Ultrahigh-Resolution Quantitative Optical Coherence Elastography of the Tumor Microenvironment In Vivo

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The understanding of cancer has evolved rapidly over the last decade. One of the key findings is that altered mechanical properties is not just a symptom of tumors, but can trigger the actual onset of malignancy, and promote tumor progression. The clinical impact of cancer mechanics research, however, is currently hampered by a lack of methods to image the mechanical properties of the tumor microenvironment with micrometer resolution in vivo. Consequently, research studies on the role of extracellular matrix (ECM) mechanics in carcinogenesis have been restricted to in vitro experiments or ex vivo measurements of tissue biomechanics. This proposal will develop and demonstrate a new imaging platform for time-lapse in vivo imaging studies of the mechanical properties of the tumor microenvironment. Acoustic radiation force (ARF) will be utilized for highly localized ‘palpation’, and ultra-precise phase-sensitive optical coherence tomography (OCT) will be employed to detect the resulting nanometer-to-micrometer scale displacements. The main hypothesis, based on a recent paper by our group, is that the use of highly localized mechanical excitation (via ‘palpation’ with tightly-focused ultrasound), combined with mechanical excitation at higher frequencies in the kilohertz regime, can be leveraged to overcome the resolution limitations of shear-wave-based approaches, and thereby enable the highest-resolution OCE imaging of the complex shear modulus, i.e. both shear storage and loss modulus. A further hypothesis is that implementation of our approach for an epi-illumination imaging geometry will enable the dynamic variations in local mechanical properties during tumor development in vivo to be quantified. Specific Aim 1 will demonstrate our approach for ultrahigh-resolution ARF-OCE that combines quantitative shear wave propagation methods with ultrahigh-resolution axial strain imaging (this utilizes an imaging scheme we have demonstrated that detects ARF-induced displacements at the same location of a tightly-focused ultrasound ‘palpation’ spot). Our ultrahigh-resolution quantitative ARF-OCE approach and a novel epi-illumination imaging setup suitable for in vivo ARF-OCE studies will be validated in side-by-side and tumor mimicking phantoms by comparison to AFM imaging of mechanical properties over the same excitation frequency range. Specific Aim 2 will apply our novel ARF-OCE system and reconstruction methods validated in Aim 1 to perform in vivo imaging of the tumor microenvironment. We will demonstrate, for the first time, longitudinal OCE imaging of the shear storage and loss moduli of the tumor microenvironment in vivo. These quantitative OCE images will be correlated to gold-standard histological analysis and second-harmonic generation (SHG) imaging of resected tumor tissues. We expect that our new approach for ultrahigh-resolution OCE will enable the burgeoning field of cancer mechanobiology to transition towards, and emphasize in vivo imaging studies of ECM mechanics. Additionally, the clinical compatibility of our noninvasive and label-free imaging platform will greatly enhance future clinical translation of cancer mechanobiology research, and broadly impact other areas of mechanobiology.