This PDF file contains the front matter associated with SPIE Proceedings Volume 11628, including the Title Page, Copyright information, and Table of Contents.

Welcome and Introduction to SPIE Photonics West BiOS conference 11628: Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXX

Welcome and Introduction to SPIE Photonics West BiOS conference 11628: Mechanisms of Photobiomodulation Therapy XVI

Ovarian cancer typically spreads throughout the peritoneal cavity, and despite standard of care treatments (surgical debulking and chemotherapy), the five-year relative survival rate remains below 50%. The use of antibody-photosensitizer conjugates (photoimmunotherapy) has emerged as a promising modality to achieve targeted photosensitizer delivery to ovarian cancer cells. In this study, we investigate epithelial growth factor (EGFR)-targeted PIT coupled with inhibition of prostaglandin E2 receptor 4 (EP4), a G-coupled-receptor that contributes to cancer progression and intracellularly transactivates EGFR. This potent triple combination significantly attenuates the metastatic behavior of ovarian cancer cells through simultaneously inducing photochemical damage and modulating protein expression.

PDT efficacy depends on the availability and dynamic interactions of photosensitizer, light, and oxygen. Tissue optical properties influence the delivered light dose and impact PDT outcome. In-vivo measurements of tissue optical properties and photosensitizer concentration enable determination of explicit and implicit dose factors affecting PDT and helps to understand the underlying biophysical mechanism of PDT. In this study, we measure tissue optical properties (absorption μa (λ) and scattering μs’ (λ) coefficients) and PpIX concentration in tissue simulating liquid phantoms with a geometry that resembles anal canal. In-vivo light fluence rate and photosensitizer fluorescence of 405nm excitation light source were acquired using a dual-motor continuous wave transmittance spectroscopy system. We characterized the tissue optical properties correction factor of fluorescence signal using a series of tissue simulating phantoms with known PpIX concentrations and with absorption coefficient between 0.1 – 0.9 cm^-1 and reduced scattering coefficient between 5 – 40 cm^-1. The results demonstrated that our spectroscopy system could determine the distribution of tissue optical properties and PPIX concentration during anal PDT.

There are multiple determinants of PDT efficacy. An in vitro study showed that the head and neck tumor lines derived from patients with an HPV infection showed a substantial decrease in the degree of photokilling by PDT directed at ER/mitochondria. We previously reported that this was not correlated with altered photosensitizer uptake, sites of sub-cellular concentration, or rate of ROS formation. PDT targeted to the ER can lead to the initiation of parapotis, a death pathway associated with ER stress. This pathway appears to be operational even cell lines with an impaired apoptotic pathway and can lead to an apoptotic response. Impaired PDT-induced photokilling in HPV(+)line was associated with a decrease of both the paraptotic response to ER photodamage and the loss of mitochondrial membrane potential (ΔΨ_m) after mitochondrial photodamage. This may explain, in part, the impaired response to PDT when BPD (benzoporphyrin derivative, Vidsudyne) was the photosensitizing agent.

Tissue optical properties are crucial for determining the light dose delivered to the tumor. Two probes are compared: the two-catheter probe is based on transmittance measurement between one point source and one isotropic detector inside parallel catheters spaced at 0.5 cm along a 1-inch diameter transparent cylinder; and a 1-inch trans-rectal diffuse optical tomography (DOT) probe designed for prostate measurements, using a multiple fiber-array with source-detector separations of 1.4-10 mm. The two-catheter probe uses an empirical model for primary and scatter light fluence rates in the cylindrical cavity condition for anal PDT to determine optical properties along the source catheter using dual motors to move the source and detector along the catheters. The DOT probe uses finite element method (FEM) to obtain distribution of optical properties in 3D. Validations for the two probes were performed in liquid and solid phantoms. For each method, validation was performed in tissue-mimicking liquid phantoms for a range of known optical properties (μ_a between 0.05 and 0.9 cm^-1 and μ_s’ between 5.5 and 16.5 cm^-1). To cross-check the two methods, solid phantoms were created of known optical properties at the University of Pennsylvania and sent for measurement to Princess Margaret Cancer Centre (PMH) to mimic realistic patient simulating conditions. Measurements were taken and optical properties were then recovered without knowing the expected values to cross-validate each probe. The results show modest agreement between the measured μ_a and μ_s’values, but high degree of agreement between the measured μ_eff performed independently using the two methods.

