lab on a chip - Speaker Deck

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What’s up in the Manz lab Andreas Manz Imperial College, London UK

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contents Why small? why small.ppt Chip technology microfabrication.ppt [Electrophoresis] electrophoresis.ppt Chemical reactions chemical reactions.ppt [PCR] pcr.ppt Bioreactor antibiotics.ppt Detection methods detection methods.ppt Analog computing analog computing.ppt

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why minitiaturize volume of 1µL 1nL 1pL (1mm)3 (100µm)3 (10µm)3 600,000,000 600,000 600 25 / cm2 2500 / cm2 250 ,000/ cm2 17 min 10s 100ms 1.5 /min / cm2 250 /s / cm2 2,500,000 /s / cm2 # molecules (1nM solution) # volumes In array diffusion time # reactions (diffusion controlled) is a cube of

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10 fold miniaturization 100 x faster reactions / bioassays 100 x faster separation 1000 x smaller volume 10 x lower reagent consumption

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human perception < 1 cm is small > 10 m is big < 100 ms is immediate > 1 min is slow factor 100: 100 ms to 1 ms: not impressive 17 h to 10 min: makes a difference 10 min to 6 s: very impressive

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-TAS electronics recorder pre-treatment sensor electronics recorder sampling electronics recorder carrier reagent mobile phases hydraulic control waste ideal sensor total analytical system -TAS

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established semiconductor fabrication techniques light-source mask (from DWL) photo-resist on substrate developing, etching 3-dimensional structure bonding sealed microfluidic device microfabrication technique

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Capillary electrophoresis on chip Jed Harrison, Carlo Effenhauser, Norbert Burggraf, Luc Bousse

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blinkermuh

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13-Nov-13 blinkermuh fluorescence [arb. units] time [s] 0 40 80 120 160 1 2 3 4 5 6 cycle # 7 8 t 7 s synchr. fluorescence [arb. units] time [s] 0 40 80 120 160 1 2 3 4 5 6 cycle # 7 8 t 7 s synchr. fluorescence [arb. units] time [s] 0 40 80 120 160 1 2 3 4 5 6 cycle # 7 8 t 7 s synchr.

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CE on chip • Scaling laws electrophoresis scaling.ppt • [Short] electrophoresis video.ppt • History electrophoresis carlo.ppt • Serial to parallel electrophoresis caliper 1.ppt • Parallel separations electrophoresis caliper 2.ppt

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separation efficiency • Number of theoretical plates is proportional to voltage drop U N 

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heating problem •Power generated per unit length should be a constant const L I U  

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separation efficiency •Number of theoretical plates is proportional to length / diameter of capillary d L N 

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separation time •Analysis time is proportional to length * diameter of capillary d L t  

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SERIAL 1 2 3 4 1 2 3 4 CONVERTER ? PARALEL

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SERIAL 2 3 4 1 1 CONVERTER PARALEL

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80 SEPARATION CHANNELS INJECTION CHANNEL

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RESULTS Serial to parallel converter : 9 plugs refilled in 10 seconds, that means 1 sample plug per second 54 samples per minute 78,000 samples per day

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double stranded DNA separation ele caliper 2 extended.ppt

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reaction with intercalating dye

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x x x x x x x x x SYBR green x x x x x x x x x x x x x double stranded DNA SYBR green x x x x x x x x x x x x x x x x x x x x x x x x SYBR green complex [fluorescing] x x x x 1) 2) 3)

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x x x x x x x x x x x x x x x x x double stranded DNA SYBR green complex [fluorescing] concentration length of plug DNA is slowing down at moving front of SYBR green SYBR green is slowing down at moving front of DNA fluorescence length of plug

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blinkermuh

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13-Nov-13 Agilent 2100 Bioanalyzer

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conclusions • High speed separations • Good quality separations • Very good fluid control • Small volumes • Commercial products •  biggest success, so far really?

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Concept chemical reactions concept.ppt the chip chemical reactions mix.ppt Bioassay chemical reactions bio.ppt Electrophoretic reaction chemical reactions electrophoretic Synthesis chemical reactions synth.ppt

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drug discovery • first step to find new active molecules • composed of – synthesis of new compound – isolation, characterisation – bioassay • a significant effort in pharmaceutical industry, involving new technologies

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COMBINATORIAL CHEMISTRY QUALITY CONTROL BIOASSAYS 100 educts A 100 educts B 10,000 products AB 10,000 assays 10,000 assays ??? 10,000 products AB

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CHEMICAL MICROPROCESSOR SYNTAS  educt A educt B is this a hit? yes/no specific reaction specific bioassay

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chemical reaction batch Time continuous flow Length

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A B C A B , A , B A B A B C , A B , C A B C A B C fluorescence detection bioassay synthesis step 1 synthesis step 2 separation separation continuous flow

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A A A A A A A B B B B B A B , A , B A B A +B A +B solvent solvent solvent solvent solvent R E A C TO R S S E P A R A T O R S S T O R A G E

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pressure induced flow local minimum for bandbroadening defines optimum flow rate How about a sequence of injected samples?

