidant based therapies may be useful in limiting disease severity.

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Figure 3. Mitochondria-targeted Sod2 mimetic, mito-carboxy proxyl (mito-CP), differentially kills bladder tumor cells based on their basal redox-tone. Clonogenicity of 200 cells seeded was analyzed following 7 days of treatment with indicated doses of mito-CP in complete media. Colonies formed were stained by crystal violet, counted and survival fraction plotted (n=6, except U-6 Sod2, n=3; mean +/- SEM; One-way ANOVA, with Tukey's post-test analysis was performed to compare treated wells to non-treated wells from each cell line; p***<0.001). Hempel N, Carrico PM, Melendez JA. Manganese superoxide dismutase (Sod2) and redoxcontrol of signaling events that drive metastasis. Anticancer Agents Med Chem. 2011 Feb;11(2):191-201. Ye H, Hempel N, Moore E P, Bagepalli L R,. Taylor M T, Bhatty V, Joseph J, Kalyanaraman B,. Mian BM and Melendez JA. Differential regulation of Erk signaling by mitochondrial superoxide controls the invasive potential of bladder cancer cells. Manuscript in Submission. Hempel N, Mian BM, and Melendez JA. Intracellular redox-control of the metastatic phenotype through reciprocal regulation of pro- and anti-migratory signaling via p130cas and PTEN. Manuscript in submission.

TOPIC 3: Redox-Control of Tularemia Pathogenesis Protective immune responses to bacterial infection are triggered by pathogenderived proteins, DNA and lipid components through a diverse array of activation signals. Upon activation, host inflammatory cells respond to the pathogen-derived insult by the production of inflammatory cytokines and cytotoxic reactive oxygen and nitrogen species (ROS/RNS). Many pathogens resist ROS/RNS by augmenting antioxidant defenses or by short circuiting the host signaling pathways that lead to their production. ROS/RNS have also emerged as second signaling messengers that can control cellular function. A pathogens antioxidant armature not only provides direct protection from oxidative attack, but may interfere with host cell signaling that regulates protective

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The Nanobioscience Constellation immunity. Thus, shifts in bacterial redox-state can have a profound impact on its immunogenic properties that can be harnessed toward the development of a potent immunogen. In support of this idea, is the finding by our group that Francisella tularensis (Ft) strains that are defective in antioxidant enzyme activity can serve as effective immunogens against the virulent Ft SchuS4(Melillo et al. 2010). We are also evaluating the use of nanomaterial as adjuvants for immune therapy.
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Figure 4: Addition of Nanoclay boosts inflammatory response of Murine Alveolar Macrophages to Francisella infection.A) IL-1 mRNA levels as measured by real time PCR after 24 hours of infection with and without nanoclay. B) IL-1 protein levels as measured by an MSD murine cytokine assay after 24 hours of infection with and without nanoclay.

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Stem Cell Biology and Bio-NEMS/MEMS (Paluh Group)


Scope: Two areas: Signaling within cells and in a multi-cellular environment for medical and biosensing applications, and adaptation of cellular nanoobjects, nanooperations, and nanosystems toward novel bio-NEMS and bio-MEMS Goal: To meet grand challenges in 1) medicine, through stem cell based therapies and nanomedicine, and 2) next generation nanomanufacturing 2011 Accomplishments TOPIC 1: Application of stem cell biology to understanding and treating human injury and disease (Stem cell biology, adult and pluripotent stem cells and their progenitors; tissue culture, 3D matrices, functionaled surfaces, microfluidics, microscopy, whole genome systemic analysis via microarrays, epigenetics, proteomics, next generation sequencing) Project 1: Pluripotent stem cells in human therapies offer unrivaled potential. Embryonic stem cells (hESCs) remain the gold standard of pluripotent cells for biomedical research and therapies and there is a need to bank hESC lines from diverse ethnic backgrounds. The moral/ethical considerations surrounding these cells as well as effects of immune status have driven research into generation of immune matched patient-derived induced pluripotent stem cells (iPSCs) that will avoid the need for immune suppressing drugs. The current procedures however, to generate iPSCs by dedifferentiation of adult somatic cells, ie. to reprogram them to an embryonic-like state are inefficient. As such iPSCs remain expensive and infeasible for general medical applications. Collaborations to generate new hESC lines from minority populations and to identify new improved regulators of dedifferentiation for iPSC lines are underway. Project 2: Our goal is to develop successful therapies for brain damage due to injury or disease based on stem-cell derived nerve cells. A key requirement is that the stem cell-derived neurons grow, survive and integrate into the damaged neuronal network and that they take over the functions of the cells that were lost. Cholesterol is vital for cells as it serves as an essential membrane component and as precursor and cofactor for signaling molecules. Nerve cells need significant amounts of cholesterol to form and maintain their morphology and function but have no access to the cholesterol supplied by the diet and by synthesis in the liver. A collaboration to study how stem cells and the derived neurons regulate their cholesterol content under normal conditions and in pathologic environments is underway.

