7.2.2. Core B. Instrumentation and systems integrationCore Leader: Mike MandellaInvestigators: Thomas Huser, Gordon Kino, Pierre Khuri-Yakub, Craig Levin, Olav Solgaard, David Paik,Dave Piston, Kenneth SalisburyAim 1. Validation of new microscopy and establishment of standards for miniaturized intravitalmicroscopes for preclinical and clinical useA key aspect of this program is the availability of tools for validating the new optical imaging methods forspecific cancer applications. We have designed part of Core B specifically for quantitative comparisonsof performance with other imaging modalities or histopathology on biopsy specimens. Such validation isnecessary prior to any clinical trial designed to demonstrate the clinical efficacy of the optical methodsbeing developed in this program. Core B will perform pre-clinical evaluation and analyses of humansamples. Since in vivo optical measurements usually preserve tissue structure, verification of opticalsignatures should then be possible by correlation with measurements in vitro. Part of the validation willbe through sharing our instruments and reagents with other programs in the Network to get externalvalidation of our tools. We will compare and share the results from our studies on optical imagingmethods, contrast agents, and software with other Network investigators to develop consensus on robustmethods for validation in the target cancer applications.
Aim 2. integration of microscopy into wide-field fluorescence systems and co-registration of datawith ultrasoundThe dual-axes microscope provides high resolution images in living tissue up to 0.5 mm deep and withina field-of-view of about 0.5 mm diameter. Because of this limited field-of-view, it will be important toprovide context by spatially registering these micro-scale images to the larger anatomical data acquiredwith both, ultrasound and wide-field fluorescence, and to develop an integrated software platform forreal-time micro and macroscopic image processing. Wide-field fluorescence imaging can be obtained bycommercially available endoscopes such as the Olympus FQ260Z GIF gastrointestinal videoscope. Byinserting the dual-axes microscope into the provided instrument channel of such a fluorescenceendoscope, we can thereby obtain meaningful microscopic fluorescence images by letting themicroscope placement be guided to the best micro-imaging sites by assistance from the wide-fieldmacro-imaging system. In addition to using the instrument channel for microscopy, we also plan tomodify the wide-field fluorescence endoscope by installing a conformal ultrasound transducer imagingarray around the -12 mm outer diameter of the endoscope's tubular housing.The wide-field fluorescence images will allow mapping of the surface of the esophagus and the 3-Dultrasound images will provide information about the underlying tissue up to several millimeters deepbelow the same surface. We will develop algorithms for co-registration of these two different types ofimages, which will provide precise locations of the lesion sites for guiding the placement of the dual-axesmicroscope as it is extended towards the tissue through the instrument channel of the endoscope. These algorithms will be developed in stages, beginning with simple registration algorithms for displaying real-timeimages of the three different imaging modalities (microscopy, ultrasound, and wide-field fluorescence). More advanced algorithms will then be implemented as they are developed, which will have increasingfunctionality, such as the addition of real-time mosaicing with the dual-axes microscope and advanced methods for displaying the data. We will work towards achieving registration of thethree different types of images to an anatomical map in real-time anddisplayed in 3-D at their respective imaging depths. In this case, the widefieldfluorescence image data would be displayed at the surface, with microscopy data extending deeper, and finally with the ultrasound data displayed at the deepest depth.
Aim 3. Integrate ultrasound and optical systemsWe propose to integrate two ultrasound devices, one therapeutic and the other one diagnostic, on anendoscope that will be used in the esophagus. The therapeutic device will be integrated with the dualaxesconfocal microscope, which is introduced through the instrument channel of the endoscope. Thetherapeutic ultrasound device will be used to enhance delivery of drugs and biomarkers. The relativeposition of the microscope and the ultrasound therapeutic device will allow real-time monitoring of theultrasound enhanced delivery of targeted molecular probes and drugs. The diagnostic imaging devicewill be mounted on the outer surface of the endoscope tube and will provide a 360-degreecircumferential image. We propose to build a focused ultrasound transducer on the back side of theparabolic focusing mirror in the dual-axes confocal microscope. The back side of the mirror is a flatsurface, circular in shape with a 5-mm diameter and a 2-mm opening in the middle for illumination andcollection beams to pass through. A 2-mm diameter ultrasound transducer will be fabricated onto atransparent window substrate providing a transparent ultrasound transducer chip (Fig. 26) that alsoserves as an optical window. This transparent transducer fits into a 2-mm diameter cut-away section of acatadioptric focusing optic, which provides a parabolic mirror for focusing the dual beams, and a centralsolid immersion lens for coupling the scanning beam into the tissue. The acoustic focus is designed tocoincide with the optical focus of the microscope where the dual beam's axes cross each other. Duringimaging, this distance varies .between 0 to 0.3 mm away from the back side surface of the combinationultrasound chip/window. In this way, the ultrasound enhanced delivery process can be monitored usingthe microscope in real time. This transducer chip will be designed to launch a surface acoustic wave(SAW) on the surface that is in contact with the tissue and then take advantage of mode conversion tolongitudinal waves to obtain a focused ultrasound beam at the desired location. The waves willpropagate in the radial direction inwardly and outwardly. The acoustic energy will leak into the medium incontact at a predetermined angle (by the Snell's law). Due to the circular symmetry of the structure thewaves propagating longitudinally in the tissue will focus at the center in the middle of the field-of-view ofthe microscope. The circular symmetry and the discontinuity at the edges help to bounce the outwardlytraveling waves back toward the center to increase the efficiency of the transducer. There are differentways of exciting SAWs on a nonpiezoelectric material. We will build two different types: An interdigitaltransducer and an edge-bonded transducer.
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