Nano-plasmonic biosensors: A review

Proceedings of the 2011 IEEEIICME Intenational Conference on Complex Medical Engineering May 22 - 25, Harbin, China Nano-plasmonic Biosensors: A Review Daryoush Motazavi, Abbas Z. Kouzani, Akif Kaynak Wei Duan School of Engineering Deakin Universiy Geelong, Victoria 3217, Australia School of Medicine Deakin Universiy Geelong, Victoria 3217, Australia {dmortaza, Kouzani, akaynak}@deakin.edu.au [email protected] Abstract - II. In this paper, irst the fundamental concept of nano-optical biosensing is studied. Since Raman scattered signal A. Raman Scattering The scattering of light is generally the redirection of light that happens when an electromagnetic (EM) wave strikes a scattering material (solid, liquid, or gas). Interaction of the EM wave with the matter periodically perturbs the electron orbits within the constituent. The oscillation of the electrons results in a periodic separation of charge within the molecules, which is called an induced dipole moment. The oscillating induced dipole moment is the main source of EM radiation resulting in scattered light. The majority of the scattered light has the same requency (vo) of the incident light, a process which is known as elastic or Rayleigh scattering. However, another process referred to as inelastic Raman scattering causes additional light to be scattered at different requencies (vo Vvib) referred to as Stokes scattering, and (vo + Vvib) which is is very weak to be recognized by current measuring equipments, the signal must be ampliied. SPR and LSPR are utilized to enhance the incident ield of the target molecules, to improve the sensitivity of the sensor. The paper focuses on the use of LSPR to enhance Raman signal in SERS technology. Diferent structures of nano-particles in LSPR to improve enhancement of the SERS signal are reviewed and compared. Indx Tersenhancement. Biosensor, I. nano-plasmonic, Raman signal INTRODUCTION A biosensor is an analytical device containing a biological recognition element immobilized on a solid surface and a transduction element which converts analyte binding events into a measurable signal [1]. There are various transducers including optical, magnetic, electrochemical, radioactive, piezoelectric, micromechanical, and mass spectrometric [2]. Optical transducers are highly sensitive to biomolecular targets, insensitive to electromagnetic interference, and present real time response to biomolecular interactions. Main optical methods employed in biosensors include luorescence spectroscopy, interferometry, and surface plasmon resonance. The later one which works based on evanescent electromagnetic ields such as surface plasmon resonance (SPR), or localized surface plasmon resonance (LSPR) can monitor a wide range of analyte surface binding interactions such as absorption of small molecules, proteins, antibody­ antigen, DNA and RNA hybridization. Both SPR nd LSPR methods are label ree sensing methods and do not require labeling of the target molecules with different types of reagents, such as luorescent dyes. In addition, surface enhanced Raman scattering (SERS) has been used as a signal transduction mechanism in biological and chemical sensing. Examples are trace analysis of pesticides anthrax [3], prostate-speciic antigen [4], glucose [5-6], and nuclear waste [7]. SERS has also been implemented for identiication of bacteria [8], genetic diagnostics [9], and immunoassay labelling [10-12]. A miniaturized and inexpensive SERS device can be used in clinics, ield, and urban settings [13]. Various biomolecular interactions have been exploited in SPR and LSPR biosensors including antigen-antibody, receptor-ligand, homone-receptor, streptatividin-biotin, protein-protein, protein-DNA [14], even detection of conformational changes in an immobilized protein [15]. 978-1-4244-9324-1111/$26.00 ©2011 IEEE CONCEPTS - called anti-Stokes scattering, where Vvib is the requency of the vibrational mode of the target molecule (see Fig. 1). Raman scattering is always extremely smaller than Rayleigh scattering [16]. In addition, Raman scattering cross sections are typically 14 orders of magnitude smaller than those of luorescence [17]. For this low cross section, large numbers of biomolecules are required to create a measurable signal. This problem can be solved by magniication of the Raman signal using SPR and LSPR. Incident EM wave (vo) wave (vo) Fig. I Light scattering by an induced dipole moment due to an incident EM wave [17]. B. Surface Plasmon Resonance ( SPR) The collective excitation of the electron gas of a conductor is called a plasmon. If the excitation is conined to the near surface region, it is called a surface plasmon. Surface plasmons can either be propagating e.g. on the surface of a grating, or localized e.g. on the surface of a spherical particle, which are called surface plasmon resonance (SPR) and localized surface plasmon resonance (LSPR), respectively. Accordingly, the study of electromagnetic response of metals to optical waves is called plasmonics, or nano-Plasmonics in 31 nano-scale. When a light beam propagating in a medium of higher reractive index meets an interface at a medium of lower reractive index at an angle of incidence above a critical angle (9), the light is totally relected at the interface and propagates back into he high reractive index medium, a phenomena which is called total intenal relection (TIR) [18]. Although the ully relected beam does not lose ny net energy across the TIR interface, the light beam leaks an electrical ield intensity called an evnescent ield wave (E) into the low reractive index medium. The amplitude of this evanescent ield wave decreases exponentially with distance rom the interface, with penetration into the optically thinner medium ofn2• Thus, if the TIR-interface is coated with a layer of a suitable conducting material, such as a metal of a suitable thickness, he p-polarized component of the evanescent ield wave may penetrate the metal layer nd excite electromagnetic surface plasmon waves propagating within the conductor surface hat is in contact with the low reractive index medium. For a non-magnetic metal like gold, his surface plasmon wave will also be p-polarized and, due to its electromagnetic and surface propagating nature, will create an enhanced evanescent wave compared to he intensity of the incident electromagnetic ield. This is used to detect mass changes of the metal ilm and dielectric, thus, to measure binding coated on the surface. The propagation constant of the surface plasma wave propagating at the interface between a semi-ininite dielectric and metal is given by the following dispersion relation: kSP = k 0 where A = Em E d w Localized Surface Plasmon Resonance ( LSP) The development of large scale biosensor array comprising highly miniaturized signal transducer elements is a great milestone in producing biosensors. In this array format, it is tried to minimize the number of analyte molecules per sensor element, to decrease the measurement time, increase accuracy, and decrease the volume of required sample, but SPR has problem in these issues as the transducer element size is limited to few lm2 depending on the excitation wavelength. Also, wavelength shit detection methods re very diicult in very large arays due to the optical complexity of the instrumentation. The third problem is that real time sensing or kinetic measurement using SPR is highly mass transport limited, e.g. by the order of 103 to 104 for a bulk concentration of analyte of the order less than 10-6 to 10-7 M. To overcome these problems, noble metal nano­ particles are employed, which guides us towards nano­ plasmonics theory [23]. In LSPR, light interacts with particles much smaller than the incident wavelength. This leads to a plasmon that oscillates locally around the nano-particle with a requency known as the LSPR [19]. Like plasmonic devices, he basic components of nno-plasmonic devices are noble metals such as gold, silver, nd copper in nano-scale coated on a substrate. Moreover, in SPR, light is in contact with the surface of the metal ilm using a prism, while in LSPR plasmon is excited by direct illumination. Theorictical Calculations of LSPR and SERS We consider the simplest model of a nano-particle consisting of a single metal sphere, small compared to the wavelengh of light, which is iradiated by a laser ield. Raman scattering arises rom molecules that are adsorbed on the surface of this sphere. Therefore, Maxwell's equations may be approximated by electrostatic Laplace's equations to determine the ield both inside and outside the sphere. The resulting ield outside he sphere, Eout, cn then be written as [21, 24-25]: . (1) Em + E d 2m D. is the incident light wavelength, w is the incident light wavelength, c is the light speed, Em the dielectric constant of the metal, Ed the dielectric constant of the 2 = denotes the ree dielectric (e.g. prism), and ko = ; � space wave-vector [19]. According to (1), the surface plasmon wave (SPW) may be supported if the metal