This CAREER project will establish the first dual-comb photoacoustic microscopy (DC-PAM) for deep-tissue high-speed spectro-imaging. After decades of development, laser microscopy now provides unrivaled spatio-temporal resolution and optical biopsy capability, where tissue histopathology is directly examined in vivo without surgical procedure. However, microscopic depiction of cellular structures deep within human tissues remains a grand challenge. Laser microscopy is therefore currently limited to superficial imaging, with compromised capability to provide comprehensive assessment of human tissues such as cerebral cortex, endothelium, and articular cartilage. By establishing a new microscopy technique, this project will enable deep tissue imaging capabilities that facilitate early disease diagnosis and management. The first biomedical application of DC-PAM is to target the early diagnosis of osteoarthritis, a major public health concern and economic burden costing $136.8 billion annually. Transformative imaging capability of DC-PAM is also applicable to other biomedical fields, including surgical guidance, cancer assessment, transcranial neuroimaging and stimulation. Moreover, innovative photonic and acoustic technologies developed in this project will provide the scientific community new tools for addressing challenges in atmospheric sensing and quantum photonics. This project is also aimed at cultivating STEM students’ passion in applying photonic technology to address real-world biomedical problems. The goal will be achieved through several fully integrated educational and outreach activities with programs across the campus, the Colorado Photonics Industry Association, and The Optical Society. The specific education objectives are to: 1) engage high-school students with summer research experience through the CU Science Discovery program; 2) provide interdisciplinary research opportunities to undergraduate students through the Discovery Learning Apprenticeship program; 3) develop a new lecture/lab course to engage first-year graduate students with state-of-the-art bioimaging and biosensing technologies; and 4) host a community college faculty every summer for collaborative research experiences and joint development of educational DC-PAM modules through the NSF funded ARETe program.
The research aims to combine theory and technology of coherent light source, device microfabrication, and bioinstrumentation to establish the first DC-PAM for deep-tissue musculoskeletal spectro-imaging. Photoacoustic microscopy (PAM) is an emerging deep-tissue microscopy technique that enables in vivo imaging with molecular absorption contrast and micrometer-scale resolution at millimeter-scale depth. Dual-comb spectroscopy (DCS) is a growing high-speed spectroscopic method that offers parallel detection of multiple molecular absorption lines with self-calibrated precision and high sensitivity in the absence of any mechanical moving part. DC-PAM will uniquely combine the advantages of PAM in imaging depth and DCS in imaging speed in a way that the techniques also compensate for each other’s drawbacks. Further, optical illumination wavelength will be extended to the recently identified fourth near-infrared window to fundamentally reduce the multiple light scattering and use the molecular specificity of lipid, collagen, and water. Finally, a super-resolution photoacoustically guided wavefront shaping (PAWS) method will be devised without employing any nonlinear effect, pushing the DC-PAM imaging depth well beyond optical diffusion limit, while maintaining cellular resolution. Specific research objectives are to: 1) demonstrate a dual-comb light source architecture and undertake a full theoretical analysis and experimental characterization; 2) develop a dual-comb ultrasonic detect system and establish a super-resolution PAWS method without nonlinearity; and 3) validate the DC-PAM through imaging studies on bovine patella cartilage tissues with naturally occurring osteoarthritis.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