This Conference Presentation, “LLL promotes engraftment of human umbilical cord blood-derived hematopoietic stem and progenitor cells,” was recorded for the Photonics West 2021 Digital Forum.

The use of controlled temporal modulated light increased in prominence since the LEDs invention, e.g., in computer monitors and light therapy devices. The benefits of using LEDs compared to old incandescent light bulbs range from environmental load to the precise control of the spectral properties and the ability to accurately control the temporal modulation of the light. The nature of LEDs also allows LED lamps to be switched on and off faster than ordinary incandescent light bulbs. The driver frequency of most LEDs (~25 kHz) is so high that the modulation of firing rates of the retinal neurons cannot time dissolve the flicker at this frequency. But in some cases, the function of the LED is to provide temporal modulation at frequencies much lower, in the range of 24-48 Hz. Knowing the Critical Flicker-Fusion Frequency (CFF), the frequency at which temporally modulated light becomes steady, is therefore important. Potential treatments of Alzheimer’s disease are currently being examined in humans using both stroboscopic and invisible spectral flickering light, using a 40 Hz temporal modulation. Ultimately, the CFF dependency on color, luminance, viewing angle and background lighting needs to be taken into account when designing and developing 40 Hz light sources for potential therapeutic use within the field of Alzheimer's disease. Here, we present a potential benefit of using the staircase method with a 2-alternative forced choice to determine the CFF. Specifically, we show a portable experimental setup that may be used directly to optimize light therapy for patients with Alzheimer’s disease.

Recently, we introduced a novel treatment of Alzheimer's disease (AD) consisting of the use of photobiomodulation (PBM) coupled with a static magnetic field . The efficiency of this approach was evidenced on a model of mice affected by a neurotoxic agent (Amyloid-β(25-35)). In this communication, we will present recent results using this approach at the scale of neural cells in culture, as an attempt to enhance the benefit of light starting from a much simpler model than an entire mammalian organism. We will highlight the interest of using imaging instead of ensemble fluorescence measurements, and comment on parameters such as the PBM wavelength, fluence and glutamate concentration.

In the last decade PhotoBioModulation therapy (PBM) gained importance in clinical practice, thanks to the technological development of low cost lights sources in a broad wavelength range. In wound management, PBM has been listed as physical therapy and blue light has been used in case of insufficient healing, as in chronic and hard-to-heal wounds. In our previous study in in vivo model, we demonstrated that blue light (410-430 nm) can modulate fibroblasts activity in superficial wounds. Here, we present a study about the effects of blue light (3.43-6.87-13.7-20.6-30.9 and 41.2 J/cm2 doses applied, 410–430 nm, 0.69 W/cm2 power density) on cellular metabolism, proliferation and viability of human fibroblasts obtained from keloid and perilesional tissues, compared with fibroblasts isolated from healthy skin. Excessive healing, where fibrotic tissue is formed, is an aberration in wound healing, denoted by keloids and hypertrophic scars. In the study, electrophysiology was used to investigate the effects on membrane currents while Raman spectroscopy revealed the mitochondrial Cytochrome C oxidase dependence on blue light irradiation. Also, the keratinocytes cell line was tested and co-cultures were prepared to perform scratch test assays. Finally, a simple model to study the effectiveness of light irradiation in cells in the depth tissue, was optimized using a dermal substitute. Overall, these data demonstrate that PBM can be used as an innovative and minimally-invasive approach in wound management not only in case of insufficient healing, but also in skin fibrosis, in association with standard treatments.

