Light emitting fabrics for photodynamic therapy: Technology, experimental and clinical applications

A homogeneous and reproducible fluence rate delivery during clinical PDT (PhotoDynamic Therapy) plays a determinant role in preventing under-or overtreatment. The development of a flexible light source able to generate uniform light on all its surface would considerably improve the homogeneity of light delivery. The integration of plastic optical fibers into textile structures offers an interesting alternative. This article aims to describe briefly the technology used to develop Light Emitting Fabrics (LEF) and their use in vitro (CELL-LEF), in vivo (VIVO-LEF) for experimental evaluation of PDT. At last, the use of LEF for clinical applications is given by 3 examples. For in-vitro applications, the CELL-LEF device allows the illumination of several 96-well cell culture plates. For the VIVO-LEF, the system developed for PDT can treat 3 mice simultaneously with a homogeneous and high irradiance The medical LEF systems developed for PDT in Dermatology for the treatment of actinic keratosis demonstrate their superiority thanks to a uniform light distribution due the flexibility of LEF. Interestingly, the technology used for manufacturing LEF is very well known by the textile industry, leading to very competitive production costs. The fact that optical fibers can transmit light from 400 nm to 1200 nm allows the connection of LEF to different laser sources covering the light spectrum of all photosensitizers used for medical applications. New developments should allow to use the LEF inside cavities such as the pleural or the peritoneal cavities.


Principle of LEF
The different technologies based on optical fibers for large area were described by Mordon et al [1]. The technology developed in Lille used optical fibers. Briefly, optical fibers are optical structures, which allow incident light, usually from an optical source, to be guided by a series of internal total reflections that occurs under angular conditions, with minimum losses [1]. Standard step-index optical fiber is composed of a core and a surrounding cladding of cylindrical shapes, and with respective refractive indices and . Geometrical optics defines a particular angle called as the smallest angle of incidence of a ray at which no refraction occurs at the boundary of two media when . General angular condition of total reflection of an incident light ray of angle is given in (1).

principle of light propagation in an optical fiber
In the optical fiber, total internal reflection occurs for light rays of smaller angles than the angle of acceptation , defined as the minimum angle of incidence to obtain a refracted light ray of angle that satisfies the general angular condition of total reflection ( 1 ).
Otherwise, the portion of the incident light rays reflected and/or refracted is described by the Fresnel equations.
( 2 ) Local microscopic variations of core medium density from manufacturing process (variation in density, orientation or molecular composition of the material) lead to local variations in the refractive index, and generate losses by scattering of the light rays. Linear attenuation corresponds to the sum of all absorption and scattering losses that occur in the optical fiber, and is defined by the attenuation coefficient [2].

( 3 )
Additional bendings can increase the optical fiber attenuation coefficient, by inducing light leakage through the core. Macrobending is defined as a mechanical stress, which can be punctual or repeated [3], and is characterized by the critical radius of curvature which represent the bending radius from which macrobending losses become significant [4].
When an optical fiber is bent with a bending radius smaller than the critical bending radius , the angle of incidence of the ray may become smaller than and the ray refracts within the cladding and part of the ray may be refracted outside the optical fiber [2] ( figure   2). The bending radius is associated with the angle of curvature which gives information on the length of the bent section[5] [6] .
( 4 ) Figure 2: principle of light emission be optical fiber due to bending Bending light losses within optical fibers are typically characterized with the objective of minimizing them as much as possible, especially for telecommunication or power transmission applications. In some cases, they are quantified to measure deformations within materials using fiber optic sensors, and maximized when homogeneous light emitting surfaces are desired [7] By integration of plastic optical fibers within knitted or woven structure, light emission can be obtained over flexible textile surfaces. Homogeneity of spatial light distribution can be obtained under the condition of controlling the density of the fibers and the angles and radii of curvature [8].
Optical fibers are generally woven as conventional yarn according to various satin weave structures along the fabrics length to control light emission [9][10][11]. As knitting involves bending radii that are too severe to be supported without risk of breakage if the optical fiber is knitted, optical fibers are mainly laid in a partial weft in a warp or weft knitted structures [12] in a straight line or in special patterns [13].
Plastic optical fibers can be gathered and glued within a metallic bundle in order to be coupled to any LASER source by the mean of 2 beam expanders (figures 3 & 4). The injection of light at each end of the textile, allows to balance the bending losses providing a more uniform and intense lateral emission [14].  However, OF can deliver light only on small areas, while LED panels provide incoherent light with broad spectral width. Although easy to use and quite inexpensive, optical fibers and LED panels do not allow an effective homogenous illumination.
In vitro PDT studies often require illumination of several cells plates either all at once or all within a short period of time. In this context, a cells illuminator, CELL-LEF, able to illuminate several 96-well cell culture plate simultaneously with a homogeneous light has been designed ( Figure 6).
CELL-LEF embeds two large LEF (total illumination surface: 750 cm 2 ) sandwiched and kept in place between two rigid, transparent plastic sheets. These sheets also allow protection of the LEF and easy disinfection of CELL-LEF before and after use. Before being sandwiched, the two LEF are jointly sewn on a white textile in order to reflect the light emitted by the bottom face and therefore increase the quantity of light on the top face. A template is placed on the top plastic sheet in order to indicate the emplacement of the 6 multi-well plates (resulting illumination surface: 657 cm 2 ). Finally, a lightproof cover can be used to protect cells from stray light, which could lead to undesired activation of the PS.

