"Quantum Leap" in Photobiomodulation Therapy Ushers in a New Generation of Light-Based Treatments for Cancer and Other Complex Diseases: Perspective and Mini-Review.

OBJECTIVE: Set within the context of the 2015 International Year of Light and Light-Based Technologies,and of a growing and aging world population with ever-rising healthcare needs, this perspective and mini-review focuses on photobiomodulation (PBM) therapy as an emerging, cost-effective, treatment option for cancer (i.e., solid tumors) and other complex diseases, particularly, of the eye (e.g., age-related macular degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa) and the central nervous system (e.g., Alzheimer's and Parkinson's disease). BACKGROUND DATA: Over the last decades, primary and secondary mechanisms of PBM have been revealed. These include oxygen-dependent and oxygen-independent structural and functional action pathways. Signal and target characteristics determine biological outcome, which is optimal (or even positive) only within a given set of parameters. METHODS: This study was a perspective and nonsystematic literature mini-review. RESULTS: Studies support what we describe as a paradigm shift or "quantum leap" in the understanding and use of light and its interaction with water and other relevant photo-cceptors to restore physiologic function. CONCLUSIONS: Based on existing evidence, it is argued that PBM therapy can raise the standard of care and improve the quality of life of patients for a fraction of the cost of many current approaches. PBM therapy can, therefore,benefit large, vulnerable population groups, including the elderly and the poor, whilehaving a major impact on medical practice and public finances.

Emerging evidence on the crystalline water-light interface in ophthalmology and therapeutic implications in photobiomodulation: first communication.

OBJECTIVE: The purpose of this study was to present preliminary evidence of the exclusion zone (EZ) and photobiomodulation (PBM) phenomena relating to ophthalmology. BACKGROUND DATA: Water is the main media and fluid found in ocular tissues. Water is also an important photoacceptor and energy storage medium. Eyes are abundantly exposed to environmental radiant energy. Therefore, multiple light-energy-absorption mechanisms may exist, including those associated with the recently discovered fourth phase of water, known as EZ. METHODS: Retrospective analysis of published data indicative of EZ phenomena related, in this first communication, to the retina and optic nerve (ON), using surgical microscopy and diffusion-weighted magnetic resonance imaging (MRI). RESULTS: Images showing removal of the internal limiting membrane (ILM) aided by preservative-free triamcinolone acetonide (TA) during macular hole surgery show continuous whitish lines indicative of water-layer ordering at the interface between collagen matrices and TA crystals. Apparent diffusion coefficient (ADC) results further exhibit an axis parallel to the ON, which may be an ocular expression of the EZ linked to the steady potential of the eye. CONCLUSIONS: Although existing results are still being decoded and analyzed in light of the state of the art studies of light-water interactions, they suggest a new understanding of the eye's bioenergetic environment, which may have deep implications in ocular physiology as well as in the pathophysiology, diagnosis, and treatment of blinding diseases using light-based therapies such as photobiomodulation. Research is needed to confirm the interpretation of these findings and validate potential ophthalmic applications.

Photobiomodulation of aqueous interfaces: finding evidence to support the exclusion zone in experimental and clinical studies.

OBJECTIVE: To present clinical and experimental evidence of the role of exclusion zone (EZ) water in photobiomodulation. BACKGROUND: Water at the interface of most hydrophilic surfaces forms a solute-free area, or EZ, that can project for hundreds of microns. To date, EZ phenomena had been documented in nafion, resins, and biologic membranes. METHODS: Retrospective analysis of published experimental and clinical data using an infrared pulsed laser device (IPLD). RESULTS: Photo-induced effects on the water dynamics of burned rat tissue monitored by 1H-NMR transverse relaxation times (1/T2) indicate significantly greater structuring of water. A microdensitometry study of T2 weighted tumor heterogeneities from a phase I clinical trial in patients with advanced neoplasias and an algorithm for tumor characterization also shows significantly increased structuring of water associated with biopolymers and macromolecules. CONCLUSIONS: To the best of our knowledge, this is the first known demonstration of the EZ in medicine. Data support the premise that photobiomodulation can increase potential energy in the EZ, which then acts as an energy repository that can selectively supplement cell energy demands. It further suggests EZ structuring may be used as a predicator of anticancer response before measurable tumor volume reduction.

Photobiomodulation of aqueous interfaces as selective rechargeable bio-batteries in complex diseases: personal view.

