The objective of this study was to evaluate the performance of a dedicated light applicator for light delivery and fluence rate monitoring during Foscan®-mediated photodynamic therapy of nasopharyngeal carcinoma in a clinical phase I/II study. We have developed a flexible silicone applicator that can be inserted through the mouth and fixed in the nasopharyngeal cavity. Three isotropic fibers, for measuring of the fluence (rate) during therapy, were located within the nasopharyngeal tumor target area and one was manually positioned to monitor structures at risk in the shielded area. A flexible black silicon patch tailored to the patient's anatomy is attached to the applicator to shield the soft palate and oral cavity from the 652-nm laser light. Fourteen patients were included in the study, resulting in 26 fluence rate measurements in the risk volume (two failures). We observed a systematic reduction in fluence rate during therapy in 20 out of 26 illuminations, which may be related to photodynamic therapy–induced increased blood content, decreased oxygenation, or reduced scattering. Our findings demonstrate that the applicator was easily inserted into the nasopharynx. The average light distribution in the target area was reasonably uniform over the length of the applicator, thus giving an acceptably homogeneous illumination throughout the cavity. Shielding of the risk area was adequate. Large interpatient variations in fluence rate stress the need for in vivo dosimetry. This enables corrections to be made for differences in optical properties and geometry resulting in comparable amounts of light available for Foscan® absorption.
An important feature of achieving low coupling losses in systems with small dimensions is the availabilty of optical fibers with larger numerical apertures while retaining the excellent loss characteristics of synthetic silica. Larger acceptance angles permit more efficient pick up of signals in smaller diameter optical fibers. Likewise broader angles can benefit illumination systems, providing larger areas of coverage with smaller components. Examples where one or both aspects are valuable include remote spectroscopic sampling and hands-free fiber optic illumination systems for hazardous environments. Optical fibers with doped synthetic silica cores are described which have numerical apertures of over 0.50 for power delivery and effective NAs approaching 0.60 for illumination, sensing or other 'low power' applications. Spectral and optical properties of these fivers are presented along with how they allow improved low loss coupling of optical components in photonic and microelectronic systems.
For most Photodynamic Therapy (PDT) applications a diffuse, broad and uniform source of irradiation is needed to obtain the most effective and consistent treatment. Since many treatments are within the patient's body, an effective compact fiber optic delivery system is needed for the activation of the photsensitizer drub at the site of the tissue to be treated. High Numerical Aperture (NA) optical fibers have benefits for PDT treatments but possibly even more so for PDT diagnostic applications These are summarized and new optical fibers with high and ultra high NAs are described. Properties of these fibers are presented as well as advantages they have over other fibers for delivering light in various PDT applications. Silica fibers with enhanced effective NAs approaching 0.6 are described.
The availability of ultra short (ps and sub-ps) pulsed lasers has stimulated a growing interest in exploiting the enhanced flexibility of femtosecond and/or picosecond laser technology for micro-machining. The high peak powers available at relatively low single pulse energies potentially allow for a precise localization of photon energy, either on the surface or inside (transparent) materials. Three dimensional micro structuring of bulk transparent media without any sign of mechanical cracking has been demonstrated. In this study, the potential of ultra short laser processing was used to modify the cladding-core interface in normal fused silica wave guides. The idea behind this technique is to enforce a local mismatch for total reflection at the interface at minimal mechanic stress. The laser-induced modifications were studied in dependence of pulse width, focal alignment, single pulse energy and pulse overlap. Micro traces with a thickness between 3 and 8 μm were generated with a spacing of 10 μm in the sub-surface region using sub-ps and ps laser pulses at a wavelength of 800 nm. The optical leakage enforced by a micro spiral pattern is significant and can be utilized for medical applications or potentially also for telecommunications and fiber laser technology.
Efficacy of PDT with new chlorin e6 photosensitizer (BLC 1010) has been tested in 72 cancer patients. 44 patients (61 %) achieved a complete response and 39 % of the patients a partial response (28 patients, including 15 patients treated for palliation). Rapid elimination of BLC 1010 from the organism solves the problem of skin phototoxicity encountered in PDT up to now. This property together with its high tumor to normal ratio makes it a promising photosensitizer for PDT. Further advantage is that portable diode lasers with proper wavelength are available.
