2004 high signal to noise ratio in low field nmr on chip, simulations and experimental results

8/8/2019 2004 High Signal to Noise Ratio in Low Field NMR on Chip, Simulations and Experimental Results

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HIGH I GNAL TO NOISE ATIO IN LOW FIELD NM R ON CHIP,SIMULATIONS AND EXPERIMENTALESULTS.H. Wensink.D. . Hermes, A . vanden BergBIOS Lab-on-a-Chip group, MESA' Institute for N anotechnology, University of Twente,Enschede, The Netherlands. Ernail: h.wensink@ utwente.nl, http://www.bios.utwente.nV

ABSTRACTA pfluidic chip with integrated microcoil was developed forNuclear Magnctic Resonance ( N M R ) spcctroscopy onlimited volume samples (nanoliters range). This chip will beused for the online monitoring of micro chemical reactions.Design rules for the microcoil to achiere the best Signal toNoise Ratio (S N R ) were obtained by finite elementsimulation. For pure water in a low field NMR magnet(60 MHz i.e. 1.4 Tesla) a SNR of 550 was achieved which isto our knowledge higher than any other pfluidic chip withintegrated detection coil. It is also shown that a spectralresolution of 0.025 ppin is obtained whe n a microchannelwith an arbitrary cross section is placed parallel to themagnetic field. A high S N R at low magnetic field for smallvolume samples is essential for the development of portableNMR ystems where mini permanent magnets of 1 Tesla areused.1. INTRODUCTIONTherc is an increasing effort to perform chemical reactions inpfluidic chips. Some of the goals are to decrease the amountof cxpensive chemicals that are used for the reactions and abetter thermal control of the reaction. A consequence is thatonly a small am ount of product is available for analysis. Thishas led to the downscaling of analytical techniques such asmass. infrared and Raman spectrometry, UV, fluorescenceand electro chemical detection and also Nuclear MagneticResonance (NMR).NMR s a powerful technique which can identify chemicalcompounds by the unique composition of electromagneticproton resonance frequencies io a large magnetic field.Relative to many other analytical techniques, however. it isinherently insensitive 11). Since the signal scales with thesquare of the static magnetic field (Ao), ne of the main aimsin N M R has been to increase Bol which has currently led to21.1 Tcsla NMR magnets. Mabmets with a large field (> 2Tesla) are typically superconductive? quite large andexpensive which limits the use of NMR to large chemicallaboratorics.N M R on limited volume samples (nanoliters range) can beachieved by placing a fluid ic chip with integrated detectioncoil inside a conventional NMR m agnet [Z, 1. A future goalfor N M R on chip is the use of small magnets to obtain a miniN M R system. which can be integrated into more complexpfluidic systems. The small sample size is an advantage inthis case since tlie homogeneous part of the magnetic fieldcan be small which is easier to obtain. NdFeB magnets havea field strenglh of about I Tesla which is large for permanentmagnets but relatively low for N M R pectroscopy. Togetherwith the small sample volume. this makes a highperformance detection coil one of the key factors for thedevelopment of such a mini N M R ystem.

This paper reports on the design and fabrication of a pfluidicchip which was used to measure NMR spectra of limitedrolume samples (56 nl) in a conventional low field 60 MHzNMR magnet (1.4 Tesla, Varian EM360L).2. N M R SIGNAL AN D COIL DESIGNThe m o un t of signal that can be retrieved from a sampledepends on the total volume and the static magnetic fieldstrength in the following way [ J]:

(1)ac Bo ' r ,with S tlie signal level, Bo the magnetic field strength and r,the sample rad~us.This shows that scaling down the samplehas a dramatic effect on the signal intensity. To maintain areasonable signal the coil must be scaled down to be close tothe sample. In our case a planar microcoil is used, which canbe defined by the num ber, height, width and separation of thewindings and the inner coil radius (Figure I).

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Lcrocoil r.4 -jSt+ 8 0 wh n n n ..................... ,r4-hnlet OutletFigure 1: Schematic cross-section o the niicro coil withthree windings on top o a f lu idi c chip.The magnetic field that is produced hy a microcoil (B,)carrying a unit current can he calculated (Figure 2). Th e 8,field inside the sample area is proportional lo the NMRsignal intensity [I]. The main noise source in the system isthe electrical resistance of the coil (Johnson Noise) [SI.Increasing the number of coil windings results in a higherNMR signal. On the other hand ever?. additional windingalso increases the electrical resistance and noise of the coil.Stocker et al. [6] analytically calculated the optimal numberof turns Tor a maximum Signal to Noise Ratio ( S N R )whiletaking these two effects into account. The electrical coilresistance at high frequencies increases more than linearlydue to the skin effect and eddy currents. The effect of theeddy currents on the resistance is difficult to calculateanalytically. An estimate fo r the upper limit of the resistancewas calculated by Eroglu et al. 171. hut only for specificconditions.In this paper the SNR of the microcoils is simulated using thefinite element method. Finite Element Method Magnetics(FEMM) is a freely available tool for analysing 2D an daxisymmetric electromagnetic problems IS]. The round spiralplanar coil is approximated by 3D circular turns that can be

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simulated in an axiisymmetty problem . A simulation of a coilwith 18 windings on top of a V-shaped channel is shown inFirmre 2.

