Noble metal nanoparticles exhibit enhanced scattering and absorption at specific wavelengths due to a localized surface plamson resonance. This unique property can be exploited to enable the use of plasmonic nanoparticles as contrast agents in optical imaging. A range of optical techniques have been developed to detect nanoparticles in order to implement imaging schemes. Here we review several different approaches for using optical interferometry to detect the presence and concentration of nanoparticles. The strengths and weaknesses of the various approaches are discussed and quantitative comparisons of the achievable signal to noise ratios are presented. The benefits of each approach are outlined as they relate to specific application goals.
© 2013 Optical Society of America
Plasmonic nanoparticles have received much recent attention as contrast agents for optical imaging due to their unique optical properties. Noble metal nanoparticles have the distinctive property of an increase in optical scattering and absorption at a plasmon resonant frequency, which depends on the nanoparticle geometry, material and dielectric surroundings. When used as contrast agents, the plasmon resonance increases the optical signal returning from a selected target such as a molecule or structure of interest.
There have been a number of reviews that focus on development and synthesis of nanoparticle structures [1–5], as well specific applications for optical imaging . However, there has been little attention paid to determining optimal methods for discriminating the presence and concentration of nanoparticles as optical contrast agents. Darkfield microspectroscopy has served as the de facto gold standard for imaging of plasmonic nanoparticles [7–10] and has been applied in a number of experiments. Other approaches have been exploited, including reflectance confocal imaging [10–12], two photon luminescence  and photoacoustic imaging  to name a few. Of particular interest here is the use of interferometric techniques for detecting nanoparticles.
Interferometry offers high sensitivity for optical imaging by providing information about the complex electric field. Using interferometry allows for measurements in changes of field amplitude which can reveal the presence of nanoparticles via their absorptive or scattering properties. However, the complex field can also be measured to determine a phase shift due to the presence of nanoparticles. The inherent phase shift due to the plasmon resonance can thus be used to detect nanoparticles. Additionally, the phase shift can be further enhanced by using a localized heating to intentionally vary the local phase as is done in the photothermal approach. Indeed photothermal excitation of nanoparticles has become a widely explored mechanism . In this review we will compare these various methods of generating contrast by measuring the optical field. The methods for detecting changes in the optical field are also discussed with the aim of connecting the capabilities of methods such as optical coherence tomography  and digital holography [17, 18] with specific biomedical imaging applications ranging from widefield imaging of tissues to detailed high resolution imaging of cell features.
2. Darkfield microspectroscopy
Darkfield microscopy is an imaging modality based on using light incident on a sample of interest at a high angle relative to the optical axis. In this approach high contrast is generated as any light transmitted or reflected by the sample is not received by the collection optics. Instead, any light that is scattered will be collected as the optical signal against a dark background. Since plasmonic nanoparticles exhibit strong scattering near the plasmon resonance wavelength, darkfield microscopy can be an ideal method for detecting their presence, especially when combined with a spectrally selective detection method (Fig. 1).
There have been a range of darkfield microspectroscopy schemes that have been developed for detecting nanoparticle signals. While they all share the common feature of delivering light at an oblique angle and collecting the scattered light, they can vary on whether spectral selection is implemented on the illumination or detection end . For example, broadband white light can be used for excitation and the entrance aperture of a spectrometer provides discrimination upon detection. In contrast, hyperspectral imaging will tune the wavelength of illumination and an ordinary CCD can provide detection. In addition, while most schemes use transmission geometries, epi-illumination schemes have also been developed .
To analyze the signal to noise ratio in dark field illumiation, we must consider the origin of the signal, its collection and spectral discrimination and compare it with the sources of noise. The optical power scattered by a single nanoparticle depends on the incident power P and can be written as
The noise that this signal is measured against depends on several factors. If the darkfield scheme is not perfect, there will be a hazy background intensity H which will set the noise floor. This can arise from stray light or from other sample structures such as when trying to measure nanoparticle in the presence of cells. The signal from the cells can reduce SNR but can be mitigated by using epi-illumination , since it is mostly forward peaked. In addition the noise will include the shot noise associated with the signal given by the shot noise associated with any dark counts and the read noise Nr2 of the sensor.