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electroosmotic flow minimum for bandbroadening at maximum speed

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pressure electroosmosis

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device for parallel lamination Fiona Bessoth

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chemical reaction • In the most simple case, a molecule A meets a molecule B and reacts to give AB • many reactions are diffusion controlled • reaction time of hours in conventional lab • reaction time of 30 min in micro well plate

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Figure 4. Separation of several amino acids using post-column derivatization for detection. D.J.Harrison, K.Fluri,N.Chiem, T.Tang,Z.Fan University of Alberta, Edmonton,Canada Transducers’95, Proc., vol.1, pp752-755 (1995)

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Y -shaped junction: 1:1 fluorescein-to-rhodamine B flowrate ratio (0.5 : 0.5 mL/min)

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Mixing – Diffusion times D d t 2 2  Before laminar mixing D n d t 2 2 2  After laminar mixing n = number of branches, d = tubing diameter, D= diffusion coefficient

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Distributive Micromixing Device: Schematic F. G. Bessoth, A. J. de Mello and A. Manz, Anal. Commun., 1999, 36, 213-215

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16 channels 256x faster !

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Distributive Micromixing Chip

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F. G. Bessoth, A. J. de Mello and A. Manz, Anal. Commun., 1999, 36, 213-215 Chip manifold volume 600 nL Observation channel 530 nL Distributive Micromixing Device

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fused silica capillary glue glass Si glass

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6 ms 14 ms 38 ms 94 ms 54 ms 78 ms 0 ms

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Fluorescein and Rhodamine B; Flow rate = 50 L min-1; Time from point of confluence to beginning of long channel = ca. 9 ms laminar flow visualisation

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fast fluorescence quenching 0 ms 6 ms

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Mixing * + further downstream reaction incomplete reaction incomplete reaction complete reaction complete reaction complete

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horseradish peroxidase assay Fiona Bessoth

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horseradish peroxidase assay 0 1 2 3 4 5 6 7 8 0 0.02 0.04 0.06 0.08 0.1 0.12 concentration HRP [g/mL] chemiluminescence signal [V] assay time 30 minutes  400 ms “incubation time” 400 ms

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conclusions • interesting • very preliminary • surface is the problem

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electrophoretic mixing Luc Bousse, Andreas Manz Caliper Technologies Inc, Mountain View, USA

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synthesis of small organic molecules Michael Mitchell, Valerie Spikmans

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Fast Reaction

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NO2 NO2 CHO NO2 P(Ph)3 NO2 purple Br- 2-nitrobenzy ltriphenyl- phosphonium brom ide p-nitrobenza ldehyde colourless NaOMe NO2 Me OH colourless P(Ph)3 + + Wittig reaction N + O O Cl Cl Cl Cl O O Cl Cl Cl N Enamine Chloranil blue 2,3,5-trichlor-6-(2-piperidin -1-yl)-[1,4]- benzoquinone Synthesis of a substituted aminovinyl-p-quinone SYNTHESIS

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N+ H H R1 R2 Cl- H H O MeOH N+ Cl- H2 O N R3 R4 R2 R1 C R1 N R2 N R4 R3 H2 O R1 N R2 N R4 R3 O R1/R2 = -CH2 (CH2 )3 CH2 - Piperidine hydrochloride + + Piperidinium cation + R3/R4 = -CH2 (CH2 )4 CH2 - Cyclohexyl isocyanide Nitrilium intermediate -Dialkylacetamide Formaldehyde N-Cyclohexyl-2-piperidin-1-yl-acetamide (1) (2) (3) (4) (5) (6) Multicomponent Chemistries: The Ugi Reaction 0oC

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Inlet capillaries Syringes Rheodyne injection valve Injection loop outlet capillary Micromixer chip / PTFE interface

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Simultaneous Observation of Reactants, Intermediates, Products and By-products 20 Lmin-1 50 nL injection loop Room temperature

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conclusions • Some syntheses do work! • What is the limitation? • Very fast mixing • Higher temperatures than usual • Better selectivity • Complicated device

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Continuous-flow polymerase chain reactor Martin Kopp, Marco Luechinger

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polymerase chain reaction • = method to amplify the amount of a specific DNA sequence in a sample • each cycle doubles the amount of DNA • most commonly used procedure in biology • commercial instruments would do 20 cycles in 50 minutes

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Figure 1. Cross section of micro-PCR test device. Figure 5. Gel electrophoretic photograph indicating that similar results were obtained with a 50ul microfabricated test device (mid-right three bands) as in much lager commercial instrument (mid-left two bands). The target sequence amplified was HIV.

