Keys to Effective Low Level Light Therapy (LLLT)3 years, 10 months ago
Posted on Jun 15, 2017, 6 a.m.
Recent advances in LED technologies increase the therapeutic effect of light therapy on cells with compromised mitochondrial function.
Low-level light therapy (LLLT) has vast potential in numerous therapeutic areas. However, despite a large body of evidence, LLLT has yet to receive wide acceptance in the scientific community. Some of the primary reasons for this reluctance is the multitude of operating parameters that may be applied clinically, the difficulty in reproducing settings used by other investigators, as well as understanding how to select an effective light energy device. While finding the appropriate settings and device may seem overwhelming it doesn’t have to be. The key to achieving effective clinical outcomes using LLLT is knowing what makes a safe and effective light energy device.
There are a number of products on the market which provide various ranges of power output, wavelength, pulse frequencies, and which deliver light energy in both short and longer time periods. In order to understand how to use this technology effectively, it is helpful to understand the fundamentals of how light therapy works. It is well known that the beneficial effects resulting from LLLT exhibit a biphasic dose response [1, 2]. This means that there is indeed a threshold at the upper and lower limit of LLLT leading to either a positive biological response, no response, or a negative response. This being said, there is no known finite set of parameters for effective LLLT dosimetry, but rather a range of effective parameters. Nevertheless, a sufficient amount of light energy must reach the target tissue in order for positive clinical outcomes to occur. Thus, in order to achieve clinical efficacy an understanding of the mechanisms involved should be considered.
The multimolecular complexes of the electron transport system have been postulated as the light receptors and increased mitochondrial activity of complexes I, II, III and IV have been observed [3, 4]. Cytochrome C oxidase, part of complex IV, generally is accepted as the primary photo-accepting molecule [3, 5, 6]. The absorption of this light energy then results in changes in reactive oxygen species (ROS) [7-9] as well as increased ATP production [10-15]. Increases of intracellular ROS and ATP activate transcription factors, which lead to activation of downstream signaling cascades resulting in the beneficial effects observed . These signaling cascades most notably activate factors known to promote anti-aging, enhance wound healing, reduce pain and improve acne, as well as other clinical benefits. While these areas of research are still actively under investigation they are relatively well characterized.
There are multiple critical parameters that promote the biological responses described, however the most critical are wavelength, energy density and duration of treatment. The wavelength is of particular importance, because it needs to match the absorbance of the desired photo-accepting molecule, but will also determine the penetration depth of the light being delivered (fig 1), regardless of the device that produces the light energy. The energy density will need to be high enough to elicit the desired effect, but low enough not to induce toxic or adverse effects. Generally, the clinical literature demonstrates that treatments delivered multiple times a week over several weeks result in greater efficacy. However, these parameters will vary depending on the desired application.
Other additional considerations are the pulse frequency and the technological source of the light energy. Currently, there are no well-accepted or established effective pulse frequencies for given clinical applications [16, 17]. However, the pulsing of light is known to increase penetration depth and has been shown, in some cases, to have additional benefit in comparison to continuous light delivery. Moreover, when comparing laser and LED sources, both have demonstrated similar efficacy when optical parameters were closely matched . Thus, at the energy levels commonly used for LLLT, laser and LED sources could be used interchangeably and achieve similar if not identical efficacy. All of these factors should be considered for then selecting an appropriate light delivery device.
Selecting an LLLT device can be challenging, particularly for new users. There are a broad range of devices available from sophisticated laser systems to basic home use LED systems. More advanced laser systems tend to require additional hardware and technical expertise in order to operate safely. In contrast, more basic devices, such as LED arrays can be used by those with little or no experience without any significant safety concerns. Furthermore, some basic systems are even programmed with multiple operating modes for specific clinical applications, circumventing the need to manually set optical parameters. However, this is a general overview and the specific needs will need to assessed on an individualized basis.
There are currently a number of commercially available devices that have been approved by the FDA for multiple indications including: arthritis, muscle spasm, muscle and joint pain, muscle tissue tension, joint and muscle stiffness, diminished local circulation and inflammatory acne vulgaris, which gives further evidence of the safety of this device. Of the available devices, LED arrays tend to be light and portable removing the need for cumbersome bulky hardware as associated with other similar devices. These devices generally deliver light at wavelengths in the red and near-infrared (600 to 1070 nm) to treat deeper tissues and (400 to 480 nm) for superficial tissue treatments and power ranging from 1 to 1000 mW. However, the configuration of the device must be given careful consideration in order to achieve clinical efficacy.
For example, two key clinical advantages of flexible LED array systems are that it offers delivery of light to a large treatment area and superior adaptation for fitting the contours of the body (fig 2). Properly fitting the contours of the body is key to optimal energy absorption. The inverse square law states that the intensity of light administered to the body will decrease as the square of the distance from the light source. Said another way, as the distance between a light source and a surface of absorption doubles, the amount of energy available for absorption decreases by four times. Accordingly, this device configuration more easily enables a constant treatment distance from the body for the duration of the treatment, which will result in more optimal energy delivery. This is a distinct advantage over other rigid light delivery systems where the distance between the light source and subject is difficult to keep constant, leading to inconsistent light delivery.
In conclusion, it is clear that there is a broad range of optical parameters reported to induce specific biological responses resulting in improved therapeutic outcomes. Here some of the key parameters leading to effective LLLT have been discussed and some considerations for selecting an appropriate light delivery device have been provided. There is a large body of evidence in the scientific literature describing the beneficial effects of LLLT, which is ever increasing. This increasing evidence is anticipated to result in more widespread acceptance and usage of LLLT.
