More than a decade into the development of gold nanoparticles for cancer therapies, with multiple clinical trials underway, ongoing pre-clinical research continues towards better understanding in vivo interactions with the goal of treatment optimization through improved best practices. In an effort to collect information for healthcare providers, enabling informed decisions in a relevant time frame, instrumentation for real-time plasma concentration (multi-wavelength pulse photometry) and protocols for rapid elemental analysis (energy dispersive X-Ray fluorescence) of biopsied tumor tissue have been developed in a murine model. An initial analysis, designed to demonstrate the robust nature and utility of the techniques, revealed that area under the bioavailability curve (AUC) alone does not currently inform tumor accumulation with a high degree of accuracy (R2=0.32), This finding suggests that the control of additional experimental and physiological variables may yield more predictable tumor accumulation. Subject core temperature are blood pressure were monitored, but did not demonstrate clear trends. An effort to modulate AUC has produced an adjuvant therapy which is employed to enhance circulation parameters, including the AUC, of nanorods and gold nanoshells. Preliminary studies demonstrated a greater than 300% increase in average AUC through the use of a reticuloendothelial blockade agent versus control groups. Given a better understanding of the relative importance of the physiological factors which impact rates of tumor accumulation, a proposed set of experimental best practices is presented.
This study adapted AuroLase® Therapy, previously reported for the treatment of brain tumors, to the treatment of
prostate disease by 1) using normal canine prostate in vivo, directly injected with a solution of nanoparticles as a
proxy for prostate tumor and, 2) developing an appropriate laser dosimetry for prostate which is which is subablative
in native prostate while simultaneously producing photothermal coagulation in prostate tissue containing
therapeutic nanoshells.
Healthy, mixed-breed hound dogs were given surgical laparotomies during which nanoshells were injected directly
into one or both prostate hemispheres. Laser energy was delivered percutaneously to the parenchyma of the prostate
along 1-5 longitudinal tracts via a liquid-cooled optical fiber catheter terminated with a 1-cm isotropic diffuser after
which the incision was closed and sutured using standard surgical techniques. The photothermal lesions were
permitted to resolve for up to 8 days, after which each animal was euthanized, necropsied, and the prostate taken for
histopathological analysis.
We developed a laser dosimetry which is sub- to marginally ablative in native prostate and simultaneously ablative
of prostate tissue containing nanoshells which would indicate a viable means of treating tumors of the prostate
which are known from other studies to accumulate nanoshells. Secondly, we determined that multiple laser
treatments of nanoshell-containing prostate tissue could be accomplished while sparing the urethra and prostate
capsule thermal damage. Finally, we determined that the extent of damage zone radii correlate positively with
nanoshell concentration, and negatively to the length of time between nanoshell injection and laser treatment.
Researchers employ increasingly complex sub-micron particles for oncological applications to deliver bioactive
therapeutic or imaging compounds to known and unknown in vivo tumor targets. These particles are often
manufactured using a vast array of compounds and techniques resulting in a complex architecture, which can be
quantified ex vivo by conventional metrology and chemical assays. In practice however, experimental homogeneity
using nanoparticles can be difficult to achieve. While several imaging techniques have been previously shown to
follow the accumulation of nanoparticles into tumor targets, a more rapid sensor that provides a quantifiable estimate
of dose delivery and short-term systemic response could increase the clinical efficacy and greatly reduce the
variability of these treatments. We have developed an optical device, the pulse photometer, that when placed on an
accessible location will estimate the vascular concentration of near-infrared extinguishing nanoparticles in murine
subjects. Using a technique called multi-wavelength photoplethysmography, the same technique used in pulse
oximetry, our pulse photometer requires no baseline for each estimate allowing it to be taken on and off of the
subject several times during experiments employing long circulating nanoparticles. We present a formal study of
our prototype instrument in which circulation half-life and nanoparticle concentration of gold nanorods is
determined in murine subjects with the aid of light anesthesia. In this study, we show good agreement between
vascular nanorod concentrations (given in optical density) as determined by our device and with UV-VIS
spectrophotometry using low volume blood samples.
