*4.1. Photobiomodulation: Short History, Basic Concepts, and Current Applications*

As an interdisciplinary field, photomedicine is growing in importance because of its relevance to light and laser therapies [121]. The whole spectrum of electromagnetic radiation is depicted in Figure 1.

Full-spectrum light or sunlight [122] covers the electromagnetic spectrum from infrared to near-ultraviolet, or all wavelengths that are useful to plant or animal life (Figure 2). Natural light is composed of various electromagnetic waves traveling in disoriented fashion, which is known as incoherent light.

**Figure 1.** The aspect of the visible light spectrum within the electromagnetic radiation spectrum.

Phototherapy is rooted in the past when Egyptian, Indian, Chinese, and later Greek civilizations used light as a therapeutic agent to cure psoriasis, rickets, vitiligo, and even skin cancers [123].

**Figure 2.** Wavelengths applied in photobiomodulation.

Since antiquity, we have known that the doctor's presence is needed where the Sun is missing. Although the therapeutic properties of light have been known for thousands of years, this therapy has been developed and applied extensively only in the last two centuries. For example, the Nobel Prize in Physiology or Medicine 1903 was awarded to Niels Ryberg Finsen "in recognition of his contribution to the treatment of diseases, especially lupus vulgaris, with concentrated light radiation, whereby he has opened a new avenue for medical science" [124].

Lighting with wavelengths ranging from near-ultraviolet to red and including near-infrared has demonstrated many beneficial effects of the stimulation, preservation, and regeneration in cells, tissues, and organs in animals and humans.

After the Nobel Prize was awarded in 1964 to researchers Townes, Basov, and Prohorov for their contributions to the development of laser-maser, applications of low-level laser therapy (LLLT) in multiple branches of medicine have spread around the world, and today, this method is called photobiomodulation (PBM).

LASER (the acronym for Light Amplification by Stimulated Emission of Radiation) was a pure invention of the human mind, which triggered a revolution.

Laser light differs from sunlight due to its three distinct properties: monochromaticity (extremely narrow wavelength range); collinearity (all quanta move into the same direction); and coherence (parallel phase run of the light waves). For example, the difference in the coherence of laser light compared to a lamp is shown in Figure 3.

**Figure 3.** Coherent and incoherent light.

The most important and useful units of measurement in laser practice are: wavelength (nm, nanometer); power (W, watt or mW, milliwatt); energy (J, joule); power density (W/cm2), and energy density (J/cm2).

Light-based treatment methods use lasers or other light sources, such as LEDs; lamps with polarized light, polychromatic, incoherent, and low energy; Super Luminous Diodes (SLD); flash lamps, etc.

These devices release energy into the irradiated tissue that will induce photophysical and photochemical reactions at different biological levels, implicating endogenous chromophores.

There are significant differences between lasers and other light sources, including the specificity of the wavelength and the physical characteristics of the generated beam.

The three unique properties of the LASER beam—monochromaticity, coherence, and collimation—which make it unique for stimulating chromophores in biological tissues that respond only to certain extremely specific wavelengths.

The depth of penetration is determined by the wavelength, the tissue composition, as well as forward and backscatter in the tissue. Coherence is very quickly lost, and the depth of penetration for a large spot (illumination area) can be substantially greater than for a smaller spot size with the same wavelength at the same irradiance (intensity) [125].

If we use PBM with LEDs, there are certain differences, among which we mention lower power delivered in a certain biological time window (for an optimal cellular response); longer wavelength band (approximately 20 nm width), compared to LASER (approximately 1 nm width); the beam is not collimated or coherent [126].

To obtain the desired photobiomodulation effect, a certain quantified amount of photonic energy is always required, and therefore, depending on the pathology, LASERs, LEDs, or other available lamps or devices can be used accordingly.

The success of therapy depends on the correct choice of a device for energy levels quantification targeting.

Today, PBM is widely used worldwide in a variety of pathologies in adult and pediatric medicine. It is a natural treatment that provides the living cells with an energy source in the form of photons. Many diseases or dysfunctional problems of a bodily system or organ can be successfully treated with this ingenious technology. Clinical practice and the scientific investigation had shown bright prospects for the further development of this trend. Lasers can be used to perform exceedingly small and delicate tasks inside the living organisms [127].