~ Written by Dr. Ryan Spitler, Ph.D.
Dr. Spitler is the Deputy Director of the Precision Health and Integrated Diagnostics Center at Stanford University. He completed his Post Doctorial Research Fellowship at Stanford University School of Medicine, conducting research in the developing field of Magnetogenetics for remote controlled cellular reprogramming and developed smart MRI cell tracking tools for oncology cell tracking studies. He has designed numerous biological models, synthetic biology approaches and worked on the development of new technologies in a number of scientific areas ranging from medical devices to gene therapy. Prior to his position at Stanford, Dr. Spitler received his Ph.D. in Cellular and Developing Biology at the Beckman Laser Institute at the University of California, Irvine. His research at the Beckman Laser Institute included developing and characterizing new nitric oxide-based drugs, laser, and LED-based multimodal wound healing therapies some of which are currently being used in the clinic as a result of his work.
Dr. Spitler received his Bachelor’s of Science degree in Molecular Cell and Developmental Biology from the University of California, Santa Cruz, where he worked in the area of structural biology. Over the past two decades he has held a number of academic and industrial positions and has served as an advisor or advisory board member for a number of Bay Area companies. Dr. Spitler is the recipient of the Stanford Cancer Imaging Fellowship Training Award, the Biophotas Research Fellowship, the Stanford Center for Biomedical Imaging Achievement Award and has authored a number of scientific articles and book chapters in many different scientific disciplines.
1. Huang YY, Chen AC, Carroll JD, Hamblin MR:
Biphasic dose response in low level light
therapy. Dose Response 2009, 7(4):358-383.
2. Huang YY, Sharma SK, Carroll J, Hamblin
MR: Biphasic dose response in low level light therapy - an update. Dose Response 2011, 9(4):602-618.
3. Yu W, Naim JO, McGowan M, Ippolito K, Lanzafame RJ: Photomodulation of
oxidative metabolism and electron chain enzymes in rat liver mitochondria. Photochem Photobiol 1997, 66(6):866-871.
4. Silveira PC, Silva LA, Fraga DB, Freitas TP, Streck EL, Pinho R: Evaluation of
mitochondrial respiratory chain activity in muscle healing by low-level laser therapy. J Photochem Photobiol B 2009, 95(2):89-92.
5. Pastore D, Greco M, Petragallo VA, Passarella S: Increase in <--H+/e- ratio of the cytochrome c oxidase reaction in mitochondria irradiated with helium-neon laser. Biochem Mol Biol Int 1994, 34(4):817- 826.
6. Karu TI, Kolyakov SF: Exact action spectra for cellular responses relevant to phototherapy. Photomed Laser Surg 2005, 23(4):355-361.
7. Chen AC, Arany PR, Huang YY, Tomkinson
EM, Sharma SK, Kharkwal GB, Saleem T, Mooney D, Yull FE, Blackwell TS et al: Low- level laser therapy activates NF-kB via generation of reactive oxygen species in mouse embryonic fibroblasts. PLoS One 2011, 6(7):e22453.
8. Huang YY, Nagata K, Tedford CE, McCarthy T, Hamblin MR: Low-level laser therapy (LLLT) reduces oxidative stress in primary cortical neurons in vitro. J Biophotonics 2013, 6(10):829-838.
9. Lindgard A, Hulten LM, Svensson L, Soussi B:
Irradiation at 634 nm releases nitric oxide from human monocytes. Lasers Med Sci 2007, 22(1):30-36.
10. Oron U, Ilic S, De Taboada L, Streeter J: Ga- As (808 nm) laser irradiation enhances ATP production in human neuronal cells in culture. Photomed Laser Surg 2007, 25(3):180-182.
11. Passarella S, Casamassima E, Molinari S, Pastore D, Quagliariello E, Catalano IM, Cingolani A: Increase of proton electrochemical potential and ATP synthesis in rat liver mitochondria irradiated in vitro by helium-neon laser. FEBS Lett 1984, 175(1):95-99.
12. Karu T, Pyatibrat L, Kalendo G: Irradiation with He-Ne laser increases ATP level in cells cultivated in vitro. J Photochem Photobiol B 1995, 27(3):219-223.
13. Conlan MJ, Rapley JW, Cobb CM:
Biostimulation of wound healing by low- energy laser irradiation. A review. J Clin Periodontol 1996, 23(5):492-496.
14. Karu T: Primary and secondary mechanisms of action of visible to near-IR radiation on cells. J Photochem Photobiol B 1999, 49(1):1-17.
15. Wilden L, Karthein R: Import of radiation phenomena of electrons and therapeutic low-level laser in regard to the mitochondrial energy transfer. J Clin Laser Med Surg 1998, 16(3):159-165.
16. Barolet D, Duplay P, Jacomy H, Auclair M:
Importance of pulsing illumination parameters in low-level-light therapy. J Biomed Opt 2010, 15(4):048005.
17. Hashmi JT, Huang YY, Sharma SK, Kurup DB, De Taboada L, Carroll JD, Hamblin MR: Effect of pulsing in low-level light therapy. Lasers in surgery and medicine 2010, 42(6):450-466.
18. Spitler R, Berns MW: Comparison of laser and diode sources for acceleration of in vitro wound healing by low-level light therapy. J Biomed Opt 2014, 19(3):38001.