The aim of this study was to compare the effectiveness of low-intensity LED radiation of the red and infrared spectra for the correction of mucositis in patients receiving radiation and chemoradiation therapy for oral and pharyngeal cancer at an energy density of less than 1 J/cm². The study included 106 patients who received radiation and chemoradiation therapy for oral cavity and pharyngeal cancer, who were randomly divided into three groups. In the first (37 patients) correction of mucositis was carried out in accordance with the clinic's standards, in the second (36 patients) and the third (33 patients), patients additionally received exposure to the oral cavity with low-intensity LED radiation at a wavelength of 635 nm at a dose of 0,3 J/cm² (prophylactic regimen) and 0.45 J/cm² (treatment regimen). When exposed to a wavelength of 780 nm, the dose was 0.6 J/cm² with a prophylactic regime and 0.8 J/cm² with a therapeutic regimen, respectively. Exposure to low-level LED irradiation at a wavelength of 635 nm significantly reduced the frequency and severity of radiation mucositis, increased the time until the onset of its first symptoms, reduced the duration of severe mucositis (grade 3) and reduced the patients' need for painkillers, including narcotic analgesics compared with the group receiving standard prophylaxis and correction of mucositis. Photobiomodulation at a wavelength of 780 nm, compared with the standard correction group, significantly increased the time to the onset of the first symptoms of mucositis and decreased the severity of pain.

This Conference Presentation, “Photoacoustic nanodroplets for oxygen enhanced photodynamic therapy,” was recorded for the Photonics West 2021 Digital Forum.

There is an ongoing need in photodynamic therapy (PDT) research to develop highly active photosensitizers (PSs) with improved characteristics combined with optimized treatment protocols to produce effective treatment with minimal side effects. While several novel PSs have undergone clinical trials or been approved in recent years, there remain few available instrumentation options for high-throughput screens (HTS) with in vitro PDT. The Modulight ML8500 was developed to address this need, facilitating HTS of potential PSs with its precisely specific control over the light component. The instrument can select from a variety of high-power, monochromatic wavelengths for screening in the context of a tumor-centered approach, whereby the light dose can be tailored to optimize for physiological conditions or limitations specific to the type of cancer. In the present case, the ML8500 was used here to characterize a series of promising ruthenium-based complexes specifically designed to target melanoma. These PSs could be activated over a broad range of wavelengths, and most importantly including in the near-infrared range, where light penetrates tissue more effectively. In a second study, osmium-based PSs were characterized with the ML8500 in normoxic and hypoxic conditions with variable light parameters (wavelength, light dose, light fluence), showing high activity even in hypoxic conditions. These are specific examples where the ML8500 successfully increased experimental flexibility, reproducibility, and throughput.

we developed mitochondrially targeted biodegradable polymerpoly(lactic-co-glycolic acid) nanocarriers incorporating a photosensitiser verteporfin, ultrasmall (2-5 nm) gold nanoparticles as radiation enhancers and triphenylphosphonium acting as the mitochondrial targeting moiety. Upon X-ray radiation our nanocarriers generated cytotoxic amounts of singlet oxygen within the mitochondria, triggering the loss of membrane potential and mitochondria-related apoptosis of cancer cells. Our X-PDT strategy effectively controlled tumour growth with only a fraction of radiotherapy dose (4 Gy) and improved the survival rate of a mouse model bearing colorectal cancer cells. It may offer a paradigm-shifting treatment alternative for patients who need neoadjuvant radiotherapy but wish to avoid long term detrimental effect on functional outcome by undergoing X-PDT using only a fraction of the conventional radiotherapy.

The aim of the work was studying the effects of photobiomodulation in doses of less than 1 J/cm2 in combination with gamma-irradiation to Hela Kyoto cells. Tumor cells were irradiated with 640 nm LED at different energy densities before and after to gamma-irradiation. Cells viability was determined 24 h after exposure for each gamma-irradiation dose and PBM mode. There was a statistically significant decrease in a number of viable tumor cells for samples that were exposed to PBM prior to gamma-irradiation and a statistically significant increase in a number of viable tumor cells for samples that were exposed to PBM after gamma-irradiation.

