KEYWORDS: Fluorescence imaging, Modulation, In vivo imaging, Image resolution, Fluorescence, Contrast agents, Tumors, Near infrared, Quantum efficiency, Cancer detection
In vivo tumor imaging and delineating tumor margins serves a critical role in early detection and treatment of cancer. Together with our industrial collaborators, InnoSense LLC (Torrance, CA), we previously have developed ThermoDots™, temperature-responsive micelles that encapsulate an FDA approved near infrared (NIR) imaging agent, indocyanine green (ICG). ThermoDots enhances the signal and enable high resolution fluorescence imaging capability. In this work, they are conjugated with PSMA antibodies for prostate cancer imaging.
High scattering in biological tissues severely degrades the spatial resolution of optical fluorescence imaging in thick tissue. As one of the most sensitive in vivo molecular imaging modalities, Fluorescence Tomography plays an essential role in preclinical studies. To overcome the limitations of FT, we introduced a novel method termed, temperature modulated fluorescence tomography (TMFT). TMFT is based on two key elements: 1) temperature sensitive fluorescent agent (ThermoDots) and 2) high intensity focused ultrasound (HIFU). TMFT localizes the position of the fluorescent ThermoDots by scanning a HIFU beam across the tissue while monitoring the variation in the measured fluorescence signals. Actually, a binary mask is built by monitoring the sudden jumps in the fluorescence signal corresponding to the HIFU scan over a position containing ThermoDots. This binary map is used as functional a priori during the FT image reconstruction process. TMFT not only allowed us to resolve ThermoDots with high spatial resolution (~1.3 mm), deep in tissue (~ 60 mm) but with high quantitative accuracy as well (< 3% error). In this paper, we present the latest prototype of TMFT. Here, the fluorescence signals are acquired using a CCD camera, which increases the sensitivity of the system compared to the previous fiber-based system.
Optical imaging has long been hindered by the high absorption and scattering of light in biological tissue. This makes it difficult to probe beyond a few millimeters beneath the surface without sacrificing image resolution and quantitative accuracy. Strong scattering and the inherent nature of the inverse problem makes fluorescence diffuse optical tomography (FT) extremely challenging. To this end, multi-modality techniques that combine anatomical imaging with the functional optical information have been used to improve the resolution and accuracy of FT. Previously, we have reported on the feasibility of a new imaging method, "Thermal Outlining using Focused Ultrasound" (TOFU), which combines the sensitivity of FT with the resolution of focused ultrasound using temperature reversible fluorescent probes. In this method, the position of the temperature reversible fluorescent probes is localized by an increase in fluorescent signal when the hot spot of the focused ultrasound beam is scanned over the medium. This a priori information is then utilized to guide and constrain conventional reconstruction algorithm to recover the position and concentration of the probes more accurately. The small size of the focal spot (~1.4 mm) up to a depth of 6 cm, allows imaging the distribution of these temperature sensitive agents with not only high spatial resolution but also high quantitative accuracy in deep tissue. In this work, the performance of the system will be evaluated using simulation and phantoms to investigate the dependence that size of the fluorescent distribution has on the TOFU system performance.
Fluorescence tomography is a non invasive, non ionizing imaging technique able to provide a 3D distribution of fluorescent
agents within thick highly scattering mediums, using low cost instrumentation. However, its low spatial resolution due to
undetermined and ill-posed nature of its inverse problem has delayed its integration into the clinical settings. In addition,
the quality of the fluorescence tomography images is degraded due to the excitation light leakage contaminating the
fluorescence measurements. This excitation light leakage results from the excitation photons that cannot be blocked by the
fluorescence filters. In this contribution, we present a new method to remove this excitation light leakage noise based on
the use of a temperature sensitive fluorescence agents. By performing different sets of measurements using this temperature
sensitive agents at multiple temperatures, the excitation light leakage can be estimated and then removed from the
measured fluorescence signals . The results obtained using this technique demonstrate its potential for use in in-vivo small
animal imaging.
Fluorescent tomography has been hindered by poor tissue penetration and weak signal which results in poor spatial resolution and quantification accuracy. Recently, it has been reported that activatable temperature responsive fluorescent probes which respond to focused ultrasound heating can improve the resolution and quantification of fluorescent tomography in deep tissue. This has lead to a new imaging modality, "Temperature-modulated fluorescent tomography." This technique relies on activatable thermo-sensitive fluorescent nanocapsules for whose fluorescence quantum efficiency is temperature dependent. Within a 4-5° C temperature range, the fluorescent signal increase more than 10-fold. In this molecular probe, Indocyanine Green (ICG) is encapsulated inside the core of a thermo-reversible pluronic micelle. Here we show the fluorescence response and temperature range of the nanocapsules which have been optimized for a higher temperature range to be used for in vivo animal imaging. We report on the feasibility of these temperature-sensitive reversible nanocapsules for in vivo applications by studying the pharmacokinetics in a subcutaneous mouse tumor model in vivo.