In search of the holy grail: engineering the stem cell niche. J.L. Paluh, J.L., G. Dai, and D.B. Chrisey, European Pharmaceutical Review 16, (2011) 28-33.

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Figure 1: Stem Cell Application Schematic.

TOPIC 2: Adaptation of Cellular Nanoobjects, Nanooperations and Nanosystems Toward Novel Bio-NEMS and Bio-MEMS to Meet Next Generation Nanomanufacturing Needs There is a national need to develop new paradigms (next generation) nanomanufacturing. This means that critical technologies, tools and strategies need to

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The Nanobioscience Constellation be developed to leverage self-assembling, dynamic and trainable biological systems that can operate largely outside of direct human input. Nanoscale biosynthetic devices that incorporate a range of biological components, including proteins, offer this incredible potential but represent a grand challenge. We have assembled a team of experts to incorporate natural and re-engineered proteins of the eukaryotic cytoskeleton into devices, bio-NEMS and bio-MEMS that will incorporate novel adaptable capacities for nanomanufacturing.

Figure 2: Proposal Overview for cytoskeleton system adaptive nanomanufacturing. Towards Nanorobotics, Nanonetworks, and Self-Assembling and Regulating Machines. J.L.Paluh, Nanotechnology Now (2011) http://www.nanotech-now.com/columns/?article=507

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Mammalian and Microbial Cell Bioprocessing (Sharfstein Group)


Scope: Production of therapeutic and diagnostic biomolecules from cultured animal and bacterial cells; development of models for in vitro testing of small molecule therapeutics; development of sensing technology to support cell culture Goal: Develop fundamental understanding of the role of cell culture conditions and cell physiology on the production of biotherapeutics 2011 Accomplishments TOPIC 1: Understanding Cellular Responses to Increased Osmolarity In an effort to understand how cultured mammalian cells respond to increased osmolarity, we performed a number of transcriptomic DNA microarray studies to identify differentially expressed genes. We identified a large number of differentially expressed

Figure 1: Method for integrating expression and pathway data. First, raw microarray data is processed to produce a list of differentially expressed genes and their corresponding fold changes. Pathway interaction databases are used to derive a biological pathway connecting the differentially expressed genes. Finally, we use the connections present in the pathway along with the observed fold changes to compute an expected fold change for each gene. Expected fold changes are finally compared to observe fold changes to highlight discrepancies thereby identifying potentially interesting genes. The gene highlighted in red would be considered interesting because the measured fold change of -2.5 is significantly different from the predicted fold change of 2.13 derived from the interactions in the pathway.

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The Nanobioscience Constellation genes and are attempting to identify those genes that are relevant to the observed phenotypes (i.e. increased productivity of antibody and decreased cell growth). To achieve that aim, we have taken a two-pronged approach, development of novel computational approaches to analyzing DNA microarrays (Figure 1) and highthroughput screening of silencing RNA molecules to determine the effects of gene knockdown on phenotypic response (Figure 2). We are also investigating the role of cell signaling, cell size, and metabolism on osmotic stress responses. To that end, we have a pending proposal to the National Science Foundation for a collaborative study with Pfizer, Inc. to perform studies in industrially relevant cell lines under industrial bioprocessing conditions.
Figure 2: High-throughput viral delivery of silencing RNA. Retroviruses containing shorthairpin RNA (shRNA) in alginate solution are spotted by a microarray contact printer onto microscope slides. Subsequently cells in alginate are spotted (60 nL spots) on top of the viruses. Viral delivery of shRNA permits gene knockdown and then cells are screened for viability using a live/dead stain in the right panel.