Photobiomodulation represents a good option, as it is highly effective in many children's and adult's disorders, offering cost-effective advantages over drug therapy, with a quicker more positive response to treatment and no side effects. Last but not least, PBM is painless and non-invasive [128].

For PBM, laser devices are used that have a low light emission power below 500 mW or less than 0.5 watts (class III), but also lasers with a high power of more than 500 mW (laser "therapeutic window" of approximately 650–1100 nm, class IV). The high-intensity laser (HIL) is used with great success especially for sports injuries (traumatic injuries, musculoskeletal strains, osteoarticular, and spine injuries—lumbar and cervical area) [129,130].

Apart from PBM, lasers with higher powers and low pulse widths are applied in surgery, ophthalmology, dermatology–cosmetology, gynecology, oncology, etc.

Figure 4 depicts some lasers applied in medicine.

**Figure 4.** Types of lasers with applications in medicine.

In PBM, from light-emitting diodes or low-level energy lasers, the photonic fluxes enter the cells, penetrating the tissues quite well and initiating a cascade of photochemical reactions on specific signaling pathways due to the endogenous photoreceptors, triggering molecular mechanisms in the mitochondrial respiratory chain, reducing nitrite to nitric oxide, and enhancing the synthesis of the cytochrome c oxidase, which is involved in the electron transport chain in mitochondria [131,132].

Based on more than 30 years of research and treatments in our laboratory, we could really emphasize that PBM is a natural, non-invasive, effective, and well-proved method of treatment for many bodily disorders. Recently, the newest tested technologies such as intravenous, intra-nasal, or sublingual PBM appear to offer the best efficacy for many diseases, from depression to cancer, from acute to chronic pain, for infants and children, to the third age [121,133–135].

PBM, as original historical form of governing and influencing life, is able to reset all the body's self-organizing mechanisms starting from the nucleus to the cellular membranes, and even much more to the cortex and heart, to imprint with information from the millions and millions of the triggered cellular reactions per second in every cell, to balance the internal energy, to normalize the oxygen levels through the two enzymatic reactions of the cytochrome c oxidase, CcO/H2O and CcO/NO, as well as to initiate life's intrinsic mechanisms and the inner biological clock. Even if the whole functional picture is very complex, and some would say that it is still unclear how this form of stimulation might work, we have to think of time in nanoseconds, and it is for sure that the future research will reveal all the cellular and molecular mechanisms underlying PBM [121,136,137].

All the important components of PBM, such as intensity, timing, duration, and wavelength are part of the mainstream process of recovery in a holistic attempt to maximize the benefits of the treatment [121,137].

Being non-invasive and painless, with very few side effects depending on the patient's health status, and with no known risks associated, PBM heightens the energy, triggering self-organizing phenomena and tissue repair, bringing relief of physical pain or symptoms, and governing the interplay of the oxidative stress by playing multiple roles; it can induce cell proliferation and enhance stem cell differentiation, assisting rejuvenation and normalizing the cellular functions [138,139].

PBM has been proven to target life itself at quantum levels, and so it brings hope for an innovative modulation of immunity, health, and youth. As a practical tool, PBM opens doors for unprecedented and fulminant advances in many nano-medical research fields, by providing the rediscovery of an energetic method for modulating life itself and allowing a systematic generation of data and knowledge through comparison, complementation, and connecting across different medical nanotechnologies [121].

The worldwide tendencies of the current medical fields of the 21st century are innovative energy-based devices and techniques that are highly effective, whether they are drug-free or combined with medication. If professionally managed, the impact on medical practice, especially in Pediatrics, can be revolutionary. The scientific confirmation of these methods is based on discoveries concerning energy and information exchange within living systems, which constitute a "quantum leap" in the understanding and use of light and its interaction with water and other relevant photoacceptors to restore physiologic function [140], cybernetics, biological theory of information, modern thermodynamic concepts, and self-organizing phenomena in complex systems [121].

