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Biomedical Optics & Medical Imaging
Accelerating the detection speed of label-free biosensors
Future medical tests can be performed four times faster by modifying the supporting substrates of nano-electronic biosensors.
8 August 2010, SPIE Newsroom. DOI: 10.1117/2.1201007.003164
Protein sensors that operate without a need for fluorescent labeling or imaging offer the exciting possibility of handheld-device development for quick quantification of biomarkers in a person's blood. Rapid and cheap access to this personalized medical information is integral to the ultimate vision of more accurate and quantitative diagnosis and treatment of illnesses. Label-free biosensors rely on intrinsic protein properties such as polarizability, mass, and electric charge. Charge-sensitive biosensors were first realized in 2001 by Lieber and colleagues1 using circuits made from nanoscale semiconductors (see Figure 1). The readout of these sensors is based on a simple resistance measurement: a change in resistance corresponds to protein absorption on the sensor surface. This nano-electronic approach is one of the most promising label-free techniques. However, researchers continue to wrestle with issues such as unknown noise sources, manufacturing reliability, spurious signals, and slow detection speed.
Charge-sensitive biosensors, based on silicon and carbon nano-electronics, have improved markedly in recent years. Sources of noise have been identified and minimized,2 new methods of nanomanufacturing have dramatically improved device yield,3,4 and spurious signals have been eliminated by better control of the sensing environment5 and on-chip pre-concentration schemes.6 In our current work, we focus on improving detection speed.
Figure 1. Charge-sensitive biosensor. A semiconducting nanomaterial (orange) connects two electrodes (gray). The semiconductor's surface is functionalized with antibodies (green). When the positively charged target protein (red) is captured, the nanomaterial changes resistance. V: Voltage. I: Current.
Our approach to accelerating detection speed is based on creating slippery surfaces. The standard support substrate for nano-electronic biosensors is glass, which is notoriously sticky for proteins. Glass can be covalently modified using polyethylene glycol (PEG) to make a slippery surface. With PEG in place, proteins do not stick to the support substrate and are transported directly to the nanoscale sensor (see Figure 2).
Figure 2. The biosensor's glass substrate is coated with polyethylene glycol, a short polymer that stops the protein (orange) from sticking to the glass.
We use single-walled, semiconducting carbon nanotubes (CNTs) as active channels in our sensors (see Figure 3). CNTs change resistance upon protein binding because of capacitive coupling between the charged protein and the free carriers (electrons or holes) in the CNTs. The number of free carriers in CNTs either increases or decreases, depending on the sign of the charged protein. We have improved the signal-to-noise ratio in our devices by carefully engineering the metal/CNT contacts. We also increased the yield of working devices by growing horizontally aligned CNTs with a chemical vapor-deposition technique that yields 95% semiconducting CNTs.7
Figure 3. A protein adsorbing to the surface of a semiconducting carbon nanotube. The resistance of the latter changes when the protein binds.
We quantified detection speed using both a standard substrate and PEG-treated glass. With the latter, detection speeds increase fourfold. Comparisons with theoretical predictions show that PEG does not behave ideally and further improvement by a factor of 10 should be possible. Nevertheless, this is the first demonstration that a slippery substrate greatly enhances nano-electronic biosensor performance.
Our work demonstrates that protein transport to nano-electronic biosensors is critical for high-performance device fabrication. The observed fourfold increase in detection speed is the difference between waiting five versus 20 minutes for a medical test. This research area is poised for further innovations. For example, a smooth substrate that weakly binds proteins but still allows their 2D diffusion would greatly enhance the rate at which they reach nano-electronic sensors. This is one of several ideas that we are pursuing, aimed at making fast, label-free biosensing a reality.
Oregon State University
Ethan Minot is an assistant professor of physics. His research group explores the the science and applications of carbon nanotubes. The impact of their work ranges from medical diagnostics to energy conversion.
3. S. J. Kang, C. Kocabas, T. Ozel, M. Shim, N. Pimparkar, M. A. Alam, S. V. Rotkin, J. A. Rogers, High-performance electronics using dense, perfectly aligned arrays of single-walled carbon nanotubes, Nat. Nanotechnol. 2, pp. 230-236, 2007. doi:10.1038/nnano.2007.77
4. E. Stern, J. F. Klemic, D. A. Routenberg, P. N. Wyrembak, D. B. Turner-Evans, A. D. Hamilton, D. A. LaVan, T. M. Fahmy, M. A. Reed, Label-free immunodetection with CMOS-compatible semiconducting nanowires, Nature 445, pp. 519-522, 2007. doi:10.1038/nature05498
6. E. Stern, A. Vacic, N. K. Rajan, J. M. Criscione, J. Park, B. R. Ilic, D. J. Mooney, M. A. Reed, T. M. Fahmy, Label-free biomarker detection from whole blood, Nat. Nanotechnol. 5, pp. 138-142, 2009. doi:10.1038/nnano.2009.353
7. L. Ding, A. Tselev, J. Wang, D. Yuan, H. Chu, T. P. McNicholas, Y. Li, J. Liu, Selective growth of well-aligned semiconducting single-walled carbon nanotubes, Nano Lett. 9, pp. 800-805, 2009. doi:10.1021/nl803496s