TOPIC 2: Epigenetic Analysis of Chinese Hamster Ovary Cells Producing Recombinant Monoclonal Antibodies In an effort to understand the role that epigenetics plays in controlling productivity in clonal cell lines producing the same recombinant monoclonal antibody with different levels of productivity, we have looked at association between transcription factors and the promoter region for our gene of interest using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays (EMSA). In addition, we have examined the methylation state of the promoter using bisulfite sequencing and 5-azacytidine treatment to explore the effects of demethylation on productivity.
H. Zhang, M-Y. Lee, M.G. Hogg, J.S. Dordick, and S.T. Sharfstein, High throughput delivery of interfering RNA in a three-dimensional cell-culture chip, Small, submitted T.R. Kiehl, D. Shen. S.F. Khattak, Z. Lee, and S.T. Sharfstein, Observations of cell-size dynamics under osmotic stress, Cytometry Part A, 79A: 560-569 (2011). Noted as a System of Interest on the Journal Cover. GOALI Supplement: Understanding the effects of hyperosmolarity on cell physiology and protein quality in CHO cell cultures, S. Sharfstein and S. Casnocha, $149,968.00, pending, proposal submitted to the National Science Foundation 7/12/2011. Collaborative with Pfizer, Inc.

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As shown in Figure 3, the A0 (low productivity) and A1 (high productivity) clones exhibit differential binding of several transcription factors, most notably CREB and AP1 which share a consensus sequence. This suggests that there are differences in the chromatin organization between the high productivity and low productivity clones that could potentially be exploited. To exploit those differences, we treated both high and low productivity clones with 5-azacytidine, a DNA methyltransferase inhibitor. As shown in Figure 4, the A0 low productivity clone shows a significant increase in specific productivity (qP) in response to azacytidine treatment, whereas the A1 clone does not. Interestingly, the C family of clones (C0-low productivity and C1 high productivity) both show enhancement upon azacytidine treatment, but not as significant as the A0 cell line.

Figure 3: Binding of transcription factors to CMV promoter region DNA as determined by chromatin immunoprecipitation.

Figure 4: Change in specific productivity of varying cell lines upon treatment with 5-azacytidine (AZA). A0 and C0 are low productivity clones, while A1 and C1 are methotrexate amplified high productivity clones. Cells were treated for 3 days with AZA and then cell counts were performed and productivity assayed.

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The Nanobioscience Constellation TOPIC 3: Metabolic Engineering Pharmaceutical Heparin of CHO Cells for the Production of

In an effort to synthesize a bioengineered heparin (the most widely used anticoagulant drug in the world) that will be free from biological and chemical contamination, we have introduced two genes not normally expressed in CHO cells into wild type CHO-S cells. These genes, human N-deacetylase/N-sulfotransferase (NDST2) and mouse heparan sulfate 3-O-sulfotransferase 1 (Hs3st1) were stably transfected under the control of the strong viral CMV promoter. qRT-PCR and western blotting were used to verify the expression of the genes of interest in transfected cell clones. Two clones were selected for further analysis. Anticoagulation assay and glycosaminoglycan profiling using liquid chromatography and mass spectrometry (LC/MS) demonstrated a marked improvement in anticoagulation when compared with the native heparan sulfate typically synthesized by CHO-S cells; however, the LC/MS analysis showed that the disaccharide forms are still quite different from pharmaceutical heparin (Figure 5).

Figure 5: Metabolic engineering of CHO cells to produce heparin. Left panel-NDST2 AND HS3ST1 activities are introduced into CHO cells to alter the glycan structure of heparan sulfate (HS) to make it more heparin-like. Center panel-engineered HS show substantially increased anti-coagulant activity, but still much lower than heparin. Right panel-the disaccharide profile is substantially altered in engineered CHO cells, but still quite different from heparin. J-Y. Baik, L. Gasimli, B. Yang, P. Datta, F. Zhang, C.A. Glass, J.D. Esko, R.J. Linhardt, and S.T. Sharfstein, Metabolic engineering of Chinese hamster ovary cells: Towards a bioengineered heparin, Metabolic Engineering, in revision.

