Intravital multiphoton microscopy has provided powerful mechanistic insights into health and disease, and has become a common instrument in the modern biological laboratory. The requisite high numerical aperture and exogenous contrast agents that enable multiphoton microscopy, however, limit ability to investigate substantial tissue volumes or to probe dynamic changes repeatedly over prolonged periods. Here, we introduce optical frequency domain imaging (OFDI) as an intravital microscopy that circumvents the technical limitations of multiphoton microscopy and, as a result, provides unprecedented access to previously unexplored, critically important aspects of tissue biology. Using novel OFDI-based approaches and entirely intrinsic mechanisms of contrast, we present rapid and repeated measurements of tumor angiogenesis, lymphangiogenesis, tissue viability and both vascular and cellular responses to therapy, thereby demonstrating the potential of OFDI to facilitate the exploration of physiological and pathological processes and the evaluation of treatment strategies. †Authors to whom correspondence should be addressed: R.K.J (jain@steele.mgh.harvard.edu) or B.E.B (bouma@helix.mgh.harvard.edu). * Authors contributed equally to this work Author Contributions BJV developed OFDI technology, designed and performed most of the experiments, developed methodology, headed all data analysis and wrote the manuscript. RML designed and performed most of the experiments, developed methodology, headed all data analysis and wrote the manuscript. JAT contributed to vascular tracing of OFDI data. TPP performed lymphangiography experiments and contributed to data analysis and manuscript preparation. LAB performed VEGF-R2 blockade in vivo experiments. TS developed and performed fractal characterization and contributed to manuscript preparation. LLM contributed to vascular data analysis. GJT contributed to OFDI technology development. DF contributed to experimental design and manuscript preparation. RKJ and BEB contributed to the design of experiments, preparation of the manuscript, and supervised the project.
Comprehensive volumetric microscopy of epithelial, mucosal and endothelial tissues in living human patients would have a profound impact in medicine by enabling diagnostic imaging at the cellular level over large surface areas. Considering the vast area of these tissues with respect to the desired sampling interval, achieving this goal requires rapid sampling. Although noninvasive diagnostic technologies are preferred, many applications could be served by minimally invasive instruments capable of accessing remote locations within the body. We have developed a fiber-optic imaging technique termed optical frequency-domain imaging (OFDI) that satisfies these requirements by rapidly acquiring high-resolution, cross-sectional images through flexible, narrow-diameter catheters. Using a prototype system, we show comprehensive microscopy of esophageal mucosa and of coronary arteries in vivo. Our pilot study results suggest that this technology may be a useful clinical tool for comprehensive diagnostic imaging for epithelial disease and for evaluating coronary pathology and iatrogenic effects.
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