The advantages of the new energy-based health-care models include the following benefits: they can address the biological processes at their energetic origins; they are able to regulate the biological processes with precision and flexibility; they bring up healing and prevent illness with interventions that can be readily, economically, and non-invasively applied; they include methods that strengthen the immune system; they tend to integrate the body, mind, and spirit, focusing not only on healing, but also on achieving a greater well-being state, especially in patients suffering from chronic diseases [121]; and in the future, they will benefit large, vulnerable population groups, including the elderly and the poor [140], and they will be utilized also at home.

The number of ill children is steadily growing, and they become resistant to some drug preparations starting even from infancy. As a result, new methods for fighting diseases should be figured out. Creative systems and devices, as well as new methods for performing PBM in children for enhanced immunity to fight specific diseases, as for example, juvenile arthritis, do have a great merit and medical value for their capacity to achieve fine-tuned applications, as further interventions for various pediatric diseases, as well as others [141].

#### *4.2. Novel Therapeutics Using Photobiomodulation in Arthritis. Where Are We?*

A generation ago, children with arthritis faced a lifetime of pain and disability. Juvenile idiopathic arthritis, an umbrella term covering multiple distinct categories, previously called juvenile rheumatoid arthritis until recent reclassification, is one of the most common chronic diseases of childhood, featuring arthritis of unknown etiology [142].

Arthritis with synovial proliferation, triggered by the secretion of pro-inflammatory factors and the formation of granular tissue with monocytes, macrophages, lymphocytes, and other immune cells, will lead to chronic pain and the progressive destruction of the articular structures and functional disability, both in children and in adults [143]. More than one-third of children have ongoing active disease into adulthood with sequelae from chronic inflammation [2,144].

Adult patients and children with moderate or severe forms of arthritis tend to have a worse prognosis, even with the early use of disease-modifying antirheumatic drugs (DMARDs). These patients have considerable morbidity from joint damage, osteoporosis, psychosocial morbidity, reduced quality of life, and educational or employment disadvantage [143,145].

Chronic pain has a large and wholly negative impact on the physical and psychological well-being of patients and their family. Most often, if the inflammation goes away after months or even years of inadequate treatment, the pain may persist for life, due to central sensitization. Childhood chronic pain is a modern public health disaster, which is only now coming to light [2].

In these cases, long-term drugs will induce moderate to severe side effects, so that PBM could be a potential non-invasive anti-inflammatory treatment with minimal side effects [143].

Although the mechanisms of photobiomodulation processes are still being debated, in order to interact with the living cell, light has to be absorbed and has to change the inner cellular state, leading to processes such as the activation of ATP and of protein (RNA, DNA) synthesis, the stimulation of enzyme synthesis, the modulation of prostaglandin synthesis, decrease in the lipid peroxidation rate, the stimulation of specific and non-specific immunity, antioxidant effects, etc. When correctly applied, PBM has the following main clinical effects: improvement of blood circulation and activation of microcirculation, enhancement of collagen synthesis, promotion of tissue regeneration, influence on skin receptors with the increase of pain threshold, improvement of nerve conductivity, acupuncture points stimulation, anti-inflammatory, antiallergic and antiseptic effects, and so on [146].

In children, it is especially valuable because it activates the immunocompetent systems and improves the neurohumoral and hormonal regulation of the metabolism. It must be applied properly and with greater care, because the health problems of children differ from those of adults, and the child's response to illness and stress varies with age. Each child reacts according to his or her development stage, and to provide the highest quality treatment, the physician requires a familiarity with age-appropriate intervention [126,128].

In certain situations, for an accurate diagnosis and the adequate treatment of infants, children, or adolescents, a multidisciplinary team with pediatric health care experts, as well as key facilities and specific protocols for PBM management of pediatric conditions are needed.

When treating a child with energy-based devices, the physician should have in mind the differences in metabolism, hormonal system, immune system (susceptible to generalized infections, allergic diseases, etc.), and central nervous system (generalization of the post-aggressive reactions in infants and little children). The unique needs of children should be considered by pediatricians and other personnel skilled at evaluating and treating children in such areas as advice, communication, prevention, and therapeutics.