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Gene Expression (Tenenbaum Group)


Scope: All areas of Molecular Biology including gene expression, genomics and cancer biology Goal: Utilize nanoscale technology to study genomics and life/medical science 2011 Accomplishments TOPIC 1: sxRNA: An RNA-based Nanoswitch Most medicines interact with proteins in the body, but more recently gene therapies have targeted DNA directly to affect bodily functions. That leaves a third class of molecules completely untapped in terms of medical interventionsRNA. We have found a way to target and report the presence of any RNA of interest in a living cell. We developed a nano-based technology called sxRNA that can be injected into cells to seek out a specific RNA molecule. If the target is found, the sxRNA switches on the expression of a reporter gene that glows literally functioning as an indicator light. Accurate reporting of the presence of an RNA molecule could be used to diagnose certain diseases in which certain genetic pathways are overactive and cause pathology. The invention has been patented as a platform technology. That means that rather than creating a single diagnostic or therapeutic tool, the Tenenbaum group is developing the process to be applicable to any medical intervention that involves RNA molecules. In the future, we envision possibilities where instead of creating a mere signal for the presence of a particular RNA, the sxRNA could switch on a gene that repairs faulty cell function or a gene that causes the self-destruction of a cancer cell. When fully developed, the sxRNA platform technology will not only represent a powerful new molecular tool but will also have tremendous potential for the development of novel therapeutics, anti-virals, and even imaging applications with substantial impact on a multibillion dollar industry.
We have developed a novel, breakthrough technology that acts as a Nano-switch mechanism to turn on and off expression of a protein using RNA rather than DNA. No
Figure 1. Structurally Interacting RNA (sxRNA) A. Wild-type mRNA Coding region Expressed protein B. Off sxRNA RNA binding protein

Coding region Translation inhibited C. On sxRNA Coding region Expressed protein

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Panel A. An RNA binding protein (RBP) binds to its naturally occurring wild-type stem-loop target sequence, which results in increased translation of an upstream gene by as much as an order of magnitude; Panel B. We informatically design an sxRNA switch with a mutated stem-loop that prevents RBP binding and inhibits translation of the gene; Panel C. In the presence of a targeted miRNA trigger, a trans-acting, 3-way structure forms that stabilizes the stemloop target structure. The RBP binds to the new sxRNA stem-loop target sequence resulting in increased translation of the upstream gene.

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other RNA based technology allows a similar control of protein expression, and we believe that this RNAbased, Nano-switch platform technology, called structurally interacting RNA (sxRNA), has the potential to replace gene therapy and create an entire new therapeutic class commanding a market value of several billion dollars.

TOPIC 2: Study the Motility of Cancer Cells on Topographically Patterned Surfaces Human breast cancer cells were grown in vitro on a patterned silicon dioxide structure fabricated using the Vistec VB300 e-beam lithography tool at CNSE. This is shown in Figure 2 below. We observe that the cells extend invasapodia, which align with the pattern features. Interestingly, normal cells of the same type of tissue do not exhibit this behavior. It is known that cancer cells metastasize throughout the body by first penetrating small gaps in the tumor tissue and blood vessel walls. It is also known that cancer cells differ morphologically from normal cells of the same tissue. This work shows early indication of the mechanisms underlying cancer cell metastasis. We have established an ongoing and active cancer metastasis-working group at CNSE, including faculty members Nadine Hempel, Andre Melendez, Scott Tenenbaum, and Timothy Groves. The group also includes Dr. Thomas Goodman, a cofounder and partner of the Upstate Hematology and Oncology Clinic located in Niskayuna, NY.

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Figure 2: Human breast cancer cells grown in vitro on a patterned silicon dioxidesurface. The cells spontaneously align with the pattern features. This provides early indication of the mechanisms underlying cancer cell metastasis. (Courtesy of William Stephenson, Ph.D. student, CNSE).