There is an urgent clinical need to monitor the intravenous delivery and bioavailability of circulating nanoparticles used in cancer therapy. This work presents the use of photoplethysmography for the noninvasive real-time estimation of vascular gold nanoshell concentration in a murine subject. We develop a pulse photometer capable of accurately measuring the photoplethysmogram in mice and determining the ratio of pulsatile changes in optical extinction between 805 and 940 nm, commonly referred to as R. These wavelengths are selected to correspond to the extinction properties of gold nanoshells. Six 30-s measurements (5 min, 2, 4, 6, 8, 10 h) are taken under light anesthesia to observe the change in R as the nanoparticles clear from the circulation. Our model describes the linear fit (R2=0.85) between R and the concentration of nanoparticles measured via ex vivo spectrophotometric and instrumental neutron activation analysis. This demonstrates the utility of this technique in support of clinical nanoparticle therapies.
Gold nanoshells (GNS) are a new class of nanoparticles that can be optically tuned to scatter or absorb light from the near-ultraviolet to near-infrared (NIR) region by varying the core (dielectric silica)/shell (gold) ratio. In addition to spectral tunability, GNS are inert and bioconjugatable, making them potential labels for in vivo imaging and therapy of tumors. We report the use of GNS as exogenous contrast agents for enhanced visualization of tumors using narrow-band imaging (NBI). NBI takes advantage of the strong NIR absorption of GNS to distinguish between blood and nanoshells in the tumor by imaging in narrow wavelength bands in the visible and NIR, respectively. Using tissue-simulating phantoms, we determined the optimum wavelengths to enhance contrast between blood and GNS. We then used the optimum wavelengths for ex vivo imaging of tumors extracted from human colon cancer xenograft bearing mice injected with GNS. Systemically delivered GNS accumulated passively in tumor xenografts by the enhanced permeability and retention (EPR) effect. Ex vivo NBI of tumor xenografts demonstrated heterogeneous distribution of GNS with a clear distinction from the tumor vasculature. The results of this study demonstrate the feasibility of using GNS as contrast agents to visualize tumors using NBI.
Gold nanoshells (GNS) are a new class of nanoparticles that can be optically tuned to scatter or absorb light from the
near-ultraviolet to near-infrared (NIR) region by varying the core (dielectric silica) /shell (gold) ratio. In addition to
spectral tunability, GNS are inert and bioconjugatable making them potential labels for in vivo imaging and therapy of
tumors. We report the use of GNS as exogenous contrast agents for enhanced visualization of tumors using narrow band
imaging (NBI). NBI takes advantage of the strong NIR absorption of GNS to distinguish between blood and nanoshells
in the tumor by imaging in narrow wavelength bands in the visible and NIR, respectively. Using tissue-simulating
phantoms, we determined the optimum wavelengths to enhance contrast between blood and GNS. We then used the
optimum wavelengths for ex-vivo imaging of tumors extracted from human colon cancer xenograft bearing mice injected
with GNS. Systemically delivered GNS accumulated passively in tumor xenografts by the enhanced permeability and
retention (EPR) effect. Ex-vivo NBI of tumor xenografts demonstrated tumor specific heterogeneous distribution of GNS
with a clear distinction from the tumor vasculature. The results of this study demonstrate the feasibility of using GNS as
contrast agents to visualize tumors using NBI.
We report on a pilot study demonstrating a proof of concept for the passive delivery of nanoshells to an orthotopic tumor
where they induce a local, confined therapeutic response distinct from that of normal brain resulting in the photo-thermal
ablation of canine Transmissible Venereal Tumor (cTVT) in a canine brain model. cTVT fragments grown in SCID
mice were successfully inoculated in the parietal lobe of immuno-suppressed, mixed-breed hound dogs. A single dose of
near-infrared absorbing, 150 nm nanoshells was infused intravenously and allowed time to passively accumulate in the
intracranial tumors which served as a proxy for an orthotopic brain metastasis. The nanoshells accumulated within the
intracranial cTVT suggesting that its neo-vasculature represented an interruption of the normal blood-brain barrier.
