Light - Red and Near-infrared
Numerous therapeutic uses in the low level light application of this frequency band
Red and Infrared light is proven to be a biologically active influence ever at very low intensities, being an almost established method to treat some problematic issues like traumatic brain injury, undesired and painful inflammations or wound repair, and with various experiments that show a variety of effects that surely involve various kind of receptors or very systemic ones. ...
As in other non-ionizing exposures, slight variations in the exposure conditions (classical intensity, time or frequency variations and other less know like the subject age, or the phase of the cell cycle) can alter the outcome drastically. As an example, in a study that are recorded somatosensory evoked potentials of rat sciatic nerves , irradiation of the same total energy concentrated in one point or separated over four points, increased or decreased respectively the somatosensory evoked potential amplitudes of nerves.
Mechanisms of action
Later it will be mentioned the possible role of water in the biological effects of low level red and infrared light exposures. To mention, for the moment, that infrared radiation on gel like microscopic structures produces an extension of exclusion zone water (EZ water) that are ordered layers of water with a charge differential and boundary that can serve to organize cellular structures , more on EZ water on section .
In general, it's believed that the primary target of low level infrared and red light is the cytochrome c oxidase in the mitochondrial respiratory chain leading to the stimulation or inhibition of the cellular metabolism and producing a transduction effect in other cell components (biomodulation effect). This view is not the best valuated here because it's excessively specific and is not probable to be the cause of the variety range of effects, and some recent experimental studies are questioning this proposed mechanism . Others suggest that this effect is due to photophysical changes on the Ca++ channels in the cell membrane. Anyways there are various possible photoreceptors in the cell, for example other enzymes apart from cytochrome, among others arylsulphatase, lactate dehydrogenase, myosin ATPase, acid phosphatase, creatine kinase and lactate dehydrogenase are show to be sensitive to light and, is proposed, the modification of the catalysis of certain enzymes, likely containing metal ions, as a significant contributor to the effects of the red and infrared low level light radiation on biological samples .
A variety of biomolecules localized in mitochondria and/or in other cell compartments including some proteins, nucleic acids and adenine nucleotides are also light sensitive with major modifications in their biochemistry when are exposed .
As is pointed in the section  since there is evidence that proteins have certain conducting or semiconducting properties, a charge moving through the protein backbone and passing different energy stages caused by different amino acid side groups can produce sufficient conditions for a specific electromagnetic radiation or absorption.
And as the resonant recognition model (RRM) proposed :
" strong linear correlation exists between the predicted and experimentally determined frequencies corresponding to the absorption of electromagnetic radiation of such proteins . It is inferred that approximate wavelengths in real frequency space can be calculated from the RRM characteristic frequencies for each biologically related group of sequences. These calculations can be used to predict the wavelength of the light irradiation, λ , that might affect the biological activity of exposed proteins . The frequency range predicted for protein interactions is from 1013 Hz to 1015 Hz. This estimated range includes IR, visible and UV light."
So is possible that IR radiation interact because it used pre-existent endogenous communication and recognition channels, as those predicted by the RRM.
As mentioned above water and their structure as EZ water can be also a target of the low level light exposure, Santana et al. are fervorous defenders of this theory, and in this section this vision is empowered because it looks very logic when is taken into account the, now evident, curious properties of water in its interaction with electromagnetic waves (see section ), and it's sufficiently extended and systemic to cover the wide range of effects that different exposures can provoke. But we can go further than a theoretical proposition (supported by studies of water-EM waves interaction as mentioned), firstly, reviewing experimental evidence of pre-existent studies in low level light therapy where some properties of water are measured, and search for data that contribute to corroborate this theory as for example is done in :
" 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."
Another Santana et al. retrospective analysis of published data in low level light therapy (LLLT) indicative of EZ phenomena that is related, in this case, to the retina and optic nerve (ON) also show evidences :
" 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."
There is an interesting summary of the investigations of the authors in .
Another experimental procedure by other authors  show that water near to proteins surface provoke the proteins order and crystallization, nucleating them, when the solute is exposed to low level infrared radiation:
" We show that a physical trigger, a non-ionizing infrared (IR) radiation at wavelengths strongly absorbed by liquid water, can be used to induce and kinetically control protein (periodic) self-assembly in solution. This phenomenon is explained by considering the effect of IR light on the structuring of protein interfacial water. Our results indicate that the IR radiation can promote enhanced mutual correlations of water molecules in the protein hydration shell. We report on the radiation-induced increase in both the strength and cooperativeness of H-bonds. The presence of a structured dipolar hydration layer can lead to attractive interactions between like-charged biomacromolecules in solution (and crystal nucleation events). Furthermore, our study suggests that enveloping the protein within a layer of structured solvent (an effect enhanced by IR light) can prevent the protein non-specific aggregation favoring periodic self-assembly."
