Nanotechnology Tools for Life Sciences

Harry Heinzelmann
VP Nanotechnology & Life Sciences

Neuchâtel, June 2009




    ...
CSEM profile


               Privately held Innovation Center, incorporated, not for profit
               Privately held...
CSEM profile

Bridge from Science to Innovation




                                Applied                           Prod...
CSEM profile

Bridge from Science to Innovation

• wide range of technologies, large experience and network               ...
CSEM profile

Technologies I (divisions in Neuchâtel)

                Microelectronics
                    Circuit Design...
CSEM profile

Technologies II (divisions outside Neuchâtel)

                Photonics (Zurich)
                    Image ...
Technologies and Applications

Nanostructuring

• extended experience in self-assembly of
  polymer and nanoparticle syste...
Nanostructuring

Top-Down vs. Bottom-Up


           10
                    classical (micro-) fabrication
           1 mm...
Nanostructuring

Polymeric Self-Assembly I : Polymer Demixing
                                                       50% P...
Nanostructuring – Polymer Demixing

Nanoporous Layers for Ink-jet Printer Paper

 Polymer paper                           ...
Nanostructuring – Polymer Demixing

Security Features for Anti-Counterfeiting Applications

• market size for counterfeit ...
Nanostructuring – Polymer Demixing

Topography Gradients for Surface Interaction Screening




PMMA / P2VP demixing on a p...
Nanostructuring

Polymeric Self-Assembly II : Microphase Separation

• block copolymer A-b-B

                            ...
Nanostructuring – Copolymer Microphase Separation

(Random) Nanostructures with Order and Function

Function:             ...
Nanostructuring – Copolymer Microphase Separation

Copolymer Lithography for Nano-Pillars and Nano-Pores

                ...
Nanostructuring – Copolymer Microphase Separation

Non-Wetting Surfaces with Nanopillar Structures

                      ...
Nanostructuring – Nanoporous Membranes

Osmotic Biosensor based on Nanoporous Membranes

• nanoporous membranes from
  cop...
Nanostructuring – Nanoporous Membranes

Wafer Scale Replication of Copolymer Lithography Patterns

• replication by polyme...
Technologies and Applications

BioMEMS for Nanotoxicity Tests

• experience in cell handling
  dedicated infrastructure
• ...
BioMEMS

Nanotoxicology – Risks of Nanoparticle Technology

• molecular nanotechnology “hype”        • new class of nano-m...
BioMEMS - Nanotoxicology

   Translocation Measurement Device – EU IP Nanosafe2

   • problem: unknown effects of nanopart...
BioMEMS - Nanotoxicology

On-Chip Electrical Characterization of Cell Layers

• microfabricated chip with cell culture wel...
BioMEMS - Nanotoxicology

Intestinal, Liver & Endothelial NP Toxicity – InLiveTox

• CSEM, 4 university partners, Helmholt...
Nanotools

Probe Array Technology – PROBART

                                     • speed up single probe operation
      ...
Nanotools – Probe Arrays

Force Spectroscopy on Cells

                                   • information about adhesion pro...
Nanotools – Probe Arrays

PROBART for Parallel Imaging


                                                                 ...
Nanotools – Probe Arrays

Cell Adhesion Forces


similar adhesion forces for cells in all
phases of the cell cycle (thus n...
Technologies and Applications

Nanotools for Ultimate Pipetting

• vast experience in Scanning Probe Methods
• MEMS design...
Nanotools – Nanoscale Dispensing

Nanoscale Dispensing – NADIS


                            deposition of liquids
       ...
Nanotools – Nanoscale Dispensing

NADIS with FIB Modified Probes

• apertures with Ø down to 200 nm
• flexibility in locat...
Nanotools – Nanoscale Dispensing

NADIS of Fluorophores in Liquid Environments


                                         ...
Nanotools – Nanoscale Dispensing

NADIS for Liquid Exchange with Living Cells

                                           ...
Conclusions

Nanostructuring

• polymer demixing
  for random but regular microstructures

• co-polymer microphase separat...
Conclusions

Nanotools

• probe array platform
  for parallel force spectroscopy in biological environments

• nanoscale d...
Thank you for your attention.
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Nanotechnology Tools for Life Sciences

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Harry Heinzelmann
VP Nanotechnology & Life Sciences
Nanotechnology Tools for Life Sciences
Neuchâtel, June 2009

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Nanotechnology Tools for Life Sciences