Tumors were thermally ablated by percutaneous, optical fiber-delivered, near-infrared radiation using a 3.5 W average,
3-minute laser dose at 808 nm that selectively elevated the temperature of tumor tissue to 65.8±4.1ºC. Identical laser
doses applied to normal white and gray matter on the contralateral side of the brain yielded sub-lethal temperatures of
48.6±1.1ºC. The laser dose was designed to minimize thermal damage to normal brain tissue in the absence of
nanoshells and compensate for variability in the accumulation of nanoshells in tumor. Post-mortem histopathology of
treated brain sections demonstrated the effectiveness and selectivity of the nanoshell-assisted thermal ablation.
Given their tunable optical properties and high optical absorption and scattering cross sections, gold nanoshells (GNS) have been explored for a number of in vitro and in vivo imaging contrast and cancer therapy agents. While it has been shown that GNSs preferentially accumulate at the tumor site, little is known about the accumulation kinetics within the tumor. We demonstrate accumulation kinetics of GNSs in bulk tumors and histology slides using two-photon induced photoluminescence (TPIP) imaging. We found that GNSs had a heterogeneous distribution with higher accumulation at the tumor cortex. In addition, GNSs were observed in unique patterns surrounding the perivascular region. These results demonstrate that direct luminescence based imaging of metal nanoparticles provides high resolution and molecular specific multiplexed images.
Researchers employ increasingly complex sub-micron particles for oncological applications to deliver bioactive
therapeutic or imaging compounds to known and unknown in vivo tumor targets. In practice, experimental homogeneity
using nanoparticles can be difficult to achieve. While several imaging techniques have been previously shown to follow
the accumulation of nanoparticles into tumor targets, a more rapid sensor that provides a quantifiable estimate of dose
delivery and short-term systemic response could increase the clinical efficacy and greatly reduce the variability of these
treatments. We have developed a pulse photometer that when placed on an optically accessible location will estimate the
concentration of near-infrared absorbing nanoparticles. The goal is to monitor the accuracy of the delivered dose and the
effective circulation time of nanoparticles immediately after intravenous delivery but prior to therapeutic intervention.
We present initial tests of our prototype using murine models to assess its ability to quantify circulation half-life and
nanoparticle concentration. Four mice were injected with nanoparticles and circulation half-life estimates ranged from 3-
43 minutes. UV-Vis spectrophotometry was used to independently verify these measurements using 5μL blood samples.
Linear models relating the two methods produced R2 values of 0.91, 0.99, 0.88, and 0.24.
In this study, high resolution backward-mode photoacoustic microscopy (PAM) is used to noninvasively image progressive extravasation and accumulation of nanoshells within a solid tumor in vivo. PAM takes advantage of the strong near-infrared absorption of nanoshells and their extravasation tendency from leaky tumor vasculatures for imaging. Subcutaneous tumors are grown on immunocompetent BALB/c mice. Polyethylene glycol (PEGylated) nanoshells with a peak optical absorption at ~800 nm are intravenously administered. With an 800-nm laser source, a prescan prior to nanoshell injection is taken to determine the background that is free of nanoshell accumulation. After injection, the 3-D nanoshell distribution at the tumor foci is monitored by PAM for 6 h. Experimental results show that accumulated nanoshells delineate the tumor position. Nanoshell accumulation is heterogeneous in tumors: more concentrated within the tumor cortex and largely absent from the tumor core. Because nanoshells have been recently demonstrated to enhance thermal therapy of subcutaneous tumors, we anticipate that PAM will be an important aid before, during, and after nanoshell thermal therapy.
Despite convincing evidence for hyperthermic radiosensitization, the invasive means of achieving and monitoring
hyperthermia and the lack of good thermal dosimetry have hindered its use in routine clinical practice. A non-invasive
method to generate and monitor hyperthermia would provide renewed enthusiasm for such treatments. Near-infrared
absorbing gold nanoshells have been shown to accumulate preferentially in tumors via the enhanced permeability and
retention effect and have been used for thermal ablation of tumors. We evaluated the use of these nanoshells to generate
hyperthermia to evaluate the anti-tumor effects of combining gold nanoshell mediated hyperthermia with radiotherapy.