used possesses a negative real and small positive imaginary dielectric constant, such as gold and silver [20]. Eout(x, y, z) = Eoz - aEo [:3 !: (xx + ,y + ZZ) ] - (2) where Eo is the amplitude of the incident electromagnetic wave, the irst term is the applied ield, and the second one is the induced dipole that results rom polarization of the sphere electron densiy; also, x, " and z are the usual Cartesian coordinates; r is the radial distance; x, y, nd Z are the Cartesian unit vectors; and a is the metal polarizability expressed as: a = ga3 D) where a is the radius of the sphere and g is deined as: g = (Em - Ed)/(Em + 2 Ed) (4) It can be seen that the maximum enhancement occurs when the denominator of g approaches zero, i.e. (Em � -2 Ed ). Also, exmining (2) reveals that the ield enhncement decays with r-3, implying the existence of a inite sensing volume around the nano-particle. Assume e is the angle between the applied ield direction and the vector r that locates positions on the sphere surface. Note that if Igl is large, then E;ut = E51g12(1 + 3cos29). This indicates that Surface Enhanced Raman Scattering ( SERS) Electromagnetic coupling between the adsorbate nd surface at optical requencies, which is the basis of plasmonic or nano-plasmonic biosensors, arises rom the dipole moment in the adsorbed [21]. Accordingly, the magnitude of the Raman scattering signal cn be greatly enhanced when the scatterer (e.g. biomolecular target) is placed on or near a roughened noble metal substrate. This enhanced scattering process which is called electromagnetic surface enhanced Raman scattering (SERS), is used for biological and chemical sensing [22]. When the Raman scatterer is subjected to these intensiied electromagnetic ields, the magnitude of the induced dipole increases, which results in SERS [13]. Experiments show large improvement in the SERS cross section per molecule in the order of 10-16 cm2 which is comparable to Raman cross section of 10-30 cm 2• his shows a high magniication of about 14 orders in the scattered light. C. 32 the largest ield intensities are obtained for angles e equal to zero or 18.°, i.e. along the polarization direction. In this case, the overall enhancement arising rom incident and scattered ields is approximately: , 2 w 2 CR = \Eout( )\ \Eout(W )\ x 161g121g'12 (5) \EO(W)\4 where the primed symbols refer to ields evaluated at the scattered requency. For small Stokes shits, Igl and Ig'l are maximize at approximately the same wavelength, this is commonly referred to as E4 enhancement or the fourth power of ield enhancement at the nano-particle surface. The Drude model can be used for wavelength above 600 n, to fmd the metal permittivity where the Plasmon resonance occurs: w2 (6) Em = 1---Pw(w+iy) where wp is the plasmon requency and y is the plasmon width. However, at wavelengths below 600 nm, the Drude model is replaced with a Lorentz oscillator model. The Drude parameters for gold were taken rom re. [26]. The exact analytical solution to the electrodynamics of spheroidal particles is very complex. If we consider a spheroid whose major axis is of length 2b and minor axis 2a, with a constant ield Eo applied along the major axis, then an explicit expression for the Raman enhancement factor for molecules that are randomly distributed on the spheroid surface (i.e. averaged over the surface) has been given by Zeman and Schatz [27] as follows: g = Em-Ed (7) the RI sensItIVIty on spectral peak posItIon in air for Au nanodisks at 750 nm wavelength, directly on glass is 175 RIU-l, when supported on 20 nm Si02 pillars is 250 RlU-l, and when supported on 80 nm Si02 pillars is 325 RIU-1 [29]. For isolated particles, with particle sizes and shapes that are commonly studied, the enhancement factors of CR = 108 is suggested. However, larger values of CR = 1010 -1011 can be obtained for dimers of silver nano-particles. These values, which are associated with the gap between the two nano­ particles, are still below the required estimates of single­ molecule SERS (SMSERS) enhancement factors (1014) or larger by a factor of 103 or more. In analyzing these enhancement-factor predictions, it is important to note that the key parameter that controls the size of the enhancement factor for a dimer of nanoparticles is the size of the gap between the particles. It is only for gaps on the order of 1 nm to 2 nm that one can obtain exceptionally large values such as CR = 1011. - Em+XEd where parameter X is the shape factor. In fact the parameter X equals 2 for a