Fibromyalgia is characterized by generalized chronic pain with many non-pharmacological therapies available for its treatment. Assessment of quality of life (QoL) for the evaluation of chronic painful patients is a key point of integral treatment. However, the relationship between fibromyalgia, Laser Therapies, and QoL is not known. Aims: to evaluate the current literature regarding the effect of LT in the quality of life of fibromyalgia patients. Methods: in 2020 a systematic review was performed according to the Preferred Reporting Items for Systematic Reviews (PRISMA) statement searching for RCTs in humans following the P.I.C.O. strategy (P=fibromyalgia, I=Laser Therapies C=control group, O= quality of life) at PubMed, EMBASE, LILACS, PeDro and Open Gray database. The quality assessment of studies was analyzed by NIH Quality Assessment Criteria and Cochrane Review Criteria. Results: a total of 822 papers were first identified but only 8 RCT were selected to results including 414 patients. The LLLT as evaluated by FIQ or SF-36 demonstrating significant difference compared with the control group for 03 studies (p = 0.01). Conclusion : So far, only 8 studies have evaluated the quality of life of patients with fibromyalgia after using LT in spite of Qol is the best outcome for chronic pain studies. The 3 studies that found positive results are the studies with the best scientific methodology with placebo controlled groups and a larger sample size, which suggests that the use of laser can be promising in improving the quality of life of fibromyalgia patients.

The photobiological destruction via direct photothermal (light alone) or indirect photodynamic (light and dye) action that have been noted to evoke a subjacent biological response. The inherently destructive nature of these approaches generates antigenic determinants that evoke a host immune response. In contrast, the use of low dose light treatments to induce a therapeutic host immune response is attributed to Photobiomodulation (PBM) therapy. The utility of PBM to shore up the immune system as potent vaccine adjuvants and induce antimicrobial peptides have been reported. This presentation will highlight Photoimmunotherapy as a novel application using multiple treatments that are primarily focused on therapeutically enhancing the host immune responses.

Despite heavy focus on the photochemical and photoelectrical mechanisms of Photobiomodulation (PBMt) and Photodynamic therapies (PDt), minimal attention has been paid to photophysical pathways. In this presentation, we will discuss non-visual phototransduction pathways including mechanotransduction, biophotonic signalling, and light-indued micro-oscillation mechanisms related to PBMt and PDt. We will also discuss the implications of these mechanisms in pathological conditions such as Parkinson’s disease, migraine with aura, and fibromyalgia, and Crigler-Najjar syndrome, and how PBMt may be effective as a potential therapy.

Many clinical trials on photobiomodulation (PBM) therapy from head to toe have been reported during the last 30 years. The benefits of PBM therapy (PBMT) include pain relief, wound healing, skin rejuvenation, hair growth, and reduction of inflammation, and etc. Recently, applications of PBMT on the nose and brain have shown to be effective in delaying the progress of the neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s diseases (PD). Various PBMT devices have been used to treat the neurodegenerative brain diseases, but the PBMT device structure, doses, irradiances, and light sources used for the clinical trials were different, which makes it difficult for users to find an appropriate treatment method. In this paper, diverse treatment methods for the neurodegenerative brain disease, and the most frequently used PBMT conditions were analyzed.

Traditionally one of the biggest challenges with light-based treatment modalities such as photodynamic therapy or different tumor ablation techniques is to determine how much light should be applied to the tissue and how that will be distributed to activate a bio-photonic process or a drug. Different tools have been developed to model light distribution in tissue, but this has not solved the problem of how to know what happens in the tissue during the treatment. Modulight has assessed this problem and developed a state-of-the-art laser platform with real-time treatment monitoring capability. Modulight ML7710i platform enables illumination and detection with up to eight illumination channels on same or different wavelength(s). Spectral measurements can be measured and collected with the same fibers that are used for illumination which is minimally invasive and eliminates the need for complicated measurement set-ups with moving fibers around in the tumor tissue or having separate monitoring probes. The system also is connected to cloud making treatment planning, data collection and analysis easy and reliable enabling machine learning and AI based medicine in the future. ML7710i type of medical device makes it possible not only to measure the light intensity at tumor margins but also monitor the progress of the treatment by measuring photosensitizer photobleaching, drug release or activation of multimodal drugs. Photobleaching monitoring with ML7710i is currently utilized in 5-ALA mediated clinical trials for glioblastoma and the data looks very promising. In addition, also drug release from novel light activated nanoparticles or other drug carriers can be effectively monitored for pharmaceuticals that possess fluorescent potential or carry fluorescence labels.

