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PATLiSci –Probe Array Technology for Life SciencesHarry HeinzelmannVP Nanotechnology & Life SciencesBern, May 2011
PATLiSci – Probe Array Technology for Life Science Applications“nano” -tera                                               ...
Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 2
Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 3
Science Museum London          “The Making of the Modern World”Copyright 2011 I Nanotechnology & Life Sciences I Harry Hei...
IBM                                                                            Drexel U, PhiladelphiaIBM      Copyright 20...
PATLiSci – Probe Array Technology for Life Science Applicationsit’s much much more than microscopy…                       ...
PATLiSci – Probe Array Technology for Life Science ApplicationsCancer is Relevant                                         ...
PATLiSci – Probe Array Technology for Life Science ApplicationsProbe Array Technology  • cantilever arrays                ...
PATLiSci – Probe Array Technology for Life Science ApplicationsA Nose for Cancer Detection                                ...
PATLiSci – Probe Array Technology for Life Science ApplicationsProject Partners                                           ...
PATLiSci – Probe Array Technology for Life Science ApplicationsCantilever Sensing – Technology                            ...
PATLiSci – Probe Array Technology for Life Science ApplicationsCantilever Sensing – ResultsDetection of mutant DNA (in liq...
PATLiSci – Probe Array Technology for Life Science ApplicationsCantilever Sensing – Outlook and Next Stepsin liquids      ...
PATLiSci – Probe Array Technology for Life Science ApplicationsForce Spectroscopy – Technology                            ...
PATLiSci – Probe Array Technology for Life Science ApplicationsForce Spectroscopy – Results                               ...
PATLiSci – Probe Array Technology for Life Science ApplicationsForce Spectroscopy – Outlook and Next Steps• Measure cell e...
PATLiSci – Probe Array Technology for Life Science ApplicationsMINACEL: Micro- and Nanofluidics for Cell Handlingbring com...
Thank you for your attention.                        Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I...
backup slides      Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 19
Probe Array Technology for Life Science ApplicationsCantilever Sensing in Gaseous and in Liquid EnvironmentsNon-Invasive D...
Probe Array Technology for Life Science ApplicationsForce Spectroscopy on Cells                                           ...
Probe Array Technology for Life Science ApplicationsLiterature – Force Spectroscopy on Cancer Cells                       ...
Probe Array Technology for Life Science ApplicationsProject Goals• develop point probe array system (microfabricated array...
Probe Array Technology for Life Science ApplicationsImpact beyond the Scope of this ProjectSafety            Production   ...
Nanotools – Probe ArraysPROBART for Parallel Imaging                                                                     V...
Nanotools – Probe ArraysArrayFM with Optical Read-out – First Results                              Copyright 2011 I Nanote...
Nanotools – Probe ArraysPROBART for Force Spectroscopy            600 pN/div                                              ...
Nanotools – Probe ArraysArrayFM with Optical Read-out                           where are we with this?                   ...
Nanotools – Probe ArraysArrayFM with Optical Read-out – Some More Tricks                                                  ...
Nanotools – Probe ArraysCell Adhesion Forceswhat is still missing?• work on arrays of cells  (immobilized arrays)• work on...
Nanotools – Nanoscale DispensingNanoscale Dispensing – NADIS                            deposition of liquids             ...
Closed Channel NADIS Cantilevers• closed channels for  - better control  - operation in liquids• new microfabrication proc...
Nanotools – Nanoscale DispensingNADIS of Fluorophores in Liquid Environments                                              ...
Nanotools – Nanoscale DispensingNADIS for Liquid Exchange with Living Cells                                               ...
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Patlisci

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This project is about further developing probe array techniques for life science applications, notably in the context of cancer research. The consortium shows the balance between experts in sensing technology as well as oncology.