The concept of patient management in infants and children is particularly important. Usually, children are afraid of the physician, or they seem to show a lack of trust toward the doctor and the consulting or treatment area. Furthermore, it is the doctor's job to cooperate with the child's parents and to have a supportive attitude to eliminate any kind of stress in the little patient. So, the model on which the doctor–child relation should be built is friendship.

The informed consent is especially important, both in adults and in children. PBM should never be performed on a child if parents or the legal guardians do not fully agree with that. It is even better to allow parents to be nearby the child during the treatment.

The physician should explain to the family and/or the patient that the disease has a chronic evolution, sometimes with little spectacular improvements.

In treating children's rheumatic conditions, one should have in mind that there are several studies affirming that the usage of PBM on growing articular cartilage may be harmful [147,148].

Consequently, in children's chronic rheumatic pathology, PBM should be applied by irradiating the blood sublingually, intranasal, venous transcutaneous, or intravenously [149–153]. Sublingual PBM is easy, non-invasive, and with high absorption on intensely vascularized buccal mucosa, triggering rapid systemic effects [134].

The initial approach to the management of patients with rheumatoid arthritis must be vigorous in all patients, to suppress articular inflammation, control systemic disease, prevent secondary deformities, and maintain muscle strength.

The primary aims of treatment in rheumatic pathology include pain relief, preservation of joint function, prevention of deformities, and avoiding drug toxicity. In the long term, minimizing side effects from disease and treatment as well as preserving vision and promoting normal growth and development should be major goals for which PBM can make an important contribution.

Therapy for patients with rheumatoid arthritis should focus on rapid suppression of the inflammatory disease.

The influence of PBM on the immune system has been documented in the medical literature; immunologic effects on leucocytes, T, B, and NK lymphocytes, macrophages, and other cells result in local and systemic effects through a complex mechanism of action that is not fully understood [154].

For a better understanding of concepts and effects, Table 1 presents PBM experimental studies [155–180].

Clinical studies [181–189] have also shown that PBM is a promising drug-free tool for inflammatory diseases and arthritis (Table 2).

Aimbire and Albertini et al. demonstrated in an animal model that depending on the dose of PBM, TNF release in acute lung lesions may decrease [190].

Albertini et al. in an experimental study of subplantar muscle in rats used a diode laser with an output power of 30 mW and wavelengths of 660 nm and 684 nm, with the laser beam covering an area of 0.785 cm2, at an energy dose of 7.5 J/cm2; they proved that COX-2 mRNA expression and edema decreased [191].

Chow R. et al. presented the results of the PBM effect in 16 randomized controlled trials, concluding a pain-reducing effect immediately after treatment in acute forms of neck pain, and up to 22 weeks after completion of treatment in patients with chronic neck pain [192].

Leal-Junior, Lopes-Martins, and Bjordal in a systematic review and meta-analysis of placebo-controlled studies or randomized PBM therapy show that despite growing evidence supporting the value of PBMT in improving and accelerating performance in patient recovery, sample quality needs to be improved to be sure of these effects. They recommend compliance with the Consolidated Test Reporting Guidelines (CONSORT) when designing a research study with PBMT, publishing the protocol with all recommended and used parameters, to allow replication of the study by other authors [193].

Stausholm et al. highlighted in a systematic review and meta-analysis of 22 randomized placebo-controlled trials in patients with pain and disability due to knee osteoarthritis that the pain was significantly reduced in PBM compared with *placebo* at the end of therapy and during follow-up 1–12 weeks later, compared to the placebo group. In addition, the pain decreased (significantly on VAS) at 2–4 weeks after completion of the recommended doses of PBM compared to placebo. There were no reported adverse events. In conclusion, PBM reduces pain and disability in knee osteoarthritis (KOA) at 4–8 J, 785–860 nm wavelength, and at 1–3 J at 904 nm wavelength per treatment site [194].

Following the retrospective evaluation of multiple experimental and clinical studies on the use of PBM on immune cells, appropriate signaling pathways, but also in clinical pathologies, we can support the immunomodulatory effect of PBM and that it is an important complementary and alternative method able to influence the evolution of arthritis and lead to the resolution of joint and systemic inflammatory phenomena through photobiomodulation.