With this high SNR, darkfield imaging has been applied widely to study the interaction of cells and nanoparticles as noted in recent reviews [6, 20]. Examples from these reviews include cell imaging using nanorods  and nanoshells . Instruments based on hyperspectral darkfield have enabled quantitative molecular imaging  and spectral multiplexing , using functionalized nanoparticles where an antibody conjugate provides molecular specificity [4, 23]. These instruments are even capable of detecting plamonic shifts due to coupling which can then be used to provide additional spatial information [24–26]. However, a key limitation of this approach is that the detailed structure of the cells is not imaged directly using the nanoparticle tagging and instead must be inferred. The outlined shapes of cells due to coverage by nanoparticles can provide some baseline structural information, but may not provide reliable or useful information on internal structures. Likewise, the darkfield scattering due to cellular structures may provide incomplete information while also diminishing SNR of the nanoparticle labels. Several different approaches are now considered to address this shortcoming.
3. Photothermal imaging
The enhanced absorption of plasmonic nanoparticles was first exploited to generate imaging contrast by Boyer et al.  In this work, gold nanoparticles are heated by optical absorption which in turn generates a change in refractive index in the surrounding medium (Fig. 2). The refractive index changes cause a phase shift in light traversing the local region which can be measured with a phase sensitive method, such as the adapted differential interference contrast method used in this study. In this approach, two orthogonally polarized laser beams at 633 nm with a power of 2.5 mW each are laterally displaced and scanned across the sample in reflection geometry enabling detection of the phase shift associated due to the refractive index change. The heating beam at 514 nm with an incident power of 20 mW at the sample was modulated between 100 kHz and 10 MHz using an acousto-optic modulation and a lock-in detector used to detect the signal with a 10 ms integration time. Although quantitative phase shifts are not given, the lock in signal is seen to vary by a factor of 10 over the range of modulation frequencies and temperature changes of 3-15 K are reported. Significantly, particles as small as 2.5 nm were detected at an SNR listed as ~2 with an SNR >10 reported for the larger particles.
Further studies with this approach by Cognet et al.  studied labeled proteins. The imaging approach was converted to a transmission geometry and a fixed modulation frequency of 900 kHz was used for the heating beam. This study included an analysis of the phase shift that is expected for a given heating power and modulation frequency. Here the heating power is focused on the same point as the probe beam, enabling lower powers. For 300 nW focused heating beam, an SNR>30 is reported for 10 nm particles. Phase shifts on the order of 0.1 mrad are reported in qualitative agreement with the proposed model.
In both of these works, the gold nanoparticle is modeled as a point source of heat and sinusoidal modulation is considered. A detailed examination of the relationship between particle heating and observed phase change, as well as the influence of particle size and optical excitation can be found in Zharov and Lapotko , where predictions are tested using a phase contrast type imaging system. This approach avoids the need for scanning across the sample; however, further advances may be gained by utilizing some of the more advanced phase imaging approaches that have been recently developed . For example, a recent study by Baffou et al.  used a Hartmann grating to measure wide field photothermal images using a regular CCD. Detailed signal to noise ratio information was not provided but an increase in data acquisition speed to 1-3 sec was cited.
The photothermal imaging approach was further advanced by employing a heterodyne scheme . In this scheme a single probe beam and a pump beam are modulated at the same frequency and the detected signal is demodulated using a lock-in amplifier set to the same frequency. This approach enabled detection of 5 nm gold nanoparticles with an SNR>100 for a heating power of 1 mW. The local temperature change was estimated to be 4 K in an aqueous solution. A systematic analysis conducted by Gaiduk et al. , points to paths that can improve SNR in this approach. These include, using a surrounding medium which exhibits large changes in refractive index for a given temperature change, and avoiding the thermal sink caused by placing nanoparticles on glass. The reflection geometry considered in this work models the signal as scattering due to the change in refractive index rather than directly measuring phase changes. However, 5 nm particles were detected with SNR of 12 using 10 ms integration and a 740 kHz modulation frequency. The acquisition time was long due to the point measurement nature of the approach.
3. Optical coherence tomography
Optical coherence tomography (OCT) is a biomedical imaging modality that permits optical sectioning with micron scale resolution . One limitation is that typical implementations of OCT do not provide molecular specificity. While several approaches have been proposed [34–36], of particular interest here is the use of plasmonic nanoparticles in OCT.
The most direct way to measure the presence and concentration of nanoparticles with OCT is through their scattering properties, which can be made to coincide with the near infrared spectral window commonly used in OCT. Among the initial attempts, Oldenberg et al. distinguished the presence of gold nanorods based on differences in backscattering albedo , providing a threshold of detection of 30 ppm in a 210 μm thick sample, corresponding to ~20 picomolar concentration. Further studies from this group with imaging of nanorods injected into human tissue samples, were able to detect smaller volumes of nanorods, listed as several microliters, at concentrations of 3-5 nanomolar . Typical data acquisition in these experiments required averaging of multiple images and required several seconds. More recent studies from our group by Li et al.  used dual window processing of spectroscopic OCT signals  to recover detailed spectra from multiple nanoparticle species bound to cell receptors. The dual window method uses a bilinear distribution to enable better sensitivity and signal fidelity than other methods like the short time Fourier transform. In this study, concentrations of 80 ppm, corresponding to ~60 picomolar, in 100 μm thick layers were detected using a single data acquisition of 20 ms.