Laser settings were optimized for hyperthermia in a mouse xenograft model to achieve a temperature rise of 40- 41°C in
the tumor periphery and 37-38°C (ΔT=4-5°C) deeper within the tumors. The ΔT measurements were verified using both
thermocouple and magnetic resonance thermal imaging (MRTI) temperature measurements. Tumor re-growth delay was
estimated by measuring tumor size after treatment with radiation (10Gy single dose), hyperthermia (15 minutes at 40°C),
and hyperthermia followed by radiation and control. Significant difference (p <0.05) in the tumor volume doubling time
was observed between the radiation group (13 days) and combination treatment group (25 days). The
immunofluorescence staining for the hypoxic, proliferating cells and the vasculature corroborated our hypothesis that the
radiosensitization is in part mediated by increased initial perfusion and subsequent collapse of vasculature that leads to
acute inflammatory response in the tumor. The increased vascular perfusion immediately after gold nanoshell mediated
hyperthermia is confirmed by dynamic contrast enhanced magnetic resonance imaging.
KEYWORDS: Tumors, Liver, Fiber lasers, Tissues, Laser therapeutics, Magnetic resonance imaging, Finite element methods, Gold, Temperature metrology, In vitro testing
Cooled fiber tip technology has significantly improved the volume coverage of laser induced thermal therapy (LITT),
making LITT an attractive technology for the minimally invasive treatment of cancer. Gold coated nanoshells can be
tuned to experience a plasmon resonance at a desired laser frequency, there introduction into the treatment region can
greatly amplify the effectiveness of the thermal treatment. The goal is to conformaly heat the target, while sparing
surrounding healthy tissue. To this end a treatment option that is self-confining to the target lesion is highly desirable.
This can be achieved in the liver by allowing nanoshells to be taken up by the healthy tissue of the liver as part of their
natural removal from the blood stream. The lesion is then incased inside the nanoshell laden tissue of the surrounding
healthy tissue. When an interstitial laser probe is introduced into the center of the lesion the thermal radiation scatters
outward until it interacts with and is absorbed by the nanoshells located around the lesion periphery. As the periphery
heats it acts as secondary source of thermal radiation, sending heat back into lesion and giving rise to ablative
temperatures within the lesion while sparing the surrounding tissue.
In order to better monitor therapy and know when the target volume has been ablated, or exceeded, accurate knowledge
is needed of both the spatial distribution of heating and the maximum temperature achieved. Magnetic resonance
temperature imaging (MRTI) is capable of monitoring the spatiotemporal distribution of temperature in vivo[1].
Experiments have been performed in vitro using a dog liver containing nanoshells (concentration 860ppm) and a tissue
like lesion phantom designed to have the optical properties of liver metastasis [2].
Gold nanoshells are a novel class of hybrid metal nanoparticles whose unique optical properties have spawned new
applications including more sensitive molecular assays and cancer therapy. We report a new photo-physical property of
nanoshells (NS) whereby these particles glow brightly when excited by near-infrared light. Specifically, we demonstrate
NS excited at 780 nm produce strong two-photon induced photoluminescence (TPIP). We characterized the
luminescence brightness of NS, comparing to that of fluorescein-labeled fluorescent beads (FB). We find that NS are 140
times brighter than FB. To demonstrate the potential application of this bright TPIP signal for biological imaging, we
imaged the 3D distribution of gold nanoshells targeted to murine tumors.
This study investigates the potential of using gold nanoshells to mediate a thermally induced modulation of tumor
vasculature in experimental prostate tumors. We demonstrate that after passive extravasation and retention of the
circulating nanoshells from the tumor vasculature into the tumor interstitium, the enhanced nanoshells absorption of
near-infrared irradiation over normal vasculature, can be used to increase tumor perfusion or shut it down at powers
which result in no observable affects on tissue without nanoshells. Temperature rise was monitored in real time using
magnetic resonance temperature imaging and registered with perfusion changes as extrapolated from MR dynamic
contrast enhanced (DCE) imaging results before and after each treatment. Results indicate that nanoshell mediated
heating can be used to improve perfusion and subsequently enhance drug delivery and radiation effects, or be used to
shut down perfusion to assist in thermal ablative therapy delivery.