Figure 2: Typical cross section of the B, jield linessimulation b v FEAa4[8].For every simulation the width of the windings (w) nd innercoil radius ( r i ) were fixed and the maximum SNR wascalculated by varying the number (N) and height (h ) of thewindings. The separation between the windings (s) was keptequal to w. The SNR of the simulations was calculated bydividing the total B , field in the sample by the square root ofthe total resistance. A small contact resistance (R,) of0.1 Ohm was included to obtain realistic noise levels. Figure3 shows the maxiinum attainable SNR for several windingwidths as calculated by F EMM . Simulations in this figure arefo r a copper coil in air at 300 MHz, with the centre of thesample located 250 pm below the coil. Note that the numberand height of the windings are listed in Table 1 for everypoint.

6.56.0- 5.5

a 5.05 4. 0

3.53.02.5

2 4. 5

0 20 40 60 80 100Windingwidth btn]

Figure 3: Si\R, versris winding w idth (sirnulation). EachSAR,, wlue has ils own coil poraiirelers (see Table 1).Frequency is 30OhfHzandr i is 250 pin in these cases.The simulation shows the general trend that windings with asmaller w an d s esult in a better SNR. Those coils have highaspect ratio windings. which makes them difficult tofabricate. Hence the general design rule for planar NMRcoils is to take the minimum i v an d s possible, and useFEMM to calculate the optimum number and height of thewindings.

Table I : The siinulatedSNRm (valuesplotted in Figure 3 )W

Ipml261015254070100

h1715141526386078

CmlN

13 84224158532

SNRi,hicl. R,bu.16.415.625.004.714.564.454.113.53

Resolution improvementNM R magnets produce a very homogeneous BO ield whichis necessary for a good resolution. An y object with slightlydifferent magnetic permeability that is placed in this field>(e.g. a pfluidic chip) can disturb this homogeneity. Carefuldesign_ choice of materials and placement of the chip in theBO ield are therefore necessaty lo maintain a good resolution(the typical minimum resolution to perform N M Rspectroscopy is about 0.1 ppm). E.g. the irregular shape ofthe microcoil can disturb the homogeneous B o field.Trumbull et al. [9]used a combination of chromium and goldto match the magnetic permeability of th e coil to air. Stockeret al. [2 ] placed the coil in a special fluid (Fluorinert) ofwhich the magnetic permeability was matched with the coilmaterial. Although placing the coil very close to the samplewill give much N M R signal, at some point this willnegatively influence the resolution [l, 21. The shape of th esample volume also influences the field homogeneity.Massin et al. [IO] predicted and measured a higher resolutionfor ellipsoid like sample volumes. In this paper a differentapproach is followed. It is clear that the m agnetic field linesare disturbed when there is a sudden change in magneticpermeability, e.g. going from glass to the sample. Anychange of channel geometry near the detection coil will(nearly always) negatively influence the field liomogeneity.This will not be the case if a long sample channel with aconstant shape is used. T he abrupt beginning and ending ofthe channel will disturb the homogenous magnetic field. Butin the middle of the channel where the coil is placed theseentmce effects have little inluence and the field is morehomogeneous.3. EXPERIMENTALET-UP AND MEASUREMENTSTwo Borofloat glass wafers were powder blasted 1111 toobtain the channels and through holes of the chip (seeFigure4). The powder blasting process gives a rough surface andthe cross section of the Channel has a rounded V-shape. Thewafers were direct bonded and annealed at 600C. The waferstack was thinned down on one side by HF etching todecrease the distance between the coil and the channel toabout 80 pm (see Figure I). copper coil was electroplatedon top of the channel.

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blasted channels are responsible for these differences inresolution.1, n I

SNR*~FWHM[l"z] norm.yp e

Figure 4: The glass .VMR chip with planar micro coil. Chipsize is 1x1 cm, channel ,size i s 500 pm.Three types of coils were designed; the dimensions andsimulated properties are listed in Table 2. Th e height for eachcoil was I5 pin and r , is 250 pin. The optimum height forinaximun SNR is annally larger and will be employed in thenext chip series. The V -shaped chann el is 500pm w ide at thetop, and 450 pin deep. This leads to a sample volume belowthe inner coil radius of about 56 nl (note that the volumeunderneath the windings also contribute slightly to th e NM Rsignal).Table 2: Siniulated values at 6 O M I z or three types of coils.

