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Optics Express

Optics Express

  • Editor: Andrew M. Weiner
  • Vol. 21, Iss. 17 — Aug. 26, 2013
  • pp: 19467–19472
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Label-free DNA sensing using millimeter-wave silicon WGM resonator

Aidin Taeb, Mohammed A. Basha, Suren Gigoyan, Mungo Marsden, and Safieddin. Safavi-Naeini  »View Author Affiliations


Optics Express, Vol. 21, Issue 17, pp. 19467-19472 (2013)
http://dx.doi.org/10.1364/OE.21.019467


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Abstract

A planar dielectric waveguide based structure for bio-sensing purpose is introduced. The proposed device is a silicon-based WGM disc resonator operating within the range of 75-110 GHz (W-band). The sensor is an integrated, miniaturized, low-cost, and easy-to-fabricate bio-sensor structure. The proposed sensor can be used for a number of DNA characterization tasks including Mutation in DNA oligonucleotide. Two types of DNAs, single strand and double strand DNAs, are successfully tested by our integrated sensor. The measurement repeatability and selectivity of the proposed sensor are examined through the different experimental lab-tests.

© 2013 OSA

1. Introduction

The description of an individual genetic background (DNA and RNA) has become a powerful tool in the diagnosis of diseases, genetic disorders and pathogen infection. The recent discovery that most cancers have widely varying genetic backgrounds indicates that successful intervention may require individualized therapeutic strategies [1

1. M. R. Stratton, P. J. Campbell, and P. A. Futreal, “The cancer genome,” Nature 458(7239), 719–724 (2009). [CrossRef] [PubMed]

]. The present technology, used to evaluate one’s individual genetic makeup, is based on the ability of an immobilized single-stranded DNA to hybridize to a complementary sequence forming a double-stranded structure, which is then detected through an optical method [2

2. S. Cagnin, M. Caraballo, C. Guiducci, P. Martini, M. Ross, M. Santaana, D. Danley, T. West, and G. Lanfranchi, “Overview of electrochemical DNA biosensors: new approaches to detect the expression of life,” Sensors (Basel) 9(4), 3122–3148 (2009). [CrossRef] [PubMed]

]. Until now this has required time-consuming modification, fluorescent labeling and enzymatic amplification of the sample being analyzed. While these techniques have proven to be sensitive, they run the risk of experimental bias as well as the cost and complicated methodology being beyond the scope of local healthcare providers. The development of an integrated, cost-effective, and ultra-high sensitivity bio-sensor holds the promise of quick and effective healthcare practices that are tailored to individuals.

Section 2 describes the design of prototype disc-shape sensor, which is fabricated, and successfully tested, for single and double strand DNA samples, after evaporation of the annealed buffer. In Section 3, the simulations results are presented. Section 4 focuses on the experimental results of loading the sensor with the DNA oligonucleotides. Finally, Section 5 concludes this paper.

2. Sensor configuration and mathematical formulation of WG mode of disc resonator

Figure 1(a)
Fig. 1 a) General configuration of the proposed sensor. b) Cross section of a general insulated DR. c) The equivalent model for calculating the radial characteristic equation. d) The equivalent two-layer slab waveguide for calculating the axial characteristic equation.
shows the schematic of the proposed sensor. The proposed sensor consists of a Dielectric Wave-Guide (DWG) and a Dielectric Resonator (DR) coupled to the waveguide. The structure is designed for unidirectional and critical coupling. The device supports WGHn,0,0y mode in which Ey is the dominant mode. The permittivity and conductivity of the high resistive Silicon, used in the DR and DWG, are estimated as 11.8 and 0.01 S/m, respectively. The top layer of the SOI-based wafer has a thickness about 500µm while the handle wafer has a thickness of 130 µm. The buried oxide layers has a thickness of 1~2 µm. The fabrication process is a simple single-mask process as similar to one which is explained in [10

10. M. Basha, B. Biglarbegian, M. Neshat, S. Gigoyan, and S. Safavi-Naeini, “Low-cost, monolithic and integrated whispering gallery mode ring resonator for sensing applications,” European Microwave Conference (EuMC), 2011 41st European, 515–518, (2011).

]. The dielectric waveguide is excited by the standard rectangular metallic waveguide (WR-10). The dielectric waveguide is linearly tapered at both ends for smooth transition to the rectangular metallic waveguide. The total length of dielectric structure is 20 mm. The dielectric waveguide is designed to support a single mode operation (E11y). The dielectric waveguide channel has a cross section of 0.5×0.6 mm2. The DR has a radius of 1.91 mm, which supports four distinct WGHn,0,0y modes within the range of 75-110 GHz.