sphere, but for prolate spheroids (i.e. those with b > a ), X is larger than 2, and for oblate spheroids (i.e. b < a) it is less than 2. When X is greater than 2, the plasmon resonance condition, Re(Em + X Ed)= 0, is satisied for a wavelength that is to the red of that for a sphere. III. ENHANCEMENT TECHNIQUES A. Morpholoy Based Enhancement Because the shape and size of a metallic nano-particle dictate the spectral signature of its plasmon resonance, the ability to change these two parameters and study the effect on the LSPR is an important experimental challenge [19]. The most popular nano-particle shapes are spheroids, triangular prisms, rods, and cubes which are shown in Fig. 2. The enhancement is directly dependant on the aspect ratio of the nano-particle, e.g. the enhancement for a nano-rod with an aspect ratio of 4, is around 26 times as much as that of a sphere nano-particle [28]. The other altenative to double the refactive index (RI) sensitivity of LSPR, is to lit the metal nano-particles above the surface by a dielectric nano-pillar to decrease the spatial overlap between substrate and the enhanced ields generated at plasmon resonance. For instance, to double the reractive index sensitivity of LSPR, the metal nano-particles are lited above the surface by a dielectric nano-pillar to decrease the spatial overlap between substrate and the enhanced ields generated at plasmon resonance. For example, it is shown that (c) (d) Fig. 2 Bright ield TEM images: (a) Gold nano-rods, (b) Gold colloids, (c) Silver triangular prisms, and (d) Silver nano-cubes [28]. An aray of dimers (see Fig. 3) of spheres with optimized spacing for producing the highest possible ield enhancement from near-ield and long-rnge effects gives CR = 109, but other structures using an array of dimers of truncated tetrahedrons, leads to SMSERS enhancement of CR = 1013. Two-dimensional arays with different spacing in each direction presents remarkably large electromagnetic enhancement factors of CR = 1013-14 [30]. DDD D D D 1 k Fig. 3 Representation of an array of dime nanospheres [30]. 33 The use of nano-wires on a gold thin ilm results in a structure that can provide reproducible performance. Also, the design of nano-wires can be customized when it is desired to meet speciic sensitivity requirement in practical applications [36]. The numerical data show that a T-proile generally results in a higher sensitivity than an inverse T-proile [36-37]. On the other hand, nanowires of a T-proile with a narrow contact area to a gold ilm exhibit smaller effective absoption than those of an inverse T-proile [38]. B. Efect of xcitation Wavelength on Enhancement Factor In addition to mophology, he excitation wavelengh has inluence on he enhancement. Wavelength-scanned surface­ enhnced Raman excitation spectroscopy (WS-SERES) involves the measurement of SERS enhancement for several laser excitation wavelengths, Aex. It is demonstrated that the maximum SERS enhancement occurs when the substrate LSPR Amax is located between Aex and AVib [31]. C. Electrophoresis Based Enhancement In another technique, a method combining SERS, to detect biomolecules in a label-ree way, with an electrokinetic preconcentration technique (electrophoresis), to ampliy bimolecular signals at low concentrations, is utilized. Therefore, increasing the number of molecules involved in the SERS by attracting molecules to the SERS substrate will ampliy the SERS signal proportionally to the preconcentration factor of the molecules. In the presence of an electric ield gradient, most of the charged biomolecules are attracted along an electric ield and then concentrated onto the oppositely charged electrode resulting in ampliication of the SERS signal for the molecules [32]. For example, the intensity of the SERS signal at 735 cm-1 for 1 mM adenine is increased by 51 times ater applying an electric ield of -0.6 V cm-1Ifor 25 min, while there was no signal ampliication in the case of a weak electric ield of -0.2 V em-1. G. Nanohole-Enhanced Raman Scattering The periodic arrays of sub-wavelength apertures (nano­ holes) in metallic thin ilms are among the most promising of these structures for applications in photonic circuits and light manipulation at the sub-wavelength range. The arrays of nano­ holes enable an increase in the transmission of light by several orders of magnitude when the SPR condition is achieved. The intensity of he nano-hole enhanced Raman scattering is directly related to he periodicity of the arays, coniming the role of SP