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25.02.2010
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119/01-2010Microsystems and Nanotechnology
NanoteknologiMuligheter og usikkerheter
Chief Scientist Liv Furuberg
Microsystems and NanotechnologyMiNaLab
SINTEF ICT
219/01-2010Microsystems and Nanotechnology
Nano - dverg
� En milliard nanometer i en meter
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319/01-2010Microsystems and Nanotechnology
10-12
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Virus Bacteria Hair ManH-atom
MEMSNanodevices Typical man-madeDevices
Lengdeskala - nanometer
419/01-2010Microsystems and Nanotechnology
Nanoski – snart slutt på smøring
� Forsiden av Dagens næringsliv 19. januar
� HVA er det som er nano??
As a result of co-operation withone of the world’s leading nanotechnologyexperts Amroy Inc,Peltonen is proud to EXCLUSIVELYannounce the world’s first crosscountryskis with HYBTONITE®nanoepoxy construction.The new ski models, Supra X and Infra Xuse the latest material technology to enchanceyour skiing experience:HYBTONITE® nanotechnology combinedwith other top features like 9-click NISplates, new XTT Extralight Carbon Tipand Tail, PRG-NANO bases with Crystal-Glide™ finish, all built up with PELTONENknow-how and quality result in a ski thatis THE choice for the most demandingskiers who want the world’s latest and
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519/01-2010Microsystems and Nanotechnology
Nanorør produksjon ved bue-utladning
� Grafitt elektroder
� Høy spenning
� Elektrisk utladning – arc discarge
� Grafittstøv – og 30% karbon nanorør
619/01-2010Microsystems and Nanotechnology
Hva med miljøet?
� Karbon nanorør kan sameliknes med asbest
� Mekanisk, spisse nåler
� Kjemi? Mange forskningsprosjekter pågår
� Sølv nanopartikler
� Sølv i elver, dreper bakterier
� SINTEF – ingen nanopartikler
� Tynne filmer på overflater, kontrollert struktur på molekylært nivå
� Nanoteknologi for rensing av f. eks vann
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719/01-2010Microsystems and Nanotechnology
MiNaLab (Mikro- and Nanoteknologi Laboratoriet i Oslo)
� Universitetet i Oslo og SINTEFSINTEF: 800 m2
Universitetet i Oslo: 600 m2
� SINTEF:
� Silicon production line with annual capacity of 10.000 150 mm wafers
� The most advanced laboratory in Norway for micro- and nanotechnology
� Situated on the campus of University of Oslo
� 240 MNOK investment in scientific equipment and laboratory
819/01-2010Microsystems and Nanotechnology
� Sensorer og aktuatorer
� Laget av silisium, glass eller polymer
� Funksjonelle filmer
� Det funksjonelle elementet harmikrometer skala
� Produseres ved å utnytteproduksjonsteknologier for integrertekretser
Hva er mikrosystemer?
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919/01-2010Microsystems and Nanotechnology
Top – downmanufacturing
Diffractive optical element
Optical filter
� Start with silicon wafer
� Lithography defines areas to be etched away
� Create 3D structures
1019/01-2010Microsystems and Nanotechnology
Eksempel på komponenter: Mikro-optikk
Anesthetic gas detector
Tomra Recycling Center
Gene technology
Food quality & security
CO2-sensor for ventilation control
Diagnostics
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1119/01-2010Microsystems and Nanotechnology
Prossesering i MiNaLab
Start point:
a silicon wafer
1219/01-2010Microsystems and Nanotechnology
Hva gjør vi i MiNaLab?
