Contents lists available at ScienceDirect Biosensors and Bioelectronics journal homepage: www.elsevier.com/locate/bios Molecular overlap with optical near-fields based on plasmonic nanolithography for ultrasensitive label-free detection by light-matter colocalization Kiheung Kim a,1 , Wonju Lee a,1 , Kyungwha Chung b , Hongki Lee a , Taehwang Son a , Youngjin Oh c , Yun-Feng Xiao d , Dong Ha Kim b , Donghyun Kim a, ⁎ a School of Electrical and Electronic Engineering, Yonsei University, Seoul 03722, Republic of Korea b Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760, Republic of Korea c OLED Division, Samsung Display, Asan, Chungcheongnam-do 31454, Republic of Korea d School of Physics, Peking University, Beijing 100871, PR China ARTICLE INFO Keywords: Biosensor Surface plasmon resonance Plasmonic lithography Sensitivity Colocalization ABSTRACT In this work, we investigate the detection sensitivity of surface plasmon resonance (SPR) biosensors by engineering spatial distribution of electromagnetic near-fields for colocalization with molecular distribution. The light-matter colocalization was based on plasmonic nanolithography, the concept of which was confirmed by detecting streptavidin biotin interactions on triangular nanoaperture arrays after the structure of the aperture arrays was optimized for colocalization efficiency. The colocalization was shown to amplify optical signature significantly and thereby to achieve detection on the order of 100 streptavidin molecules with a binding capacity below 1 fg/mm 2 , an enhancement by more than three orders of magnitude over conventional SPR detection. 1. Introduction Numerous optical biosensing schemes have emerged for detecting molecular interactions. One of the most successful techniques has been the one based on surface plasmon resonance (SPR), which relies on the dependence of plasmon excitation on the changes of surface states as a result of biointeraction. In contrast to optical sensors that take advantage of labels such as fluorescent dyes and quantum dots, SPR detection measures refractive index change due to the change in mass bound to the sensor surface and is performed label-free, thus allows kinetics of target interactions to be measured without labeling inter- ference in a quantitative manner and in real-time for a large range of analyte molecular weights (McDonnell, 2001). However, the label-free nature of SPR detection is accompanied by relatively moderate sensitivity as well. To achieve enhanced sensitivity, many strategies have been pursued, for example, by using molecular intermediaries such as nanoparticles and aptamers to amplify optical signatures (He et al., 2000; Moon et al., 2010; Bai et al., 2013). Also, phase detection has been conducted to measure phase changes caused by an interac- tion, rather than intensity (Nelson et al., 1996; Wu et al., 2004; Halpern et al., 2011). Binding area has been increased by surface corrugation which was often on a nanometer scale using nanowires or nanogrids (Kim et al., 2006; Byun et al., 2007b; Moon et al., 2012; Yu et al., 2013), while effects of surface curvature on the detection sensitivity were investigated (Lee and Kim, 2016). SPR detection has been combined with other sensing schemes that include magneto-optic modulation, microcavities and electron field-effects (Sepúlveda et al., 2006; Dantham et al., 2013; J. Oh et al., 2010). Of particular interest is colocalized detection between fields and target binding molecules that has been explored to improve sensitivity by spatially overlapping near- fields produced by 2D or 3D metallic surface nanostructures with target molecules (Shalabney and Abdulhalim, 2010; Lee and Kim, 2012), i.e., if a target molecule perturbs an ambient evanescent field, resonance shift δk may be represented as ∫ ∫ δk k δ E Edr E Edr ≅ 2 ∈ * ∈ * i V i f V i i P (1) where k i is the wave vector of incident light (Abdulhalim, 2007). The integral in the numerator is an overlap integral between distributions of binding molecules expressed as the difference in permittivity δε and light fields before (E i ) and after (E f ) the binding. The integral at the http://dx.doi.org/10.1016/j.bios.2017.04.046 Received 14 February 2017; Received in revised form 19 April 2017; Accepted 27 April 2017 ⁎ Corresponding author. 1 These authors contributed equally to this work. E-mail address: kimd@yonsei.ac.kr (D. Kim). Biosensors and Bioelectronics 96 (2017) 89–98 Available online 28 April 2017 0956-5663/ © 2017 Elsevier B.V. All rights reserved. MARK