On the other hand in  is argued that the specific environment of each cell causes one kind or other of effect and that membrane receptors are the target:
" According to our homeostasis theory , we have suggested that the membrane receptors of cells or organelles were the primary photoreceptors of LIL, and LPBM was mediated by receptor-activated signal transduction pathways . Several signaling pathways have been identified that target COX including protein kinase A and C, receptor tyrosine kinase, and inflammatory signaling ."
Finally it is interesting to keep in mind data provided by  that suggest that non-coherent light sources with power-densities about 1000 times lower than contemporary low-power laser settings remain effective in generating photobiostimulatory effects.
Low level laser light or LED light therapy is a globally expanding intervention method that now includes post-traumatic brain disorders, nerve regeneration, diabetic wound repair, arthritis, cancer radiation protection (oral mucositis), dental, sports medicine and skeletal muscle disorders (trauma and pain), etc.
Numerous studies are now oriented to the extracraneal application of red and near infrared light and the therapeutic outcomes that generate.
LLLT cause increased neurogenesis in the hippocampus and subventricular zone, and better learning and memory scores, in mice after traumatic brain injury . In an experimental study with humans suffering from mild traumatic brain injury  therapeutic application of LLLT provides improved sleep, and fewer post-traumatic stress disorder (PTSD) symptoms, if present, and better ability to perform social, interpersonal, and occupational functions.
Similar results can be extracted from a recent review on the topic  where is concluded that application of red/near-infraret LED light in subjects with traumatic brain injury causes significant improvements in executive function and verbal memory of the subjects and fewer reports of post-traumatic stress disorder symptoms.
Moreover, in another review  there are highlighted the positive outcomes of LLLT to treat various mental dysfunctions apart from traumatic disorders, like depressive disorders:
" Studies suggest the processes aforementioned are potentially effective targets for PBM to treat depression. There is also clinical preliminary evidence suggesting the efficacy of PBM in treating major depressive disorders, and comorbid anxiety disorders, suicidal ideation, and traumatic brain injury."
On the other hand, red light irradiation also increase lymphocyte count in subjects in wich this cell count was reduced after a stroke provoked middle cerebral artery occlusion . Some experiment are done with in-vitro neurons with results that are supposed to be majorly maintained when transcraneal light is applied, and for example in  it was found that low intensity near-infrared radiation (NIR) can protect neurons against oxygen-glucose deprivation by rescuing mitochondrial function and restoring neuronal energetics.
Also in primary cultured rat cortical neurons where oxigen-glucose deprivation is provoked it's show a augmented neurite outgrow with a increase in levels of synaptic markers such as PSD 95, GAP 43, and synaptophysin after infrared LED treatment .
Another experimental study with in vitro neurons and, in this case, with far infrared radiation (FIR) , suggest the possible therapeutic use to treat some kind of neuronal disorders, like Spinocerebellar ataxia type 3, that are characterized by progressive and selective loss of neuronal cell bodies, dendrites and/or axons in the central nervous system. In this case is demonstrated that FIR treatment individually rescued ataxin-3-78Q and ataxin-3-26Q expressing cells, that have decreased viability, from pathological and non-pathological mechanisms involved, by preventing mutant PolyQ protein accumulation and protecting mitochondrial function in both cells. The data also suggested that FIR triggers autophagy as a major rescue mechanism and that did not seem to involve reactive oxygen species scavenging.
Regeneration is also a medical field of research where red and infrared light are increasingly used as a possible therapeutic tools, for example in  is studied the effect of low intensity laser irradiation (LILI) on the growth potential and cell-cycle progression of cultured myoblasts, that are a type of myogenic progenitor cells and considered as the major candidates responsible for muscle regeneration, and it's viewed that exposure increased the expression of cellular proliferation marker and the amount of cell subpopulations in the proliferative phase and upregulated expressions of cell-cycle regulatory proteins:
" These results suggest that LILI at certain fluences could promote their proliferation, thus contributing to the skeletal muscle regeneration following trauma and myopathic diseases."
