A- BACKGROUND INFORMATION AND POTENTIAL SIGNIFICANCE
The emergence of non-invasive anti-aging therapies has gained popularity over the past decade as they are painless procedures that help in delaying and reversing the signs of aging [1]. Light therapy is a non-invasive Anti-aging treatment that emits specific wavelengths of light on the skin [2]. Low Laser light therapy (LLT), also known as photobiomodulation (PBM) therapy, has been around for 50 years but has not gained its deserved popularity as its mechanisms of action is still unclear [3]. At first, light therapy was mostly conducted in clinics by dermatologists and beauty clinics. Then, the emergence of home-use Light therapy devices has offered an easier alternative to visiting the clinic frequently [4].
There are 3 types of highly effective light therapies: Red, infrared and Blue light therapy [5] [6].
Red and infrared light act by emitting photons of specific frequency carrying a defined amount of energy that travels deep into the skin and activates collagen-producing cells, the fibroblasts, reducing wrinkles, scars, and inflammation [5]. With blue light therapy, the photons emitted have been shown to have a broad antimicrobial effect specially on the acne-causing bacteria, Propionibacterium [6]. By killing bacteria in oil glands, blue light has been proven to shrink these glands, reducing acne breakouts [6].
Red and Infrared Light therapy share the same mode of action but act on different levels of the skin [5]. The way red and infrared light therapy works is by photo stimulation of the electron transport chain and thus increasing the ATP concentration inside the cell [5]. Studies have shown that it mostly acts on the cytochrome c oxidase (unit four in the mitochondrial respiratory chain) which contains copper and heme and absorbs the near-infra-red spectrum of wavelengths [3]. In Brief, these photons absorbed by the cytochrome will dissociate NO, leading to an increase in ATP production, increase in mitochondrial permeability and increase in the electron transport across the ETC (electron transport chain) [3].
Detailed gene expression profiles in human fibroblasts shows 111 different genes influenced by low intensity red light (628nm wavelength) [7]. The genes influenced are involved in cellular functions such as apoptosis, cell proliferation, stress response, mitochondrial metabolism and DNA synthesis and repair [7] [3]. A wide range of transcription factors is activated following photobiomodulation (PBM) leading to increased proliferation and migration, improved cell survival, and new protein synthesis [8].
One of the mechanisms that increases fibroblast proliferation and motility after exposure to red and infrared light therapy is due to the elevation in reactive oxygen species (ROS) in these fibroblasts that can enhance the cell’s function through mitogen-activated protein kinase (MAPK) signaling pathways [5]. When used alone without any external photosensitizer, red light (Wavelength 620-670nm) induced free radical formation significantly increases the concentration of ROS in human skin [5]. The increase in ROS increases the cell redox activity in the cytoplasm and in turn induces transcriptional changes [9]. Nuclear factor B (NF-kB) is one of the most important factors activated by LLLT which causes transcription of and stimulatory and protective gene products [9].
In addition, exposure of a 3D model of a human skin to red light of 660nm 50 mW/cm, 4 J/cm2 LED significantly upregulated collagen production as well as downregulated Matrix Metallopeptidase 1 (MMP-1) levels [1]. In addition, the effects of Red light therapy have been also shown to be mediated through the increase in the cell’s ATP, increase in nitric oxide, and modulation of calcium levels [8]. In the cell, nitric oxide produced inside the mitochondria can inhibit respiration by displacing oxygen competitively and specially in hypoxic or stress cells [10]. An increase in nitric oxide concentration can be detected after LLLT (Low level laser therapy) on animal cell cultures due to its release from cox and mitochondria [9]. One proposed mechanism of LLLT is through the photodissociation of NO (nitric oxide) from COX which will consequently reverse the mitochondrial inhibition due to excessive NO [11] [12].
Moreover, there has been a strong correlation between fibroblast activity and dermal matrix remodeling with the increase in skin collagen density that leads to a reduction in signs of aging [13]. The increase in collagen production in human skin significantly decreases fine lines and wrinkles [14] and thus this is why antiaging treatments target skin collagen.
Using the right dose of light therapy is crucial to obtain optimal effects. The dosage depends on the light’s power density (in mW/cm2) as well as the exposure time to the surface of the skin.