In this study, high resolution reflection-mode (backward-mode) photoacoustic microscopy (PAM) is used to noninvasively image progressive extravasation and accumulation of nanoshells within a solid tumor in vivo. This study takes advantage of the strong near-infrared absorption of nanoshells, a novel type of optically tunable gold nanoparticles that tend to extravasate from leaky tumor vasculatures (i.e., passive targeting) via the "enhanced permeability and retention" effect due to their nanoscale size. Tumors were grown in immunocompetent BALB/c mice by subcutaneous inoculation of CT26.wt murine colon carcinoma cells. PEGylated nanoshells with a peak optical absorption at ~800 nm were intravenously administered. Pre-scans prior to nanoshell injection were taken using a 584-nm laser source to highlight blood content and an 800-nm laser source to mark the background limit for nanoshell accumulation. After injection, the three-dimensional nanoshell distribution inside the tumor was monitored by PAM for 7 hours. Experimental results show that nanoshell accumulation is heterogeneous in tumors: more concentrated within the tumor cortex and largely absent from the tumor core. This correlates with others' observation that drug delivery within tumor cores is ineffective because of both high interstitial pressure and tendency to necrosis of tumor cores. Since nanoshells have been recently applied to thermal therapy for subcutaneous tumors, we anticipate that PAM will be important to this therapeutic technique.
Laser induced thermal therapy is used in conjunction with gold coated silica core nanoshells and magneticresonance
temperature imaging (MRTI). The nanoshells are embedded in phantom or in vivo tumors and
heat preferentially compared to surrounding tissue when the laser is applied. The tissues thermal response
is varied by either the laser power or the nanoshell concentration. In this way precise control of the heating
can be achieved. This results in the ability to quantitatively monitor therapeutic temperature changes that
occur in a spatiotemporally controlled way. This provides an unprecedented means proscribing and
monitoring a treatment in real time and the ability to make precise corrections when necessary.
Accurate detection of the full extent of lethal thermal injury during and immediately after heating in interstitial thermal therapy is necessary to control the treatment volume while conserving surrounding tissues. A red zone of thermal injury forms in most tissues within thirty seconds as a result of physiologic response to heat in vivo. The red zone is formed by accumulation of blood due to hemostasis, hemorrhage and hyperhemia. The distinct outer boundary of this zone has been found to correspond to the outer boundary of tissue necrosis in rat livers examined 3 days after thermal coagulation. We have developed a minimally invasive fiberoptic probe that can detect this boundary using changes in white light absorption spectra of hemoglobin compared to native tissue. Decreased reflected light intensity marks the development of the outer boundary of the red thermal damage zone that is a hallmark of the full extent of lethal thermal damage.
Qualitative and quantitative histopathologic procedures were used to study the chronology of healing and mechanism(s) of wrinkle removal using pulsed CO2 laser irradiation. Lesions placed on 'Fuzzy' rat skin were examined pathologically at 0, 2 and 10 days and 2, 4, 8 and 12 weeks. Re-epithelialization began before 2 days and was complete by 10 days. Lethal thermal damage of the epidermis and superficial dermis led to necrosis and slough of the necrotic tissue. Fibrous dermal scar formation was well established at 10 days and, over the next 10 weeks the scar matured and contracted. The proposed mechanisms of wrinkle removal are (1) lethal thermal damage to the upper layers of the skin, (2) slough of the necrotic tissue and (3) re-epithelialization and (4) fibrous scar formation producing a smooth skin surface.
Oblique incidence relfectometry is a simple and accurate method for measuring the absorption and reduced scattering coefficients of turbid media. We used this technique to deduce absorption and reduced scattering spectra from wavelength resolved measurements of the relative diffuse reflectance profile of white light. In this study we measured the absorption and reduced scattering coefficients of chicken breast in the visible with the oblique incidence probe oriented at 0, 30, 60, and 90 degrees relative to the muscle fibers. We found that the reconstructed optical properties varied with probe orientation. This experiment demonstrates (1) the application of oblique-incidence fiber- optic reflectometry to measurements on biological tissue and (2) the effect of structural anisotropy on optical properties.