OBJECTIVE: In this personal view, we propose that the modulation of the structure and function of water by light may come to embody a new mechanistic approach for the treatment of complex diseases. BACKGROUND DATA: Long considered an innocuous medium, water has increasingly been found to be a key player in numerous mechanisms, including first-contact events in which cells decide between survival and apoptosis. Consequently, externally applied electromagnetic energy (light) may selectively target the organization of water to steer biological function. METHODS: We survey light-water research with particular emphasis on the quasi-crystalline exclusion zone (EZ), part of the cell's aqueous interface that is just now beginning to be decoded. The current state of research, the technical challenges involved in obtaining evidence in biological systems, and some potential uses and implications of EZ water in medicine are presented. RESULTS: Though existing data have not yet proven the role of EZ water in photobiomodulation, research shows that EZ water can store charge and can later return it in the form of current flow, with as much as 70% of the input charge being readily obtainable. Macroscopic separation of charges can be stable for days to weeks and has unusual electric potential. Water is, thus, an unexpectedly effective charge separation and storage medium. CONCLUSIONS: We propose that the EZ may be selectively targeted in photobiomodulation as an efficient energy reservoir, which cells can use expeditiously to fuel cellular work, triggering signaling pathways and gene expression in the presence of injury-induced redox potentials.

Theoretic, experimental, clinical bases of the water oscillator hypothesis in near-infrared photobiomodulation.

The objective of this review is to propose and document a role for the water oscillator in near-infrared (NIR) photobiomodulation. Greater understanding of the role of the water oscillator may add to a more-coherent description of central effects of NIR light on redox centers and key transmembrane enzymes such as cytochrome c oxidase (CcO). In addition, water provides a complementary pathway for absorption and transportation of NIR energy in photobiomodulation. Because of its unexpected potential, we propose terming it the "water oscillator paradox." Photobiologic mechanisms involved in the treatment of complex diseases are discussed in light of the present state of the art.

Photo-infrared pulsed bio-modulation (PIPBM): a novel mechanism for the enhancement of physiologically reparative responses.

OBJECTIVE: The present manuscript describes the non-invasive, long-range, energy transport of a singular infrared pulsed laser device (IPLD) and the upstream components of the original action mechanism, designated photo-infrared pulsed bio-modulation (PIPBM). BACKGROUND DATA: Major strides have been taken in recent years towards scientifically acceptable clinical applications of low-energy lasers. Nevertheless, challenges still abound. For instance, the range of potential target tissues for laser therapy in medicine has been, until now, limited by the optical penetration of the beam or to sites accessible by fiberoptics. In addition, much needs to be learned about the action mechanisms of pulsed lasers, which can induce unique biological effects. METHODS: We present a review of the IPLD laser technology and the PIPBM mechanism. RESULTS: The studies reviewed suggest that the PIPBM enhances physiologically reparative processes in a non-toxic and selective manner through the activation and modulation of chaotic dynamics in water. These, in turn, lead not only to local, but also long-distance (systemic) effects. CONCLUSIONS: Though additional studies are necessary to fully explore the biological effects of the PIPBM induced by the IPLD, this mechanism may have multiple potential applications in medicine that are the subject of active current and future investigations.

Microdensitometry of T2-weighted magnetic resonance (MR) images from patients with advanced neoplasias in a phase I clinical trial of an infrared pulsed laser device (IPLD).

BACKGROUND AND OBJECTIVE: The aim of this study was to determine whether an infrared pulsed laser device (IPLD)-induced pathophysiologic changes could be identified before measurable modifications in tumor volume. STUDY DESIGN/PATIENTS AND METHODS: Pre-and post-IPLD treatment magnetic resonance (MR) images of tumor heterogeneities and peritumoral tissues were digitized and a linear transformation was performed to convert images to 256 intensity levels. Data were analyzed by using the Student's t-test and the Kolmogorov-Sminov test (alpha = 0.05). RESULTS: The post-treatment mean intensity values of tumor heterogeneities increased significantly (P < 0.001) for all of the seven patients (n = 7) evaluated. For peritumoral tissues, a significant increase (P < 0.001) was measured in four patients (n = 4). The Kolmogorov-Sminov test showed significant values for the tumor tissue of six (n = 6) patients. CONCLUSION: This is the first study of early evidence of anti-cancer activity of a novel IPLD showing a significant increase in the water content of tumor heterogeneities before measurable changes in tumor volume.

