Objective: The goal of this study is to investigate the efficacy, safety, and mechanism of ABL for inactivating Candida albicans (C. albicans), and to determine the best wavelength for treating candida infected disease, by experimental measurements and dynamic modeling. Methods: The changes in reactive oxygen species (ROS) in C. albicans and human host cells under the irradiation of 385, 405, and 415nm wavelengths light with irradiance of 50mW/cm2 were measured. Moreover, a kernel-based nonlinear dynamic model, i.e., nonlinear autoregressive with exogenous inputs (NARX), was developed and applied to predict the concentration of light-induced ROS, whose kernels were selected by a newly developed algorithm based on particle swarm optimization (PSO). Results: The ROS concentration was increased respectively about 10-12 times in C. albicans and about 3-6 times in human epithelial cells by the ABL treatment with the same fluence of 90J/cm2. The NARX models were respectively fitted to the data from the experiments on both types of cells. Besides, four different kernel functions, including Gaussian, Laplace, linear and polynomial kernels, were compared in their fitting accuracies. The errors with the Laplace kernel turned out to be only 0.2704 and 0.0593, as respectively fitted to the experimental data of the C. albicans and human host cells. Conclusion: The results demonstrated the effectiveness of the NARX modeling approach, and revealed that the 415nm light was more effective as an anti-fungal treatment with less damage to the host cells than the 405 or 385nm light. Significance: The kernel-based NARX model identification algorithm offers opportunities for determining the effective and safe light dosages in treating various fungal infection diseases.

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The therapeutic properties of light have been known for thousands of years, but photodynamic therapy (PDT) was only developed in the last century. Currently, PDT is in clinical trials for the oncology-the treatment of head and neck, brain, lung, pancreas, abdominal cavity, breast, prostate, and skin cancer. Advantages of the light-based therapies include rapid action and avoidance of drug resistance. The underlying mechanism of PDT is that the photosensitizers (PS) transform from their ground state (singlet state) into a relatively long-lived electronically excited state (triplet state) by the absorbing the photo energy, which, in turn, produces highly toxic reactive oxygen species (ROS) in cells. One difficulty of PDT is the administration of PS. Since the PS does not naturally exist, PDT relies on the exogenous PS which is administered by intravenous injection or topical application to the skin. This makes three disadvantages: first, the PS needs to be approved before it can be applied to patients; second, the adverse reaction of importing the exogenous PS can not be eliminated even if it is approved; and third, for the tumor under deep tissue, it is hard to import the PS to incidence area. Similar to PDT, the antimicrobial blue light (ABL) only relies on the endogenous PS (flavin and porphyrin molecules) to inactivate the microbes, which is safer to use. However, as it is named, ABL can be only used for treating diseases whose pathogen is microbes, but the tumor. The most common application of ABL is treating various microbial superficial infections, e.g., skin or membranes. Traditionally, topical antimycotic/ antibiotic drugs and more convenient oral azole agents are the main treatments for microbial infections. However, most pathogens have shown increased resistance to these drugs. Especially, the most famous one, methicillin-resistant Staphylococcus aureus (MRSA), was called ”superbug” which has evolved resistance to most antibiotic drugs. Fortunately, ABLwas proved to be effective in the inactivation of most pathogenic microbes, including MRSA, Candida Albicans, Escherichia coli. Further studies show that the inactivation effect did not significantly decrease after repeated ABL irradiation, which demonstrates the avoidance of resistance to ABL...@en

Objective: The macroscopic singlet oxygen (MSO) model for quantifying the light-induced singlet oxygen ($^{1}O_{2}$) always contain a set of nonlinear dynamic equations and therefore are generally difficult to be applied. This work was devoted to analyze and simplify this dynamic model. Methods: Firstly, the nonlinearity of the MSO model was analyzed with control theory. The conditions, under which it can be simplified to a linear one, were derived. Secondly, in the case of ample triplet oxygen concentration, a closed-form exact solution of the $^{1}O_{2}$ model was further derived, in a nonlinear algebraic form with only four parameters that can be easily fitted to experimental data. Finally, in vitro experiments of anti-fungal light therapies were conducted, where the fungi, Candida albicans, were irradiated respectively by the 385, 405, 415, and 450 nm wavelength light. The singlet oxygen concentration levels in the fungi were measured, and then used to fit the developed models. Results: The parameters of the closed-form exact solution were estimated from both the simulated and the measured experimental data. Based on this model, a functional relationship between the photon energy, fluence rate and singlet oxygen concentration was also established. The fitting accuracy of this model to the data was satisfactory, which therefore demonstrates the effectiveness of the proposed modeling techniques. Conclusion: The results from simulating the closed-form model indicate that the photon energy within the range of either 2.7 $\sim$ 2.8 eV or 3.0 $\sim$ 3. 2 eV (388 $\sim$ 413 nm or 443 $\sim$ 459 nm in wavelength) is more effective in generating singlet oxygen in the fungi studied in this work. Significance: It is the first attempt of applying control theory to analyze the photochemical reaction dynamics of light therapies in terms of their nonlinearity. The proposed modeling techniques also offer opportunities for determining the light dosages in treating fungal infection diseases, especially those on the surface tissues of human body.

