Scars

Dermatol Surg. 2016 Apr;42(4):526-34. doi: 10.1097/DSS.0000000000000680.

Prevention of Thyroidectomy Scars in Asian Adults With Low-Level Light Therapy.

Park YJ1, Kim SJ, Song HS, Kim SK, Lee J, Soh EY, Kim YC.

Author information

  • 1Departments of *Dermatology, and †Surgery, Ajou University School of Medicine, Suwon, South Korea.

Abstract

BACKGROUND:

Abnormal wound-healing after thyroidectomy with a resulting scar is a common dermatologic consultation. Despite many medical and surgical approaches, prevention of postoperative scars is challenging.

OBJECTIVE:

This study validated the efficacy and safety of low-level light therapy (LLLT) using an 830/590 nm light-emitting diode (LED)-based device for prevention of thyroidectomy scars.

METHODS AND MATERIALS:

Thirty-five patients with linear surgical suture lines after thyroidectomy were treated with 830/590 nm LED-LLLT. Daily application of 60 J/cm (11 minutes) for 1 week starting on postoperative day 1 was followed by treatment 3 times per week for 3 additional weeks. The control group (n = 15) remained untreated. Scar-prevention effects were evaluated 1 and 3 months after thyroidectomy with colorimetric evaluation using a tristimulus-color analyzer. The Vancouver Scar Scale (VSS) score, global assessment, and a subjective satisfaction score (range: 1-4) were also determined.

RESULTS:

Lightness (L*) and chrome values (a*) decreased significantly at the 3-month follow-up visit in the treatment group compared with those of controls. The average VSS and GAS scores were lower in the treatment group, whereas the subjective score was not significantly different.

CONCLUSION:

Light-emitting diode based LLLT treatment suppressed the formation of scars after thyroidectomy and could be safely used without noticeable adverse effects.

Curr Dermatol Rep. 2016; 5: 121–128.
Published online 2016 Apr 16. doi:  10.1007/s13671-016-0141-x
PMCID: PMC4848333

Visible Red Light Emitting Diode Photobiomodulation for Skin Fibrosis: Key Molecular Pathways

Andrew Mamalis, Daniel Siegel, and Jared Jagdeocorresponding author
Department of Dermatology, University of California at Davis, Sacramento, CA USA
Dermatology Service, Sacramento VA Medical Center, Mather, CA USA
Department of Dermatology, SUNY Downstate, Brooklyn, NY USA
Jared Jagdeo, Phone: 917 837 9796, moc.liamg@oedgajrj.
corresponding authorCorresponding author.
Author information ? Copyright and License information ?

Abstract

Skin fibrosis, also known as skin scarring, is an important global health problem that affects an estimated 100 million persons per year worldwide. Current therapies are associated with significant side effects and even with combination therapy, progression, and recurrence is common. Our goal is to review the available published data available on light-emitting diode-generated (LED) red light phototherapy for treatment of skin fibrosis. A search of the published literature from 1 January 2000 to present on the effects of visible red light on skin fibrosis, and related pathways was performed in January 2016. A search of PubMed and EMBASE was completed using specific keywords and MeSH terms. “Fibrosis” OR “skin fibrosis” OR “collagen” was combined with (“light emitting diode,” “LED,” “laser,” or “red light”). The articles that were original research studies investigating the use of visible red light to treat skin fibrosis or related pathways were selected for inclusion. Our systematic search returned a total of 1376 articles. Duplicate articles were removed resulting in 1189 unique articles, and 133 non-English articles were excluded. From these articles, we identified six articles related to LED effects on skin fibrosis and dermal fibroblasts. We augmented our discussion with additional in vitro data on related pathways. LED phototherapy is an emerging therapeutic modality for treatment of skin fibrosis. There is a growing body of evidence demonstrating that visible LED light, especially in the red spectrum, is capable of modulating key cellular characteristic associated with skin fibrosis. We anticipate that as the understanding of LED-RL’s biochemical mechanisms and clinical effects continue to advance, additional therapeutic targets in related pathways may emerge. We believe that the use of LED-RL, in combination with existing and new therapies, has the potential to alter the current treatment paradigm of skin fibrosis. There is a current lack of clinical trials investigating the efficacy of LED-RL to treat skin fibrosis. Randomized clinical trials are needed to demonstrate visible red light’s clinical efficacy on different types of skin fibrosis.