20 B 20 4.73 1.00111 80 B 70 15.7 0.31 0.87II 3 0 ~0 12 158 2.32 0.95

NM R set-upThe e lectronic set-up forN M R was copied from M assin et al.[3). The NM R chip was placed on a holder. filled manuallywith purc water and matched and tuned to 50 Ohm at 60MHz by using two variable capacitors. The holder \\'as thcncarefully positioned in the conventional 60 MH z NMRmagnet (Varian EM360L) with the pfluidic channel in linewith the large magnetic field. A single 90' pulse with alength of 28 psec initiated the NMR measurement. The NMRtime signal was acquired by an Agilent oscilloscope(5462112) and Fo urier transformed to the frequency dom ainby Agilent VEE sofhmre. All acquisition parameters (e.g.acquisition timc, number of data points, filter settings etc.)were kcpt constant. The resolution (in parts per million:ppm) w a s defined as the Full Width at Half Maximum(FWHM) of the peek in the frequency domain divided by theN M R frequency of 60MHz. The SNR in the frequencydomain was calculated by dividing the peak height hy thenn s noise value between 540 and 600 Hz (9 and 10 ppm).ResultsA singleNMR measurement is shown in Figure 5 . In total 15chips have been measured with at least 8 measurements perchip. The resolution ranged between 0.019 and 0.074 ppinfrom chip to chip. We believe local differences in the power

SNR, , SNhi. incl. R,Ia.u.1 [all.]

? 0.6 -m6 0.4 -VI-.-

405 410 415 420 4 5-0.2Frequencywz]

Figure 5: hMR spectrum ofpure water. Tvpe I coil, singlescan, SAR = S O , FWHM = 1.3H z , resolution = 0022ppin .Th e SNR that is measured in the frequency domain dependson the exact coil to channel distance (ranging from 60-110pm), and on the rcsolution (not the peak height but the areaof the peak is related to the total NMR signal that is retrievedfrom the sample). To properly compare severdl S N Rmeasurements with different resolutions thc SNR value isinultiplied with the square root of th e FWHM [IO]. Secondly,SNR m easurements from one coil type with different channelto coil distances were combined to calculate theSNR*dFWHM for that type at a channel to coil distance of80 pm. hese final values are shown in Table 3.Table 3: A i . ~ r a g e alues of the SAR times the square root ofthe resolution in comparison with the simulated SNR.

584 0.90 0.95 0.891111 j 280 0.43 I 0.87 0.49The average values of SNR*dFWHM are also normalisedwith respect to the type 1 coil value. The SNR*dFWHMvalues can be compared with the simulated SNR valueswhich shows that the agreement is not good. Especially forthe type 111 coil, where a value of 0.87 relative to the type Icoil was expected from simulations, and a value of 0.43 wasmeasured.This is on account of the high R, of 0.8 Ohm, dueto long (7 cm) and thin (70 pm) opper wires that were usedto connect the chip. After including this R , in the noise level,the simulated SNR values are much more in line with themeasurements (laa column in Table 3).ResolutionPlacing the chip in the N M R magnet with the channelperpendicular to the large field (in Uie wrong way): resultedin a resolution of no more than 0.5 ppm. With the same chipa resolution of 0.022 ppm was obtained when placedcorrectly in the magnet. which shows the importance of aproper chip orientation. The good resolution is reflected inthe NMR spectrum of ethanol, which revcals the spincoupling of the triplet (F igure 6).

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I.6CU0.4 5

0.20

[M&l 1 [n11 I

5 4 3 2 1Frequencyshift [ppm] -0

Figure 6: Single scan NUR spectrum of 100% Ethanolmeasured with a tvpe I coil (see Tahle 2).

[ppml

4. DISCUSSIONSThe measured relative performance of each coil type wascorrcctly predicted by simulations. Thc typc I coil with thesmallest M an d s produces the best SNR. as expected. Thetypical SNR of 550 is better compared to other authors, asshown in Table 4. This is remarkable since our magneticfield is five times lower, which gives an inherently 25 timesweaker signal.Tahle 4: Conrparison of iWfR results with other authors (coiland channel integrated in chip). Results ohtained with wafe r.Freo. I Volume I SNR I Resolution I ref.