  1. 1. Nanotechnology Tools for Life Sciences Harry Heinzelmann VP Nanotechnology & Life Sciences Neuchâtel, June 2009 v1.19
  2. 2. CSEM profile Privately held Innovation Center, incorporated, not for profit Privately held Innovation Center, incorporated, not for profit since 1984, from watchmaking since 1984, from watchmaking about 70 shareholders (mostly private) about 70 shareholders (mostly private) 2008: 2008: >65 Mio. CHF annual turnover, 395 employees >65 Mio. CHF annual turnover, 395 employees 30 start-ups created since 2000 30 start-ups created since 2000 Activities: Activities: Applied research (contract with Swiss Government) Applied research (contract with Swiss Government) Industrialization of technologies, product development Industrialization of technologies, product development Technologies: Technologies: Micro- and Nanotechnology, Information Technology, Micro- and Nanotechnology, Information Technology, and System Engineering and System Engineering Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 1
  3. 3. CSEM profile Bridge from Science to Innovation Applied Product Basic Research Res & Dev Development Marketing PhD programs Industrialisation Sales Teaching Customers Science & Market Education Success • technologies for innovations • research partners: Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 2
  4. 4. CSEM profile Bridge from Science to Innovation • wide range of technologies, large experience and network innovative solutions • highly qualified and experienced staff fast developments • IP portfolio to support the customers’ application protected business • shareholders include • technologies for Green Solutions Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 3
  5. 5. CSEM profile Technologies I (divisions in Neuchâtel) Microelectronics Circuit Design, RF, Information Processing Nanotechnology & Life Sciences Optical and Bio MNT, Self-assembly, Sensors Systems Engineering Mechatronics, Signal Processing, Communication Time and Frequency Atomic Clocks, Optical Advanced Systems Microsystems MEMS, Cleanroom Infrastucture, Microscopy & Analysis Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 4
  6. 6. CSEM profile Technologies II (divisions outside Neuchâtel) Photonics (Zurich) Image Sensing, Optoelectronics Robotics (Alpnach) Lab Automation, Packaging, Assembly Thin Film Optics (Basel) Optoelectronics, Replicated Optics Nano Medicine (Landquart) Imaging, Medical Sensors CSEM UAE CSEM Brazil Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 5
  7. 7. Technologies and Applications Nanostructuring • extended experience in self-assembly of polymer and nanoparticle systems • block copolymer microphase separation and copolymer lithography / MEMS • molecular grafting chemistries, from and to • controlled self-assembly of beads • partnerships & projects: • industrial collaborations: Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 6
  8. 8. Nanostructuring Top-Down vs. Bottom-Up 10 classical (micro-) fabrication 1 mm 100 MEMS: Micro Electro Mechanical Systems lithography: 10 VIS 1 µm UV, X-ray, e – beam 100 FIB (serial) 10 1 nm molecular self-assembly 1 Å “molecular nanotechnology” 250 nm 4 µm Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 7
  9. 9. Nanostructuring Polymeric Self-Assembly I : Polymer Demixing 50% PMMA / 50% PS 90% PMMA / 10% PS • demixing of immiscible polymer blends • qualitative structures on the micron scale • control over feature size and properties • large variety of polymers available 80 µm 5 µm • simple deposition technique • selective solvent can remove one polymer type • scalable to large surfaces large 5µm med 2µm small <1µm inexpensive and flexible method to control surface properties on a micron scale Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 8
  10. 10. Nanostructuring – Polymer Demixing Nanoporous Layers for Ink-jet Printer Paper Polymer paper Nanoporous paper Nanoporous layer Polymer layer (Alumina film) Cellulose Cellulose stable images fast up-take, small spot size slow ink uptake, big spot size image fading (light, gas,…) polymer film transferred on paper paper, 5 µm x 5 µm polymer on Si Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 9
  11. 11. Nanostructuring – Polymer Demixing Security Features for Anti-Counterfeiting Applications • market size for counterfeit goods (2004): 500 Bill. US$ for art pieces: >10 Bill. US$ (Europe) • nanoscale structures are difficult to counterfeit, and are mass-producible • self-assembly structures are random and unique *patent pending • security features can be mass produced at low cost, both for mass id and unique fingerprints Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 10
  12. 12. Nanostructuring – Polymer Demixing Topography Gradients for Surface Interaction Screening PMMA / P2VP demixing on a pre-prepared surface chemistry gradient • surface coatings with controlled properties, varying over short length scales • combinatorial studies of cell-substrate interactions: effect of surface roughness on cell adhesion and proliferation, with gradients adapted to typical distances travelled by cells study of cell locomotion Blondiaux et al., submitted Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 11