To overcome the strong scattering in biological tissue that has long afflicted fluorescence tomography, we have
developed a novel technique, "temperature-modulated fluorescence tomography" (TM-FT) to combine the sensitivity of
fluorescence imaging with focused ultrasound resolution. TM-FT relies on two key elements: temperature sensitive ICG
loaded pluronic nanocapsules we termed ThermoDots and high intensity focused ultrasound (HIFU). TM-FT localizes
the position of the fluorescent ThermoDots by irradiating and scanning a HIFU beam across the tissue while
conventional fluorescence tomography measurements are acquired. The HIFU beam produces a local hot spot, in which
the temperature suddenly increases changing the quantum efficiency of the ThermoDots. The small size of the focal spot
(~1 mm) up to a depth of 6 cm, allows imaging the distribution of these temperature sensitive agents with not only high
spatial resolution but also high quantitative accuracy in deep tissue using a proper image reconstruction algorithm.
Previously we have demonstrated this technique with a phantom study with ThermoDots sensitive in the 20-25°C range.
We recently optimized the ThermoDots for physiological temperatures. In this work, we will demonstrate a new HIFU
scanning method which is optimized for in vivo studies. The performance of the system is tested using a phantom that
resembles a small animal bearing a small tumor targeted by ThermoDots.
KEYWORDS: Luminescence, Fluorescence tomography, Ultrasonography, Modulation, Tissues, In vivo imaging, Image resolution, Signal detection, Temperature metrology, Transducers
Low spatial resolution due to strong tissue scattering is one of the main barriers that prevent the wide-spread use of fluorescence tomography. To overcome this limitation, we previously demonstrated a new technique, temperature modulated fluorescence tomography (TM-FT), which relies on key elements: temperature sensitive ICG loaded pluronic nanocapsules and high intensity focused ultrasound (HIFU), to combine the sensitivity of fluorescence imaging with focused ultrasound resolution. While conventional fluorescence tomography measurements are acquired, the tissue is scanned by a HIFU beam and irradiated to produce a local hot spot, in which the temperature increases nearly 5K. The fluorescence emission signal measured by the optical detectors varies drastically when the hot spot overlays onto the location of the temperature dependent nanocapsules. The small size of the focal spot (~1.4 mm) up to a depth of 6 cm, allows imaging the distribution of these temperature sensitive agents with not only high spatial resolution but also high quantitative accuracy in deep tissue using a proper image reconstruction algorithm. Previously we have demonstrated this technique with a phantom study with nanocapsules sensitive to 20-25°C range. In this work, we will show the first nanocapsules optimized for in vivo animal imaging.
Since the TWA flight 800 accident in July 1996, significant emphasis has been placed on fuel tank safety.
The Federal Aviation Administration (FAA) has focused research to support two primary methods of fuel tank
protection - ground-based and on-board - both involving fuel tank inerting. Ground-based fuel tank inerting
involves some combination of fuel scrubbing and ullage washing with Nitrogen Enriched Air (NEA) while the
airplane is on the ground (applicable to all or most operating transport airplanes). On-board fuel tank inerting
involves ullage washing with OBIGGS (on-board inert gas generating system), a system that generates NEA
during aircraft operations. An OBIGGS generally encompasses an air separation module (ASM) to generate
NEA, a compressor, storage tanks, and a distribution system. Essential to the utilization of OBIGGS is an
oxygen sensor that can operate inside the aircraft's ullage and assess the effectiveness of the inerting
systems. OBIGGS can function economically by precisely knowing when to start and when to stop. Toward
achieving these goals, InnoSense LLC is developing an all-optical fuel tank ullage sensor (FTUS) prototype
for detecting oxygen in the ullage of an aircraft fuel tank in flight conditions. Data would be presented to show
response time and wide dynamic range of the sensor in simulated flight conditions and fuel tank
environment.
Significant emphasis has been placed on fuel tank safety since the TWA flight 800 accident in July 1996. Upon investigation the National Transportation Safety Board (NTSB) determined that the probable cause of the accident was an explosion of the center wing tank (CWT), resulting from ignition of the flammable fuel/air mixture in the tank. The Federal Aviation Administration (FAA) has focused research to support two primary methods of fuel tank protection -- ground-based and on-board -- both involving fuel tank
inerting. Ground-based fuel tank inerting involves some combination of fuel scrubbing and ullage washing with Nitrogen Enriched Air (NEA) while the airplane is on the ground (applicable to all or most operating transport airplanes). On-board fuel tank inerting involves ullage washing with OBIGGS (on-board inert gas generating system), a system that generates NEA during aircraft operations. An OBIGGS generally encompasses an air separation module (ASM) to generate NEA, a compressor, storage tanks, and a distribution system. Essential to the utilization of OBIGGS is an oxygen sensor that can operate inside the aircraft's ullage and assess the effectiveness of the inerting systems. OBIGGS can function economically by precisely knowing when to start and when to stop. Toward achieving these goals, InnoSense LLC is developing an all-optical fuel tank ullage sensor (FTUS) prototype for detecting oxygen in the ullage of an
aircraft fuel tank in flight conditions. Data would be presented to show response time and wide dynamic range of the sensor in simulated flight conditions and fuel tank environment.
Access to the requested content is limited to institutions that have purchased or subscribe to SPIE eBooks.
You are receiving this notice because your organization may not have SPIE eBooks access.*
*Shibboleth/Open Athens users─please
sign in
to access your institution's subscriptions.
To obtain this item, you may purchase the complete book in print or electronic format on
SPIE.org.
INSTITUTIONAL Select your institution to access the SPIE Digital Library.
PERSONAL Sign in with your SPIE account to access your personal subscriptions or to use specific features such as save to my library, sign up for alerts, save searches, etc.