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For all measurements, CELL-LEF was connected to a 635 nm laser (ONCO THAI, Lille, France) set to achieve a target mean irradiance of 1 mW/cm 2 . Different tests were performed in order to evaluate the homogeneity of irradiance, temperature evaluation of cell during illumination of 96-well cell culture plates. The measurement methodology has been already described [17] With the CELL-LEF illuminator, irradiance values range from 0.81 to 1.18 mW/cm 2 (mean: 0.98 mW/cm 2 ; standard deviation: 0.11 mW/cm 2 ). To obtain these values, a laser output power of 2.6 W was required. Homogeneity was determined using an automatic measurement system specifically developed for this purpose. A homogeneity of 90.9% was recorded. CELL-LEF was classified exempt risk group for all hazard groups according to the IEC 62471 standard, and does not exceed Accessible Emission Limits of class 1 defined by IEC 60825 standard At last, temperature elevation measurements inside 96 well plate gave the following results 45 minutes of CW illumination: for a well with cells with 5-ALA, an increase of +1.14 °C was measured but it was only +0.88 °C inside a well with cells without 5-ALA [18] .

LEF for in vivo experimental evaluation of PDT (VIVO-LEF)
In the framework of the development of an original humanized SCID mouse model of ovarian peritoneal carcinomatosis, a specific device dedicated to mice illumination. A mice box, called VIVO-LEF was developed to illuminate three mice simultaneously with a homogeneous light (Figure 9). VIVO-LEF consists of two separated white 3D-printed plastic bases, on which two light emitting fabrics (LEF) are fixed. The bases are designed to form three cavities, in which mice can be placed in prone position ( Figure 10). The materials used make VIVO-LEF strong and lightweight. The total surface of illumination of 250 cm 2 allows to cover the whole body of the three mice. For the in vivo experiments performed on the SCID mouse model of ovarian peritoneal carcinomatosis, an irradiance of 11.08 0.58 mW/cm 2 is delivered. Since, LEF are secondary light source, VIVO-LEF does not emit heat. Thanks to these performances, VIVO-LEF is far superior to OLED which are limited by their low irradiance and important temperature increase [21].  In dermatology, PDT is used to treat actinic keratosis. Actinic keratosis are common preinvasive cancerous lesions in sun-exposed skin which negatively affect the quality of life in patients and may progress to invasive squamous cell carcinoma. Actinic keratosis usually develop on areas that are frequently exposed to the sun (e.g., face, ears, scalp, neck, forearms, and back of the hands). Studies have shown that if actinic keratosis are untreated, actinic keratosis may regress, or alternatively, may progress to squamous cell carcinoma, with significant morbidity and possible lethal outcome. Predicting which actinic keratosis may progress to squamous cell carcinoma is not possible, nor is the conversion rate for an actinic keratosis to squamous cell carcinoma clear: the transformation rate from an actinic keratosis lesion to squamous cell carcinoma within one year has been reported to be <1:1000. The malignant potential and the fact that it is impossible to predict which actinic keratosis will evolve into squamous cell carcinoma, have led to the common consensus that actinic keratosis have to be treated. Because of the high prevalence of actinic keratosis, their treatment represents a substantial workload, and must therefore be efficacious and easy to    However, the incidence of adverse effects was lower with P-PDT than with C-PDT (161 vs.

264).
The more important observation was the quasi-absence of pain with P-PDT. With all the pain scores ranging from 0 to 2.7, P-PDT was reported to be almost pain-free. Regarding the first PDT session (46 patients), the treatment-related pain at the end of irradiation is significantly lower with P-PDT compared to C-PDT (0.3 ± 0.6 vs. 7.4 ± 2.3, p<0.0001). The same finding was also observed for the second PDT session (18 patients) ( Figure 4) [29]. PDT is also studied [30][31][32][33]  The PAGETEX® device was developed to fit the body shapes and provides a homogeneous light at the entry of the vagina, under the lips and on perianal region safely, [7,14]. During the PDT treatment, the PAGETEX® device is placed over the vulva and maintained by pants (figures 13,14). Patients can even slightly move during the illumination session, and also be accompanied while keeping intimacy.  This clinical study is in progress and reporting of results is expected in 2022.

Conclusion
The different applications of Light Emitting Fabrics for photodynamic treatment show that this technology is well suited for homogeneous illumination of large areas. The technology used for manufacturing this LEF is very well known by the textile industry, leading to very competitive production costs. The fact that optical fibers can transmit light from 400 nm to 1200 nm allows the connection of LEF to different laser sources covering the light spectrum of all photosensitizers used for medical applications. New developments should allow to use the LEF inside cavities such as the pleural or the peritoneal cavities. At last, other applications such as baby jaundice treatment are already forecast.

Conflicts of interest
The LEF technology is now commercialized by the company, MDB Texinov in France.
However, no author of this article has financial interest in the development of the LEF device with this company and consequently the authors have no conflicts to declare.