Molecular Contrast Optical Coherence Tomography and Its Applications in Medicine

Abstract

The growing need to understand the molecular mechanisms of diseases has prompted the revolution in molecular imaging techniques along with nanomedicine development. Conventional optical coherence tomography (OCT) is a low-cost in vivo imaging modality that provides unique high spatial and temporal resolution anatomic images but little molecular information. However, given the widespread adoption of OCT in research and clinical practice, its robust molecular imaging extensions are strongly desired to combine with anatomical images. A range of relevant approaches has been reported already. In this article, we review the recent advances of molecular contrast OCT imaging techniques, the corresponding contrast agents, especially the nanoparticle-based ones, and their applications. We also summarize the properties, design criteria, merit, and demerit of those contrast agents. In the end, the prospects and challenges for further research and development in this field are outlined.

Keywords: molecular contrast OCT; molecular contrast agent; molecular imaging; nanoparticles; optical coherence tomography.

Figure 1

Schematic diagram of generalized OCT systems. A TD-OCT and a spectral-domain OCT are demonstrated in (a,b), respectively. The arrow in (a) indicates the movement of the reference arm. The arrows in (b) show the light travel paths. Adapted with permission from [11]. Copyright 2018 J-STAGE.

Figure 2

(a) Schematic drawing of a GV, the gas-filled interior of which has a refractive index (red) different from that of the surrounding H₂O (blue). (b) Representative transmission electron microscopy (TEM) and (c) OCT images of GVs from Halobacterium salinarum NRC-1 (Halo), Anabaena flos-aquae (Ana), and Bacillus megaterium (Mega). GVs were embedded in agarose hydrogel for OCT imaging. (d) Representative TEM images of Ana GVs before and after ultrasound treatment. (e) Diagram of the IPTG-inducible expression of ARG1 GVs inside E. coli. (f) Representative C-scans of colonies expressing GVs or green fluorescent proteins (GFPs), in the presence or absence of the inducer, and subjected to ultrasound or left intact. Adapted with permission from [40]. Copyright 2020 American Chemical Society.

Figure 3

Energy level diagram for a ground-state recovery pump–probe experiment. The pump radiation transfers the ground state population into the excited state. The probe radiation then measures the population transfer induced by the pump, which is manifested as a reduction in ground state absorption and an increase in excited state stimulated emission. Adapted with permission from [43]. Copyright 2006 Optical Society of America.

Figure 4

(a) Volumetric OCT image of tadpole. (b) Cross-sectional image in the x, z plane. (c) Cross-sectional image in the y, z plane. (d,e) are cross-sectional cuts along the yellow lines depicted in (b,c). (d) OCT image and (e) OCT image overlaid with the pump–probe signal from blood. Adapted with permission from [49]. Copyright 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 5

(a) Absorption spectra of the two states of PhyA. (b) The 750 nm OCT B-scan with PhyA in Pr state (1.5 mm wide × 2 mm deep); the OCT B-scan with PhyA in Pfr state appears very similar (not shown). (c) molecular contrast OCT differential scan. (d) Unwrapped MCOCT scan. (e) A-scans with PhyA in Pr and Pfr state extracted from the locations indicated by the arrows in b. (f) A-scans with PhyA in Pr and Pfr state extracted from the locations indicated in b. Adapted with permission from [9]. Copyright 2005 American Society for Photobiology.

Figure 6

(a) Setup of the interferometric CARS measurement system. DM, dichroic mirror; BS, beamsplitter; M, mirror; HPF, high pass filter; PH, pinhole; PMT photomultiplier tube; PC, personal computer. (b) CARS interferogram detected at the beamsplitter BS2 of the setup shown in (a). In the inset is shown a detail of the interference pattern and its fit by the real part of the degree of coherence function (open circles: experimental data; solid line: fit). L_c is the coherence length of the pulse. λ_AS is the wavelength of the CARS signal. Adapted with permission from [61]. Copyright 2004 Optical Society of America.

Figure 7

(a) SH-OCT image showing an area of 100 × 50 μm in the rat-tail tendon, where many cable-like, parallel oriented, and slightly wavy collagen fiber bundles (fascicles) can be visualized; (b) 60× polarization microscope image of the same sample (scale bar: 10 μm). Adapted with permission from [71]. Copyright 2005 AIP Publishing LLC.

Figure 8

(a) Experimental flowchart of MM-OCT imaging of in vivo MH-treated melanoma-bearing mice. (b) Simultaneously acquired in vivo OCT (left) and MM-OCT (right) depth-resolved cross-sectional images of melanoma tumor tissue with high overall and local cellularity, (c) low overall and local cellularity. Adapted with permission from [96]. Copyright 2021 The author(s).

Figure 9

(a) Transmission electron micrographs of GNR demonstrating unaltered morphology following surface functionalization. (b) OCT in vivo image of day 5 laser-induced choroidal neovascularization lesions with disrupted RPE (white arrowhead). (c) PTOCT of untargeted and targeted GNR in vivo. Average PTOCT signal density for each cohort, with error bars representing standard error of the mean. There is a significant increase in this signal associated with both untargeted and targeted GNR injections versus PBS control. * p ≤ 0.05; ** p ≤ 0.001. (d–f) Representative OCT B-scans of mice injected with PBS (b; n = 21 eyes), untargeted GNR (c; n = 14 eyes), and targeted GNR (d; n = 14 eyes), respectively, with lesion-associated photothermal signal overlaid in gold. Note the increased concentration of photothermal signal associated with passive accumulation of GNR in the lesions, and the greater increase associated with the injection of targeted GNR. Adapted with permission from [116]. Copyright 2019 The author(s).

Figure 10

Representative results of mapping the lipid distribution function and comparison with the corresponding histology sections. The first, second, and third rows show the results for lipid-rich plaque (a–c), fibrous plaque (d–f), and no lesion (g–i), respectively. Gray-scale OCT images (a,d,g) only provide morphological information, whereas the mapping results of the lipid distribution function derived from S-OCT (b,e,h) provide information about lipid composition, which corresponded well with ORO-stained histological sections (c,f,i). Scale bars, 500 µm. Adapted with permission from [128]. Copyright 2016 SPIE.

Figure 11

PS-OCT sagittal images of the zebrafish. (a–f) Intensity, degree of polarization uniformity, accumulative retardation, local retardation, accumulative optic axis, and local optic axis image, respectively. The iris (I), cornea (Co), adductor mandibulae (AM), opercle (O), gill (G), pectoral fin (PecF), scales (Sc), skin (Sk), trunk musculature (TM), swim bladder (SB) and vertebral column (VC) can be identified in (a). Scale bars are 500 μm. Adapted with permission from [143]. Copyright 2020 Optical Society of America.