  13. 13. Nanostructuring Polymeric Self-Assembly II : Microphase Separation • block copolymer A-b-B -A-A-A- -B-B-B- • Microphase Separation • inexpensive & flexible method to generate 10 -100 nm ordered structures on the molecular scale • wide choice of functions and chemistries: mechanical, chemical / catalytic, optical, electrical, magnetic, … high high A-fraction B-fraction Krishnamoorthy et al., materials today (September 2006) Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 12
  14. 14. Nanostructuring – Copolymer Microphase Separation (Random) Nanostructures with Order and Function Function: Order: • PI-b-PFS poly(isoprene-b-ferrocenylsilane) • random and short range • spincoating of 30nm thin film, plasma etch • can be improved by templating • high density magnetic pattern: 4 1011 /cm2 • topographical, chemical, temp, fields, … H CH3 Fe Si CH3 n-Bu m n PI-b-PFS different FexOy stochiometries PS-PFS from Korczagin, Vancso et al., Mesa+ from Stoykovich et al., Science (2005) Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 13
  15. 15. Nanostructuring – Copolymer Microphase Separation Copolymer Lithography for Nano-Pillars and Nano-Pores etch mask from inverted micelles etch mask copolymer patterns from polymer constituents with different etch rates in some cases it is necessary to provide an “amplification” of RIE the etch contrast Krishnamoorthy et al., Nanotechnology (2008) Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 14
  16. 16. Nanostructuring – Copolymer Microphase Separation Non-Wetting Surfaces with Nanopillar Structures • self-cleaning surfaces by functionalization with perfluorosilane (wet or PVD) transition from Wenzel to Cassie-Baxter wetting mode for structure aspect ratio > 2:1 planar SiNx silanised with perfluorosilane: contact angle 111° Nanopillars in SiNx, 90nm high, 100nm periodicity silanised with perfluorosilane: water contact angle 150˚, highly mobile drop WCA adv 160° (compare to 110° on a flat surface) Krishnamoorthy et al., Nanotechnology (2008) hysteresis 5°, rolling angle 6°, 10ml droplet Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 15
  17. 17. Nanostructuring – Nanoporous Membranes Osmotic Biosensor based on Nanoporous Membranes • nanoporous membranes from copolymer lithography • macro prototyping of osmotic sensor • size selectivity supported specific binding chemistry Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 16
  18. 18. Nanostructuring – Nanoporous Membranes Wafer Scale Replication of Copolymer Lithography Patterns • replication by polymer casting • replication by embossing into PC foil master by Ni electroplating wafer scale PDMS casting • PMMA nanoporous membranes small medium large • nanostructured surfaces for cell studies influence on: • cell growth • protein expression • cytoskeleton organ. Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 17
  19. 19. Technologies and Applications BioMEMS for Nanotoxicity Tests • experience in cell handling dedicated infrastructure • established knowledge in microfabrication and replication technologies, in house fab • nanotechnology / nanoparticle handling • microfluidics design and prototyping • partnerships & projects: InLiveTox • industrial collaborations: Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 18
  20. 20. BioMEMS Nanotoxicology – Risks of Nanoparticle Technology • molecular nanotechnology “hype” • new class of nano-materials with “unknown” • “grey goo” & “green goo” properties: carbon (CNT, buckyballs, …), TiO2, SiO2, metallic (Au…), quantum dots (CdS, CdSe, CdTe, etc.), polymeric… gold latex Catalytic CO Oxidation by a Gold CNTs Nanoparticle, N. Lopez and J.K. Norskov, J.Am.Chem.Soc.(2002) • … in widespread applications: catalysts, sunscreens, fuel cells, solar panels, … Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 19
  21. 21. BioMEMS - Nanotoxicology Translocation Measurement Device – EU IP Nanosafe2 • problem: unknown effects of nanoparticles on human organisms • microfabricated chip for the in vitro study of model epithelia transport properties nanoparticle suspension coming in confluent layer of epithelial cells porous Si3N4 electrodes for TEER membrane measurements detection of nanoparticles that cross the cell layer detection of inorganic nanoparticles off-line using inductively coupled plasma mass spectrometry (ICP-MS) Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 20
  22. 22. BioMEMS - Nanotoxicology On-Chip Electrical Characterization of Cell Layers • microfabricated chip with cell culture wells • porous membranes at the basis of each well to allow toxins or drugs to pass through • TransEpithelial Electrical Resistance (TEER) to determine the tightness of a cell layer Calu-3 cells grown in one of five wells • electrical contacts • plastic holder • glass support, to seal the fluidic network • PDMS fluidics • SiN membrane • PDMS in plastic holder, electrical contacts at the bottom Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 21