Also, nerve regeneration can be a therapheutical target, in a study where histological examination is done on rats sciatic nerve, after lesion, it is showed that low level light treatment for some days causes better organized myelin sheets with fewer areas of myelin debris . Here, related to the above mentioned possible role of water is interesting to note that myelin fiber has been theorized to be an optical fiber for biophotons (like microtubules), see section , and that is proposed that ordered water have a crutial function in this, where collective behavior of water molecules is characterized by coherent water states analogous to Bloch states, whose main feature is to trap biophotons in a collective fashion .
One of the most promising therapeutic use to be promptly standardized is to reduce inflammation of many kinds. In a review  is pointed out its utility to treat oral mucositis (an inflammation derived from cancer treatment), and there are a lot of recent experiments on this topic with more supporting results, moreover, in  experimental results shown that monocromatic light (LED) is at least as effective as low level light theray (LLLT) in treating mucositis, an LED light is more cheap and affordable than laser, so implementation can be faster and more extended. Another interesting review on infrared light treatment to address inflammation can be found in  were among other facts are commented various experimental findings in which the therapeutical light application have better results than classical pharmacological therapy.
Inflammation is also as we know, part of the wound healing process, and this process in general is also target of LLLT in numerous studies, because it is known that amejorate the process in numerous ways, in this  experimental study it can be read:
" We demonstrated the possible utility of a GaAlInP laser with an appropriate energy density (4 J/cm2) as an adjunctive modality for wound healing in clinical practice as well as a correlation between epidermal MMP-2 expression and angiogenesis. In fact, LLLT improved wound healing, especially at 14 days, as evidenced by wound contraction, anti-inflammatory activity, neocollagenesis, and neoangiogenesis."
In  LED phototherapy with 940 nm wavelength reduced the areas of edema, the number of mononuclear cells present in the inflammatory infiltration, and increased functional recovery scores.
Other possible therapeutic use is for cancer treatment and there are some efforts in this direction . In  it is pointed that previous studies show that low level infrared radiation significantly inhibited cell proliferation in several breast cancer cells but did not affect the growth of normal breast epithelial cells, and that in this study irradiation.
" caused G2/M cell cycle arrest, remodeled the microtubule network to an astral pole arrangement, altered the actin filament formation and focal adhesion molecule localization, and reduced cell migration activity and invasion ability."
Anyways this possible use of light against cancer is not sufficiently certain and free of possible counterproducent effects for the moment, for example in  LLLT promotes cancer aggressiveness in anaplastic thyroid cancer cell line. Therefore more research is needed to expose the specific conditions (of the exposure or the exposure target) that causes some outcomes or others. It is mentionable that other non-ionizing electromagnetic waves like those that fall in the extremely low frequecies are also subject of study  as possible anty-cancer treatment, and maybe have less risks than LLLT.
Another therapeutic approach would be the improvement sperm function and reproductive performance, in this case in an experiment in  it is observed and underlined an extremely interesting fact:
" .. effects observed rely upon the specific pattern used. In this way, it is worth noting that Procedure #1 (10-10-10; L-phase: 10 min, D-phase: 10 min and L-phase: 10 min) was the most effective. In contrast, patterns with longer exposure times to light, such as Procedures #2 (15-10-15) and #3 (20-10-20) had less effect. Additionally, our preliminary experiments conducted before setting the experimental conditions also showed that continuous light-exposure patterns without a D-phase, of 5 min, 10 min, 15 min and 20 min of continuous L-phase, were much less effective than the 10-10-10 photo-stimulation pattern. These data clearly point out that the improving effect on boar sperm function induced by red LED-based light depends on the photo-stimulation pattern. A similar phenomenon has been described when laser systems are applied to sperm from other mammalian species like dog, buffalo and human . Therefore, it seems that light-effects on mammalian sperm rely on precise rhythms and rates of application, regardless of light source and wavelength range."
So rhythms are important… we must have in mind that this include the wavelength or frequency itself, as it can be view in numerous examples, in this  concrete example, when light is applied to cell population in vitro, variations in the frequency can provoke that population increases or not.
Also included in the therapeutic array of uses of non-thermal photobiomodulation (other of the nomenclatures of low level light therapy) are photorejuvenation oriented ones. As an example in this study  treated subjects experienced significantly improved skin complexion and skin feeling, better profilometrically assessed skin roughness, and improved ultrasonographically measured collagen density.
In this last paragraph of possible therapeutic uses, only as an extract of the variety of possibles uses, it will be mentioned some more uses. As the title of  explicitly says combination of laser light and LED light “is beneficial in improvement of muscular performance (strength and muscular endurance), dyspnea, and fatigue sensation in patients with chronic obstructive pulmonary disease”. In  improvements in functional and anatomical outcomes in dry AMD (a retinal degenerative disease) subject has reached. In  increased stem cell proliferation was observed. While other non necessarily therapeutic but interesting results include, for example, the increase in growth rate and overall length and width of C. elegans (a nemanode) after low level laser light exposure .
