Optimization of Spectral and Spatial Light Beam Distribution of Optical Systems for Photodynamic Therapy

Abstract

INTRODUCTION
Optical devices are widely applied in science, technology, and medicine. Modern medicine is developing, giving way to the use of optical devices for phototherapy of various diseases. Among the current phototherapy technologies one can highlight photodynamic therapy.
Photodynamic therapy (PDT) is an advanced method of treatment that provides for the penetration of a photoactive dye (photosensitizer) into biological tissue. The photosensitizer is delivered to pathogenic cells, where, effected by light, it triggers a photochemical reaction with the release of singlet oxygen destroying the pathogenic cells. For PDT those photosensitizers are used that effectively absorb light in the wavelength range of 600-700 nm. This range falls within the so-called "therapeutic window" encompassing the most transparent biological tissues resulting from the low absorption of blood in this spectral area [1]. The second generation of e6-chlorin-based photosensitizers are considered the drugs-of-choice. PDT is successfully used in oncology and is now being developed gaining new fields of applications. Including PDT of onychomycosis that is an infectious nail disease of fungal etiology. For effective and safe photodynamic treatment of onychomycosis it is necessary to selectively impact the photosensitizer absorbed by the nail tissue affected by the fungus and develop extremely high-intensity light sources. In that regard it is important to optimize the spectral, temporal and spatial distribution of the light source, including matching the spectrum of its radiation with the absorption spectrum of the photosensitizer, minimizing the procedure time, creating a uniform distribution of radiation on the area of the nail containing the dye affected by the fungus. The result of the interaction of light and biological tissue during photodynamic therapy depends, among other things, on the spatial distribution of light, The optimization of that distribution allows impacting biological tissue effectively and safely for the surrounding tissues, it is being particularly important in the treatment of onychomycosis and in the development of new effective optical devices for the treatment of this disease, as well as for a wide range of medical applications.
The goal of this work is to optimize the spatial distribution of the optical systems’ light flux for photodynamic therapy. To achieve this goal, it is necessary to solve the following tasks: Investigate the absorption spectrum of the modern chlorin-containing drugs at different concentrations in an aqueous solution, at different intensities and different timing of light exposure with a wavelength of 656±10 nm. To define requirements for the optimal dynamics of the light exposure for PDT. Development of a computer optical model of onychomycosis. Calculation of light distribution in this model Establishing correlation between the distribution of light on the surface of the model and in the area containing the photosensitizer. Developing requirements for light distribution on the surface of fingers affected by onychomycosis optimal for PDT.

SPECTRAL INVESTIGATION
The absorption spectra of the photosensitizing drugs "Revixan" (Areal Ltd., Russia) and "Chloderm"(DPT Laboratory Ltd, USA) were studied. The spectra of those drugs in the range of 600–700 nm proved to be close to each other that is obviously associated with the use of chlorine e6 as a photodynamic agent in both drugs. The absorption band maximum for both drugs is equal to 654±1 nm. The behavior of the absorption spectra of an aqueous solution of photosensitizing drugs at different intensities and different timing of exposure to light with a wavelength of 656±10 nm was investigated. For photosensitizing drugs illumination, the LED device for PDT “LED Forester 660” (Nela Ltd., Russia) with intensity of radiation up to 180±20 mW/cm2 was used. The intensity of radiation on the surface of biological tissue is limited by thermal damage to an organ or tissue (for skin ~ 200 mW/cm2 [2]).
One can describe the dependence of the "Revixan" absorption coefficient at a wavelength of 654 nm corresponding to the peak of its absorption band on the intensity of exposure to LED radiation with a wavelength of 656±10 nm with the function:
k_(R_654 ) (I)=1.3*〖(I+0.001)〗^(-0.18), (1)
where: I – intensity of radiation, W/m2, and on the time of exposure with the intensity up to 180±20 mW/cm2 with the function:
k_(R_654 ) (t)=〖(t+0.001)〗^(-0.08), (2)
where: t- time of exposure to radiation, s.
One can describe the dependence of the "Chloderm" absorption coefficient (at a wavelength of 654 nm corresponding to the peak of its absorption band) on the intensity of exposure to LED radiation with a wavelength of 656±10 nm with the function:
k_(Ch_654 ) (I)=〖1.34*(I+0.001)〗^(-0.165), (3)
where I - intensity of radiation, W/m2, and on the time of exposure with the intensity up to 180±20 mW/cm2 with the function:
k_(〖Ch〗_(_654) ) (t)=〖2*(t+0.001)〗^(-0.12), (4)
where t – time of exposure to radiation, s.
Thus, the effect of LED radiation changes the absorption spectra of chlorin-containing photosensitizing drugs for photodynamic therapy, while an increase in the intensity and time of exposure to LED radiation results in decreasing absorption of those photosensitizers in the range of 600-700 nm and a shift of their peak absorption band being within that range in the IR area. When chlorin-containing photosensitizing drugs are exposed to LED radiation with a wavelength of 656±10 nm and a constant intensity of 180±20 W/cm2, the absorption coefficient at a wavelength corresponding to the absorption peak of drugs changes over time according to
k(t)=A*(t+0.001)^B, (5)
where the coefficient A is in the range 1-2; coefficient B - in the range -0.12 ÷ -0.08.
Therefore, the change in the intensity of LED radiation with a wavelength of 656±10nm over time according to
I=〖(A*(t+0.001)^B)〗^(-1), (6)
where coefficient A - stays in the range 1÷2; coefficient B - in the range -0.12÷-0.08, provides a constant, during PDT with an initial intensity of 180±20 mW/cm2, the rate of absorption of light energy by a chlorin-containing photosensitizing drug
The results obtained in this work can help to get deeper understanding of the processes occurring during photodynamic therapy of various diseases, including PDT of onychomycosis, to construct the models describing interaction of light with photosensitizers in biological tissue, as well as to develop recommendations on photodynamic therapy scenario that takes into account the process of photobleaching of the photodynamic agent and the dynamics of its absorption at the wavelength of the exciting radiation.
Information on the behavior of the photosensitizer absorption coefficient resulting from the exposure to light or as a result as well as changing photosensitizer concentration while penetrating biological tissue combined with the attenuation of the exciting radiation intensity during its propagation in biological tissue will enable finding adequate light radiation power absorbed by the photosensitizer and choosing the best radiation wavelength, intensity and exposure time necessary for the most effective photodynamic therapy of neoplasms localized at different depths in biological tissue.

