Image Deeper with Synthetic Waves: A Novel Non-Invasive Optical Approach for Skin Lesion Assessment at Multiple Scales - ABSTRACT Optical imaging techniques have revolutionized medical care due to their high sensitivity, safety, affordability, and ability to assess both structure and function in accessible tissues (e.g., vascular intima, oral cavity epithelium) and transparent organs (e.g., the eye). Despite significant advances over the past decades, imaging deep clinically relevant structures within highly scattering tissue remains a challenge. These limitations are particularly evident in imaging of skin cancer—the most prevalent malignancy worldwide. Current imaging systems are typically limited to very narrow specifications, restricting their adaptability to image a wide range of skin lesions at different depths. Optical methods using visible to near infrared wavelengths (such as confocal microscopy or optical coherence tomography) offer superior contrast and resolution at shallow tissue depths. However, their short wavelengths (<1.5μm) result in high scattering, making them inadequate for critical “deep” applications such as assessing tumor invasion and treatment response. Acoustic “long wavelength” approaches like ultrasound imaging provide an alternative to image deeper layers, although at lower resolution. Moreover, the physical properties of the acoustic wave typically yield insufficient contrast for effective skin cancer imaging. Similarly, hybrid approaches such as photoacoustic imaging primarily only detect absorption changes, limiting tumor visualization to unreliable vascular alterations, melanin presence, or exogenous contrast agent uptake. To overcome these limitations, we propose the novel Synthetic Wavelength Imaging (SWI) to visualize non- melanoma skin cancers (NMSC) at a wide range of depth. By mixing two captured optical fields, SWI generates a long synthetic beat wave carried by optical waves. This long synthetic wave makes the approach robust to scattering while preserving the high contrast of the optical carrier wavelengths, enabling high-resolution imaging of small structures within the synthetic wave’s near field. With SWI we aim to break the conventional resolution- depth-contrast tradeoff. Our system will enable the fast (a few ms) measurements of subtle tissue changes in NMSC at significantly greater depths than existing optical imaging methods while offering high resolution and greater contrast than long-wave or hybrid approaches. This advancement will facilitate the first clinical demonstration of SWI in the critical, unmet need of NMSC assessment. Furthermore, SWI’s wide tunability enables future multi-scale imaging for applications such as brain vasculature or tumor assessment. Our objective is to develop the first clinical implementation of SWI and evaluate its performance for NMSC characterization. We hypothesize that our non-invasive imaging system will overcome existing limitations, addressing the pressing need for improved skin cancer imaging across tumors of varying sizes and depths during therapeutic interventions and surveillance. To test this hypothesis, we will pursue three specific aims: 1) technology development, 2) imaging models of normal skin and NMSC, and 3) human pilot testing.