The disc surface area is suitable for placing the exact 10 μl DNA sample. In addition, the designed DR provides the non-radiative WG modes (n>6) within the desired frequency range. It should be notified that a disc with larger diameter supports relatively higher order WGHn,0,0y modes, which are essentially more confined. In this case, the field outside the resonator has a shorter evanescent tail as compared to that in a smaller resonator. Thus, the excitation of the resonator would be more challenging. Also, larger radius of DR decreases the sensitivity of the device. Figure 1(b) shows a general configuration of an insulated DR placed on a ground plane. In this paper, the approximate Effective Dielectric Constant (EDC) method is adopted to calculate the resonance frequency of an insulated image resonator [11

11. A. Taeb, M. Neshat, S. Gigoyan, and S. Safavi-Naeini, “A low-cost millimeter-wave whispering gallery-mode-based sensor: design considerations and accurate analysis,” Int. Journal of Microwave and Wireless Tech. 4(3), 341–348 (2012). [CrossRef]

,12

12. M. E. Tobar and A. G. Mann, “Resonant frequencies of higher order modes in cylendrical anisotropic dielectric resonators,” IEEE Trans. Microw. Theory Tech. 39(12), 2077–2082 (1991). [CrossRef]

]. Following the method, the electromagnetic parameters are obtained by solving two dependent characteristic dependent radial and axial characteristic equations respectively.

The radial characteristic equation of the structure, shown in Fig. 1(b), is obtained by matching the tangential electromagnetic fields at the side wall of an infinite dielectric cylinder with permittivity of εe [Fig. 1(c)]:
[Jn(kρa)(kρa)Jn(kρa)+Kn(αρa)(αρa)Kn(αρa)][Jn(kρa)(kρa)Jn(kρa)+Kn(αρa)εe(αρa)Kn(αρa)]=[n(εe-1)kyk0kρ2],
(1)
whereJn,Kn are the first Bessel and Hankel functions, respectively. Also, kρ,αρ and ky are the radial wavenumber, radial attenuation constant, and axial wavenumber, respectively. The effective permittivity,εe, is approximated in [13

13. R. K. Mongia, “Resonant frequency of cylendrical dielectric resonator placed in an MIC environment,” IEEE Trans. Microw. Theory Tech. 38(6), 802–804 (1990). [CrossRef]

]. The axial characteristic equation for TMy, which corresponds to WGH mode, is obtained by matching the tangential fields at the boundaries of a grounded two-layer slab waveguide [Fig. 1(d)]
[1+(α1εr2kyεr1)tanh(α1h1)tanh(kyh2)]=kzα0εr2[tan(kyh2)+(α1εr2kyεr1)tanh(α1h1)],
(2)
whereα0andαρ are the axial attenuation constants in air and in the substrate, respectively. Solving (1)-(2) numerically, using the algorithm explained in [11

11. A. Taeb, M. Neshat, S. Gigoyan, and S. Safavi-Naeini, “A low-cost millimeter-wave whispering gallery-mode-based sensor: design considerations and accurate analysis,” Int. Journal of Microwave and Wireless Tech. 4(3), 341–348 (2012). [CrossRef]

], one can find the common axial wavenumber, ky=ky. Afterward, the resonance frequency of the resonator is calculated. The achieved results are approximate ones due to the assumption of zero-field at the corner regions of the DR. The accuracy of the calculated values can be improved by using a variational expression for the resonant frequency [11

11. A. Taeb, M. Neshat, S. Gigoyan, and S. Safavi-Naeini, “A low-cost millimeter-wave whispering gallery-mode-based sensor: design considerations and accurate analysis,” Int. Journal of Microwave and Wireless Tech. 4(3), 341–348 (2012). [CrossRef]

,14

14. L. A. Bermudez and P. Y. Guillon, “Application of variational principle for calculation of resonant frequencies of cylendrical dielectric resonators,” Electron. Lett. 22(1), 31–33 (1986). [CrossRef]

].

3. Simulation results

The resonance characteristics of the DR for different WGMs are obtained from the full-wave Eigen-mode simulation, performed by HFSS (Ansys), and compared to those calculated by the EDC and variational method (Table 1

TABLE 1. Comparison between the Resonance FREQUENCIES Obtained from EDC-variational Method and Full-wave Simulation for an Insulated SOI Disc

table-icon
View This Table
). Obviously, a good agreement is achieved between the results. However, the proposed numeric method is much faster than the HFSS one.

