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When choosing an appropriate light source for PDT there are several aspects to consider. Firstly, the wavelengths have to match the absorption bands of the photosensitiser so that a sufficient amount of singlet oxygen is produced. The illumination area has to be sufficient to treat the selected region and the irradiance has to be high enough to provide a good treatment response without causing too much pain. There are also aspects of the equipment that have to be considered such as cost and user friendliness. The type of light source chosen is often dic- tated by the location of the lesion, the light dose that is required as well as the photosensitiser that is used.

To enable deep penetration within the skin tissue, the absorption properties of tissue have to be considered. Figure 1.8 shows the absorbance of the main chromophores in skin tis- sue. Melanin and hemoglobin are strongly absorbing in the shorter blue wavelength range while water is strongly absorbing at longer wavelengths. Wavelengths between these two re- gions ensures deeper penetration within biological tissue. This wavelength range is typically referred to as the therapeutic window. The targeted wavelength range for PDT is however between 600 nm and 800 nm. Longer wavelengths do not provide enough energy for triplet state conversation to subsequently excite oxygen molecules. When using the photosensitiser PpIX, it is common to target the absorption peak at 630 nm to ensure the deepest possible penetration[1, 3].

1.8. Light sources

Figure 1.8: Figure showing the absorbance of the main absorbing chromophores in tissue which demonstrates the therapeutic window in which deeper tissue penetration is achieved.

The main absorbers are melanin, hemoglobin and water. Reproduced with_[73_]

Three main classes of light sources have been adopted for PDT: lasers, filtered lamps and light emitting diodes (LED). Even though lasers provide a monochromatic high powered light source, they are not optimal light sources for topical applications when treating larger lesions due to the requirement of expanding the beam, which requires the addition of optical in- struments. In addition the lasers tend to be expensive and associated with additional safety requirements. In addition, the requirement for technical support makes these less attractive for topical PDT applications; however, successful results have been reported for internal PDT application where the laser has been coupled to an optical fibre. Different lamps have the ad- vantage of being cheap and easy to maintain as well as providing a portable device. However due to the wide spectrum, more care is required to calculate the desired light dose. Coupling lamps into optical fibres tends to limit the output power which limits lamps to topical applic- ations such as to treat skin lesions. Currently, LED-based light sources are commonly adopted in PDT with the main advantage of being cheap and versatile with a reliable power output.

They provide a portable device with the flexibility of arranging the LEDs in different geomet- ries for different body locations [1, 74]. Valentine et al (2011) performed a theoretical study comparing different non-laser light sources, demonstrating the importance of an appropriate choice of light source[75].

The light source adopted for clinical treatment at Ninewells Hospital in Dundee is the Aktilite, which is an array-based red LED light source. The arrangement of LEDs can be adjusted so that the illuminating region is appropriate relative to the size of the lesion. An image of the device is shown in figure 1.9.

Figure 1.9: Image of Aktilite, which is the light source adopted at Ninewells Hospital_[72_].

By delivering the light during a longer period of time at a lower irradiance, it is thought that the oxygen consumption is also slower. This is therefore considered to be as effective, if not more so, compared to the conventional high-dose PDT using e.g. Aktilite[69]. The lower levels of pain reported for the low-dose PDT has shown a clinical advantage. Successful results have been reported using a portable LED low irradiance light source (Ambulight; Ambicare

1.8. Light sources

Health Ltd, Scotland). The Ambulight provides a convenient wearable source associated with a lower experienced pain_[76, 77_]. Unfortunately, these devices are still limited in size and therefore not appropriate for treating larger affected areas, typically associated with AK. The same theory of delivering light during a longer period at a lower irradiance supports the investigation of daylight activated PDT, where daylight is used as the excitation light source [76, 78, 79].

1.8.1 Daylight activated PDT

One of the limitations with many light sources used in PDT is the restriction in the size of the possible treated area. By using daylight, the only restriction is in the ability to expose the affected region to daylight. With conventional treatment modalities, only a few lesions can be treated during the same hospital visit. Utilising daylight as the therapeutic light source would lead to a reduction in the number of treatment sessions for patients with extensive coverage of lesions. Efficient daylight PDT would lead to a more convenient treatment modality for both patient as well as the treating clinic, leading to a higher throughput of patients.

The first clinical study of daylight PDT took place during the summer of 2006 in Denmark (Copenhagen). 29 patients with AK of the face and scalp were included in the study. Each pa- tient received both daylight PDT and conventional PDT (using a red LED) on separate lesions. This allowed the patients to compare the two treatment methods. During the conventional PDT the area was occluded for three hours after the application of the cream (containing MAL) after which a total light dose of 37 J cm 2_{was delivered. For daylight PDT the area was} occluded for only 30 minutes after which the area was treated with daylight for 2.5 hours. The weather conditions varied although most patients were treated on days with no or few clouds. The study showed no significant difference in the treatment response between the two treatment protocols (79 % vs. 71 %). Treatments using daylight PDT resulted in a sig- nificantly lower pain score compared to conventional treatment modalities. The study also successfully demonstrated that daylight PDT was the preferred choice of treatment for 62% of the patients[80].

Since this first study, several supporting studies on AK have been published in Europe [81–88], Australia [89], North America [90] and Latin America [91] with response rates between 70 - 89%. All studies show no inferior response rates to conventional PDT with lower recorded pain scores and better skin reactions such as reduced erythema. Daylight PDT has

also been shown to be the preferred choice of treatment by patients. The European consensus recommends 2 hours of daylight exposure, 30 minutes after application of MAL cream. The treatment is suggested to be possible in all weather conditions however a minimum temperat- ure of 10 C is recommended for the comfort of the patient (it is also recommended that the temperature should not be too high to cause discomfort or danger to the patient). A shorter exposure is thought to result in an insufficient amount of PpIX produced within the lesion and for a longer exposure the probability of extensive erythema (without improved treatment results) is increased[78]. The recommended effective light dose is typically suggested to be 8 J cm 2 _{(weighted by the normalised absorption properties of the photosensitiser)[92]. To} protect patients from damaging UV radiation, a sunscreen should be applied to all exposed areas. Typically sunscreens only overlap the absorption spectrum of PpIX by a small amount and are not thought to reduce the penetration of the light, and thereby not affect the efficacy of the treatment[93].

The reason for the reduced pain is not only due to the lower irradiance, but also due to the continuous build-up of PpIX. During conventional PDT the PpIX builds up during 3 hours after which the region of interest is exposed to a light source of high irradiance during a short period of time[94]. This results in a high concentration of reactive oxygen species (including singlet oxygen) shortly after the start of the illumination, thought to be one of the reasons for the high levels of experienced pain. During daylight PDT the PpIX is produced continuously during the illumination resulting in a continuous production of reactive oxygen species and considerably lower levels of pain[78].

So far it is only common to treat AK of grade I and II[95]using daylight PDT; however a study in Denmark reports successful results using daylight PDT to treat BCCs. The response rate at the 3 months follow up was 90 % [34], again comparable to results achieved using conventional PDT[51, 96]. The response was reduced to 74% after 12 months and the high recurrence rate has been speculated to be due to the thickness of the lesion making this treatment less suitable for thicker lesions such as BCC[78].

Unpredictable weather conditions altering the treatment conditions as well as the lack of supervision during the treatment are the main limitations with daylight PDT. In northern Europe daylight treatments can only be scheduled for the summer months of the year and in warmer climates the heat of direct sunlight is an additional restriction. If the treatment is per-