Biomedical Applications of Random Lasing: History
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Contributor:
R. Gayathri
,
C. S. Suchand Sandeep
,
C. Vijayan
,
V. M. Murukeshan

A disordered photonic medium is one in which scatterers are distributed randomly. Light entering such media experiences multiple scattering events, resulting in a “random walk”-like propagation. Micro- and nano-scale structured disordered photonic media offer platforms for enhanced light–matter interaction, and in the presence of an appropriate gain medium, coherence-tunable, quasi-monochromatic lasing emission known as random lasing can be obtained.

  • random lasing
  • media
  • light
  • biomedical applications
  • imaging applications
  • sensing applications

1. Introduction

The ramifications of light–matter interactions, as well as the quest for a control over these interactions, have opened new pathways to achieve a deeper understanding as well as novel applications in photonics. The presence of imperfections in the medium, specifically, scattering caused by micro- and nano-scale disorders are often treated as detrimental. A deep understanding of these disorders and their interactions with light is crucial for overcoming the limitations in such media and, thus, rendering them useful for applications in optics. Recent studies have revealed a wealth of interesting physics in systems with micro and nano-scale disorders [1]. These findings offer new paradigms of the physical process with potential for yet-unexplored applications in a variety of fields, given that most of the micro- and nano-scale structures around us, from beetle scales to human skin, for example, are disordered in nature.
Scattering centers are distributed randomly in a disordered medium, and light undergoes multiple scattering events in such media. The consequent “random walk”-like light propagation prolongs its path, thereby increasing the number of interactions with the medium that can potentially modify the optical processes involved. Properly harnessing light transport in micro- and nano-scale disordered materials opens up possibilities for light harvesting, sensing, limiting, and other applications [2]. The incorporation of appropriate optical gain mechanisms into such disordered structures gave rise to another exciting field of research called random lasing. The longer interaction time of light in disordered structures in the presence of a gain medium facilitates the amplification of light [3]. Thus, scattering-induced light localization acts as a cavity and provides feedback for lasing under appropriate conditions.
Unlike conventional lasers, random lasers are quasi-monochromatic, coherence-tunable, and multidirectional [4][5][6]. The degree of disorder in the medium primarily determines the emission characteristics of a random laser. This has several implications, one of which is the use of random lasing emission to probe phenomena involving disorder changes in the medium, making it an effective tool for sensing applications [7][8][9]. It also facilitates fundamental research on Anderson localization and other transport phenomena in disordered media [10][11]. Furthermore, the possibility of “mirrorless” cavity lasing leads to miniature laser sources. The complexity of random laser physics, as well as the diversity of materials that are capable of random lasing, motivates more fundamental research in this area. It also provides a scope for engineering random lasers tailored to the desired application. Random lasers have become increasingly popular for biomedical applications in recent years.
Random lasers piqued the attention of various scientific disciplines soon after their first demonstration. Some early notions of the applications of random lasers were to use them as stable optical frequency standards and laser paint [3][12]. Also, they were suggested for studying laser action in substances that cannot be manufactured in the form of homogenous large crystals, which led to the emergence of powder random lasers [13][14]. Furthermore, the mirror-less cavity model has enabled lasing emission at frequency ranges where obtaining high reflecting mirrors is difficult or expensive. Currently, random lasing frequencies range from deep UV to infrared and terahertz [15][16][17][18]. They are also suitable for display applications due to their wide angular distribution over the entire solid angle of 4π. Most importantly, the tunable spatial coherence, multimode behavior, and mode sensitivity with external disturbances make random lasers particularly interesting in biomedical applications such as imaging and bio-sensing [5]. The significant advancements which have been achieved in this direction are discussed in the following sections.