TOPIC 3: Development of a High-Throughput Nanoscale Immunoassay Platform Immunoassays, and more specifically microarray-based immunoassays, are gaining in importance as a platform for the high-throughput detection of proteins. This technology has advanced greatly, with the development of new signal generation and detection techniques, surface chemistries and various assay formats. The applicability of current antibody based assays for profiling complex biological samples is still restricted at the moment and if simple strategies are used, such as protein labeling with dyes, detection is very limited. Some of the known limiting factors affecting immunoassays include low stability of antibody molecules, strong background signal due to inevitable protein adsorption on many kinds of surface supports, insufficient sensitivity of detection and most pronounced, the limitation of the mass-transport constraints on the reaction kinetics of many typical antibody-based assays. Due to a small binding area of most microarray based immunoassays and microspot kinetics the assay times frequently require many hours, which is compounded by limitations on the ability to achieve ideal masstransport and independent incubation conditions using a traditional 2-dimensional support surface. Optimization of masstransport limitations represents an extremely important concern in immunoassay design. Equally important is the limited ability to simultaneously investigate multiple (many) antibodies simultaneously. To address these issues, in collaboration with CNSE colleague, Jim Castracane, we have developed a novel nanotechnology wafer that employs a multiplexed, high-throughput assay that enables the simultaneous survey or capture of multiple proteins/nucleic acids of interest in a single reaction. This technology focuses on the fabrication of multiporous structures from a variety of materials including silicon, aluminum, SU8, etc. that serve as a host matrix to help in the attachment, filtering and analysis of selected chemicals of interest. The ability to create a high surface area in a minimal volume makes this process ideal for biological processing applications.

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The Nanobioscience Constellation The flexibility in the fabrication process of these porous structures allows for the architectures which range from ordered through-holes (chambers) with diameters in the 10-50 micron range, to more random structures with sponge-like features and porosity. This new nanoassay platform is being optimized to perform high-throughput chromatin immunoprecipitation (ChIP-Chip) assays and RIP-Chip assays but it is likely that the custom process we are developing can be used to produce multiplexed, microporous wafers that maximize the impact on high-throughput biological immunoassay analysis. TOPIC 4: Studying the mRNP Regulatory Code Post-transcriptional gene expression is primarily mediated by RNA-binding proteins (RBPs), which represent the primary area of expertise for our research. While most gene expression research is centered on transcriptional regulation, we now know that most eukaryotic genes are also highly regulated at the level of post-transcription. Unfortunately, our understanding of post-transcriptional regulation is comparatively limited, with only a handful of these regulatory elements being experimentally characterized. Successful post-transcriptional control of gene expression depends on the actions of RBPs, which provide a connection between transcriptional and translational regulation and play essential roles in many fundamental regulatory processes including RNA splicing, export, stability and translation. Our team is engaging in a new type of research, called systems biology or genomics, which emphasizes studying all genes and how they are interconnected. Our research targets RBPs to better understand post-transcriptional gene-expression networks. Previously, we developed genomic-based technologies for capturing RBPmRNA complexes from cellular extracts and identifying the associated messages using microarray technology. This new approach to post-transcriptional functional genomics (termed Ribonomic or RIP-Chip profiling) greatly facilitated the quantitative identification of mRNA targets of many RBPs. It also facilitated the analysis of the structural and functional relationship of the genes encoded by these mRANAs. Data generated using RIP-Chip profiling led to several basic observations about the mRNA infrastructure in the cell and a proposal, called the post-transcriptional operon model that predicts a functional relationship for groups of genes regulated by RBPs.

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Nanobioengineering Stem Cell Technology (Xie Group)


Scope: Nanobioengineering embryonic microenvironments, normal and diseased tissues Goal: Understand and restrict cancer metastasis, obesity and eye diseases 2011 Accomplishment TOPIC 1: Bioengineering Embryonic Stem Cell Microenvironments to Restrict Cancer The interaction between cancer cells and their microenvironments plays a crucial role in breast cancer metastasis. Invasive cancer cells have been linked to embryonic stem (ES) cells, in which embryonic signaling pathways are mis-expressed and disregulated. Our results demonstrate that bioengineered embryonic microenvironments using 3D hydrogel inhibits the proliferation and migration of highly invasive breast cancer cells, indicating the potential to reprogram metastatic cancer cells to a less malignant phenotype. This bioengineering approach provides a new avenue for better understanding and restricting tumorigenesis and metastasis.

