Zhengbin Xu

Random lasing in bone tissue

Owing to the low-loss and high refractive index variations derived from the basic building block of bone structure, we, for the first time to our knowledge, demonstrate coherent random lasing action originated from the bone structure infiltrated with laser dye, revealing that bone tissue is an ideal biological material for random lasing. Our numerical simulation shows that random lasers are extremely sensitive to subtle structural changes even at nanoscales and can potentially be an excellent tool for probing nanoscale structural alterations in real time as a novel spectroscopic modality.

Random laser spectroscopy for nanoscale perturbation sensing

We report a spectroscopic method using coherent random lasers for a simple, yet nanoscale, sensing approach. Unique spectral properties of coherent random laser emission can be detectably altered when introducing nanoscale perturbations to a simple nanocomposite film that consists of dielectric nanospheres and laser-dye-doped polymer to serve as a transducer. Random lasing action provides a means to amplify subtle perturbations to readily detectable spectral shifts in multiple discrete emission peaks. Owing to several advantages, such as large-area detection, narrow and multiple emission peaks, straightforward detection, and simple fabrication, random laser spectroscopy has the potential for ultrasensitive, yet simple, biosensors in various applications.

Detection of nanoscale structural changes in bone using random lasers

We demonstrate that the unique characteristics of random lasing in bone can be used to assess nanoscale structural alterations as a mechanical or structural biosensor, given that bone is a partially disordered biological nanostructure. In this proof-of-concept study, we conduct photoluminescence experiments on cortical bone specimens that are loaded in tension under mechanical testing. The ultra-high sensitivity, the large detection area, and the simple detection scheme of random lasers allow us to detect prefailure damage in bone at very small strains before any microscale damage occurs. Random laser-based biosensors could potentially open a new possibility for highly sensitive detection of nanoscale structural and mechanical alterations prior to overt microscale changes in hard tissue and biomaterials.

Back-directional Gated Spectroscopic Imaging for Diffuse Light Suppression in High Anisotropic Media and Its Preclinical Applications for Microvascular Imaging

There is emerging evidence that microvascular alterations may occur early, even at early stages of carcinogenesis, as indispensable participants in tumor growth. However, the exact spatial extents of such alterations remain unclear, in part, because detailed microvascular alterations in relatively deep tissue over a relative large area are not easily visualized. Due to the heterogeneous nature of tissue microvasculature, microscopic evaluations with a small field of view often fail to provide a representative assessment. On the other hand, conventional whole-body small-animal optical imaging techniques suffer from unwanted diffuse light, which would otherwise deteriorate image contrast and resolution. To fill such a gap, we take advantage of the high anisotropic property of biological tissue by implementing back-directional gating into an imaging platform to suppress unwanted diffuse light. We further combine a spectral analysis of microvascular hemoglobin (Hb) absorption with back-directional gated imaging to improve image resolution, contrast, and penetration depth that are required for subcutaneous mouse xenograft models. In tissue phantom and pilot animal studies, we demonstrate that our diffuse-light-suppressed spectroscopic imaging platform can be a simple, yet effective, imaging setup to visualize subcutaneous microvascular Hb content over a relatively large area.

Spatiotemporal Assessments of Dermal Hyperemia Enable Accurate Prediction of Experimental Cutaneous Carcinogenesis as well as Chemopreventive Activity

Field cancerization refers to areas of grossly normal epithelium that exhibit increased risk for tumor occurrence. Unfortunately, elucidation of the locoregional changes that contribute to increased tumor risk is difficult due to the inability to visualize the field. In this study, we use a noninvasive optical-based imaging approach to detail spatiotemporal changes in subclinical hyperemia that occur during experimental cutaneous carcinogenesis. After acute inflammation from 10 weeks of UVB irradiation subsides, small areas of focal hyperemia form and were seen to persist and expand long after cessation of UVB irradiation. We show that these persistent early hyperemic foci reliably predict sites of angiogenesis and overlying tumor formation. More than 96% of the tumors (57 of 59) that developed following UVB or 7,12-dimethylbenz(a)anthracene/phorbol 12-myristate 13-acetate (DMBA/PMA) treatment developed in sites of preexisting hyperemic foci. Hyperemic foci were multifocal and heterogeneously distributed and represented a minor fraction of the carcinogen-treated skin surface (10.3% of the imaging area in vehicle-treated animals). Finally, we also assessed the ability of the anti-inflammatory agent, celecoxib, to suppress hyperemia formation during photocarcinogenesis. The chemopreventive activity of celecoxib was shown to correlate with its ability to reduce the area of skin that exhibit these hyperemic foci, reducing the area of imaged skin containing hyperemic foci by 49.1%. Thus, we propose that a hyperemic switch can be exploited to visualize the cancerization field very early in the course of cutaneous carcinogenesis and provides insight into the chemopreventive activity of the anti-inflammatory agent celecoxib.