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T.M.Woudenberg, E.S.Winn-Deen, M.Albin [Applied Biosystems, Foster City, CA] High-density PCR and beyond, u-TAS 96, p 55-59 (1996) First data from polycarbonate “chip”

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95oC Melting 77oC Extension 60oC Annealing PCR - Continuous Flow Chip 20 identical cycles Time ratio of 4:4:9 (melting:annealing:extension) Theoretical amplification factor of 220

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PCR - Continuous Flow Chip

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Cold start PCR Tricine (pH 8.4) 10 mM Tween 20 0.01% (w/v) KCl 50 mM NTP 20 M each MgCl2 1.5 mM PVP 1.4 M Primer 1 M Taq polymerase 0.25 U/L Template ca. 108 copies

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PCR - Continuous Flow Chip

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Efficiency of amplification On the chip: Template 108 copies Product 5.1011 copies Factor 5,000 = 1.5320 commercial thermocycler: Factor 7,030 = 1.5620

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Advantages of Continuous Flow PCR Chip variable volumes – 1nL to1mL low carryover high speed 12 to 60s per cycles low band-broadening High speed chemical amplifier

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Bioreactor on a chip Paul Monaghan

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Bioreactor on a chip • Permits the growth of a bacterium on-chip • Goal: antibiotics screening • Uses PDMS device for gas permeability

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Monitoring the growth of bacterial cultures • The sampling of a growing culture at various time intervals (by viable counts,dry weight of the biomass or optical density measurements) • Real-time monitoring • miniaturized systems • reduction of biological waste Conventional bulk growth techniques Microbiology microfluidic

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Fused silica capillaries Graphite ferrules Temp. sensor Heating Block PDMS device Fluidic connections a b PDMS Device and Set-up

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Photomicrographs of Cell Growth on-Chip 0hr 1hr 2hr 3hr 4hr 5hr

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Fluorescence measurements - Plots of PMT signal versus sampling time 0 1 2 3 4 5 0 10 20 30 40 50 60 70 80 90 100 sampling t (s) PMT sig. (V) 0hr 1hr 2hr a. Over the initial two hours, the data suggests that there is not a great deal of increase in the biomass. 0 1 2 3 4 5 0 10 20 30 40 50 60 70 80 90 100 sampling t (s) PMT sig. (V) 3hr 4hr b. After 3hr that there is any appreciable increase in the signal as indicated by figure b. At 4hrs, the signal has significantly increased.

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0.10 1.00 10.00 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Time (hr) Average PMT signal (V) 0.5mg/L 1mg/L 2mg/L Control antibiotics testing, chloramphenicol

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conclusions • Simple design • Gas permeability • Optical interrogation • A little bit faster than conventional

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plasma emission C:\WINDOWS\Desktop\talk 03-01\plasma.ppt electro-chemiluminescence C:\WINDOWS\Desktop\talk 03-01\ecl.ppt potentiometry Fourier transform methods C:\WINDOWS\Desktop\talk 03-01\scoft.ppt

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Plasma emission detector Jan Eijkel, Herbert Stoeri, Omar Naji, Fiona Bessoth, Gareth Jenkins, Darwin Reyes

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State-of-the-art • inductively coupled plasma • 1 kW power consumption • gas temperature 6,000K • safety radius 1 m • very low detection limits for metals • liquid nebulizing interfaces

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Scaling laws for dc glow discharge • pressure 1/d • el.current 1 • voltage 1 • # of charged particles 1/d2 • electron temperature 1 • plasma core gas temperature 1/d

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detector volume 50 nL

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Spectroscopy, carbon 300 400 500 600 700 800 -5000 0 5000 Emission (AU) Wavelength (nm) helium helium + methanol ~ ~ ~

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Calibration curve for methane • Detection limit 2·10-14 g/s C 10 100 1000 104 1 10 100 1000 emission intensity minus background / A.U. CH 4 concentration / ppm 3*Noise

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Calibration for hexane 10 100 1000 104 10 100 1000 104 Plasma chip peak height (AU) FID peak height (pA)

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0 500 1000 1500 2000 2500 3000 3500 4000 4500 200 300 400 500 600 700 800 900 Wavelength (nm) Emission Intensity (AU) CH2 Cl2 CCl Cl CH He C/C2 C2 He H He Spectroscopy, Cl