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Patlisci

  1. 1. PATLiSci –Probe Array Technology for Life SciencesHarry HeinzelmannVP Nanotechnology & Life SciencesBern, May 2011
  2. 2. PATLiSci – Probe Array Technology for Life Science Applications“nano” -tera Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 1
  3. 3. Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 2
  4. 4. Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 3
  5. 5. Science Museum London “The Making of the Modern World”Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 4
  6. 6. IBM Drexel U, PhiladelphiaIBM Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 5
  7. 7. PATLiSci – Probe Array Technology for Life Science Applicationsit’s much much more than microscopy… U PennsylvaniaMüller and DufrêneNature Nanotechnology (2008) Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 6
  8. 8. PATLiSci – Probe Array Technology for Life Science ApplicationsCancer is Relevant • how do cancer cells differ in cell mechanical properties ? • how do cancer cells adhere to substrates, or to other cells ? • can we find better ways to detect cancer in an early stage ? • can we bring a test device to POC? bfs.admin.ch Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 7
  9. 9. PATLiSci – Probe Array Technology for Life Science ApplicationsProbe Array Technology • cantilever arrays • point probe arrays for nanomechanical sensing for parallel force spectroscopy • measure the presence of minute • measure interaction forces and concentrations of analytes (N channels) mechanical properties (N statistics) • use for R&D, optimization, integration • proof of principle, use for R&D Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 8
  10. 10. PATLiSci – Probe Array Technology for Life Science ApplicationsA Nose for Cancer Detection Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 9
  11. 11. PATLiSci – Probe Array Technology for Life Science ApplicationsProject Partners E. Meyer H. Heinzelmann Ch. Gerber CSEM (Coord) Uni Basel Probe array Cantilever sensors technologies H.P. Herzig EPFL-IMT Optics H. Vogel EPFL N. de Rooij, P. Vettiger, J. Brugger Membr protein EPFL-IMT, MEMS design & fab immobilisation A. Mariotti P. Romero CePO, CHUV LICR U Lausanne Melonoma Head & neck D. Rimoldi F. Beermann progression carcinoma LICR U Lausanne ISREC, EPFL Melanoma Tumorigenesis Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 10
  12. 12. PATLiSci – Probe Array Technology for Life Science ApplicationsCantilever Sensing – Technology detection in liquids: • biomarkers for cancer in DNA/cell samples • measured by optical beam deflection detection in the gas phase: • volatile organic compounds (VOCs) in patient‘s breath – non-invasive early recognition of cancer • measured with integrated piezoresistorsCantilever is a Nanomechanical Sensor specific adsorption/docking of molecules creates mechanical stress  bending J. Fritz et al., Science 288, 316-318 (2000); D. Schmid et al., Eur. J. Nanomedicine 1, 44-47 (2008) Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 11
  13. 13. PATLiSci – Probe Array Technology for Life Science ApplicationsCantilever Sensing – ResultsDetection of mutant DNA (in liquid) Detection of VOCs (in gas phase) (National Cancer Inst.)B-Raf oncogene, in 50-60%of all melanoma tumors DNA from normal cells DNA from melanoma cells 20 0 -20differential deflection /nm -40 injection of DNA -60 -80 -100 -120 -140 -160 -180 -200 20 40 60 80 100 120 140 160 180 200 time /min Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 12
  14. 14. PATLiSci – Probe Array Technology for Life Science ApplicationsCantilever Sensing – Outlook and Next Stepsin liquids in gas phaseDNA, mRNA, and tumor cell detection Breath analysis of from cancer patients• melanoma associated antigens • feasibility EBS of head & neck cancer patients• test of mutation/antigen and cell binding • representative study on EBS of head & neck or lung cancer patients• detection limits of the assays• optimization of DNA and antigen binding • optimization of readout hard-/software• optimization of cell capture • functionality and reliability tests • portable device prototype• implementation of a microfluidic system for an initial cell sorting step • implementation of a micro bioreactor (PATLiSci extension MINACEL) in combination with cantilever arrays (PATLiSci extension MINACEL) Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 13
  15. 15. PATLiSci – Probe Array Technology for Life Science ApplicationsForce Spectroscopy – Technology • information about adhesion proteins, cell mechanics, kinetics, … • statistics! parallel force spectroscopy  novel cantilever deflection readout  probe array microfabrication  living melanoma cell array source: JPK Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 14
  16. 16. PATLiSci – Probe Array Technology for Life Science ApplicationsForce Spectroscopy – Results A por B e C cell D E F M. Favre et al., J. Mol. Recogn. 24 (2011) 446) Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 15
  17. 17. PATLiSci – Probe Array Technology for Life Science ApplicationsForce Spectroscopy – Outlook and Next Steps• Measure cell elasticity at different growth phases• Analysis of cell adhesion (cell-surface, cell-cell) in the presence of extra cellular matrix proteins• Compact optical cantilever deflection read-out• Individual cantilever actuation (force control)• implementation of cell separation and sorting (PATLiSci extension MINACEL) Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 16