An alternative method for detecting plasmonic nanoparticles with OCT is to excite them photothermally and then use phase sensitive detection to observe the signal. The first efforts in this area by Skala et al  used a low frequency modulation to detect functionalized nanospheres which targeted epidermal growth factor receptor in three dimensional cell cultures. This study obtained a sensitivity threshold of 14 ppm in a 100 μm thick sample, corresponding to a concentration of ~10 picomolar. Significantly, this study included a calculation of the expected phase shift due to a single nanosphere of 0.4 mrad and compared with the system sensitivity of 1 mrad. However, the low modulation frequency used (25 Hz) required long acquisition time to realize this sensitivity and 10 second averages were needed. Further studies  with this approach showed a sensitivity threshold of 7.5 picomolar in a 150 μm thick sample and a 100 msec integration time. Powers of 30-40 mW were used for both of these experiments and focused into spots of 10-20 μm in diameter.
Follow up studies using photothermal excitation and OCT detection were conducted by Adler et al.  and Kim et al. . The Adler study  used gold nanoshells which exhibit a resonance peak in the near infrared, which was excited using an 808 nm pump laser with 300mW output power. This study explored the influence of modulation frequency on SNR, describing an optimal frequency of 15 kHz for their setup. Detection of high modulation rates were enabled by the use of a swept source operating at 240 kHz. At this modulation frequency, the relationship between the SNR and integration time was also characterized and found to be linear. SNR’s in the 5-20 range were obtained for integration times of 2-5 ms for 1010 nanoshells/mL in a 400 mm thick sample, corresponding to a concentration of ~16 picomolar. One significant finding in these studies was that continued modulation of the high power photothermal beam caused sample heating which placed the few milliradian oscillating signal arising from the nanoparticles atop a rising trend that increased 4-6 radians over the observation period. Such a phase change corresponds to a temperature increase of up to 9 K, which can be damaging to biological samples. To address this concern, our group conducted studies using single pulse photothermal excitation . Here nanoparticles at a concentration of 2.3 x 1010/mL corresponding to 38 picomolar were observed in a 140 μm thick layer using single pulse excitation (Fig. 3). For pulses in the range of 20-400 μsec at powers of 20mW, SNR’s were recorded in the 10-60 range for integration times of 3 msec. The higher sensitivity was achieved by using the more gentile excitation of the individual pulses where the phase was observed to return to baseline after each pulse.
A recent publication by Pache et al.  demonstrated the potential utility of combining OCT with photothermal lock-in methods. Rather than use the phase sensitive detection as previous photothermal OCT experiments, they instead use a lock-in approach by modulating the heating beam and the reference field. A non-modulated probe beam is also delivered to the sample in a dark-field configuration, providing dark field optical coherence microscopy data when the returned beam is mixed with the same reference field by simply tuning its modulation to zero frequency. The spectral domain OCT setup had a line rate of 3.9 kHz and required 5 to 20 minutes per image depending on the lock-in integration time (0.25 – 1 ms). This approach allows imaging of individual nanoparticles with SNR of 25-34 dB for heating beam powers of 10-12 mW.
4. Digital holography
Digital holography is an approach that records holographic data using digital sensors such that information can be extracted and processed using a computer [17, 18].The sensitivity of digital holography to phase makes the combination with photothermal excitation of nanoparticles potentially very useful. Among the first efforts to exploit this approach was in a work by Atlan, et al.  who identified that widefield imaging of photothermal excitation of nanoparticles would alleviate issues with point scanning schemes. This work employed a heterodyne imaging scheme which used acousto-optic modulators to set the photothermal excitation frequency modulation with a close frequency of the reference beam. The camera exposure would then capture adjacent frames, each with different phase shifts, in a similar approach to asynchronous digital holography . In this work photothermal excitation was implemented using an evanescent wave with nanoparticles localized on the face of a prism. Excitation was 10 mW and acquisition of the two frames took 100 ms. The noise floor arises from the shot noise of the reference beam but coherent noise in this setup reduces SNR to an apparent value of ~10, although a theoretical SNR of >90dB is identified if limited by the shot noise of the reference field. While this approach showed the potential of the combination of photothermal excitation and digital holography, the evanescent field excitation limited the amount of information that could be recovered about the rest of the sample, such as the presence and structure of cells. A more detailed study from this group  characterized the approach in more detailed and identified that using larger particles enabled improvement of SNR to 90 and again confirmed the 90dB potential SNR when coherent noise could be avoided. This latter study identified that this approach would trail single particle photothermal interferometry by an order of magnitude or greater in SNR and that the need for a widely distributed reference field might cause sample damage when imaging cells. This limitation was explored further by this group , where they imaged nanoparticles in the presence of cells using a similar scheme. The interface of the cell with the evanescent field showed the cell structure in contact with the prism. The need for lower power (80 mW) resulted in a longer data acquisition time of 100 ms and 32 frames were averaged to enable visualization of an individual 40 nm gold particle. This study also identified the combination of focused illumination and wide field imaging.