PBM could directly control the autoimmune mechanism by reducing the local and systemic inflammatory response, as in the model we propose in Figure 5.


*Int. J. Mol. Sci.* **2020**, *21*, 6565

**Table 1.**

Experimental

photobiomodulation

 (PBM) studies applied to immune cells and signaling pathways. IL: interleukin,

 LLLT: low-level laser therapy, MMP:


**Table1.***Cont*.


**Table1.***Cont*.



fluid.


**Table1.***Cont*.


**Table 1.** *Cont*.






#### **Table 2.** *Cont*.

**Figure 5.** How photobiomodulation could regulate the immune response in arthritis. Possible mechanisms of action on excessive T cell immune response, regulation of pro- and anti-inflammatory cytokines balance, and the process of stopping the proliferative synovium and the osteocartilaginous destruction.

Figure 5 shows many cells and the resulting cytokines, which participate with different roles in the occurrence and evolution of rheumatoid arthritis. The synovial membrane is penetrated by cells of the immune system (innate and adaptative), and in the synovial fluid appear pro-inflammatory mediators that trigger an inflammatory cascade, activating fibroblast-like synoviocytes and dendritic cells, monocytes, macrophages, mast cells, as well as the T cells and the B cells. An extensive network of new blood vessels is formed, which will lead to the appearance of a synovial hyperplasia, osteocartilaginous erosion, and all the secondary systemic effects.

PBM can very gently modulate the balance between Treg and Th17 cells, i.e., between physiological regulation and the stimulation of the inflammatory process.

An established philosophy in the management of a patient with rheumatoid arthritis is to begin with the safest and simplest therapy judged to be effective. PBM applied in different stages of rheumatoid arthritis is safe, effective, and free of side effects. PBM exerts a positive influence on the synovial membrane and the immune system.

In the inflammatory phase of rheumatoid arthritis, PBM improves the macrophages and lymphocytes activity, decreases the level of immune complexes, and regulates the level of immunoglobulins A (IgA), immunoglobulins M (IgM), immunoglobulins G (IgG), and the balance between pro-inflammatory and anti-inflammatory cytokines [195–200].

Photobiomodulation activates the non-specific cellular immune mechanisms, improves the microcirculation of the central and peripheral nervous system, adjusts the functional activity of the hypothalamus and all marginal systems, activates the energetic metabolism, and modulates the immune and vegetative responses. The anti-inflammatory, anti-nociceptive (which elude peripheral and central sensitivity that is the cause for psychological chronic pain) and immunomodulatory effects

of PBM allow the reduction, even up to elimination, of the pharmacological drugs and promote the disease remission [201,202].

In recent years, photobiomodulation has become an increasingly mainstream modality, especially in the areas of physical medicine and rehabilitation [130].

Moreover, despite the best efforts of "big pharma," distrust of pharmaceuticals is growing in general because of uncertain efficacy and troublesome adverse effects. Photobiomodulation has no reported adverse effects, and no reports of adverse events can be directly attributed to laser or light therapy. The high benefit/risk ratio of photobiomodulation should be better appreciated by medical professionals in the rehabilitation and physical medicine specialties [203–206].

Every patient is unique, and the medical doctor must treat him in an integrative manner for the mind, soul, and physical body.

In the situation of chronic arthritis as in other pathological conditions, a clinician should have a solid knowledge of the disease to be addressed, be up-to-date with its pathogenesis, the modern therapies, and their mode of action, and consider alternatives and complementary therapies that are much older than the pharmacological ones. Only these data should be the basis of the attitude he would have when deciding whether to turn to PBM.

The successful management of PBM in arthritis is based on the clinician's ability to evaluate correctly the inflammatory status of the patient, to seek the optimal solution, to choose the best technology with the best physical parameters and mode of action, so that the treatment can target very precisely the immune system and the molecular signaling pathways at the molecular level with the exact amount of quantum light energy in order to obtain the desired immune modulation and the remission of the disease.