L~ >0.100~~~ I [lo300 30 26 060 1 56 I 55 0 I 0.022 ThispaperSeveral reasons are responsible fo r this. Firstly this coil

design was fully optimised while taking into account theeddy currents. Secondly, the effect of eddy currents and skineffect on the coil rcsistance is not so large due to OUT owworking frequency. In addition> the contact resistance doesnot degrade the SNR much in our case due to the relativelylugh coil resistance. Finally, the low NMR frequency (60MHz) makes it possible to use coils with a lugh self-induction (L). This high L results in a low coil resonancefrequency which prevents the coil to be tuned to high NMRfrequencies for use in large magnetic fields. In that case thcoptimum SNR is limited by thc maximum L that allowsresonance at the frequency of interest. Funh er improvementof th e SNR in our system can be achieved by getting the coilcloser to the channel and by decreasing Lhe width andseparation of the windings. Simulations also indicate that acoil uith an inner radius that is smaller than the sampleradius also improves the SN R.5. CONCLUSIONSThis paper reported on the design and fabrication of apfluidic N M R chip. The finite element simulations of themicro detection coils qualitatively agreed with themeasurements. T he general design rule fo r planar N M R oils

is to take the width and scparation of the windings as smallas possible and calculate by simulation the number andheight of the windings that result in the largest Signal toNoise Ratio (SNR).In a five times lower magnetic field (theoretically giving a 25times lowcr signal) a SNR was measured which is evenhigher compared to results from other authors. The goodspectral resolution of 0.022 ppm was acheved by simplyplacing the long pfluidic channel in parallel witli themagnetic field. Any entrance effects that disturbed thehomogcncity of the field are in this way brought far awayform the detection coil, and have little influence at thesample volume. Spin coupling of the ethanol triplet wasobserved. Further project aims are the monitoring ofchemical reactions online on chip, and the development of aportable mini NM R system using small magnets. The highSNR at a low magnetic field and sinall sample volumeachieved in this papcr mak cs such a system possible.6. ACKNOWLEDGEMENTThe authors would like to thank Charles Massin @PE:Lausanne), Hans Janssen and Am0 Kentgens (KUN,Nijmcgen) and Michiel Hilbers (Bijvoet CBR Utrecht) foruseful discussion.7. REFERENCES1 A.G. Webb, S.C. Grant, Signa-to-Noise and MagneticSusceptibility Trade-offs in Solenoidal Microco ils for NIvC?,Jounial ofMagnetic Resonance B 1I3 (1996) pp. 83-872 J.E. Stocker, T.L. Peck A.G. Wchh, M.Feng, R.L.Magin,Nanoliter Volume, High-Resolution N M R MinospectroscopyUsing a 60-um Planer Microcoil, IEEE Trans. Biomed. Eng. 44(1997)pp. 1122-11273 C. Massin, G.Boero, P.Eichenberger, P.A. Bs se , R.S.Popovic:Iligh-Q Factor RF Planar Microcoils on Glass Substrates for N M RSpectroscopy, Sensors on dAchra fors4 97-98 (2002) pp. 280-2884 D.I. Hoult, R.E. Richards, The signal-to-noise ratio of thenuclear magnetic resonance experiment, Jounial of MagneticResononce 24 (1976)pp.71-855 T.L. Peck, R.L. Magin; P.C. Lauterhur, Design and Analysis ofMicrocoils for N M R Microscopy, Jounial ofMagmric Reso,ra,rceB lOS(1995)pp 114-1246 J.E. Stocker, T.L. Peck, A.G. Webb, MFeng, R.L.Magin,Wanoliter Volume, High-Resolution NM R MicrospectroswpvUsing a 60-um Planer M icrocoil, IEEE Tmirs. Biomcd. Eng. 4;11 1 9 9 7 ) ~ ~ .122-11277 S . E&u, G. Friedman, R.L. Magin, Estimate of losses andsignal-to-noise ratio in, lanar inductive micro-coil detectors usedfor NMR,EEE Tmn. oirA4agnelics 37 (2001) pp. 2787-27898 site:http://fem.foster-miller.net/e-mail: [email protected] David Meeker)9 J.D. Tnunbull, I.K.Glasgow, D.J.Beebe, RLM agi n , IntegratingMicrofabricated Fluidic Systems and N M R S ~ c ~ o s c o p y ,EEETrons.Biomed. Eirg. 47 (2000) pp. 3-710 C.Massin, F.Vincent, A.Homsy, K.Ehr~nann, G.Boero, P.A.Besse, A.Daridon, EVerpoorle, N.F.de Rooij, R.S.Popovic,Planarmicrocoil-based inicrotluimc N M R probes, Journal of MagneticResonance 164 (2003) pp. 242-2551 1 H. Wensink, M.C. Elwenspock, Reduction of side\vaIlinclination and blast lag of powder hlastd channels,Sensors andAcrfrarorsA102 (2002)p p. 157-164

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2004 high signal to noise ratio in low field nmr on chip, simulations and experimental results

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