resonances [39]. Miniaturized LED Based Sensor Monochromatic light is usually obtained through lasers, but lasers are rather costly. In this system, the laser source is substituted by LEDs, and the spectrum analyzer and subsequent signal processing devices are replaced by a single source of monochromatic light and a photodiode as detector. The resulting photocurrent output could then be converted into a voltage by an operational ampliier with a resistor in a feedback loop (I/V converter) and detected by a voltmeter [40]. H Tip-Enhanced Raman Spectroscopy TERS) An encouraging method for generalizing SERS to a wide variety of substrates is the development of tip-enhanced Raman spectroscopy (TERS). In this technique, the electromagnetic ield enhancement is provided by the excitation of the LSPR of a scanning probe. This eliminates the need to use noble-metal substrates to observe SERS. The probe can be a scanning tunnelling microscopy probe, a metal­ coated atomic force microscopy probe, a tapered optical ibre with a nano-particle or thin metal ilm at the tip, or any other nano-scale-sharpened metallic object. In recent experiments, which employed silver nano-particles and ractal colloidal clusters as the SERS active media, enhancements of up to 1014 fold in the Raman signal have been claimed [33]. D. E. IV. One solution for enhancement of Raman signal is manipUlation of the shape of the metal nano-particles to increase either the nano-particle in-plane width or its out-of­ plane height. Another important factor in enhancement is the interaction area of the nno-particle with the substrate. Decreasing the interaction area of the nano-particle with the molecule, can also increase the enhncement by orders rom 10 tol04. This phenomenon is due to accumulation of the surface charges on sharp edges which is the result of reducing the interaction area. Enhancement by using a scanning probe in TERS eliminates the need to use noble-metal substrates to implement the SERS phenomenon. This method can increase the spatial resolution of detection and enhancement up to 1014 fold in the Raman signal. Another effort in enhancement is pushing the low density target molecules toward the metal nano-particles using the Electrophoresis technique, to increase the density of he absorbed molecules on nano-particles, which results in ampliication of the SERS signal for the molecules. Also, PRET has been developed by intentionally matching the plasmon resonance requency of a GNP with the requency of the electronic transition energy of a biomolecule to increase the sensitivity of the system up to the order of 1000, or an enhancement of 1012. Table I summarizes the enhncements achieved with diferent structures of SERS with respect to Raman scattering. Plasmonic Resonance Enery Transfer ( PRE) Recently a plasmonic resonance energy transfer (PRET)­ based nano-spectroscopy has been developed by intentionally matching the plasmon resonance requency of a gold nano­ particle (GNP) with the requency of the electronic transition energy of a biomolecule. When the requencies of electronic transitions of a molecule overlap with the plasmon resonance requency of gold nano-particle upon conjugation of the particle with the molecule, this intentional spectral overlap allows the selective energy transfer and generates distinguishable spectral resonant quenching dips on the Rayleigh scattering spectrum of the particle. This method presents 100 to 1,000 times more sensitivity than other organic reporter-based methods [34-35]. F. DI SCUSSIONS Nano-wire Nano-particles Based Enhancement 34 TABLE I SUMMARY OF ENHANCEMENTS ACHIEVED WITH DIFFERENT STRUCTURES OF SERS WITH RESPECT TO RAMAN SCATTERING Structure Enhancement Isolated spherical nano-particle 108 Isolated dimer of nano-particle (with gaps on the 1010 1011 order of I to 2 nm beween particles) SMSERS 104 SMSERS with an array ofspherical nano-particles 106 SMSER S with an array of dimers of spherical nano109 particles SM SER S with an array ofdimers of truncated 1013 tetrahedrons nano-particles SMSERS with a 2D array of dimers of spherical 1013 - 1014 nano-particles Eletcorphoresis SERS 107 TERS 1014 PRET 1012 [7] _ [8] [9] [10] Another important factor in enhancement is the nano­ particle LSPR, molecule vibration, and excitation requencies. Maximum enhancement will be achieved if nano-particle LSPR wavelengh (Amax)is located between excitation and molecule vibration wavelengths (Aex and AVib respectively). 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