SEMICONDUCTOR DEVICES

Cantilever with immobilized antibody for liver cancer biomarker detection

Shuaipeng Wang1, 2, Jingjing Wang1, 2, Yinfang Zhu1, 2, Jinling Yang1, 2, and Fuhua Yang1

+ Author Affiliations

 Corresponding author: Yang Jinling, Email:jlyang@semi.ac.cn

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Abstract: A novel cantilever array-based bio-sensor was batch-fabricated with IC compatible MEMS technology for precise liver cancer bio-marker detection. A micro-cavity was designed in the free end of the cantilever for local antibody-immobilization, thus the adsorption of the cancer biomarker takes place only in the local region of the cantilever instead of the whole lever, and the effect of adsorption-induced $k$ variation can be dramatically reduced. These structural features offer several advantages:high sensitivity, high throughput, high mass detection accuracy, and a portable system. In addition, an analytical model has been established to eliminate the effect of the adsorption-induced lever stiffness change and has been applied to the precise mass detection of the cancer biomarker AFP; the experimentally detected AFP antigen mass by the sensor (7.6 pg/mL) is quite close to the calculated one (5.5 pg/mL), two orders of magnitude better than those of the fully antibody-immobilized cantilever sensor. These approaches can promote real applications of the cantilever sensors in cancer diagnosis.

Key words: MEMS cantilevermass detectionliver cancer biomarkerlocal reactionadsorption-induced stiffness change



[1]
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[2]
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[3]
Alvarez M, Lechuga L M. Microcantilever-based platforms as biosensing tools. Analyst, 2010, 135:827 doi: 10.1039/b908503n
[4]
Hierlemann A, Brand O, Hagleiter C, et al. Microfabrication techniques for chemical/biosensors. Proc IEEE, 2003: 839
[5]
Lavrik N V, Sepaniak M J, Datskos P G, et al. Cantilever transducers as a platform for chemical and biological sensors. Review of Scientific Instruments, 2004, 75:2229 doi: 10.1063/1.1763252
[6]
Johnson B N, Mutharasan R. Biosensing using dynamic-mode cantilever sensors:a review. Biosensors and Bioelectronics, 2012, 32:1 doi: 10.1016/j.bios.2011.10.054
[7]
Lee J H, Kim T S, Yoon K H. Effect of mass and stress on resonant frequency shift of functionalized Pb(Zr0.52Ti0.48)O3 thin film microcantilever for the detection of C-reactive protein. Appl Phys Lett, 2004, 18:3187 https://www.google.co.il/patents/US20110172565
[8]
Hwang K S, Eom K, Lee J H, et al. Dominant surface stress driven by biomolecular interactions in the dynamical response of nanomechanical microcantilevers. Appl Phys Lett, 2006, 89:173905 doi: 10.1063/1.2372700
[9]
Hwang K S, Lee S M, Kim S K, et al. Micro-and nanocantilever devices and systems for biomolecule detection. Annu Rev Anal Chem, 2009, 2:77 doi: 10.1146/annurev-anchem-060908-155232
[10]
Albrecht T R, Grutter P, Horne D, et al. Frequency modulation detection using high-Q cantilevers for enhanced force microscope sensitivity. J Appl Phys, 1991, 69:668 doi: 10.1063/1.347347
[11]
Thundat T, Warmack R, Chen G, et al. Thermal and ambient-induced deflections of scanning force microscope cantilevers. Appl Phys Lett, 1994, 64:2894 doi: 10.1063/1.111407
[12]
Sony P, Puschnig P, Nabok D, et al. Importance of van der Waals interaction for organic molecule-metal junctions:adsorption of thiophene on Cu(110) as a prototype. Phys Rev Let, 2007, 99:176401 doi: 10.1103/PhysRevLett.99.176401
[13]
Yi X, Duan H L. Surface stress induced by interactions of adsorbates and its effect on deformation and frequency of microcantilever sensors. Journal of the Mechanics and Physics of Solids, 2009, 57:1254 doi: 10.1016/j.jmps.2009.04.010
[14]
Chen G Y, Thundat T, Wachter E A, et al. Adsorption-induced surface stress and its effects on resonance frequency of microcantilevers. J Appl Phys, 1995, 77:3618 doi: 10.1063/1.359562
[15]
Wormer P E S, van der Avoird A. Intermolecular potentials, internal motions, and spectra of van der Waals and hydrogen-bonded complexes. Chem Rev, 2000, 100:4109 doi: 10.1021/cr990046e
[16]
Pace C N, Fu H L, Fryar K L, et al. Contribution of hydrophobic interactions to protein stability. J Mol Biol, 2011, 408:514 doi: 10.1016/j.jmb.2011.02.053
.  (Color online) Illustration of the cantilever arrays, the micro cavity on the free end of the cantilever with pillar arrays.

Fig. 2.  (Color online) Fabrication process flow of the cantilever.

Fig. 3.  (a) Cantilever array. (b) Enlarged view of the cantilever.

Fig. 4.  (Color online) (a) Functional process of the cantilever surface with AFP antibody. (b) The bright-field and dark-field fluorescent images of the fluorescence CY5 labeled antibody which are localized on the free end of the cantilever.

Fig. 5.  Resonance spectrum of the cantilever measured in air and in a vacuum.

Fig. 6.  Schematic for the cantilever covered with a uniform AFP antigen layer.

Fig. 7.  Frequency response of a fully immobilized lever to the AFP antigen solution of 5.5 pg/mL.

Fig. 8.  Frequency shift of the locally antibody-immobilized cantilever responding to an AFP antigen solution of 5.5 pg/mL.

Fig. 9.  Sensor response to an AFP antigen solution of 5.5 pg/mL, 15 pg/mL, 18 pg/mL.