Spectroscopic visualization of nanoscale deformation in bone: interaction of light with partially disordered nanostructure

Given that bone is an intriguing nanostructured dielectric as a partially disordered complex structure, we apply an elastic light scattering-based approach to image prefailure deformation and damage of bovine cortical bone under mechanical testing. We demonstrate that our imaging method can capture nanoscale deformation in a relatively large area. The unique structure, the high anisotropic property of bone, and the system configuration further allow us to use the transfer matrix method to study possible spectroscopic manifestations of prefailure deformation. Our sensitive yet simple imaging method could potentially be used to detect nanoscale structural and mechanical alterations of hard tissue and biomaterials in a fairly large field of view.

Diffuse light suppression of back-directional gating imaging in high anisotropic media

We experimentally demonstrate that back-directional gating in an imaging setup can potentially remove unwanted diffuse light to improve the contrast of an object embedded in a high anisotropic surrounding medium. In such back-directional gating, the high anisotropic property of the surrounding medium can serve as a waveguide to deliver the incident light to the embedded object and to isolate the ballistic or snake-like light backscattered from the object in a moderate depth. We further discuss the effects of back-directional gating in the image formation in terms of the image resolution and the depth of field. Although backscattering detections of biological tissue have recently received considerable attention, we, for the first time to our knowledge, show its potential advantage for the contrast improvement in high anisotropic media.

Enhancement factor in low-coherence enhanced backscattering and its applications for characterizing experimental skin carcinogenesis

We experimentally study potential mechanisms by which the enhancement factor in low-coherence enhanced backscattering (LEBS) can probe subtle variations in radial intensity distribution in weakly scattering media. We use enhanced backscattering of light by implementing either (1) low spatial coherence illumination or (2) multiple spatially independent detections using a microlens array under spatially coherent illumination. We show that the enhancement factor in these configurations is a measure of the integrated intensity within the localized coherence or detection area, which can exhibit strong dependence on small perturbations in scattering properties. To further evaluate the utility of the LEBS enhancement factor, we use a well-established animal model of cutaneous two-stage chemical carcinogenesis. In this pilot study, we demonstrate that the LEBS enhancement factor can be substantially altered at a stage of preneoplasia. Our animal result supports the idea that early carcinogenesis can cause subtle alterations in the scattering properties that can be captured by the LEBS enhancement factor. Thus, the LEBS enhancement factor has the potential as an easily measurable biomarker in skin carcinogenesis.

Scattering anisotropy-weighted mesoscopic imaging

Abstract. We report that when tissue images are formed via a small solid angle in the backward direction (i.e., back-directional gating), the image intensity is dominantly determined by tissue scattering anisotropy. Thus, this configuration allows for scattering anisotropy-weighted imaging that can provide an intrinsic contrast by capturing tissue structures and organizations. To demonstrate the immediate feasibility, we apply scattering anisotropy-weighted imaging to tissue blocks including basal-cell carcinomas as a pilot study. The main feature of our imaging approach is the high sensitivity to tumor locations and the simplicity for large-area visualization. We further envision that scattering anisotropy-weighted imaging could potentially be used to visualize tissue microenvironments in a mesoscopic (between microscopic and macroscopic) imaging setting.

Spatiotemporal Characterization of Extracellular Matrix Microstructures in Engineered Tissue: A Whole-Field Spectroscopic Imaging Approach

Quality and functionality of engineered tissues are closely related to the microstructures and integrity of their extracellular matrix (ECM). However, currently available methods for characterizing ECM structures are often labor-intensive, destructive, and limited to a small fraction of the total area. These methods are also inappropriate for assessing temporal variations in ECM structures. In this study, to overcome these limitations and challenges, we propose an elastic light scattering approach to spatiotemporally assess ECM microstructures in a relatively large area in a nondestructive manner. To demonstrate its feasibility, we analyze spectroscopic imaging data obtained from acellular collagen scaffolds and dermal equivalents as model ECM structures. For spatial characterization, acellular scaffolds are examined after a freeze/thaw process mimicking a cryopreservation procedure to quantify freezing-induced structural changes in the collagen matrix. We further analyze spatial and temporal changes in ECM structures during cell-driven compaction in dermal equivalents. The results show that spectral dependence of light elastically backscattered from engineered tissue is sensitively associated with alterations in ECM microstructures. In particular, a spectral decay rate over the wavelength can serve as an indicator for the pore size changes in ECM structures, which are at nanometer scale. A decrease in the spectral decay rate suggests enlarged pore sizes of ECM structures. The combination of this approach with a whole-field imaging platform further allows visualization of spatial heterogeneity of EMC microstructures in engineered tissues. This demonstrates the feasibility of the proposed method that nano- and micrometer scale alteration of the ECM structure can be detected and visualized at a whole-field level. Thus, we envision that this spectroscopic imaging approach could potentially serve as an effective characterization tool to nondestructively, accurately, and rapidly quantify ECM microstructures in engineered tissue in a large area.