SPATIAL DISTRIBUTION MODELING
The structural model of a nail affected by onychomycosis is shown in Figure 1. It was the first time when the model takes into account the role of the anterior part of the toe and the proximal nail fold. The proximal nail fold and the anterior part of the toe are covered by skin epidermis. When constructing the model, for the first time, the fact was taken into account that in different parts of the nail the sizes of the layers forming it, as well as their shape, can differ. At the preparation stage for PDT a hardware pedicure is performed while the nail plate is polished, leaving about 50 microns of its thickness. For this reason, the nail plate is divided into two parts: from the anterior of the finger to the proximal nail fold, its thickness amounts to 50 µm, under the nail fold - 300 µm.

Figure 1: The structural model structure of the nail affected by onychomycosis

The fungus was modeled by a layer of a photosensitizing drug that is found behind the papillary dermis and completely absorbing all the light incident on it. The optical properties of the layers included in the developed model were selected basing on the analysis of literature data [3-7]. Optical modeling was performed by means of TracePro-Expert 7.0.1 Release program (Lambda Research Corporation, USA). The light source was a platform emitting in the direction of the nail plate oriented parallel to the surface of the nail plate, the radiation wavelength was equal to 660 nm. The distribution of the light intensity of the source could be preset; besides it could be uniform. The intensity of the light radiation from the source is 200 mW/cm2. As a result of calculations, it was found that with a uniform distribution of light on the surface of the nail model in the area under the grinded nail plate the density of the light power absorbed by the photosensitizing drug is 155 mW/cm2, and in the area under the nail fold - 8 mW/cm2, i.e. the distribution of the power absorbed by the drug in this case is not uniform in space (despite the uniform spatial distribution of the source) that can lead to excessive or, on the contrary, insufficient photodynamic effect in different parts of the fungus (drug) localization area. In order to achieve a uniform spatial distribution of the power absorbed by the photosensitizing drug, and therefore the optimal photodynamic effect with an effect of hypothermia, restricted by the intensity of the light source (200 mW/cm2), two methods are suggest.
First method. A source with an uneven spatial distribution of intensity. Set the intensity of light incident on the surface of area B (see Figure 1) located under the nail fold as high as possible (restricted by the effect of hyperthermia and equal to 200 mW/cm2), and reduce the intensity of light incident on the surface of area A (see Figure 1) located under grinded nail plate by 19-20 times (up to 10-10.5 mW/cm2), while the timing of light exposure on the nail plate and on the nail fold should be equal to each other.
Second method. Source with uneven temporal distribution. Set the intensity of the light incident on the surface of the areas under the grinded nail plate and under the nail fold at the same and maximum rate, but increase the irradiation time for area B under the nail fold by 19-20 times compared to the time of irradiation of the area under the grinded nail plate.
Figure 2 shows the distribution of light intensity created on the surface of the optical model of a nail affected by onychomycosis by a source with an uneven distribution of intensity in space. The border line between the source light intensity distributions is oriented along the nail cuticle. Within each of those two distributions, light is evenly distributed in space.

(a)
(b)
Figure 2: The light intensity distribution on the surface of the optical model of the nail affected by onychomycosis created by a source with an uneven spatial distribution of intensity (a) and absorbed by the photosensitizing drug (b) from this source in the area under the grinded off nail plate (red color) and in the area under the proximal nail fold (blue color).

One can see that with an uneven distribution of light on the surface of a developed nail model in the area under the grinded nail plate, the density of the light power absorbed by the photosensitizing preparation is 8 mW/cm2 and is equal to the density in the area under the nail fold, i.e. the distribution of the power absorbed by the photosensitizing drug in this case is uniform in space (despite the uneven spatial distribution of the source) that allows for the same photodynamic effect in different parts of the fungus (drug) localization area.

CONCLUSION
It has been demonstrated that exposure to LED radiation with a wavelength of 656±10 nm changes the absorption spectra of chlorin-containing photosensitizing drugs for photodynamic therapy, while an increase in the intensity and time of exposure to LED radiation leads to a decrease in the absorption of these photosensitizers in the range of 600-700 nm and a shift of their peak absorption band lying in this range in the IR area.
It was found that in case chlorin-containing photosensitizing drugs are exposed to LED radiation with a wavelength of 656±10 nm and a constant intensity of 180±20 W/cm2, the absorption coefficient at a wavelength corresponding to the drug absorption peak changes over time according to the formula: k(t)=A*(t+0.001)^B, where the coefficient A is in the range 1-2; coefficient B - in the range -0.12 ÷ -0.08.
The original computer optical model of a nail affected by onychomycosis was described. It has been demonstrated that if the spatial distribution created by LED radiation with a wavelength of 656±10 nm on the surface of toes or hands affected by onychomycosis is divide into two areas and if the intensity in each of them areas make different by several times and if the border line between those areas will be oriented along the cuticle of the nail, then in this case possible forming up a uniform spatial distribution of light intensity in an area affected by onychomycosis and located under the nail.

References
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Speaker

Andrey Belikov
ITMO University
Russia

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