� Produserer � Mikro-trykksensorer (for oljebrønner … hofteimplantater)
� Mikro-akselerometre (for biler, fly)
� Strålingsdetektorer (tannrøntgen, vitenskapelige eksperimenter ala CERN, materialanalyser)
� Diffraktive optiske filtre og linser – og mikro-lyspærer
� Utvikler nye produksjonsprosesser� Laboratorier på brikker
� Energihøstere -
� Fleksible linser for mobilkameraer
� In-vivo medisinsk prøvetakning
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1319/01-2010Microsystems and Nanotechnology
In-vitro diagnostics
Virus diagnostics detecting mRNA in cervical cell smear
Active capsule endoscope for colon cancer
In-vivo sensors
1419/01-2010Microsystems and Nanotechnology
In Vitro Diagnostics (IVD):Analysis of samples drawn from patients
� Blood
Whole Blood, Serum or Plasma
� Urine
� Stool
� Secretion fluids� Saliva
� Gastric juice
� Mucous secretion
� Tissue samples� Tissue fluids
�Spinal fluid
�Synovial fluid
� Mucous membranes
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1519/01-2010Microsystems and Nanotechnology
Point of Care IVD platforms
� Doctors offices
� Nursing homes
� Remote testing
� In field / off shore
� Ambulance
� Home testing
� Hospitals;
� Children’s clinics
� Bedside
� Emergency wards
� Acute care
� Surgery rooms
1619/01-2010Microsystems and Nanotechnology
“MicroActive”Automatic Detection of
Disease Related Molecular Cell Activity
FP6 STREP IST-NMP-CT-2005-017319
December 2005 - January 2009Michal Mielnik, Ib-Rune Johansen, Anja Gulliksen, Lars Solli, Tobias Baier, Cara Martin,
John O’Leary, Lutz Riegger, Peter Koltay, Frank Karlsen
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1719/01-2010Microsystems and Nanotechnology
The main objective for The MicroActive projectwas to develop an instrument for molecular diagnosticsintended for use in the doctor’s office
• Human Papilloma Virus • Cervical cancer• mRNA • Two microchips• Instrument• Liquid based cytology specimens in (cervical
epithelial cells) • Diagnosis on 5 HPV viruses out
1819/01-2010Microsystems and Nanotechnology
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1919/01-2010Microsystems and Nanotechnology
The technology platform is generic –HPVs were the viruses chosen for proof-of-principle
� Platform for groups of disease markers with similar symptoms, such as our set of mRNAs, transcribing active genes of HPV types
� Screening
� Diagnostics
� Monitoring of treatment
Microfluidics: several virus can be detected simultaneously with high
sensitivity
2019/01-2010Microsystems and Nanotechnology
Human Papilloma VirusHPV 16, 18, 31, 33, 45,
39, 51, 52, 56, 58, 59, 66, 68, and 73
High to medium risk of cancer
Second most common cause of mortality due to cancer among women worldwide
� Persistent infections – cancer
� Cytology based screening of population
� If cytology ambiguous – HPV (DNA or mRNA test)
� Vaccination of young girls (HPV 16 and HPV 18)
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2119/01-2010Microsystems and Nanotechnology
The sensitivity challenge of miniaturization is met
� Is it possible to miniaturize the macroscopic mRNA HPV detection?
� Dilution series experiments showed:� Sample prep chip: extracts
from down to 5 cell linecells (CaSki) is amplifiable
� NASBA chip: down to 1.25 cell line cells (Caski) per droplet amplifiable
20 ul
20 ul
500 nl
3 mlout of 20 ml
2219/01-2010Microsystems and Nanotechnology
We compared chip results with commercial macroscopic results, using clinical specimens
Voyager sample preparation instrument
Qiagen M48 BioRobot
NASBA amplification & detection instrument
NorChip PreTect HPV Proofer
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2319/01-2010Microsystems and Nanotechnology
A sample preparation chipwas manufactured
� Purification of nucleic acids
� Start material (3 ml): liquid based cytology
� Output (40 µl): mRNA suitable for NASBA amplification
� Functions
� Cell filter
� Lysis buffer, wash buffers, elution buffer
stored on-chip
� Nucleic acid capture filters
Macro: Qiagen M48
MicroActive chip (IMM)
2419/01-2010Microsystems and Nanotechnology
A NASBA amplification and fluorescent detection chiphas been manufactured
Input: 20 µl of purified nucleic acids
Split fluid volume into 10 droplets of 500 nl
Dried reagents stored on chip
3 droplet stop positions controlled by hydrophobic patches in channels
Metering
Dissolution of reagents
Dissolution of reagents and detection
SINTEF injection molded chip
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2519/01-2010Microsystems and Nanotechnology
Biofunctional layers for polymer, silicon dioxide and gold
� Patterned or non-patterned surfaces for specific binding of
� proteins (e.g. antibodies)
� DNA probes
� Surface anchors (e.g. silanization, thiol)
� Attach biotin-ylated antibodies, DNA probes
� Anti-binding of proteins
K.W. Wee et al. 2005
2619/01-2010Microsystems and Nanotechnology
Tilbake til nanoskiene!!!Hydrophobic Patterning: Coating
� Superhydrophobic surface, very good visibility in restrictions
� Preferred solution for the hydrophobic patterning
chip patterning DI-water droplet on Teflon-CB
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2719/01-2010Microsystems and Nanotechnology
NASBA of HPV-16 mRNA in 500 nlplugs in microchip� Optimization of drying
agents� Wall roughness� Wall coating� Re-hydration of dried
reagents
� NASBA amplification in sample plugs using dried enzymes
Instrument� Pump
� Heating (for amplification)
� Fluorescent readout of 10 chambers
2819/01-2010Microsystems and Nanotechnology
Conclusion MicroActive
� First time mRNA analysis of clinical specimen using microchip sample preparation and microchip amplification
� Proof-of-principle: on-chip NASBA based diagnostics is possible!