4. Experimental results and discussion

To examine the capabilities, sensitivity, and selectivity of our proposed sensor we prepared a number of DNA samples. Complementary 38 base pair synthetic oligonucleotides (short and single-stranded DNA molecules), were obtained from Sigma Genosys Canada.

Oligo #1: 5`- GGT GCT ACA GTT GCT CAT GAG CTG GGG CAC AAC TTG GG −3`

Oligo #2: 5`- CCC AAG TTG TGC CCC AGC TCA TGA GCA ACT GTA GCA CC- 3`

The individual oligonucleotides used for single strand DNA tests were denatured at 95°C for 3 minutes in annealing buffer (10 mM Tris, pH 7.5, 50 mM NaCl, 1 mM EDTA) and then rapidly cooled on ice. A double stranded DNA was generated by combining oligonucleotide 1 and 2 at equimolar concentration. The samples were denatured at 95°C for 3 minutes in a heat block. The block was then allowed to cool to room temperature over 1 hour. Annealed oligos were stored on ice. Single and double stranded oligos were tested at equal molar concentrations, 20 nmol, with total weight of 2.33×109g and 4.67×109g, respectively.

The loaded quality factor of the resonator can be calculated based on the coupling coefficient, κ, and total attenuation of the resonator, α. α and κ are obtained by the expressions given in [15

15. M. S. Kheir, H. F. Hammad, and A. Omar, “Graphical representation and evaluation of attenuation and coupling parameters of whispering-gallery-mode resonators,” IEEE Trans. Instrum. Meas. 60(8), 2942–2950 (2011). [CrossRef]

]. The calculated κ for the mode WGH9,0,0 is around 0.94, which is close to critical coupling value. The calculated loaded quality factor for this mode is about 1100. Therefore, the unloaded Q-factor is Q0=QL(1+κ)=2134.

In the aforementioned experiments the temperature was controlled around 23±10C, which guarantee the accuracy of our resonance frequency within ±2 MHz. In order to coat the DR with DNA, approximately 10 μl of the oligonucleotide in annealed buffer is pipetted on the top surface of DR. The liquid is evaporated and resulting in a uniform thin layer (~250nm) of DNA. The DNA samples can be modeled as a thin dielectric layer, with specific permittivity, placed on top of the DR [16

16. M. Nagel, P. H. Bolivar, M. Brucherseifer, H. Kurz, A. Bosserhoff, and R. Büttner, “Integrated planar terahertz resonators for femtomolar sensitivity label-free detection of DNA hybridization,” Appl. Opt. 41(10), 2074–2078 (2002). [CrossRef] [PubMed]

]. In the first set of experiments, two DNA oligonucleotides of the same length but with different base pair order are used. Figure 3
Fig. 3 The measured resonance frequency shift for single strand (SS) and double strand (DS) DNA samples. The repeatability is validated for each sample.
shows changes in the resonance frequency of the transmission response after loading the DR with oligo #1. A 380 MHz resonance frequency shift is achieved. The same measurement procedure is followed for oligo #2 resulting in a 390 MHz shift. These results describe a distinct 10 MHz difference in resonance frequency shift for the two DNA oligos. To ensure repeatability, multiple trials of each test are conducted. After each measurement, the resonator is completely washed using distilled. The resonance frequency and its depth are re-checked with the reference point before evaluating the subsequent DNA sample.

5. Conclusion

An integrated, compact, and low-cost W-band (75-110GHz) sensor has been designed, fabricated, and successfully tested. The structure is realized using SOI technology. The proposed sensor is a dielectric disc resonator, operating in resonant WGM resonance. The resonator is designed and analyzed using a fast numerical method based on EDC and variational technique. The calculated WGHn,0,0 resonance frequencies are verified by full-wave simulation and experiment. The sensing mechanism is based on the changes in the frequency of the WGM resonance of a disc resonator in the absence and the presence of the sample.

The sensor was tested for its ability to repeatedly distinguish two complementary DNA oligos of the same length. We were able to measure distinct 10 MHz shift (2.5%) between the resonance frequencies of each individual oligo. We then demonstrated the proposed sensor ability to discriminate between single and double-stranded DNA samples. The new sensor, proposed in this research, easily and accurately identifies individual single-stranded oligonucleotide sequences as well as double-stranded molecules. The experimental results demonstrate the efficiency of device in distinguishing different types of DNAs. As such the planar Silicon-based WGM sensor can be considered as a low-cost, fast and reliable alternative for the commonly used optical-based detectors of DNA hybridization. The Introduced VNA-based measurement system is essentially for proof-of-concept. Our ultimate goal is to implement the sensor with a simple diode detector and a low-cost tunable source for particular class of sensing over a narrow range of frequencies.