Andrei Reshetnickov, Stefan Spaniol, N. Neugodova, G. Sapozhnikova, Olga Abakumova, Tatyana Tsvetkova, Igor Zalevsky, S. Goncharov, Artashes Karmenyan, Gelii Ponomarev
Five novel photosensitizers for photodynamic tumor therapy have been offered as potential drug substances for the prospective clinical usage. A complex of pre-clinic biological studies has been performed, unambiguously demonstrating low systemic toxicity and high photodynamic potential of the substances proposed. The one named 'Photodithazine/Photochlorin I' has already successfully passed a number of clinical test on patients having immergent vital indications.
Rectangular core multimode fibers with core dimensions of (10 - 22) micrometers X (170 - 200) micrometers and numerical aperture of 0.15 have been designed for high power diode lasers coupling with maximum preservation of laser radiation power density and laser radiation linear state of polarization.
For most applications in laser medicine suitable delivery systems are required. We developed fiber optic based diffusing tips especially for photodynamic therapy (PDT) and laser induced thermotherapy (LITT). To realize an adequate emitting cylindrical diffuser the fiber core was abraded by a precision cutter. Hence, the use of scattering media such as TiO2-doped polymers is avoided. Because the diffuser size is mainly determined by the manipulated fiber and a surrounding glass capillary, one can realize small diameters ((phi) approximately equals 3 mm). The laser light is distributed mainly by surface scattering and total reflection at the fiber air boundary. Because the use of absorbing media is avoided, it is possible to apply high laser power as necessary in LITT and pulsed PDT. We produced diffusing tips with lengths of several centimeters and typical diameters of 3 mm. By controlling the fiber-shaping process, a homogeneous intensity profile or even special designs can be achieved. The control is done by either on-line camera surveillance or calculated predictions. A delivery system especially for the photodynamical treatment of female cervix dysplasia has been designed.
The aim of this study was to calculate the light fluence for various PDT applications with a Monte Carlo method. Different applicator geometries and the related illuminations are computed in a 3D-multilayer tissue model. The applicators we calculated include various surface geometries, intensity and angular profiles as well as tissue parameter variations, and different wavelengths. The resulting fluence contours in conjunction with a certain dye concentration allow a prediction of the expected damage zone after PDT in the tumor tissue. To measure tissue parameters ex vivo we built up a spectrometer consisting of two integrating spheres. The light source we use is a cw Ti:sapphire laser tunable from about 670 nm to 760 nm without change of optics. We use a combination of direct and indirect measurements. By estimating the specular reflection and direct transmission from a tissue sample (approximately 490 micrometers ) we get the refractive index n and the extinction coefficient (mu) (tau ). We also measure the diffuse reflection as well as the diffuse transmission with the integrating spheres. To calculate the missing parameters (mu) a and g we use an inverse Monte Carlo simulation (MCS) with the Henyey-Greenstein phase function. Simulation of the tissue sample including the boundary and geometry effects leads to absorption coefficients that are up to a factor of 3 lower in comparison to good analytical models. The loss of diffuse light can be taken into consideration.
We compared the photodynamic efficiency of pulsed to cw laser irradiation in a cell culture experiment with a NIH ovarian cancer cell line (NIH-OVCAR3). Our photosensitizer was a cationic Zn(II)-phthalocyanine with an absorption maximum near 675 nm. The laser systems we use are an excimer laser pumped DCM-dye laser ((tau) equals 15 ns) and a cw Ti:sapphire laser. The photodynamic activity of the photosensitizer strongly depends on the pulse fluence and decreases with increasing fluence due to saturation of the sensitizer. In another experiment no changes in the light penetration depth into the tissue for pulsed irradiation could be detected up to a pulse intensity of 3 MW/cm2.
We developed a Monte Carlo model to estimate the light distribution in tissue. The underlying assumption of the calculation is the knowledge of the microscopic tissue optical parameters. In the simulation we start with a single point illumination in a 3-D multi-layer tissue model. To get the light distribution for extensive irradiation we convolve the `single point solution' with the expanded irradiance profile. The aim of our simulation is the development and design of diverse PDT-applicators for dosimetry reasons and as an inverse method, the calculation of microscopic tissue optical parameters for different tumor samples from ex vivo measurements.
We developed a new water-soluble phthalocyanine, activated for coupling to antibodies by N- hydroxysulfosuccinimide. The efficiency of anti-CA125-phthalocyanine conjugates was compared to free phthalocyanine in a human ovarian carcinoma model in tissue culture. In both cases a dose dependent cell killing was observed after irradiation with a Titanium sapphire laser at 675 nm and 50 J/cm2, but incubation with antibody-coupled phthalocyanine resulted in 90% cell mortality with a 60-130-fold lower dye application.
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