  18. 18. PATLiSci – Probe Array Technology for Life Science ApplicationsMINACEL: Micro- and Nanofluidics for Cell Handlingbring competence in fluidics to PATLiSci• micro Bioreactor with tumor cells producing VOCs for gas phase analysis• Cell Sorting device to isolate CTC and adherent cells• Nanofluidics for single cell microinjection using NADIS technology Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 17
  19. 19. Thank you for your attention. Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 18
  20. 20. backup slides Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 19
  21. 21. Probe Array Technology for Life Science ApplicationsCantilever Sensing in Gaseous and in Liquid EnvironmentsNon-Invasive Diagnostics for early Detection of melanoma specific somaticdetection of eg. lung, head & neck cancer mutations in blood samples• higher specificity and sensitivity to VOC with • detection of dissolved tumor specific coatings based on natural odorant receptors markers with suitable anti-bodies, or direct• piezo-resistive cantilevers binding of melanoma cells (CTC)• handheld device for POC applications • no prior amplification or labeling Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 20
  22. 22. Probe Array Technology for Life Science ApplicationsForce 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 and parallel operation will greatly improve statistics and allow high throughput screening formats source: JPK Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 21
  23. 23. Probe Array Technology for Life Science ApplicationsLiterature – Force Spectroscopy on Cancer Cells all cells Tumor cells normal cells from S.E. Cross et al., Nanotechnology (2008) from S.E. Cross et al., Nature Nanotech (2007) Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 22
  24. 24. Probe Array Technology for Life Science ApplicationsProject Goals• develop point probe array system (microfabricated array and read-out system)• demonstrate parallel measurement of cell mechanics• demonstrate cell adhesion measurements with improved statistics• assess potential in diagnostics and cell based screening• improve performance of cantilever array sensors• demonstrate detection of cancer via breath analysis• improve sensitivity and demonstrate detection of disorders in patients’ blood samples via various biomarkers (library)• integrate system into a handheld cantilever-based diagnostic device prototype Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 23
  25. 25. Probe Array Technology for Life Science ApplicationsImpact beyond the Scope of this ProjectSafety Production NEMS / nano Research, ScreeningDiagnosticsEnvironment ICT / teraFoodQuality Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 24
  26. 26. Nanotools – Probe ArraysPROBART 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 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 25
  27. 27. Nanotools – Probe ArraysArrayFM with Optical Read-out – First Results Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 26
  28. 28. Nanotools – Probe ArraysPROBART for Force Spectroscopy 600 pN/div √ √ Force resolution √ = 160 pN √Polylysin PBS (0.01M)(5mg/l) glass surface √ sufficient for most √ donor/acceptor complexes √ in “expert reviews in molecular medicine”, 18µm http://www-ermm.cbcu.cam.ac.uk 6.4µm Mapping of the elastic response of a cell Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 27
  29. 29. Nanotools – Probe ArraysArrayFM with Optical Read-out where are we with this? • first demonstration in ambient conditions and on solid substrates • topography detail reproduced down to nm scale and nm sensitivity what is still missing? • improve sensitivity / noise equivalent force • adapt optics to operation in liquids • adapt optics to large arrays • interface with software, data transfer Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 28
  30. 30. Nanotools – Probe ArraysArrayFM with Optical Read-out – Some More Tricks • solving phase ambiguity • LabView based software interface • Si and sol-gel replicated cantilevers Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 29
  31. 31. Nanotools – Probe ArraysCell Adhesion Forceswhat is still missing?• work on arrays of cells (immobilized arrays)• work on arrays of vesicles, and assess feasibility• for cell-cell (vesicle-vesicle) studies, develop protocols on how to get these on the probe tip• work on probes, tip geometry, functionalization• work probe actuation• work on probe array homogeneity, and alignment issues Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 30
  32. 32. Nanotools – Nanoscale DispensingNanoscale Dispensing – NADIS deposition of liquids in ultrasmall volumes from microscopic tips • functional biomolecules for microarrays, such as proteins or DNA Molecules in solution • metallic nanoparticles to form connects, catalyst particles, optical and chemical functions, …Nanoparticle suspensions • etch resist materials, sol-gel precursors, … Materials for processing Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 31
  33. 33. Closed Channel NADIS Cantilevers• closed channels for - better control - operation in liquids• new microfabrication process • single probes • 1-dim arrays • one and two channel design, on-chip reservoirs Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 32
  34. 34. Nanotools – Nanoscale DispensingNADIS of Fluorophores in Liquid Environments 3 μm 1 Intensity [a.u.] 0.5 0 0 2 4 6 8 applied pressure ~ 2mbar Copyright 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 33
  35. 35. Nanotools – Nanoscale DispensingNADIS 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 2011 I Nanotechnology & Life Sciences I Harry Heinzelmann I page 34

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