H-NMR spin-lattice and correlation times of burned soft-tissue after treatment with an infrared pulsed laser device.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the spin-lattice (T(1), 1/T(1)) and correlation times (tau(c)) of burned soft-tissue after treatment with an infrared (IR) pulsed laser device (IPLD, 904 nm pulsed at 3 MHz). STUDY DESIGN/MATERIALS AND METHODS: Seven groups (GI-GVII), each consisting of four albino rats, were used. Groups I-VI were anesthetized and burned with a hot tip: GI, GIII, GV were not irradiated; GII, GIV, GVI were irradiated at 0; 0 and 24; and 0, 24, and 48 hours, respectively. A control group (GVII) was neither burned nor irradiated. Samples from all groups were evaluated using a 90 MHz hydrogen nuclear magnetic resonance (H-NMR) spectrometer. An unpaired Student's t-test and an ANOVA I were preformed (alpha = 0.05). RESULTS: At 0 and 24 hours, 1/T(1) and tau(c) data revealed significant differences between GVII and both the non-irradiated (GI, GIII), and irradiated (GII, GIV) groups. At 48 hours, only the difference in tau(c) between GVII and the irradiated group (GVI) remained significant. CONCLUSIONS: Spin-lattice data reflected significant changes in tissues induced by the burn and a tendency towards control values for all burned groups. Meanwhile, the tau(c) value of GVI suggests the possibility of enhanced reparative effects attributable to chaotic intra- and inter-molecular energy transport to biopolymers in injured soft-tissue.

Phase I trial of an infrared pulsed laser device in patients with advanced neoplasias.

PURPOSE: The objective of this study was to evaluate the toxicity/radiant exposure/time relationship of an infrared pulsed laser device (IPLD) treatment in patients with advanced neoplasias. Karnofsky performance status (KPS), Spitzer quality of life index (QLI), and potential antitumor activity, if any, were also assessed. EXPERIMENTAL DESIGN: Seventeen patients (n = 17) received a daily IPLD radiant exposure of 4.5 x 10(5) J/m(2) (904 nm pulsed at 3 MHz) under a one-dose schedule and procedure design. Toxicity was evaluated under the parameters of the WHO; indirect toxic ocular effects were also monitored. KPS and QLI measurements were conducted before treatment and at six 3-months intervals. Scores for the seventh interval are the last available (range, 19-39 months). For statistical purposes, patients were classified into group 1, those alive at the end of the study, and group 2, those who had died. RESULTS: Dose-limiting toxicity was not observed. Five patients (n = 5) reported occasional headaches (grade 2), and four (n = 4) referred local pain (grade 2). In group 1 (n = 7), statistically significant increases in KPS and QLI were observed in all of the follow-up intervals compared with pretreatment values. One patient had a complete response, 1 a partial response, 4 stable diseases > or =12 months, and 1 progressive disease. In group 2 (n = 10), statistically significant increases in QLI were observed during the first two intervals. Eight patients had stable disease > or =6 months and 2 had uninterrupted progressive diseases. CONCLUSIONS: The IPLD treatment studied is safe for clinical use and may have potential effects on KPS, QLI, and antitumor activity in patients with advanced neoplasias.

Photo-induced cytomorphologic changes in an advanced cancer phase I clinical trial.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate whether the application of an Infrared Pulsed Laser Device (IPLD) photo-induced significant cytomorphologic changes during the monitoring of advanced cancer patients participating in a phase I clinical trial. MATERIALS AND METHODS: Patients were irradiated with an IPLD (904 nm pulsed at 3 MHz) under a one-dose, one-schedule, and one-procedure design. Total daily dose consisted of a Radiant Exposure of 4.5x10(5) J/m(2). Thirty-one tissue samples from eleven patients with progressive solid neoplastic diseases (TNM IV, UICC) were obtained at three intervals: Time 0 (15-90 days pre-treatment, n=11); Time I (2-5 months post-treatment; n=11); Time II (6-12 months post-treatment, n=09). Three blinded pathologists evaluated samples; scores were determined by consensus. Data were evaluated by using the Wilcoxon matched-pairs signed-rank test and Spearman rank correlation coefficient. The level of statistical significance was alpha=0.05. RESULTS: Increased apoptosis (Time I, P<0.003; Time II, P<0.007), necrosis (Time I, NS; Time II, P<0.01), cytoplasmic vacuoles (Time I, P<0.03; Time II, P<0.02), and nuclear vacuoles (Time I, NS; Time II, P<0.01), reduced cell size (Time I, P<0.007; Time II, P<0.01) and intercellular adhesion (Time I, P<0.01; Time II, P<0.02) were present in neoplastic cells after IPLD treatment. No apparent changes were noted in non-neoplastic cells. The Spearman rank correlation coefficient between apoptosis, necrosis, nuclear vacuoles, cytoplasmatic vacuoles, intercellular adhesion, and cell size was positive and highly significant (P<0.006). CONCLUSIONS: Although further research is necessary, our preliminary results support the novel possibility that the IPLD photo-induces chaotic dynamics that modulate complex physiologically reparative bioeffects.