� A molecular marker based cancer diagnostics
� That has higher specificity (and higher PPV) than DNA based methods (and cytology)
� That is possible to miniaturize
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2919/01-2010Microsystems and Nanotechnology
New: Sensor principles based on detecting non-labeled biomolecules
SINTEF: Piezoelectric
resonance shift
Electrical:Impedance
Electrochemical
SINTEF: Piezoresistive
mechanical stress
SINTEF: Photonic crystal: refractive index change
3019/01-2010Microsystems and Nanotechnology
Translating biomolecular recognition into nanomechanicsScience 288, 2000
Bulk silicon micromachining
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3119/01-2010Microsystems and Nanotechnology
Detection of prostate cancer
� Detection of Prostate Specific Antigen, PSA, in blood
� Cantilever composed of SiNx
� Au added on the top side of the cantilever
� Cantilever 1: 200 x 20 x 0,5
� Background 1 mg/ml HSA
� Deflection 20 nm
� 6 ng/ml
� Cantilever 2: 600 x 20 x 0,65
� Background 1 mg/ml BSA
� Deflection 20 nm
� 0,2 ng/ml
Ref.: G. Wu et al. Nature Biotechnology 19 (2001)
3219/01-2010Microsystems and Nanotechnology
Photonic crystal biosensor – new!
� 200 nm sized holes forming a lattice
a) b) c) d)
e) f) g) h)
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3319/01-2010Microsystems and Nanotechnology
In-vivo sensors and actuatorsImportant:- Low energy
consumption- Robust- Biocompatible
3419/01-2010Microsystems and Nanotechnology
Smart Microsystems for Diagnostic Imaging in Medicine (SMIDA)
� En ultralyd-probe som kan gåinn i en blodåre
� Man antar at 80% av plutselige hjerteattak skyldes skadelig plakk (avleiringer) i blodårer som løsner og gir en blodpropp
� Genererer ultralyd ca 30MHz (elektrostatisk) og leser ut reflektert lyd (kapasitivt) med et array av små nitridmembraner
m/NTNU
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3519/01-2010Microsystems and Nanotechnology
VECTORVersatile Endoscopic Capsule for gastrointestinal
TumOr Recognition and therapy
FP6 ICT Integratedproject
SINTEF ICT og Helse i samarbeid med 19 partnere i Europa
SINTEF MiNaLab: Utvikle ultralydprobe som detekterer cancer i tykktarmen ved ultralyd
Utfordring: Trådløs pille, energi minimalisering
SINTEF Helse, medisinsk teknologi: navigasjonskontroll
3619/01-2010Microsystems and Nanotechnology
Pressure sensor can be integrated in stentgraft for monitoring functionality of stent
� AAA: Abdominal Aortic Aneurism
� Mission - improving the long term reliability of AAA stent grafts
� The Product - introducing an add-on to the AAA stent grafts to enable a real time monitoring device to alert for possible sudden rupture and endo-leaks
Orhere
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3719/01-2010Microsystems and Nanotechnology
Nano- og mikroteknologi
Mikroteknologi er allerede i mange produkter
De kan få nye funksjoner med nanometer tynne lag påoverflaten
Miljøfarer for nanopartikler blir nå utforsket
Teknologien kan også brukes i rensesystemer
Små komponenter krever mindre ressursbruk, mindre energi etc..