Total Skin Electron Therapy (TSET) utilizes high-energy electrons to treat cancers on the entire body surface. The otherwise invisible radiation beam can be observed via the optical Cherenkov photons emitted from interaction between the high-energy electron beam and tissue. Cherenkov emission can be used to evaluate the dose uniformity on the surface of the patient in real-time using a time-gated intensified camera system. Each patient was monitored during TSET by in-vivo detectors (IVD) as well as Scintillators. Patients undergoing TSET in various conditions (whole body and half body) were imaged and analyzed. A rigorous methodology for converting Cherenkov intensity to surface dose as products of correction factors, including camera vignette correction factor, incident radiation correction factor, and tissue optical properties correction factor. A comprehensive study has been carried out by inspecting various positions on the patients such as vertex, chest, perineum, shins, and foot relative to the umbilicus point (the prescription point).

Malignant tissues can be effectively treated by Total Skin Electron Therapy (TSET) over the entire body surface using 6 MeV electron beams. During the radiation treatment, Cherenkov photons are emitted from the patient’s skin, and can potentially be used for in-vivo imaging of the radiation dose distribution. A Monte Carlo (MC) simulation toolkit TOPAS is used to study the generation and propagation of Cherenkov photons that are generated from the interaction of electron radiation with human tissues, and to understand the relationship between the dose distributions and the Cherenkov photon distributions. Validation of MC simulations with experiments are performed at 100 SSD and 500 SSD, and simulations of a patient phantom in realistic clinical treatment setups have been done. These simulations with TOPAS show that the emitted Cherenkov distributions at phantom surfaces closely follow their corresponding dose distributions.

Photosensitizer fluorescence emission during photodynamic therapy (PDT) can be used to estimate for in vivo photosensitizer concentration. We built a surface contact probe with 405nm excitation light source to obtain Photofrin fluorescence signal during clinical PDT. The probe was equipped with multiple detector fibers that were located at distances between 0.14 to 0.87 cm laterally from the excitation source fiber. In this study, we investigated the probing depth of fluorescence in biological tissue with different source-detector separation using our contact probe setup. We used Monte Carlo method to simulate the 405nm excitation light and 630nm fluorescence probing depth at various source and detector (SD) separations. The results provided insight to the most probable depth of origin of detected fluorescence at each SD separation and help to understand the in vivo depth distribution of clinically measured Photofrin concentration.

Nowadays, the application of nanoparticles for biomedical purposes is a promising and innovative tool for the thermal therapy of tumors. Gold nanoparticles are distinguished by their tunable optical properties, biocompatibility, and ease of synthesis. The ability of gold nanoparticles to absorb light at near-infrared region (NIR) to generate localized heat allows temperature elevation and optimizing the temperature distribution during short-time laser ablation. The synthesized 20-nm gold nanoparticles injected on the surface of the tissue demonstrated rapid and diffused heat increase enlarging the shape of the treated region compared to the pristine tissue. Another advantage of this work is the proposed optical fiber distributed sensing network over the laser ablation assisted with nanomaterials. The sensing system uses single-mode enhanced-backscattering optical fibers doped with MgO nanoparticles; it achieves narrow spatial resolution, which demonstrates accurate temperature distribution monitoring in real time, in 2-dimensions over 5.4 cm² area at 16 sensing points per fiber. The obtained sensing data allowed to calculate the treated area and provided the information when the ablation process should be terminated in order to avoid the vaporization of tissue after reaching the temperature of 100 °C. The calculated damage threshold (>60 °C) areas are 2.57 cm² with gold nanoparticles, compared to 1.33 mm² pristine. The results of this work provide the solution to two issues existing during laser ablation that are possible damage of undesired area and the ability to precisely monitor the temperature in real time that is compatible to MRI.