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Anti-fungal blue light (ABL) therapies are based on the photochemical reaction of endogenous photosensitizer (PS) in fungal cells. Knowing the spectral sensitivity of these cells for the ability to generate singlet oxygen is thus important to determine the most effective wavelength of such light therapies, and thereby to design ABL therapeutic devices, e.g., by light emitting diodes. We propose a modeling method of such spectral sensitivity in this work, based on the absorption spectra of cells and other inherent characteristic parameters, i.e., singlet oxygen quantum yield and the extinction coefficient of the endogenous PS. Specifically, the absorption spectra are determined by the PSs inside the fungus Candida albicans and human epithelial cells. Then, the concentration of PS in those two types of cells was measured by high-performance liquid chromatography (HPLC) assays. The HPLC assays show that the coproporphyrin (CP) is the main PS in C. albicans, accounting for 60% of the total PS. The simulation results demonstrate that the 390420nm light can stimulate the PS in the cells to generate more singlet oxygen in C. albicans than in epithelial cells; and this range is the same as the CP Soret band. In contrast, the light with wavelengths >450nm is less effective in exciting the PS in C. albicans, and leads to more singlet oxygen generation in V.E. cells than shorter wavelength. We thus conclude that 390420nm light is the most effective range for inhibiting C. albicans with the least damage to human host cells.

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Anti-fungal blue light (ABL) therapies have been widely studied to treat various microbial infections in the literature. The blue light with wavelengths ranging from 400 to 470 nm has been reported to be effective to inhibit various kinds of bacteria and fungi. The existing studies usually report the viability rates of the pathogens under the irradiation of the blue light with different dosage parameters. However, to the best of our knowledge, there is still no work especially focusing on studying the effect of ABL therapies on treating candida vaginitis, where it is important to study the viability of both the Candida albicans (C. albicans) and the human vaginal epithelial cells. It is the purpose of this work to conduct ABL experiments on both of these two cells, analyze the effects, and determine the best ABL wavelength out of three candidates, i.e., 405-nm, 415-nm, and 450-nm wavelength. The viability rates of the C. albicans and the human vaginal epithelial cells irradiated by the three blue LED light sources were measured, whose irradiance (power density) were all set to 50 mW/cm². The dynamic viability models of the C. albicans and the epithelial cells were built based on the experimental data. Moreover, in this work, we also built a functional relationship between the viability of these two types of cells, by which we further compared the effects of the blue light irradiation on both the C. albicans and vaginal epithelial cells. The experimental data showed that when an approximately 80% inhibiting rate of the C. albicans was achieved, the survival rates of the epithelial cells were 0.6700, 0.7748, and 0.6027, respectively for the treatment by the 405-nm, 415-nm, and 450-nm wavelength light. On the other hand, by simulating the functional relationship between the viability of the two types of cells, the survival rates of the epithelial cells became 0.5783, 0.6898, and 0.1918 respectively using the 405-nm, 415-nm and 450-nm wavelength light, when the C. albicans was completely inhibited. Therefore, both the experimental data and the model simulation results have demonstrated that the 415-nm light has a more effective anti-fungal result with less damage to the epithelial cells than the 405-nm and 450-nm light.

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Light therapies can be used to treat fungal infections. A general mechanism is attributed to the generation of cytotoxic reactive oxygen species (ROS) due to light stimulation. The effectiveness of these therapies has been widely studied in the literature via conducting biological experiments, where fungi are exposed to light with various wavelengths and power. However, despite the large amount of work reporting the experimental results, few efforts have been given to build a mathematical model that describes the amount of generated ROS as a function of the photon energy and power of the stimulating light. The lack of such a model still hinders the optimization of the light doses. In this work, we propose a novel modeling method based on experimental data, so as to establish a mathematical relationship between the ROS concentration and the stimulating photon energy and light fluence (energy density). The anti-fungal experiments were performed on Candida {}albicans (C. {}albicans) using four LED light sources with different wavelengths ranging from 385nm to 450nm. Both the viability of the fungi and the ROS concentration therein were measured during the experiments. High fitting accuracy has been achieved by the model, which therefore demonstrates the effectiveness of the proposed modeling techniques.

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Microbial infection is one of the most common diseases in the world, which gives rise to morbidity and mortality. At present, the main treatment is using antibiotic drugs. However, the side effects range from fever and nausea to major allergic reactions cannot be ignored. Moreover, the increasing drug resistance also necessitates a new safe alternative therapeutic approach against the microbial infections. As non-antibiotic methods, photodynamic therapies (PDT) and anti-microbial blue light (ABL) therapies have been investigated in this field. However, one challenge of the PDT is the introduction of photosensitizers to the specific pathogens rather than the host cells. In contrast, ABL therapies inactivate the microbes without the involvement of exogenous photosensitizers. The general mechanism of ABL therapies is that ABL can excite the endogenous photosensitizers, and trigger the accumulation of cytotoxic reactive oxygen species (ROS), which in turn leads to cell damage. In this study, we investigated the inhibitive capability of the 405nm LED light source on Candida albicans (C. albicans). C. albicans is the most common pathogen of fungal infections. The intracellular ROS level of C. albicans was detected after the ABL irradiation. The results obtained from this study demonstrated that irradiation of 405nm LED significantly inactivated the C. albicans. The viability of C. albicans was reduced to 1% after 25 minutes of ABL exposure of 50mW/cm². On the other hand, the intracellular ROS was increased by the ABL irradiation. This study demonstrates the effectiveness of applying 405nm LED to threat the infection caused by C. albicans, as the result of the stimulated accumulation of the intracellular cytotoxic ROS by this light.

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