Early detection of structural or functional changes in dysplastic epithelia may be crucial for improving long-term patient care. Recent work has explored myriad non-invasive or minimally invasive "optical biopsy" techniques for diagnosing early dysplasia, such as high-resolution microendoscopy, a method to resolve sub-cellular features of apical epithelia, as well as broadband sub-diffuse reflectance spectroscopy, a method that evaluates bulk health of a small volume of tissue. We present a multimodal fiber-based microendoscopy technique that combines highresolution microendoscopy, broadband (450-750 nm) sub-diffuse reflectance spectroscopy (sDRS) at two discrete source-detector separations (374 and 730 μm), and sub-diffuse reflectance intensity mapping (sDRIM) using a 635 nm laser. Spatial resolution, magnification, field-of-view, and sampling frequency were determined. Additionally, the ability of the sDRS modality to extract optical properties over a range of depths is reported. Following this, proof-of-concept experiments were performed on tissuesimulating phantoms made with poly(dimethysiloxane) as a substrate material with cultured MDA-MB-468 cells. Then, all modalities were demonstrated on a human melanocytic nevus from a healthy volunteer and on resected colonic tissue from a murine model. Qualitative in vivo image data is correlated with reduced scattering and absorption coefficients. References and links 1. P. Sharma and E. Montgomery, "Gastrointestinal dysplasia," Pathology 45(3), 273-285 (2013). 2. P. M. Speight, "Update on oral epithelial dysplasia and progression to cancer," Head Neck Pathol. 1(1), 61-66 (2007). 3. Y. Zhang, "Epidemiology of esophageal cancer," World J. Gastroenterol. 19(34), 5598-5606 (2013). 4. N. Harpaz and A. D. Polydorides, "Colorectal dysplasia in chronic inflammatory bowel disease: pathology, clinical implications, and pathogenesis," Arch. Pathol. Lab. Med. 134(6), 876-895 (2010). 5. M. Ponz de Leon and C. Di Gregorio, "Pathology of colorectal cancer," Dig. Liver Dis. 33(4), 372-388 (2001). 6. M. J. Arends, C. H. Buckley, and M. Wells, "Aetiology, pathogenesis, and pathology of cervical neoplasia," J.Clin. Pathol. 51(2), 96-103 (1998 170-173 (2005). 11. M. Gu, H. Bao, and H. Kang, "Fibre-optical microendoscopy," J. Microsc. 254(1), 13-18 (2014) properties of pigmented skin lesions including melanoma using oblique incidence diffuse reflectance spectrometry," J.
Intraepithelial dysplasia of the oral mucosa typically originates in the proliferative cell layer at the basement membrane and extends to the upper epithelial layers as the disease progresses. Detection of malignancies typically occurs upon visual inspection by non-specialists at a late-stage. In this manuscript, we validate a quantitative hybrid imaging and spectroscopy microendoscope to monitor dysplastic progression within the oral cavity microenvironment in a phantom and pre-clinical study. We use an empirical model to quantify optical properties and sampling depth from sub-diffuse reflectance spectra (450–750 nm) at two source-detector separations (374 and 730 μm). Average errors in recovering reduced scattering (5–26 cm−1) and absorption coefficients (0–10 cm−1) in hemoglobin-based phantoms were approximately 2% and 6%, respectively. Next, a 300 μm-thick phantom tumor model was used to validate the probe’s ability to monitor progression of a proliferating optical heterogeneity. Finally, the technique was demonstrated on 13 healthy volunteers and volume-averaged optical coefficients, scattering exponent, hemoglobin concentration, oxygen saturation, and sampling depth are presented alongside a high-resolution microendoscopy image of oral mucosa from one volunteer. This multimodal microendoscopy approach encompasses both structural and spectroscopic reporters of perfusion within the tissue microenvironment and can potentially be used to monitor tumor response to therapy.
Background Colorectal cancer remains the second leading cause of cancer death in the United States, and increased risk in patients with ulcerative colitis (a subset of inflammatory bowel disease) has motivated studies into early markers of dysplasia. The development of clinically translatable multiphoton imaging systems has allowed for the potential of in vivo label-free imaging of epithelial crypt structures via autofluorescence and/or second harmonic generation (SHG). SHG has been used to investigate collagen structures in various types of cancer, though the changes that colorectal epithelial collagen structures undergo during tumor development, specifically colitis-associated tumors, have not been fully investigated. Methods This study used two murine models, using A/J mice, one for spontaneous carcinoma and one for colitis-associated carcinoma, to investigate and quantify SHG image features that could potentially inform future study designs of endoscopic multiphoton imaging systems. The spontaneous tumor model comprised a series of six weekly injections of azoxymethane (AOM model). The colitis-associated tumor model comprised a single injection of AOM, followed by cycles of drinking water with dissolved dextran sodium sulfate salt (AOM-DSS model). SHG images of freshly resected murine colon were acquired with a multiphoton imaging system, and image features, such as crypt size, shape and distribution, were quantified using an automated algorithm. Results The comparison of quantified features of crypt morphology demonstrated the ability of our quantitative image feature algorithms to detect differences between spontaneous (AOM model) and colitis-associated (AOM-DSS model) murine colorectal tissue specimens. There were statistically significant differences in the mean and standard deviation of nearest neighbor (distance between crypts) and circularity between the Control cohort, AOM and AOM-DSS cohorts. We also saw significance between AOM and AOM-DSS cohorts when calculating nearest neighbor in images acquired at fixed depths. Conclusion The results provide insight into the ability of SHG imaging to yield relevant data about the crypt microstructure in colorectal epithelium, specifically the potential to distinguish between spontaneous and colitis-associated murine models using quantification of crypt shape and distribution, informing future design of translational multiphoton imaging systems and protocols. Electronic supplementary material The online version of this article (10.1186/s12885-019-5639-8) contains supplementary material, which is available to authorized users.
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