Figure 1: Inhibitory Effects of Bioengineered PSC Microenvironments on Metastatic Breast Cancer Cell Proliferation (a) and Migration (b & c). Bioengineering Embryonic Stem Cell Microenvironments for the Study of Breast Cancer, N. Abdul Raof, B. Mooney, and Y. Xie, International Journal of Molecular Sciences 12, (2011), 7662-7691. http://www.mdpi.com/1422-0067/12/11/7662/ Bioengineering Embryonic Stem Cell Microenvironments for Exploring Inhibitory Effects on Metastatic Breast Cancer Cells. N. Abdul Raof, W.K. Raja, J. Castracane, and Y. Xie, Biomaterials 32, (2011), 4130-4139. http://www.sciencedirect.com/science/article/pii/S0142961211001876

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The Nanobioscience Constellation TOPIC 2: Bioengineering Adipogenesis Embryonic Stem Cell Microenvironments for

Adipocytes play a major role in energy imbalance and show therapeutic potential for obesity. The ability to manipulate the differentiation of embryonic stem cells to fat cells will advance the understanding of early events during adipogenesis and lead to the prevention and treatment of obesity. Stem cell microenvironments are critical in regulating adipogenesis. Our results showed that 2D and 3D microenvironments could be engineered using laser direct-write (LDW) and hydrogel microstrands, respectively, and supported adipogenesis of embryonic stem cells with high efficiency.

Figure 2: Fat in a Microtube. Optical Image (a) and Fluorescent Images of DAPI-Stained Nuclei (b), Adipocyte Marker of Perilipin (c) and Brown Adipocyte Marker of UCP-1.

Figure 3: Precisely Placed Embryonic Stem Cells Using LDW. (a) Optical Image. (b) Viable Cells in Green. (c) Expression of Stem Cell Marker Oct4 in Nuclei. One-dimensional Self-assembly of Mouse Embryonic Stem Cells Using an Array of Hydrogel Microstrands. N. Abdul Raof, M.R. Padgen, A. Gracias, M. Bergkvist, and Y. Xie, Biomaterials 32, (2011), 4498-4505. http://www.sciencedirect.com/science/article/pii/S0142961211002511 The maintenance of pluripotency following laser direct-write of mouse embryonic stem cells. N. Abdul Raof, N.R. Schiele, Y. Xie, D.B. Chrisey, and D.T. Corr, Biomaterials 32, (2011),1802-1808. http://sd.zjpharma.cn/science/article/pii/S0142961210014377

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The Nanobioscience Constellation TOPIC 3: Bioengineering Trabecular Meshwork for High-Throughput AntiGlaucoma Screening Human trabecular meshwork (hTM) controls the aqueous humor flow and determines the intraocular pressure (IOP) which is the only modifiable risk factor of glaucoma. Advances in understanding outflow physiology and discovering IOP-lowering anti-glaucoma therapeutics are limited by the lack of a proper in vitro model of the hTM. We demonstrated the feasibility to develop 3D hTM by culturing hTM cells on SU-8 porous filters or alginate nanofibrous matrices. We demonstrated that the bioengineered hTM can mimic the morphology, biological feature and flow physiology of hTM in vivo and offer an in vitro model system for understanding TM physiology and highthroughput screening of pharmacological or biological agents that affect trabecular outflow facility in human.

Figure 4: Bioengineered hTM on Alginate Nanofibers. (a) SEM Image of Nanofibers (Scale Bar = 1 m). (b) Optical Image of hTM Cells on Nanofibers (Scale Bar = 100 m). Fluorescence Images Revealed the Expression of hTM Markers, F-actin (b), -SMA (c) and Myocilin (d) (Scale Bar = 20 m).

Figure 5: SEM Images of Bioengineered hTM on SU-8 Porous Filter. Scale bar = 20 m. A.M. Unser, M.R. Zonca Jr, N. Abdul Raof, and Y. Xie. Alginate Hydrogel-based Nanofibrous Matrices for Embryonic Stem Cell Maintenance. Submitted.

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