Pulsed carbon-dioxide laser skin resurfacing is a purportedly 'non-thermal' procedure enjoying wide application as a cosmetic treatment for skin wrinkles. Treatment success has been based on clinical assessments of skin smoothness. Skin lesions (1 cm2) created by one, two or three superimposed carbon-dioxide laser passes were placed on the backs of 28 'fuzzy' Harlan Sprague Dawley rats. The variable laser irradiation parameters included measured energies ranging from 112 to 387/pulse with pulse widths of 65 and 125 microseconds and a repetition rate of 8 Hz. The square, flat laser beam measured 3 mm2 at the focal point. The lesions were collected from 0 to 10 days after treatment for qualitative and quantitative histopathology. Thermal damage and treatment effect tended to increase in severity and, to a lesser extent, depth with increased delivery parameters. In acute lesions, the vacuolated and fragmented, desiccated and thermally coagulated epidermis was partially removed exposing the underlying thermally coagulated dermal collagen and cells. Epidermal and dermal necrosis and slough occurred between 24 to 72 hours after treatment. Epithelial regeneration originated from the adnexa and the lesion edges. Dermal fibrous scar formation began at 5 days below the regenerated epidermis and became more prominent at 7 and 10 days.
In preparation for photodynamic therapy clinical trials, a research class IV argon ion-pumped dye laser was modified to allow delivery of laser radiation from the Laser Biology Research Laboratory (LBRL) to a surgical operating room (OR) located one floor below and over 50 meters away. Optical fibers and coaxial cable, protected by flame retardant conduit, were fed from the LBRL to the OR. A remote control box was constructed to allow physician control of the laser output from the OR. A safety-off and output-power control wee included in the control system. Safety issues involved calculations of maximum permissible exposure of OR staff to optical radiation, the classification of the laser output in the OR and dealing with the placement of relatively high-flux carrying optical fiber placed in utility chases. Operational considerations involved the calculation and measurement of optical transmission losses, the procedure for relaying operational status between the OR and laser facility and the necessity of conducting practice runs with the laser and OR staff.
We determined the optical properties of the human prostate, in vivo, over multiple wavelengths for 6 men, in an outpatient setting. Analysis of these data reveal reliable determination of the optical properties in the 650 - 800 nm range, however, values in the shorter wavelengths (400 - 625 nm) were not interpretable due to a low signal to noise ratio. To the best of our knowledge, this is the first report of the optical properties i.e. reduced scattering coefficient [(mu) s' (cm-1)], absorption coefficient [(mu) a (cm-1)], and penetration depth [(delta) (cm)], for the in vivo human prostate over multiple wavelengths in the white light spectrum.
This study determine the threshold radiant exposure from a 10-ns pulsed laser (532 nm) which caused bovine melanosomes to present various observable endpoints of disruption. The endpoints tested were (1) a visible region of clearing in a uniform field of melanosomes under a glass cover slip, (2) an audible sound, and (3) the increase in melanin photoreactivity due to photodisruption of melanosomes. The thresholds were tested for different starting temperatures by pre-equilibrating the melanosomes in aqueous solution at various temperatures. Lower temperatures required larger exposures to attain a given endpoint. The data suggest that bovine RPE melanosomes are about 4-fold denser in melanin content than cutaneous melanosomes.