  23. 23. BioMEMS - Nanotoxicology Intestinal, Liver & Endothelial NP Toxicity – InLiveTox • CSEM, 4 university partners, Helmholtz Zentrum Berlin, Kirkstall Ltd, Alma • objectives: • develop in vitro test system to reduce/replace animal tests of nanoparticle toxicity • replace the “lab rat” ‘Gastro Intestinal tract’ ‘Intestinal epithelium’ by a setup of (co-culture of epithelial cells, ‘Bloodstream’ • microfluidics and monocytes and dendritic cells) • cell cultures ‘Vascular endothelium’ of model organs (endothelial cells) ‘Liver’ (hepatocytes) Nanoparticles Sampling ports • 3Rs: Replace, Reduce and Refine animal tests • REACH: Registration, Evaluation, Authorisation & Restriction of Chemical Substances Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 22
  24. 24. Nanotools Probe Array Technology – PROBART • speed up single probe operation by parallel imaging and sensing • PROBART for Life Science applications, for nisenet.org - bioarrays - cells but: operation in liquids! Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 23
  25. 25. Nanotools – Probe Arrays Force Spectroscopy on Cells • information about adhesion proteins, cell mechanics, kinetics, … • cell-surface, cell-cantilever, cell-cell • meaningful only with sufficient statistics, which makes experiments rather tedious • at current rate of a few cells per day, not useful for screening formats • array format would improve statistics and make high throughput screening formats more accessible source: JPK Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 24
  26. 26. Nanotools – Probe Arrays PROBART for Parallel Imaging VEE (- 6V) Rlever Rref (~ 20 kohm) R ref Vout R1 R2 R lever probe #6 4x4 array imaging in buffer solution with probe continuous zoom-in #13 probe #15 Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 25
  27. 27. Nanotools – Probe Arrays Cell Adhesion Forces similar adhesion forces for cells in all phases of the cell cycle (thus no need for synchronization in future studies) Human osteoblasts, growing on hemispherical pits (a, diameter 27 µm) and nanopillars (b, 45nm high, replicated in a non- metallic bone implant material Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 26
  28. 28. Technologies and Applications Nanotools for Ultimate Pipetting • vast experience in Scanning Probe Methods • MEMS design and fabrication in house • fluidics design and fabrication • surface chemistry and characterization • experience in handling biomaterials, nanoparticles in solutions • partnerships & projects: • industrial collaborations: first contacts with instrument makers Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 27
  29. 29. Nanotools – Nanoscale Dispensing Nanoscale Dispensing – NADIS deposition of liquids in ultrasmall volumes from microscopic tips • functional biomolecules for microarrays, such as Molecules in solution proteins or DNA • metallic nanoparticles to form connects, catalyst Nanoparticle suspensions particles, optical and chemical functions, … • etch resist materials, sol-gel precursors, … Materials for processing Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 28
  30. 30. Nanotools – Nanoscale Dispensing NADIS with FIB Modified Probes • apertures with Ø down to 200 nm • flexibility in location (off-center, …) • possible to keep sharp AFM tips 1 µm sub-attoliter volumes Meister et al., App.Phys.Lett. (2004) Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 29
  31. 31. Nanotools – Nanoscale Dispensing NADIS of Fluorophores in Liquid Environments 3 µm 1 Intensity [a.u.] 0.5 0 0 2 4 6 8 applied pressure ~ 2mbar Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 30
  32. 32. Nanotools – Nanoscale Dispensing NADIS for Liquid Exchange with Living Cells • injection after perforation of the cell membrane • extraction of cytoplasm for remote analysis • towards patch clamping viable neuroblastoma cells Cell TrackerTM green staining Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 31
  33. 33. Conclusions Nanostructuring • polymer demixing for random but regular microstructures • co-polymer microphase separation for well-arranged functional nanostructures and lithography THANK YOU ! • collaborators from CSEM: AM Popa, M Klein, W Li, F Montage, R Pugin, … • cleanroom team from COMLAB and CMI EPF Lausanne • partners from U Mulhouse, U Twente, EPFL, … Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 32
  34. 34. Conclusions Nanotools • probe array platform for parallel force spectroscopy in biological environments • nanoscale dispensing (NADIS) for liquid arraying and cell manipulation THANK YOU ! • collaborators from CSEM: J Przybylska, M Favre, J Polesel, A Meister, M Liley, … • cleanroom team from COMLAB and CMI EPF Lausanne • partners from IMT U Neuchâtel, U Lund, U Trento, ETHZ, EPFL, … Copyright 2009 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 33
  35. 35. Thank you for your attention.
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