Acknowledgments

This work was supported by National Science and Engineering Council (NSERC) of Canada, Blackberry, and ISTP Canada.

References and links

1.

M. R. Stratton, P. J. Campbell, and P. A. Futreal, “The cancer genome,” Nature 458(7239), 719–724 (2009). [CrossRef] [PubMed]

2.

S. Cagnin, M. Caraballo, C. Guiducci, P. Martini, M. Ross, M. Santaana, D. Danley, T. West, and G. Lanfranchi, “Overview of electrochemical DNA biosensors: new approaches to detect the expression of life,” Sensors (Basel) 9(4), 3122–3148 (2009). [CrossRef] [PubMed]

3.

M. Baaske and F. Vollmer, “Optical resonator biosensors: molecular diagnostic and nanoparticle detection on an integrated platform,” ChemPhysChem 13(2), 427–436 (2012). [CrossRef] [PubMed]

4.

J. D. Suter, I. M. White, H. Zhu, H. Shi, C. W. Caldwell, and X. Fan, “Label-free quantitative DNA detection using the liquid core optical ring resonator,” Biosens. Bioelectron. 23(7), 1003–1009 (2008). [CrossRef] [PubMed]

5.

K. De Vos, P. De Backere, R. Baets, and P. Bienstman, “Label-free biosensors on silicon-on-insulator optical chips based on microring cavities and surface plasmon interferometry,” Transparent Optical Networks. ICTON 2008(2), 88–91 (2008).

6.

C. Vedrenne and J. Arnold, “Whispering gallery modes of dielectric resonators” IEE Proceedings Microwaves, Optics and Antennas, 129(4), 183–187, (1982). [CrossRef]

7.

E. N. Shaforost, N. Klein, A. I. Gubin, A. A. Barannik and A. M. Klushin “Microwave-millimetre wave WGM resonators for evanescent sensing of nanolitre liquid substances,” Microwave Conference EuMC 2009. European, 45–48, (2009).

8.

F. Vollmer and S. Arnold, “Whispering-gallery-mode biosensing: label-free detection down to single molecules,” Nat. Methods 5(7), 591–596 (2008). [CrossRef] [PubMed]

9.

H. Quan and Z. Guo, “Simulation of single transparent molecule interaction with an optical microcavity,” Nanotechnology 18(37), 375702 (2007). [CrossRef]

10.

M. Basha, B. Biglarbegian, M. Neshat, S. Gigoyan, and S. Safavi-Naeini, “Low-cost, monolithic and integrated whispering gallery mode ring resonator for sensing applications,” European Microwave Conference (EuMC), 2011 41st European, 515–518, (2011).

11.

A. Taeb, M. Neshat, S. Gigoyan, and S. Safavi-Naeini, “A low-cost millimeter-wave whispering gallery-mode-based sensor: design considerations and accurate analysis,” Int. Journal of Microwave and Wireless Tech. 4(3), 341–348 (2012). [CrossRef]

12.

M. E. Tobar and A. G. Mann, “Resonant frequencies of higher order modes in cylendrical anisotropic dielectric resonators,” IEEE Trans. Microw. Theory Tech. 39(12), 2077–2082 (1991). [CrossRef]

13.

R. K. Mongia, “Resonant frequency of cylendrical dielectric resonator placed in an MIC environment,” IEEE Trans. Microw. Theory Tech. 38(6), 802–804 (1990). [CrossRef]

14.

L. A. Bermudez and P. Y. Guillon, “Application of variational principle for calculation of resonant frequencies of cylendrical dielectric resonators,” Electron. Lett. 22(1), 31–33 (1986). [CrossRef]

15.

M. S. Kheir, H. F. Hammad, and A. Omar, “Graphical representation and evaluation of attenuation and coupling parameters of whispering-gallery-mode resonators,” IEEE Trans. Instrum. Meas. 60(8), 2942–2950 (2011). [CrossRef]

16.