The light power density is dependent on the distance between the source and the surface of the skin as well as on the wavelength of the emitted light. Thus, by changing these parameters one can compare the dosage spectrum and can assess which has optimal effects. Moreover, study has shown that combining Red and infrared therapy can have significantly better antiaging effects than using each individually [15]. After a 12 week face exposure to Red and Infrared light therapy in combination, 81% of subjects claimed to have significantly improved periorbital wrinkles [15].
LLLT (Low level light therapy) follows a biphasic dose response. When too much energy is applied then the photobiostimulation is replaced by bioinhibition and when too little energy is applied there will be no response [9] . An illustration done by Sommer elaborates this concept (figure 1) [16].
Figure 1: Idealized biphasic dose response curve (often termed Arndt-Schulz curve) typically reported in LLLT studies.
Photobiomodulation therapy (Light therapy) is now available as a home-use device due to the creation of the led light face mask.
The FDA has regulated the right dose of Red, Infrared and blue light therapy that targets the photobiostimulation range spectrum of the therapy.
The Revilin Collagen Booster mask is FDA 510K cleared and thus complies with all of the FDA rules and regulations of Light Therapy.
B- ACRONYM DEFINITION LIST
COX: Cytochrome C Oxidase
ETC: Electron Transport Chain
LED: Light-Emitting Diode
LLLT: Low-Level Light Therapy
MAPK: Mitogen-Activated Protein Kinase
MMP-1: Matrix Metallopeptidase
NF-kB: Nuclear Factor B
NO: Nitric Oxide
PBM: Photobiomodulation
ROS: Reactive Oxygen Species
C- REFERENCES
1. Avci, P., et al., Low-level laser (light) therapy (LLLT) in skin: stimulating, healing, restoring. Semin Cutan Med Surg, 2013. 32(1): p. 41-52.
2. Tao, L., et al., Intense pulsed light, near infrared pulsed light, and fractional laser combination therapy for skin rejuvenation in Asian subjects: a prospective multi-center study in China. Lasers Med Sci, 2015. 30(7): p. 1977-83.
3. de Freitas, L.F. and M.R. Hamblin, Proposed Mechanisms of Photobiomodulation or Low-Level Light Therapy. IEEE J Sel Top Quantum Electron, 2016. 22(3).
4. Nestor, M.S., et al., Efficacy and Tolerability of a Combined 445nm and 630nm Overthe- counter Light Therapy Mask with and without Topical Salicylic Acid versus Topical Benzoyl Peroxide for the Treatment of Mild-to-moderate Acne Vulgaris. J Clin Aesthet Dermatol, 2016. 9(3): p. 25-35.
5. Wunsch, A. and K. 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. Photomed Laser Surg, 2014. 32(2): p. 93-100.
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7. Zhang, Y., et al., cDNA microarray analysis of gene expression profiles in human fibroblast cells irradiated with red light. J Invest Dermatol, 2003. 120(5): p. 849-57.
8. Hamblin, M.R., Mechanisms and applications of the anti-inflammatory effects of photobiomodulation. AIMS Biophys, 2017. 4(3): p. 337-361.
9. Huang, Y.Y., et al., Biphasic dose response in low level light therapy. Dose Response, 2009. 7(4): p. 358-83.
10. Brown, G.C., Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochim Biophys Acta, 2001. 1504(1): p. 46-57.
11. Lane, N., Cell biology: power games. Nature, 2006. 443(7114): p. 901-3.
12. Lane, P. and S.S. Gross, Cell signaling by nitric oxide. Semin Nephrol, 1999. 19(3): p. 215-29.
13. Lee, S.Y., et al., A prospective, randomized, placebo-controlled, double-blinded, and split-face clinical study on LED phototherapy for skin rejuvenation: clinical, profilometric, histologic, ultrastructural, and biochemical evaluations and comparison of three different treatment settings. J Photochem Photobiol B, 2007. 88(1): p. 51-67.
14. Proksch, E., et al., Oral intake of specific bioactive collagen peptides reduces skin wrinkles and increases dermal matrix synthesis. Skin Pharmacol Physiol, 2014. 27(3): p. 113-9.
15. Russell, B.A., N. Kellett, and L.R. Reilly, A study to determine the efficacy of combination LED light therapy (633 nm and 830 nm) in facial skin rejuvenation. J Cosmet Laser Ther, 2005. 7(3-4): p. 196-200.
16. Sommer, A.P., et al., Biostimulatory windows in low-intensity laser activation: lasers, scanners, and NASA's light-emitting diode array system. J Clin Laser Med Surg, 2001. 19(1): p. 29-33.