Melanin in vivo is usually packaged in melanosomes with protein coats that restrict direct interaction of the melanin with the surrounding medium. We found that disruption of the melanosomes by exposure to a pulsed laser increased the ability of the melanin radicals to oxidize NADPH in a photochemical reaction. Retinal pigment epithelial (RPE) melanosomes were prepared from fresh bovine eyes in 0.25 M sucrose. A reaction mixture of 7 mM NADPH, approximately 7500 RPE melanosomes, and 80 mM Tris buffer, pH 7.2, was prepared in a volume of 60 (mu) l. Of the two 25-(mu) l aliquots taken from this mixture, one was pre-exposed to the 2nd-harmonic output of a Q-switched Nd:YAG laser (532 nm, 1800 10-nsec pulses at 10 Hz), and then was exposed to an Argon ion continuous wave (CW) laser (488.1 and 514.5 nm) for five minutes. The other aliquot was exposed only to the Argon laser. The CW exposure excited the melanin radicals to a reactive state that oxidized NADPH, as assayed by the loss of absorbance at 340 nm. Native melanosomes oxidized less NADPH during Ar+ laser pumping than did melanosomes pre-exposed to the YAG laser. The YAG laser's stimulatory effect on melanosomes reactivity increased as the total energy it delivered rose above 3.5 J (0.14 J/cm2/pulse X 1800 pulses), up to a maximum NADPH oxidation at about 20 J (0.2 J/cm2/pulse X 1800 pulses, beam broadened at higher pulse energy). Electron microscopic analysis of the melanosomes confirmed the progressive physical disruption of melanosomes as the YAG pulse energy increased.
The protoporphyrin IX (PPIX) levels in rat liver, skin, and tumors in vivo in response to i.p. injection of delta-aminolevulinic acid were monitored by fluorescence spectroscopy. A pharmacokinetic model describes the PPIX dosimetry.
Electron radiation presents a peril to the qualification and use of glass on space-based optical systems. Radiation testing of glass for use in harsh radiation environments commonly centers around x-ray, gamma-ray, neutron, and proton radiation. Because of their relatively low energy and density, the effect of electron radiation is often considered negligible. However, during qualification of the TOPEX laser retroreflector array glass, 250 krad (Si) doses of 1.25 MeV electrons were shown to cause significant damage in several glass samples. Electron radiation will generate centers of high potential within the glass and when large enough cause a dielectric breakdown, whereby forming Lichtenberg patterns. These patterns significantly reduce transmission and are good scattering centers. The effect of electron radiation on six types of glass at incremental dosages between 0.25 Mrad and 55 Mrad is presented. The results of electron radiation on a magnesium fluoride anti-reflection coating also are discussed.
The ablation of ex vivo human samples of meniscus using the pulsed holmium:YAG (Ho:YAG) laser was studied. Delivery was by optical fiber in contact with the tissue. The rate of ablation was determined as (mm/pulse) for a range of pulse energies. Ablation with tissue in air versus under saline yielded similar rates of ablation, with the under-saline rate slightly higher. Experiments with two optical fiber sizes (200 micrometers and 600 micrometers ) suggested that total pulse energy [J/pulse] rather than radiant exposure [J/cm2/pulse] may be the better predictor for ablation rate. For comparison, results of a study of continuous Nd:YAG laser ablation of chicken breast using two beam sizes are also presented which suggest that total beam power [W] rather than irradiance [W/cm2] may be the better predictor for ablation rate. Comparison with the efficiency of simple boiling water indicates that laser ablation (both pulsed and continuous) is only about 10% as efficient as boiling water.
Photothermal coagulation and ablation lesions were produced in exposed livers of anesthetized rats with a cw Nd:YAG laser ((lambda) equals1064 nm; beam power 3.2 to 10 W; exposure times 3 to 10 s, and spot diameter, 0.7 to 1.9 mm). The surface temperatures produced by the irradiations were derived from IR camera images calibrated with temperature controlled black bodies present in the scene. Targetoid lesions with central white and outer red zones marked areas of surface and deep coagulation grossly. The animals were sacrificed 30 minutes after irradiation. The lesions and surrounding normal liver were collected for light microscopy. Microscopically, characteristic, thermally-induced red blood cell alterations were found in the white and red zones and at the boundaries separating them. The boundaries of the concentric surface zones were measured grossly from the lesion centers and compared to the thermal images to determine the temperatures associated with the red blood cell changes. The temperatures for the surface and deep morphologic isotherms defined by the white/red and red/normal boundaries of rat liver irradiated in vivo are 68+/- 5.0 degree(s)C and 55+/- 2.7 degree(s)C.
