1 PI: Christian Schnenberger Department of Physics and Swiss Nanoscience Insitute @ University of Basel Nanowire Sensor Integrateable Si Nanowire Sensor Platform forIon- and Biosensing 2 Bio- / chemical Sensor mechanically a) mass change (QCM) b) strain (cantilever) optically a) labelled (DNA chip) b) refractive index c) plasmonics electricallya) impedance spectroscopy b) CV spectroscopy c) potentiometric how can this informationbe read ? a device that can detect molecules in a with some specificity 3 Ion Sensitive FET (IS-FET) sourcedrain channel conductance (i.e. threshold)dependson gate charge (gate potential) (source-drain current) - - - --- - e.g. heparime binding on protamie SHIFT p-channel, threshold regime 4 Concept & Team Analyte Receptor Transducer Signal processing 5 Nanowire fabrication 6 Nanowire fabrication PMMA 80nm 145nm ~10nm p-type (100) SOI SiO2 Si handle wafer Si step 1. step 4.+5.step 6.+7. step 11.to14. metal SU-8 step 2.+3. wire length:6um width: 100nm-1um silicon silicon oxide resist metal ALD oxide epoxy 100nm Weff = Wtop + 2Wwalls Kristine Bedner et al. 70 nm300 nm 7 Nanowire fabrication operation enhancement mode insulator Layer HfO2, tins = 5 nm, poly-Si Gates wg = 25 nm, hg = 50 nm fin Body hSi = 100 nm, wSi = 50nm doping Na = 51016 A partially double-gated fin field effect transistor (DG-FinFET) is the electronic sensing architecture. S.Rigante, M.Najmzadeh and A. M. Ionescu, EPFL _ _ _ _ __ _ 8 Nanowire fabrication Solid nanowire array Particle based nanowire array 9 SOI-NW (working horse) PMMA 80nm 145nm ~10nm p-type (100) SOI SiO2 Si handle wafer Si step 1. step 4.+5.step 6.+7. step 11.to14. metal SU-8 step 2.+3. wire length:6um width: 100nm-1um silicon silicon oxide resist metal ALD oxide epoxy 100nm Weff = Wtop + 2Wwalls Kristine Bedner et al. 70 nm300 nm 10 SOI-NW (working horse) (non-implanted, Al-contacts) (p+-implanted and alloyed contacts) -0.5 0.0 0.5 1.0 1.5 2.002468Vsd=0.1V NW 1 NW 2G (S)Vref (V)Vbg=-6VpH 710-1010-910-810-710-610-5width =1m G (S)120mV/dec-0.5 0.0 0.5 1.0 1.5 2.00.01.53.04.56.07.59.0120mV/decVsd=0.1VG (S)Vref (V)width =1mpH 3, 5, 7, 9Vbg=-6V10-1010-910-810-710-610-5G (S)back-gate G (S) G (S) G (S) G (S) Vref (V) Vref (V) 11 Ion-sensitive FET (basics) sensitivity selectivity (what can be detected in the first place and what not) detection limit signal-to-noise (origin of noise) scalability stability and reproducibility in the following examples: the ionic solution is in direct contact with a thin oxide layer (SiO2, Al2O3, HfO2) capping the conducting channel of the transistor.The OH-terminals are then the main ion-active functional groups12 IS FET for pH sensing taken from an application note P. Bergveld / Sensors and Actuators B 88 120 (2003) Honeywell: Durafet III Endress+Hauser :CPS441 and CPS441D pH sensors 13 pH sensing on oxide surface site binding (SB) model for SiO2 surface (iii) surface charge density oS (ii)bSiOHH SiOHKaS=++2vv(i) aSiOHH SiOKaS=+ vvP. Bergveld / Sensors and Actuators B 88 120 (2003) P. Bergveld, IEEE Sensor Conference Toronto (2003) (i-iii) can be used to expresssurface charge o0 as a functionof +SHa||.|

\|+ +=+ ++b a b H Hb a HS SK K K a aK K aqNS SS22o14 pH sensing on oxide surface P. Bergveld / Sensors and Actuators B 88 120 (2003) P. Bergveld, IEEE Sensor Conference Toronto (2003) convert surface ion to bulk ion concentration |.|

