How sunshine can be used to undo the damage it caused
It’s that time of year again. Summer is here, and out comes that which many of us (in Scotland at least) crave more than anything during the cold, dark months of winter: the sun! Although most of us will be excited at the prospect of heading down to the beach, enjoying a drink in the sun or going ‘taps aff’ around the streets of Glasgow, dermatologists at our clinic at Ninewells Hospital in Dundee get excited for a different reason - as ironically, this is a great time to treat sun-damaged skin.
Sun damage of the skin (actinic keratosis) is primarily caused by over-exposure to ultra-violet (UV) light. Too much UV exposure can cause damage to the DNA in the skin cells, which can lead to skin cancer, a trend which is increasing in the UK.
Although it seems counterintuitive, a technique known as daylight photodynamic therapy (dPDT) is a treatment method that uses the visible part of daylight to treat sun-damaged skin. This works by using visible wavelengths of light to activate light sensitive molecules which accumulate in, and then kill diseased tissue.
The light sensitive molecules (photosensitisers) are delivered to the skin via a cream, which contains a pro-drug called 5-aminolevulinic acid (ALA) or methyl aminoluvenate (MAL). Via something known as the heme pathway, ALA and MAL are converted in to protoprophyrin-9 (PpIX), which is the photosensitive molecule of interest. In the presence of light and oxygen, PpIX will produce reactive oxygen species which are toxic to cells, essentially killing any that they have accumulated in.
Treatments typically last between two and two-and-a-half hours, with the patients instructed to stay out in direct sunlight for the duration (patients wear sun-screen so they are protected from the UV light during treatment). Many patients take the opportunity to do things like gardening, or going for a walk, and it is partly because of this freedom that patient satisfaction with dPDT is excellent.
Another reason that dPDT is so well tolerated is that it is virtually pain-free. This is best explained by a simple equation for calculating the light dose, which is “Dose = Irradiance X Time”. The irradiance is the light falling on a surface per unit area (this has the units Watts per metre squared), and the time is simply the length of exposure to the irradiance. To keep the same light dose, one can simply lower the irradiance and increase the time, or vice versa. Coming back to the original point, it is found that the higher the irradiance, the higher the pain associated with treatment.
In conventional PDT, a bank of (typically) red LEDs is placed close to the patient’s skin to deliver a high irradiance of light over a shorter treatment time, anywhere up to 17 minutes. This high irradiance can cause high levels of pain in many patients. In dPDT the irradiance is much lower, hence why the treatment times are much longer, in order to deliver a similar dose of light. The typically lower irradiance experienced during dPDT means that patients experience much less pain overall.
So now that we have established that dPDT is an effective, well tolerated and pain-free treatment, what are the drawbacks? The one real downside to dPDT is that it is entirely weather dependent. It is generally agreed upon that there is a lower limit to the dose of light needed to get an effective treatment – below this light dose and the treatment efficacy declines.
However, our recent data suggests that even in some of the winter months around midday, there could be enough light on clear days for good treatment, particularly in the southern parts of the UK. The limiting factor here becomes the temperature. Quite simply, it is too cold to expect patients to sit outside for a couple of hours in January. The generally accepted outdoor temperatures for treatment are no less than 10˚C, which rules out most of the winter months, and even in to the months of say March, and October in many locations. This isn’t a problem for patients who have a conservatory, however, or in hospitals fortunate enough to have rooms with large south-facing windows. Window glass cuts the incoming daylight by around 25%, so keeping that in mind this does present an opportunity to do dPDT when the outside temperature is too low, but when there is also ample daylight.
An alternative is a relatively new method called artificial dPDT. The idea is to use low irradiance lighting, e.g. from a light bulb, to activate the photosensitiser and create an effect mimicking that of dPDT – after all, the light from the sun and the light from a light bulb is exactly the same stuff. Groups in Denmark and Ireland have experimented with different light sources for low-irradiance artificial dPDT. The Denmark group, led by Prof. Wulf in Bispebjerg Hospital, Copenhagen, compared different light sources, such as halogen lamps and LED panels, to see if these existing and common sources could be viable. The way they measured the suitability was by measuring how much the photosensitiser is ‘photobleached’.
An important property of PpIX is that it glows (fluoresces) red (635nm) in the presence of UV (365nm) and blue (405nm) light. By measuring or observing this fluorescence, it is possible to get an idea of how much of the photosensitiser is present in the skin. When the photosensitiser is activated by light, it is effectively ‘used up’, and will no longer fluoresce, hence the term photobleaching. While this is not an end-point for treatment, measuring the photobleaching of PpIX can give an indication of how effective a light source might be. Using this method, the group state that many of these light sources are suitable alternatives for artificial dPDT, further strengthening the case for indoor dPDT.
All of this ultimately depends on the light actually reaching the diseased tissue. If the light doesn’t reach the tissue, then there is no activation of the photosensitiser and hence, no treatment. We can understand how light propagates through tissue by utilising Monte Carlo simulations.
The Monte Carlo method is a probabilistic method of gaining numerical solutions, basically meaning that you can set up a computer model with various input parameters, run it multiple times (often thousands or more) and get a picture of how you might expect that system to behave. For example, by inputting parameters such as the absorption and scattering coefficients of the skin and tumour tissue in to such a model, one can simulate the how far the light propagates through the tissue model for any given simulated light source.
Researchers at Ninewells Hospital Dundee and the University of St. Andrews have recently developed 3D fractal models to simulate light transport through tissue containing clusters of healthy and diseased tissue in order to better understand exactly what is going on under the surface of the skin during PDT. Using their 3D fractal models, they found that the light penetrated deeper in to the tissue than previously thought, when compared to the standard homogenous Monte Carlo models of skin tissue.
It is also known that red light will penetrate deeper into the skin than blue light, hence why red LEDs are used in conventional PDT - to reach deeper lesions. Although PpIX absorbs light at this wavelength, it most strongly absorbs in the blue region.
This means that in dPDT, the majority of the effect comes from PpIX absorbing in the blue region, which in turns means that dPDT is more suitable for superficial lesions, as opposed to much deeper lesions. Having an understanding of how the light behaves in tissue gives us a better understanding of how appropriate each different type of light-based treatment, be that conventional PDT or dPDT, is for a given lesion.
Daylight PDT is becoming more common across the UK, with the dawning realisation across many centres that this is an effective and worthwhile treatment, while simple and convenient for both patients and clinicians. Through further research and collaboration with national and international teams, we hope to shine a light on dPDT, and provide confidence in this initially counter-intuitive proposal.