This project investigates the use of fluorescence to discriminate cancerous margins from surrounding normal tissues during neurosurgery. This paper presents a study of the excitation/emission matrix for in vivo rat brain tissue and ex vivo human brain tissue. Measurements were made with an optical fiber fluorimeter, consisting of excitation with a nitrogen/dye laser and detection with a spectrograph and optical multichannel analyzer. The ex/em pair of wavelengths (nm) for excitation and emission of fluorescence are summarized for three types fluorophores. Measurements of these fluorophores types were measured in ex vivo human normal and cancerous tissues, in vivo rat normal brain and glioma, and cell culture aggregates (GBM cells). In general, the magnitude of fluorescence decreases in cancerous tissues. The ratio F`flavin'/F`NADH' is an indicator of metabolic activity and a potential assay for normal vs cancerous tissues. Pilot studies with in vivo rat glioma model and with ex vivo human samples tested the use of this ratio for discriminating tissue types. The results did not show obvious trends but more work is still needed.
Thermal coagulation of albino rat skin heated in vitro results in prominent changes of light scattering but relatively little in light absorption based on measurements using an integrating sphere spectrometer. The reduced scattering coefficients, (mu) s(1-g), gradually increase as temperatures increase from room temperature to 55 degree(s)C then rapidly decrease to plateau after 70 degree(s)C is reached. The differences among the (mu) s(1-g) values for the different wavelengths were greater at the lower temperatures than at higher temperatures. The absorption coefficient, (mu) a, changed very little over the test temperature range (room temperature to 90 degree(s)C) and then only at higher temperatures and for longer wavelengths. The optical property changes were associated with thermally induced light microscopic and ultrastructural changes in the dermal collagen, a major tissue component of skin.
The Er:YAG laser ablation of hard dental tissues and artificial dental stones was studied. The hole depth after ablation was measured as a function of pulse energy and pulse number. The dental gypsum products allowed systematic study of how pulse energy, pulse number, and water content affected ablation. The studies on human teeth compared teeth stored in saline vs teeth stored in formalin.
Experiments in dog and rat liver compared the 805-nm wavelength of the diode laser and the 1064-nm wavelength of the Nd:YAG laser. (1) The major optical differences are in the absorption. The optical properties of dog liver were determined by integrating sphere experiments. The scattering coefficients were similar at both wavelengths, but the absorption was 3.5-fold greater for the diode laser wavelength. Consequently, the diode laser penetrated less deeply and heated the liver surface more strongly than the Nd:YAG laser. (2) Blood is a major component of liver absorption. When blood accumulated in the lower region of a rat liver held sideways, surface heating (measured by infrared camera) by the diode laser increased due to increased absorption by the pooled blood. (3) Tissue optics and irradiance geometry together affect the zone of thermal coagulation caused by each laser. The sizes of coagulation lesions in rat liver in vivo indicated larger zones of coagulation with the Nd:YAG laser. Our working hypothesis is that the diode laser caused greater surface heating and water evaporation which means less energy remained in the tissue. Enlarging the spot size of irradiance should alleviate such surface overheating and evaporation losses and maximize the zone of coagulation. The similarities between the two lasers are more striking than the differences.
KEYWORDS: Space operations, Optical communications, Space telescopes, Telescopes, Cameras, Signal detection, Satellites, Transmitters, Time multiplexed optical shutter, Receivers
The Galileo Optical communications from an Earth-based Xmtr (GOPEX) demonstration is designed to exhibit deep-space optical communications using the Galileo spacecraft. The optical transmitter consists of a Nd:YAG laser coupled to a 24-in. telescope at the Table Mountain Observatory (TMO), and the receiver is the Solid-State Imaging camera on board Galileo. The objectives of the demonstration are to understand the issues involved in blind-pointing to a spacecraft in deep space, and to assess the quality of the optical uplink by comparing the experimental results with theoretical predictions. The demonstration is proposed for December 1992 during the second earth-flyby period of Galileo''s trajectory.
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