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0 500 1000 1500 2000 2500 3000 3500 4000 4500 200 300 400 500 600 700 800 900 Wavelength (nm) Emission Intensity (AU) Background (He) Bromopropane 470.2 478.2 481.5 Bromopropane Br Spectroscopy, Br

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conclusions • simple layout and operation • 10-50 mW power consumption • gas temperature 400K • can be touched during operation • acceptable detection limits for volatiles • problem: liquid samples plasma liq.ppt analog computing.ppt

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liqid samples ? 50 nL of gas (1 atm) corresponds to 50 pL of liquid spraying not succesful  sputtering off sample surface

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Schematic of Electrolyte as Cathode Discharge (ELCAD) Optical Emission Detector Chip

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Cathode Connection Gas / sample outlet Spectrometer connection / plasma chamber H.V. Anode Gas inlet (Argon or Helium) Sample Inlet

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Experimental Setup of ELCAD Optical Emission Detector Chip

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Top trace : 0.1M CuSO4 in 1M HCl Bottom trace : 1M HCl

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Top trace : 0.1M CuSO4 in 1M HCl Bottom trace : 1M HCl Possible CuI bands at 485nm & 488nm Cu lines at 511nm, 515nm & 522nm

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electro-chemiluminescence Arun Arora

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6 x 10-12 4 x 10-12 2 x 10-12 0 40 20 0 concentration / mol dm-3 emission intensity / a.u. figure 4

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Sensitivity of electrochemiluminescence detector for Ru(bpy)2 Detector cell volume 100 nL concentration number of molecules light intensity 5.10-13 M 30,000 2.1 + 0.5 1.10-12 M 60,000 5.2 + 0.4 2.10-12 M 120,000 11.1 + 0.7 4.10-12 M 240,000 28.0 + 0.6 5.10-12 M 300,000 34.1 + 0.4

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floating electrodes pH changes indicate ox and red

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electrode electrode Pt Pt Pt ox red ox red ox red ox red ox red ox red red ox 1-2 V applied voltage

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ECL and CE chip glass device with Pt electrode

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ECL and CE chip

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ECL and CE chip Ru (bpy)3 light emission increases with voltage

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ECL and CE chip direct measurement of Ru2+

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TBR -3 -2 -1 0 1 -6.5 -6 -5.5 -5 -4.5 -4 -3.5 -3 Log C (M) Log Signal (arbitrary units) Calibration Curve

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indirect detection possible

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conclusions • interesting and simple • problem: electrolysis of water • not satisfactory detection limit

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potentiometric detector Ratna Tantra

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potentiometry

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potentiometry liquid chromatography S.Muller, D.Scheidegger, C.Haber, W.Simon, J. High Res. Chromatogr. 14, 174 (1991)

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potentiometry selectivity Ba2+ vs Mg2+ 2.10-5 Ba2+ vs Ca2+ 3.10-3 Ba2+ vs Cu2+ 3.10-5 Ba2+ vs Na+ 4.10-3 Ba2+ vs K+ 8.10-3 M.W.Laubli, W.Simon, F.Vogtle, Anal. Chem. 57, 2756 (1985) this selectivity is not enough for Ba2+ in presence of Na+

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CE combined with potentiometry resolution Ba2+ vs Mg2+ n/a Ba2+ vs Ca2+ 16 Ba2+ vs Cu2+ n/a Ba2+ vs Na+ 20 Ba2+ vs K+ 36 T.Kappes, P.Schnierle, P.C.Hauser, Anal. Chim. Acta 393, 77 (1999)

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CE combined with potentiometry FIA, potentiometry CE, potentiometry Ba2+ Ba2+ Na2+, Ba2+ Na2+

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CE potentiometry chip glass microstructure with PDMS wells

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potentiometry chip glass microstructure with PDMS wells

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potentiometry chip

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potentiometry chip

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potentiometry CE chip conc [arb. units] 0 1 2 3 4 5 6 0 10 20 30 40 50 60 time [s] EMF [V] 0 0.05 0.1 0.15 0.2 0.25 0 10 20 30 40 50 60 time [s]

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potentiometry CE chip main problem •membrane liquid is moved out when voltage is applied • reproducibility • lifetime

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Shah convolution, Fourier transform velocimetry John Crabtree, Toby Jeffery, Yien Kwok, Jan Eijkel

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Shah Convolution - FT- Detection Typical detections - single point injection detection e.g. Fluorescence Electrochemical Conductance …. separation