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2. Trevors, J. T., and G. H. Pollack. "Origin of microbial life hypothesis: A gel cytoplasm lacking a bilayer membrane, with infrared radiation producing exclusion zone (EZ) water, hydrogen as an energy source and thermosynthesis for bioenergetics." Biochimie 94.1 (2012): 258-262.
5. Passarella, Salvatore, and Tiina Karu. "Absorption of monochromatic and narrow band radiation in the visible and near IR by both mitochondrial and non-mitochondrial photoacceptors results in photobiomodulation." Journal of Photochemistry and Photobiology B: Biology 140 (2014): 344-358.
9. Santana-Blank, Luis, Elizabeth Rodríguez-Santana, and Karin E. Santana-Rodríguez. "Photobiomodulation of aqueous interfaces: finding evidence to support the exclusion zone in experimental and clinical studies." Photomedicine and laser surgery 31.9 (2013): 461-462.
10. Rodríguez-Santana, Elizabeth, and Luis Santana-Blank. "Emerging evidence on the crystalline water-light interface in ophthalmology and therapeutic implications in photobiomodulation: first communication." Photomedicine and laser surgery 32.4 (2014): 240-242.
14. Wu, Hsia-Pai Patrick, and Michael A. Persinger. "Increased mobility and stem-cell proliferation rate in Dugesia tigrina induced by 880nm light emitting diode." Journal of Photochemistry and Photobiology B: Biology 102.2 (2011): 156-160.
15. Xuan, Weijun, et al. "Transcranial low-level laser therapy enhances learning, memory, and neuroprogenitor cells after traumatic brain injury in mice." Journal of biomedical optics 19.10 (2014): 108003-108003.
16. Naeser, Margaret A., et al. "Significant improvements in cognitive performance post-transcranial, red/near-infrared light-emitting diode treatments in chronic, mild traumatic brain injury: open-protocol study." Journal of neurotrauma 31.11 (2014): 1008-1017.
17. Naeser, Margaret A., et al. "Transcranial, Red/Near-Infrared Light-Emitting Diode Therapy to Improve Cognition in Chronic Traumatic Brain Injury." Photomedicine and Laser Surgery 34.12 (2016): 610-626.
18. Cassano, Paolo, et al. "Review of transcranial photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative stress, and neurogenesis." Neurophotonics 3.3 (2016): 031404-031404.
21. Choi, Dong-Hee, et al. "Effect of 710nm visible light irradiation on neurite outgrowth in primary rat cortical neurons following ischemic insult." Biochemical and biophysical research communications 422.2 (2012): 274-279.
22. Chang, Jui-Chih, et al. "Far-infrared radiation protects viability in a cell model of Spinocerebellar Ataxia by preventing polyQ protein accumulation and improving mitochondrial function." Scientific Reports 6 (2016).
23. Zhang, Cui-Ping, et al. "Stimulative effects of low intensity He-Ne laser irradiation on the proliferative potential and cell-cycle progression of myoblasts in culture." International Journal of Photoenergy 2014 (2014).
30. de Medeiros, Melyssa Lima, et al. "Effect of low-level laser therapy on angiogenesis and matrix metalloproteinase-2 immunoexpression in wound repair." Lasers in Medical Science 32.1 (2017): 35-43.
34. Rhee, Yun-Hee, et al. "Low-Level Laser Therapy Promoted Aggressive Proliferation and Angiogenesis Through Decreasing of Transforming Growth Factor-β1 and Increasing of Akt/Hypoxia Inducible Factor-1α in Anaplastic Thyroid Cancer." Photomedicine and laser surgery 34.6 (2016): 229-235.
38. Wunsch, Alexander, and Karsten Matuschka. "A controlled trial to determine the efficacy of red and near-infrared light treatment in patient satisfaction, reduction of fine lines, wrinkles, skin roughness, and intradermal collagen density increase." Photomedicine and laser surgery 32.2 (2014): 93-100.
39. Miranda, Eduardo Foschini, et al. "Phototherapy with combination of super-pulsed laser and light-emitting diodes is beneficial in improvement of muscular performance (strength and muscular endurance), dyspnea, and fatigue sensation in patients with chronic obstructive pulmonary disease." Lasers in medical science 30.1 (2015): 437-443.
Very related sections:
↑ text updated: 16/01/2017
↓ tables updated: 27/03/2018