M. Nagel, P. H. Bolivar, M. Brucherseifer, H. Kurz, A. Bosserhoff, and R. Büttner, “Integrated planar terahertz resonators for femtomolar sensitivity label-free detection of DNA hybridization,” Appl. Opt. 41(10), 2074–2078 (2002). [CrossRef] [PubMed]

OCIS Codes
(230.5750) Optical devices : Resonators
(230.7390) Optical devices : Waveguides, planar
(350.4010) Other areas of optics : Microwaves
(280.1415) Remote sensing and sensors : Biological sensing and sensors

ToC Category:
Sensors

History
Original Manuscript: June 3, 2013
Revised Manuscript: July 19, 2013
Manuscript Accepted: August 1, 2013
Published: August 12, 2013

Citation
Aidin Taeb, Mohammed A. Basha, Suren Gigoyan, Mungo Marsden, and Safieddin. Safavi-Naeini, "Label-free DNA sensing using millimeter-wave silicon WGM resonator," Opt. Express 21, 19467-19472 (2013)
http://www.opticsinfobase.org/oe/abstract.cfm?URI=oe-21-17-19467


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References

  1. M. R. Stratton, P. J. Campbell, and P. A. Futreal, “The cancer genome,” Nature458(7239), 719–724 (2009). [CrossRef] [PubMed]
  2. S. Cagnin, M. Caraballo, C. Guiducci, P. Martini, M. Ross, M. Santaana, D. Danley, T. West, and G. Lanfranchi, “Overview of electrochemical DNA biosensors: new approaches to detect the expression of life,” Sensors (Basel)9(4), 3122–3148 (2009). [CrossRef] [PubMed]
  3. M. Baaske and F. Vollmer, “Optical resonator biosensors: molecular diagnostic and nanoparticle detection on an integrated platform,” ChemPhysChem13(2), 427–436 (2012). [CrossRef] [PubMed]
  4. J. D. Suter, I. M. White, H. Zhu, H. Shi, C. W. Caldwell, and X. Fan, “Label-free quantitative DNA detection using the liquid core optical ring resonator,” Biosens. Bioelectron.23(7), 1003–1009 (2008). [CrossRef] [PubMed]
  5. K. De Vos, P. De Backere, R. Baets, and P. Bienstman, “Label-free biosensors on silicon-on-insulator optical chips based on microring cavities and surface plasmon interferometry,” Transparent Optical Networks. ICTON2008(2), 88–91 (2008).
  6. C. Vedrenne and J. Arnold, “Whispering gallery modes of dielectric resonators” IEE Proceedings Microwaves, Optics and Antennas, 129(4), 183–187, (1982). [CrossRef]
  7. E. N. Shaforost, N. Klein, A. I. Gubin, A. A. Barannik and A. M. Klushin “Microwave-millimetre wave WGM resonators for evanescent sensing of nanolitre liquid substances,” Microwave Conference EuMC 2009. European, 45–48, (2009).
  8. F. Vollmer and S. Arnold, “Whispering-gallery-mode biosensing: label-free detection down to single molecules,” Nat. Methods5(7), 591–596 (2008). [CrossRef] [PubMed]
  9. H. Quan and Z. Guo, “Simulation of single transparent molecule interaction with an optical microcavity,” Nanotechnology18(37), 375702 (2007). [CrossRef]
  10. M. Basha, B. Biglarbegian, M. Neshat, S. Gigoyan, and S. Safavi-Naeini, “Low-cost, monolithic and integrated whispering gallery mode ring resonator for sensing applications,” European Microwave Conference (EuMC), 2011 41st European, 515–518, (2011).
  11. A. Taeb, M. Neshat, S. Gigoyan, and S. Safavi-Naeini, “A low-cost millimeter-wave whispering gallery-mode-based sensor: design considerations and accurate analysis,” Int. Journal of Microwave and Wireless Tech.4(3), 341–348 (2012). [CrossRef]
  12. M. E. Tobar and A. G. Mann, “Resonant frequencies of higher order modes in cylendrical anisotropic dielectric resonators,” IEEE Trans. Microw. Theory Tech.39(12), 2077–2082 (1991). [CrossRef]
  13. R. K. Mongia, “Resonant frequency of cylendrical dielectric resonator placed in an MIC environment,” IEEE Trans. Microw. Theory Tech.38(6), 802–804 (1990). [CrossRef]
  14. L. A. Bermudez and P. Y. Guillon, “Application of variational principle for calculation of resonant frequencies of cylendrical dielectric resonators,” Electron. Lett.22(1), 31–33 (1986). [CrossRef]
  15. M. S. Kheir, H. F. Hammad, and A. Omar, “Graphical representation and evaluation of attenuation and coupling parameters of whispering-gallery-mode resonators,” IEEE Trans. Instrum. Meas.60(8), 2942–2950 (2011). [CrossRef]
  16. M. Nagel, P. H. Bolivar, M. Brucherseifer, H. Kurz, A. Bosserhoff, and R. Büttner, “Integrated planar terahertz resonators for femtomolar sensitivity label-free detection of DNA hybridization,” Appl. Opt.41(10), 2074–2078 (2002). [CrossRef] [PubMed]

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