\|+ =+ +kTea aSH HB Sexpdef. of pH) log(+ =BHBa pHS+ surface potential Debye length if Cdl is large, then S dl SC+ ='o15 pH sensing on oxide surface threshold shift Cgat e oxi de Cdl CSCgat e oxi de Cdl Csa = b Cgat e oxi de Cdl CsA= Bmaximum sensitivity given by Nernst limit:2.3 kT/e = 59.5 mV/pH O. Knopfmacher et al. Nano Lett. 10, 2268 (2010) P. Bergveld / Sensors and Actuators B 88 120 (2003) P. Bergveld, IEEE Sensor Conference Toronto (2003) Cgate-oxide 1HfO2 Vbg= -3VVbg=-4V(100nm)Vbg=-2V(400nm)Vbg=0V(1m) W(top)=100nm W(top)=200nm W(top)=300nm W(top)=400nm W(top)=500nm W(top)=1m Vref=-1.3VSV/V2 ds (10Hz) (1/Hz)R (MO)p=1Vsd=0.09Vset-upwirecontact oVth ~210-4 V/Hz0.5 (@ 10Hz) 33 Detection limit / resolution different wire width Al2O3 and HfO2 oVth ~1-410-4 V/Hz0.5 (@ 10Hz) threshold noise: 0.1 1 10 1001E-51E-4Vsd=0.09V W(top)=100nm W(top)=400nm W(top)=1maveraged AVth (V) by Weff at 10Hz (V/Hz1/2)R (MO) NW regimecontact regimes can reach 200 ppm of pH compares to one electron per wire (for the narrowest ones) K. Bedner et al. 170 ppm 600 ppm detection limit~ 200 ppm of pH (1 Hz BW at 10Hz)better for wider wires ! 34 Conclusions 1. maximum sensitivity (Nernst limit) can be achieved (Al2O3 and HfO2) 2. oxide surfaces (Al2O3 and HfO2) can be highly selective to protons (yielding ideal pH sensor up to buffer conc. of 1-10 mM)3. maximum sensitivity also for the narrowest nanowires 4. charge detection limit best for the narrowest wire, but 5. highest resolution in concentration best for wide wires 35 Specificity / selectivity OHOHOHOH is it possible at all to suppress the high selectivity and responsivity of oxidesurfaces to protons (pH) ? 36 Passivation (against pH) -1 0 1 2 3 4 5 6 7 8-10010203040506070 pH sensitivity [mV/pH]passivation time [days]020406080100120CA measurements: SiO2 SiO2 Al2O3contact angle [] nanowiremeas.octadecyldimethylmethoxysilane(C18 alkane silane)pH sensitivity [mV/pH] contact angle -0.10.00.12 4 6 8 10 12after 24 hafter 6hpHB+0[mV]pH in bulk surface potential dependence is getting exceedingy nonlinear A. Tarasov et al. 37 Passivation theory A. Tarasov et al. long time (1 hour) detection limit < 1 surface site / (10nm)2(includes drift) experiment 38 Conclusions 1. maximum sensitivity (Nernst limit) can be achieved (Al2O3 and HfO2) 2. oxide surfaces (Al2O3 and HfO2) can be highly selective to protons (yielding ideal pH sensor up to buffer conc. of 1-10 mM)3. maximum sensitivity also for the narrowest nanowires 4. charge detection limit best for the narrowest wire, but 5. highest resolution in concentration best for wide wires 6. full passivation possible ideal reference electrode 39 Towards a ChemFET we can sense electrostatic potential (after passivation) we can sense the chemical potential of protons (pH sensing) can we sense also K or other ions ? KCl A. Tarasov et al. 40 ChemFET PVC membrane cocktail dissolved in THF valinomycin potassium ionophore drop functionalization (~0.2l) PVC membranes with ionophore Valinomycin: K+ ionophore M. Wipf et al. 41 ChemFET All the wires show the same pH sensitivity, indicating that the PVC membrane is fully permeable to the liquid and all (most) OH groups remain active 5 6 7 8 9-1.2-1.1-1.0 without PVC membraneVth [V]pH~50 mV/pHwith PVC membraneM. Wipf et al. 42 ChemFET Arrays without PVC membrane show regular behavior with increasing salt (black) PVC+ ionophore coated arrays show negative shift in Vth indicating adsorption of positive charges (red) Differential measurement (red-black) results in a KCl sensitivity of ~-40mV/dec 1E-3 0.01 0.1 1-1.40-1.35-1.30-1.25without K+ ionophore Vth [V][KCl] with K+ ionophore1E-3 0.01 0.1 1-0.15-0.10-0.050.00 AVth[V][KCl]-42 3 mV/decdifferential measurement M. Wipf et al. 43 ChemFET All wires show the same response to increasing MgCl2 concentration PVC + ionophore only adsorbs K+ Differential measurement (red-black) results in a MgCl2 sensitivity of ~ 0mV/dec differential measurement 1E-3 0.01 0.1 10.000.050.100.15 AVth[V][MgCl2]~0 mV/pH1E-3 0.01 0.1 1-1.15-1.10-1.05-1.00-0.95without K+ ionophore Vth [V][MgCl2] with K+ ionophoreM. Wipf et al. 44 ChemFET Covalently bound ionophore; a K+ trap was used here (18-Crown-6) 1E-3 0.01 0.1 1-0.10.00.10.20.3without K+ ionophore, in KClwith K+ ionophore, in NaCl Vth[V]c[mol/l]with K+ ionophore, in KClR. Stoop et al.J. Kurz et al. 45 Conclusions 1. maximum sensitivity (Nernst limit) can be achieved (Al2O3 and HfO2) 2. oxide surfaces (Al2O3 and HfO2) can be highly selective to protons (yielding ideal pH sensor up to buffer conc. of 10 mM)3. maximum sensitivity also for the narrowest nanowires 4. charge detection limit best for the narrowest wire, but 5. highest resolution in concentration best for wide wires 6. full passivation possible ideal reference electrode 7. full sensitivity with high selectivity to other ions can be achieved (here tested K) on functionalized electrodes 46 Targets for Biosensing Affinity Determination of Receptor-Ligand Interactions (lectin-sugar interaction) GalNAc immobilized on a Si-NW CRD of ASGP-R I. Human Asialoglycoprotein-Receptor (ASGP-R) plays an important role in the endocytosisin liver cells binds to terminal GalNAc (N-acetyl-D-galactosamine) residues CRD of FimH n-heptyl-man immobilized on a Si-NW II. Bacterial lectin FimH plays an important role during the invasionof uropathogenic bacteria binds to n-heptyl-mannose OHONHAcOOnOHHONHOSiOHONHAcOOnOHHONHOSiOHONHAcOOnOHHONHOSiSiOHOHOOHOOHNHOSiOHOHOOHOOHNHOSiOHOHOOHOOHNHOKD ~ 70 MKD ~ 50 nM Beat Ernst et al. 47 Ligand Immobilization (I) 1 2 3 4 5 6 R = R = GlcNAc (control) GalNAc (ligand) OHONHAcOOOHHOnOHONHAcOOOHHOOHONHAcOOnOHHONHOSiOHONHAcOOnOHHONHOSiOHONHAcOOnOHHONHOSiJolanta Kurz et al. ASGP-R 48 Protein Sensing I (ASGP-R) frequency change (Hz) time (min) buffer ASGP-R Jolanta Kurz and Arjan Odedra et al. OHONHAcOOOHHOnOHONHAcOOnOHHOQCM 50 Ligand Immobilization (II) 1 2 3 4 5 6 Jolanta Kurz et al. R = R = control n-heptyl-man (ligand) OHOHOOHOOHHOSiOHOHOOHOOHNHOSiOHOHOOHOOHNHOSiOHOHOOHOOHNHOFimH 51 Protein Sensing II (FimH) buffer frequency change (Hz) time (min) FimH Jolanta Kurz and Arjan Odedra et al. HOOHOOHOHOOHOOHOHOQCM 52 Protein Sensing II (FimH) strongly lectin binding glycoconjugate ligand inactive glycoconjugate control UniBas2-FHNW-ETHZ-UniBas1-PSI buffer: 20mM HEPES, 150 mM NaCl, 1mM CaCl2, pH=7.4 2 g/mL =107 nM FimH10 g/mL = 536 nM FimH OHOHOOHOOHOHO2 g/mL =107 nM FimH10 g/mL = 536 nM FimH Jolanta Kurz and Arjan Odedra et al. 53 Conclusions 1. maximum sensitivity (Nernst limit) can be achieved (Al2O3 and HfO2) 2. oxide surfaces (Al2O3 and HfO2) can be highly selective to protons (yielding ideal pH sensor up to buffer conc. of 10 mM)3. maximum sensitivity also for the narrowest nanowires 4. charge detection limit best for the narrowest wire, but 5. highest resolution in concentration best for wide wires 6. full passivation possible ideal reference electrode 7. full sensitivity with high selectivity to other ions can be achieved (here tested K) on functionalized electrodes 8. first signals from protein sensing 54 upscaling 55 System Concept PCBSi-NW chipCMOS chip Micro fluidics low-noise circuitry on chip biasing and modulation technique A/D conversion nanowires can be integrated on the chip or can be interfaced via a PCB board 56 System Architecture Paolo Livi et al. 16 nanowires can be interfaced in parallel voltage across each nanowire is kept constant, and the current flowing through is measured Two different analog-to-digital converter architectures are used (12 bits resolution) Current range: 1 nA to 5 A 57 System Architecture 16 channel bias and read out 16 slots foron-chip nanowires Paolo Livi et al. 58 System Architecture Nanowire Sensor Chip CMOS Readout Chip Paolo Livi et al. VDS = 200 mV sigma-delta modulatorread-out of 4 Si-NW, 9.-10. Nov. 2011 59 Working System Paolo Livi et al. 60 Thanks to.... Michel Calame Uni Basel physics OrenKnopfmacher Wangyang Fu Alexey Tarasov ChristianSchnenberger Beat Ernst EPFL Adrian IonescuKristine Bedner BerndDielacher Jolanta KurzUwe Pieles AndreasHierlemann Paolo Livi Arjan Odedra Sara Rigante MohammadNajmzadeh Janos Vrs RobertMacKenzie Yihui Chen Birgit Pivnranta Vitaliy Guzenko Christian David ETHZ UniBas pharma Jens Gobrecht PSI D-BSSE FHNW Matthias Sreiff Sensirion Mathias Wipf Renato Minamisawa Ralph Stoop Floriian Binder