Light-tissue interactions for developing portable and wearable optoelectronic devices for sensing of tissue condition, diagnostics and treatment in Photodynamic therapy (PDT)

Abstract

This thesis presents the development and in-vivo applications of wearable and portable devices for the investigation of light interaction with tissue involved in Photodynamic therapy (PDT) and during contraction of muscles. A hand-held device and a clinical method were developed for time course in-vivo imaging of the fluorescence of the photosensitizer Protoporphyrin IX (PpIX) in healthy and diseased skin with the aim to guide improvement of PDT protocols. The device was used in a small clinical study on 11 healthy volunteers and 13 patients diagnosed with non-melanoma skin cancer (NMSC). Two types of PpIX precursors were administered: Ameluz gel and Metvix® cream. The fluorescence was imaged with a 10 minute time step over three hours which was the recommended metabolism time before commencing PDT treatment at Ninewells Hospital, Dundee. The fluorescence time course was calculated by integrating the areas with the highest intensity. The fluorescence continued to grow in all subjects during the three hours. The time course varied between individuals. There was no statistical significance between either healthy volunteers or patients in Ameluz vs Metvix® groups; nor was there statistical difference between the three lesions groups (Actinic keratosis (AK) Ameluz vs AK Metvix® vs Basal cell carcinoma (BCC) Metvix®). The p-value was larger than 0.05 in a two sample t-test with unequal variances for all the groups. However, there was strong body site dependence between the head & neck compared to the lower leg & feet, or the trunk & hands body site groups (p-value<0.01). One of the possible explanations for this was temperature and vasculature variation in skin at different body sites: the temperature is higher and the vasculature structure is denser at the head and the neck compared to the lower leg or the trunk. The temperature was not measured during the study. So in order to support this hypothesis, typical skin temperatures at the lesion sites were taken from the IR thermal images of healthy skin available in literature. PpIX fluorescence had a positive correlation to temperature. If this hypothesis is true, it will be highly important to PDT treatment. Increasing the temperature could speed up the metabolism and reduce the waiting time before starting the treatment; ambient temperature should be taken into account for daylight PDT; cooling air as pain management should be administered with caution. Potential improvements for wearable PDT light sources were investigated by modelling light transport in skin for the current LED-based Ambulight PDT device, a commercial OLED for future devices and a directional OLED developed in the group. The optical models were implemented in commercial optical software (with intrinsic Monte Carlo ray tracing and Henyey-Greenstein scattering approximation) which was validated on diffuse reflectance and transmittance measurements using in-house made tissue phantoms. The modelling was applied to investigate the benefits from diffusive and forward scattering properties of skin on light transmission in treatment light sources. 1 mm thick skin can only compensate approximately 10% of non-uniform irradiance. It means that uniform illumination is crucial for the treatment light sources. Forward scattering in skin showed a 10% improved light transmission from a collimated emission compared to a wide angle Lambertian emission. However, depth-dependent transmission measurements of directional vs Lambertian emission from organic light emitting films (a nano-imprinted grating was fabricated to provide directional emission in one of the films), collimated vs diffused HeNe laser light through fresh porcine skin did not show the expected improvement. This could be explained by skin roughness which was previously found to change the optical properties and may also affect light coupling. The modelling was applied to guide an optical design of another wearable device – a muscle contraction sensor. Muscle is fibrous and because of that scatters light differently in different directions. The sensor detects the change in backscattered light in parallel and perpendicular directions with respect to muscle fibres. The sensor was implemented on a wearable bandage on fully flexible substrate with flexible OLED and organic photodiodes. The major advantages of organic optoelectronic sensing compared to conventional electromyography (EMG) sensors are the ability to distinguish two types of contractions (isotonic and isometric), insensitivity to electromagnetic interference and the absence of an immune response due to non-invasive electrode-free sensing. Optical modelling was performed to understand the operation of the sensor. A 3D anisotropic optical model of scattering in muscle was created by geometrical manipulations with the standard Henyey-Greenstein scattering volumes. The penetration depth from the Super Yellow OLED was found to be 20-25 mm; the optimal separation between the source and the detector was found to be 20 mm. This distance provided a still detectable signal along with the best discrimination between the two backscatterings. When a 2 mm thick layer of skin and a 2 mm thick layer of adipose tissue were added to the model, the signal was hugely diffused. The discrimination between the two backscatterings decreased by three orders of magnitude, the penetration depth in muscle was reduced, and the intensity of the signal dropped down but was still detectable. With 5 mm thick adipose tissue and 2 mm thick skin the signal was too diffused and interacted with very shallow layers of muscle which approached the limits of the optical sensing of muscle activity.