Physical Sciences Inc. (PSI) proposes to develop a handheld two-photon microscopy (TPM) probe that will enable in vivo diagnosis and screening of various diseases, including cancers. This novel, clinically usable TPM instrument will provide three-dimensional (3-D) sub-micron resolution images of tissue pathology in situ. The images generated based on the two-photon excitation signals of intrinsic bio-molecules, such as the two-photon excited fluorescence (TPEF) of endogenous fluorophores and the second-harmonic generation (SHG) of collagen, will render important morphological and molecular information specific to various pathologies. Noninvasive optical biopsy based on two-photon microscopy is considered as the next-generation technology for disease diagnosis and has already been investigated in many pre-clinical studies. However, a suitable clinical TPM instrument has not yet been demonstrated, which is largely due to the technical and cost barriers in developing such a sought-after system. These include difficulty in transmitting high-power broadband femtosecond pulses from the bulky laser to a hand-held probe through a flexible fiber cord; challenges in miniaturizing the imaging probe with no sacrifice of imaging performance; and the high cost of the ultrafast laser source needed for efficient excitation of the nonlinear optical processes. Therefore, this R&D program directly addresses these barriers to widespread clinical use of TPM for noninvasive pathology. A laboratory prototype will be developed in the Phase I to demonstrate feasibility, while further optimization, advanced engineering and clinical testing will be performed in Phase II. Innovative technologies, including the development of a specialty fiber module for delivery of high-power ultrashort pulses and generation of a coherent supercontinuum (SC) based on the fiber-delivered laser pulses, as well as novel technological approaches for building a compact light-weight imaging probe, are being proposed. This will be possible by leveraging the expertise of a multidisciplinary team of investigators from PSI, with a proven track record on developing the next generation clinical devices, a leading research group from University of Illinois at Urbana-Champaign, and experienced clinical researchers and pathologists from Memorial Sloan Kettering Cancer Center.
The purpose of this proposed research is to develop a clinical two-photon microscopy (TPM) imager. The proposed instrument will include a handheld imaging probe that will be demonstrated during the Phase I program. This instrument will enable crucial and extensive clinical investigations of the TPM based ?optical biopsy? method for noninvasive and real-time diagnosis of human diseases, such as skin melanoma and oral cancer during the second phase of development. Successful completion of the TPM imager development and application will eventually lead to a new ?gold standard? for biopsy and histopathological analysis.