2. Imaging Applications

Wide-field imaging is one of the most commonly used microscopic imaging technique due to its simple configuration and low cost. It is a prominent technique for real-time, in vivo bio-imaging because of its potential to provide a larger field of view and higher temporal resolution, unlike other imaging techniques where the speed of acquisition is limited by the scanning optics, intricate illumination, and post-processing requirements. In wide-field imaging, the entire field of view is illuminated and imaged, and the image quality is largely dependent on the nature of the illumination source. Lasers are highly desirable sources for imaging applications due to their intense narrowband emission and spectral control. Nevertheless, because of the high spatial coherence, conventional lasers are often incompatible with wide-field imaging. Upon illumination with a highly coherent laser, light scattered from dust particles, the optical surfaces, inherent imperfections in the system, and the sample surface interfere, creating speckles and interference patterns [19]. Such interference patterns and speckles created by the coherent lasers are often known as coherent artefacts. They deteriorate the image quality in wide-field microscopy, making it difficult to interpret the information contained in the images. Several optical and computational techniques have been developed to suppress these coherent artefacts so that lasers can be used for wide-field imaging [19][20]. The most commonly used techniques involve vibrating multimode fibers, scanning micromirrors, and phase randomization techniques [21][22][23][24][25][26][27]. However, all of these methods are sequential decorrelation techniques producing time-varying independent speckle patterns that are to be averaged over many images. For instance, the use of rotating diffusers produces uncorrelated speckles in the images, and the averaging of N such images with independent speckle patterns helps to reduce the speckle contrast by a factor of N1/2 [22][24]. A simple estimation revealed that nearly a thousand images need to be captured and processed in order to reduce the speckle contrast to below the human perception level (speckle contrast ratio, C~3%) using this technique [28][29]. Hence, these techniques cannot be used for dynamic imaging or for real-time in vivo wide-field bioimaging applications because of the lengthy acquisition times, vibration noise caused by mechanical movements, and post-processing requirements [20].
Commercial wide-field imaging systems employ spatially incoherent sources such as LEDs, mercury vapor lamps, and xenon arc lamps in combination with excitation filters to avoid coherent artifacts. However, these are broadband sources relying on spontaneous emission and have low photon degeneracy, which implies that even if the source is bright, the number of photons available per mode is sparse. It was in this context that Redding et al. proposed and demonstrated the use of a random laser as an illumination source in wide-field imaging for the first time in 2012 [30]. Low spatial coherence and high photon degeneracy are the two key characteristics that make random lasers appealing for imaging applications. This unique combination is absent in other light sources (e.g., conventional lasers, thermal light sources, or LEDs); see Figure 1 for a comparison of different illumination sources. Previous works have also shown that random lasers perform as well as LEDs, even in scattering environments [30]. The findings suggest that random lasers could be used to image through turbid media. Ma et al. developed a multi-mode random fiber laser in 2019, and to demonstrate its potential for bio imaging, they used a cuvette filled with milk before and after the imaging sample in order to create a bio-scattering environment [31]. In the same year, Lee et al. used a curvature-tunable random laser to exhibit low-noise speckle contrast imaging of dynamic phenomena, such as the blood flow patterns in the ear skin of mice [32]. Random fiber laser has also been used to obtain high-contrast in vitro dental imaging in the backscattering configuration [33]. Recently, in 2021, Pramanik et al. developed a portable and low-cost continuous wave random laser for imaging applications [34]. Further, the tunable coherence of random lasers presents unique possibilities for tailoring light sources to specific imaging applications.
Nanomaterials 13 02466 g009
Figure 1. Comparison of light sources based on their spatial coherence and photon degeneracy.
Recently, random lasers have been investigated for wide-field fluorescence bio-imaging applications [35][36]. It has been observed that in both trans-illumination and epi-illumination configurations, random lasers outperform LEDs and conventional laser sources and provides high-contrast images with all the finer structural details. The photon degeneracy and the spectral characteristics of the illumination source have a significant impact on the emission intensity in fluorescence imaging. LEDs have broad emission spectra and low photon degeneracy by nature. Despite the fact that the LED’s bandwidth was limited to 25 nm using bandpass filters (similar to the filters commonly used in fluorescence microscopes), they were still inefficient in comparison to laser sources for the excitation of fluorescent molecules. Conversely, despite having a narrow band width and high photon degeneracy, the images recorded using the conventional laser had lower contrast than the images recorded using the random laser. This has been explained based on the non-uniform excitation caused by the inherent coherent artefacts in the case of the conventional laser, which led to output distortion, a decrease in overall intensity, and degradation of the image quality. The non-uniform excitation also causes the loss of information that may lead to misinterpretations and errors in quantitative fluorescence imaging. Random laser illumination was also demonstrated to provide better contrast and a higher signal-to-noise ratio in multi-layered diffusive tissue samples [35].

3. Sensing Applications

The spectral features of random lasers exhibit a strong dependence on the scattering environment. As a result, they display sensitivity to various external factors, including temperature, refractive index, pH, humidity, etc. [7][8][37][38]. This inherent sensitivity allows for a wide range of sensing applications using random lasing [39]. Random lasers that can sense multiple parameters simultaneously have also been developed [40]. A random-laser-based sensor using gold nanoparticles has demonstrated the ability to detect even nanomolar levels of dopamine (a neurotransmitter found in brain tissues) [41]. This has significant implications for the detection and management of Parkinson’s and Huntington’s diseases. Random lasing signals have been instrumental in identifying the morphological and structural alterations triggered by mutations in the Huntingtin gene [42]. In another recent report, a fiber-based plasmonic random laser was utilized to detect human immunoglobulin (IgG) and quantitatively monitor its concentration through specific binding interactions with protein A [8].
Chemical sensors based on random lasers, when operated near or above the threshold, exhibit a sensitivity more than 20 times higher than those relying on spontaneous emission or fluorescence [43]. Further, the use of biocompatible polymers has facilitated random-laser-based wearable sensors that may be transferred or implanted on the skin for the purpose of monitoring physical activities, detecting sweat, etc. [44][45]. Furthermore, recent research has successfully demonstrated self-healing random lasers which can self-recover their lasing action after being chopped into tens of pieces in only a few minutes [46]. Wearable systems like soft bioimaging implants, portable laser gadgets, and photonic skins could benefit greatly from such random lasers with stretchability, high deformability, and self-healing properties.
Random lasing has been conducted in various biological tissues and is being utilized for biosensing and biodiagnostic applications. Polson et al. used random lasing emission from tissues to identify cancer regions [9]. They observed that the cancerous tissues generated more laser lines than the healthy tissues did. This indicates the presence of more laser resonators as a result of increased tissue disorder associated with cancer progression. The random lasing thresholds were found to be related to the tumor malignancy grade, and could, thus, be utilized to classify tissues for diagnostic purposes [47]. Further, the cavity length of the laser resonators can be estimated by the power Fourier transform of random lasing spectra, which aids in the mapping of cancerous regions [48]. The random-laser-based biosensor developed by Song et al. could detect nanoscale structural and mechanical deformation in the bones [49]. Such mechanical behavior testing with random lasing emission has been extended to soft tissues as well [50]. In these techniques, the tissue acts as the scatterer, and the gain medium is a suitable fluorophore impregnated to the tissues. Recent research has also shown novel strategies for random lasing without the need to infiltrate the biological samples with dyes. Instead, the gain medium is encapsulated in a transparent spherical cell and attached at the ends of an optical fiber, allowing for non-invasive diagnostics of biological samples [51]. Proceeding one step further, a recent study demonstrated that random laser emission can be used to differentiate tissues, for example, fat, nerve, muscle, and skin tissues, even under room light conditions [52].

This entry is adapted from the peer-reviewed paper 10.3390/nano13172466

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