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injection Imaging detection Injection separation function detection SIGNAL RECORDED Shah Convolution - FT- Detection injection Delta function convolution Shah function SIGNAL RECORDED DECONVOLUTION separation Fourier transform f (frequency) Electrophoretic mobility 1/f Electrophopherogram

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Shah Convolution - FT- Detection µ-TAS device – ideal geometries - LIF 55 Slits – 700µm spacing, 300µm transparent Channel 15µm deep, 50µm wide slit array Cr layer sample carrier electrolyte waste waste injection detection area

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Shah Convolution - FT- Detection

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detection during re-mixing detector signal A (t) mobility spectrum X

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multiple injection detector signal B (t) mobility spectrum X scoft multi inj.ppt scoft particles.ppt

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0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 16 20 24 28 32 36 40 time (sec) PMT Signal (V) 1st 2nd 1st 2nd 3rd 2-plugs 3-plugs

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0 150 300 450 600 750 900 0.5 1 1.5 2 2.5 3 frequency (Hz) FT Magnitude (arb. units) 1.675 Hz fundamental 1.8 Hz fundamental 2-plugs 3-plugs -0.5 0.5 1.5 2.5 3.5 4.5 5.5 0 5 10 15 20 25 30 35 time (sec) PMT Signal (V) 2-plugs 3-plugs Fourier Transform

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Table 3: S/N vs Number of Sample Plugs Number of Sample Plugs S/N a Standard deviation 1 46 2.5 2 69 5 3 102 1 (a) average of two runs for each number of sample plugs

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SR SW BW Electrophoretic Channel Cr film with micromachined slits 40 m wide slit 30 m gap

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0 0.02 0.04 0.06 0.08 0.1 50 55 60 65 70 time (s) PMT Signal (V)

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0 5 10 15 20 25 30 5 7 9 11 13 15 17 Frequency (Hz) FT Magnitude (arb. units)

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0 30 6.4 7 7.6 Frequency (Hz) FT Magnitude (arb. units) are these fine lines single particles?

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wavelet transform 7Hz area time [s] 20 0 frequency [Hz] single particle 10

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7 Hz 14 Hz

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mobility spectrum X detector signal C (t) frontal analysis scoft frontal.ppt

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0 2 4 6 0 10 20 time (sec) PMT Signal (V) 50 100 150 200 0.5 1 1.5 2 frequency (Hz) FT(Magnitude) (arb. units) FT ~1 Hz fundamental (A) (B) -10 190 390 590 0 1 2 frequency (Hz) FT(Real-B)^2 (arb. units) 1 Hz fundamental (C) FT -0.004 0 0.004 0.008 0.012 0 10 20 time (sec) Differentiated PMT Signal (arb. units) (D) Differentiation 0 1 2 3 0 1 2 frequency (Hz) FT(Magnitude) (arb. units) FT (E) 1 Hz fundamental

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conclusions • Not clear what advantages are • Interesting • Hope to increase resolution [?]

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Analog computing Darwin Reyes

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2 + 2 = ? What is the optimum linear velocity for minimum band broadening? What is the optimal street modification for London’s daily traffic jam?

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Very simple approach to a mathematical problem: • Provide the problem as a micro channel system • Pose the question by addressing electrodes • Get the answer visualized by plasma emission MAZES

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given: the most simple maze question: What is shortest connection between A and B? A B He in-, outlet electrodes

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Increased mathematical complexity same time to find solution

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Victoria station Imperial College

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Interesting paper by Whitesides group on “maximum clique” problem solving by particle counting in microfluidic device PNAS 2001 …

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conclusion • interesting • fun ! • search the problem for a solution • not clear, how useful

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Acknowledgment Coworkers and Ph.D. students Jan Eijkel Chao-Xuan Zhang Michael Mitchell Fiona Bessoth Omar Naji Darwin Reyes postdocs Arun Arora Yien Kwok Gareth Jenkins Silvia Valussi Nicole Pamme Oliver Hofmann Paul Monaghan Melanie Fennah Valerie Spikmans Nils Goedeke Dimitrios Iossifidis Pierre-Alain Auroux

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FUNDING INSTRUMENTATION SmithKline Beecham (UK) Zeneca (UK) BBSRC, UK EPSRC, UK European Commission, B Schlumberger, UK Casect, UK Agilent, D Forensic Lab, UK Asahi Kasei, Japan Lab of the Government Chemist, UK CSEM, Switzerland Amersham Pharmacia, UK Kodak, UK Glaxo Wellcome, UK Glaxo-Wellcome Heidelberg Instruments Hybaid MICROFABRICATION Alberta Microelectronics Centre, Canada Caliper Technologies, California MESA, University of Twente, The Netherlands CSEM, Switzerland !