Another study using digital holography showed that using dark field excitation could enable visualization of gold nanoparticles without the need for photothermal excitation . Here the nanoparticles were excited with darkfield illumination and the scattered light was imaged with on axis holography. Although no SNR analysis was conducted, the study showed localization of 100 nm gold particles with exposure times of 1 ms and within a 0.25 mm thick sample.
As a final illustration of the combination of nanoparticle imaging and digital holography, we conducted studies of an experimental system that used darkfield illumination to image nanoparticle location with high sensitivity with digital holographic imaging of phase changes due to photothermal excitation (Fig. 4). Darkfield imaging was accomplished by illuminating the sample with an LED ring (RL1360m, Advanced Illuminations) which causes light to be incident on the sample such that any reflected light will fall outside of the NA of the imaging objective. The digital holography scheme was a standard off axis holography scheme and phase images were obtained via standard methods . As an initial examination, we characterized the measured phase change as a function of nanoparticle concentration. Figure 5 shows the measured phase change versus concentration of nanoparticles. For this experiment, a 10x objective (0.25 NA) was used which focused the photothermal excitation of 37 mW to a 6 μm wide beam across the 120 micron thick sample. Thus for a concentration of 1 x 1011 nanoparticles/ml, approximately 340 nanoparticles were detected. For the first arrangement, a slope of 0.004 radians/nanoparticle was achieved for nanoparticles in water. The noise floor of these measurements was 0.0413 radians. Thus for this arrangement, individual nanoparticles could not be visualized.
To enable single particle detection, several modifications were made. First different media surrounding the nanoparticles were employed. For all photothermal media the phase change depends linearly on the nanoparticle concentration (Fig. 5). Using glycerol increased the slope by a factor of 3 to 0.01 radians/nanoparticle (green line) and a combination of glycerol and ethanol (50:50) further increased the slope to 0.03 radians/nanoparticle (blue line) but still did not enable single particle detection. Instead, we further focused the beam by switching to a 40x objective, producing a 2.3 μm diameter beam. With this approach the noise floor was reduced to 7.8 mrad RMS which should enable single particle imaging. Upon using the more tightly focused beam however, the incident intensity striking the nanoparticle increases and individual particles could be visualized with an SNR of 26dB (Fig. 6), with a phase change of 0.16 radians observed for a single 5 ms exposure. Note that the use of the glycerol/ethanol mix causes some unusual features. In addition to the clear nanoparticle signature, there is also a pluming effect in the medium which might reduce effective SNR in more complex imaging situations.
We have reviewed several different methods for observing plasmonic metal nanoparticles using interferometric detection. These are summarized in Table 1. Darkfield microscopy offers the highest SNR but does not permit imaging of other sample structures. In contrast, Optical Coherence Tomography enables excellent sample visualization but has limited sensitivity to nanoparticles, via either enhanced scattering and absorption or spectroscopic contrast. Use of photothermal excitation can improve sensitivity but on its own will not allow visualization of transparent samples, such as cells. Advanced photothermal schemes employ heterodyne detection and can greatly extend sensitivity but have limited ability to visualize cell features without incorporating an additional modality. Digital holography allows quantitative phase images of cell features and by using a focused photothermal excitation source, individual plasmonic nanoparticles can be visualized. Multimodal approaches have shown the ability to provide good sensitivity to nanoparticles, even individual particles, and then visualize other structures as well. However, incorporation of additional imaging modalities within a single platform increases complexity and can require careful co-registration efforts. Thus, sensitivity of digital holography to nanoparticles can be further improved compared to the results here by inclusion of heterodyne photothermal detection, for example; however, the additional complexity may not be warranted as sufficient SNR for nanoparticle localization can be realized.
This work was supported by a grant from the National Science Foundation (CBET-1039562).
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