[1]
Arlett J L, Myers E B, Roukes M L, et al. Comperative advantages of mechanical biosensors. Nature Nanotechnology, 2011, 6:203 doi: 10.1038/nnano.2011.44
[2]
Raiteri R, Grattarola M, Butt H J, et al. Micromechanical cantilever-based biosensors. Sensors and Actuators B, 2001, 79:115 doi: 10.1016/S0925-4005(01)00856-5
[3]
Alvarez M, Lechuga L M. Microcantilever-based platforms as biosensing tools. Analyst, 2010, 135:827 doi: 10.1039/b908503n
[4]
Hierlemann A, Brand O, Hagleiter C, et al. Microfabrication techniques for chemical/biosensors. Proc IEEE, 2003: 839
[5]
Lavrik N V, Sepaniak M J, Datskos P G, et al. Cantilever transducers as a platform for chemical and biological sensors. Review of Scientific Instruments, 2004, 75:2229 doi: 10.1063/1.1763252
[6]
Johnson B N, Mutharasan R. Biosensing using dynamic-mode cantilever sensors:a review. Biosensors and Bioelectronics, 2012, 32:1 doi: 10.1016/j.bios.2011.10.054
[7]
Lee J H, Kim T S, Yoon K H. Effect of mass and stress on resonant frequency shift of functionalized Pb(Zr0.52Ti0.48)O3 thin film microcantilever for the detection of C-reactive protein. Appl Phys Lett, 2004, 18:3187 https://www.google.co.il/patents/US20110172565
[8]
Hwang K S, Eom K, Lee J H, et al. Dominant surface stress driven by biomolecular interactions in the dynamical response of nanomechanical microcantilevers. Appl Phys Lett, 2006, 89:173905 doi: 10.1063/1.2372700
[9]
Hwang K S, Lee S M, Kim S K, et al. Micro-and nanocantilever devices and systems for biomolecule detection. Annu Rev Anal Chem, 2009, 2:77 doi: 10.1146/annurev-anchem-060908-155232
[10]
Albrecht T R, Grutter P, Horne D, et al. Frequency modulation detection using high-Q cantilevers for enhanced force microscope sensitivity. J Appl Phys, 1991, 69:668 doi: 10.1063/1.347347
[11]
Thundat T, Warmack R, Chen G, et al. Thermal and ambient-induced deflections of scanning force microscope cantilevers. Appl Phys Lett, 1994, 64:2894 doi: 10.1063/1.111407
[12]
Sony P, Puschnig P, Nabok D, et al. Importance of van der Waals interaction for organic molecule-metal junctions:adsorption of thiophene on Cu(110) as a prototype. Phys Rev Let, 2007, 99:176401 doi: 10.1103/PhysRevLett.99.176401
[13]
Yi X, Duan H L. Surface stress induced by interactions of adsorbates and its effect on deformation and frequency of microcantilever sensors. Journal of the Mechanics and Physics of Solids, 2009, 57:1254 doi: 10.1016/j.jmps.2009.04.010
[14]
Chen G Y, Thundat T, Wachter E A, et al. Adsorption-induced surface stress and its effects on resonance frequency of microcantilevers. J Appl Phys, 1995, 77:3618 doi: 10.1063/1.359562
[15]
Wormer P E S, van der Avoird A. Intermolecular potentials, internal motions, and spectra of van der Waals and hydrogen-bonded complexes. Chem Rev, 2000, 100:4109 doi: 10.1021/cr990046e
[16]
Pace C N, Fu H L, Fryar K L, et al. Contribution of hydrophobic interactions to protein stability. J Mol Biol, 2011, 408:514 doi: 10.1016/j.jmb.2011.02.053
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    Received: 10 April 2014 Revised: 04 May 2014 Online: Published: 01 October 2014

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      Shuaipeng Wang, Jingjing Wang, Yinfang Zhu, Jinling Yang, Fuhua Yang. Cantilever with immobilized antibody for liver cancer biomarker detection[J]. Journal of Semiconductors, 2014, 35(10): 104008. doi: 10.1088/1674-4926/35/10/104008 S P Wang, J J Wang, Y F Zhu, J L Yang, F H Yang. Cantilever with immobilized antibody for liver cancer biomarker detection[J]. J. Semicond., 2014, 35(10): 104008. doi: 10.1088/1674-4926/35/10/104008.Export: BibTex EndNote
      Citation:
      Shuaipeng Wang, Jingjing Wang, Yinfang Zhu, Jinling Yang, Fuhua Yang. Cantilever with immobilized antibody for liver cancer biomarker detection[J]. Journal of Semiconductors, 2014, 35(10): 104008. doi: 10.1088/1674-4926/35/10/104008

      S P Wang, J J Wang, Y F Zhu, J L Yang, F H Yang. Cantilever with immobilized antibody for liver cancer biomarker detection[J]. J. Semicond., 2014, 35(10): 104008. doi: 10.1088/1674-4926/35/10/104008.
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      Cantilever with immobilized antibody for liver cancer biomarker detection

      doi: 10.1088/1674-4926/35/10/104008
      Funds:

      Project supported by the State Key Development Program for Basic Research of China (Nos. 2011CB933102, 2013YQ16055103) and the National Natural Science Foundation of China (Nos. 61234007, 61201104)

      the National Natural Science Foundation of China 61201104

      the National Natural Science Foundation of China 61234007

      the State Key Development Program for Basic Research of China 2011CB933102

      the State Key Development Program for Basic Research of China 2013YQ16055103

      More Information
      • Corresponding author: Yang Jinling, Email:jlyang@semi.ac.cn
      • Received Date: 2014-04-10
      • Revised Date: 2014-05-04
      • Published Date: 2014-10-01

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