Keywords: Skin fibrosis, LED, Visible light, Red light, Fibroblast, Low level light therapy, Photobiomodulation, Reactive oxygen species, Collagen

Introduction

Skin fibrosis, also known as skin scarring, is a significant international health problem with an estimated incidence of greater than 100 million persons affected per annum worldwide [1, 2]. Skin fibrosis is the key clinical characteristic of several diseases including systemic sclerosis, morphea, keloids, hypertrophic scars, chronic graft versus host disease, and gadolinium-induced nephrogenic systemic fibrosis. Skin fibrosis often results from chronic tissue injury, infection, inflammation, or immune response leading to fibroblast activation. The hallmarks of skin fibrosis are increased fibroblast proliferation, increased collagen production, increased extracellular matrix (ECM) deposition, and upregulation of pro-fibrotic signaling pathways (Fig. 1). Despite the morbidity and socioeconomic burdens associated with skin fibrosis, there are limited effective therapeutic options for skin fibrosis. Current therapies are associated with significant side effects and even with combination therapy, progression, and recurrence often occurs [3, 4].

Fig. 1

a Normal fibroblast function. Fibroblasts are the primary resident cell in the dermis and are the major contributor to skin fibrosis. Fibroblasts typically proliferate and produce collagen at a basal rate to maintain dermal integrity. b Abnormal fibroblast

Ultraviolet (UV) phototherapy is a non-invasive modality that has been used to treat several diseases associated with skin fibrosis including morphea, systemic sclerosis, chronic graft versus host disease, and nephrogenic systemic fibrosis [57]. However, UV phototherapy causes thymidine dimer DNA damage that is associated with an increased incidence of skin cancers and premature photoaging [810]. In addition to these safety concerns, UV phototherapy units are often prohibitively expensive for home use and require fluorescent or incandescent bulbs that limit portability. Therefore, UV phototherapy requires frequent office visits that patients often find burdensome [11, 12]. In contrast, light-emitting diode-generated red light (LED-RL) phototherapy is a safe, non-invasive, inexpensive, and portable treatment that may be combined with existing treatment modalities. Furthermore, the visible red light spectrum has superior depth of penetration, when compared to UV light, that allows it to penetrate the epidermis and reach the dermis to affect fibroblast function [13]. LED-RL is not known to cause thymidine dimer DNA damage or to be associated with an increased incidence of skin cancer [14]. However, the underlying biochemical mechanisms and clinical effects of visible light photobiomodulation of skin fibrosis are not well characterized.

The purpose of this review is to review the available evidence on LED-RL phototherapy for the treatment of skin fibrosis, with a special emphasis on the key molecular pathways involved. Herein, we also highlight several strengths and limitations of visible red light phototherapy and suggest enhancements and future directions to evaluate their clinical utility. We anticipate that as the understanding of LED-RL’s biochemical mechanisms and clinical effects continue to advance, additional therapeutic targets in related pathways may emerge. We believe that the use of LED-RL, in combination with existing and new therapies, has the potential to alter the current treatment paradigm of skin fibrosis.

Methods

A search of the published literature from 1 January 2000 to present on the effects of visible red light on skin fibrosis and related pathways was performed in January 2016. A search of PubMed and EMBASE was done using specific keywords and MeSH terms. “Fibrosis” OR “skin fibrosis” was combined with (“light emitting diode,” “LED,” “laser,” or “red light”). The articles that were original research studies that investigated the use of visible red light to treat skin fibrosis or related pathways were selected for inclusion. Non-English articles were excluded.

Results

A schematic of our search strategy is outlined in Fig. 2. Our systematic search returned a total of 1376 articles. Duplicate articles were removed resulting in 1189 unique articles, and 133 non-English articles were excluded. From these articles, we identified six articles related to LED effects on skin fibrosis and dermal fibroblasts. We augmented our discussion with additional in vitro data on related pathways.

Fig. 2

Schematic of the search strategy listing the number of articles matching inclusion or exclusion criteria

Discussion

Molecular Mechanism of Red Light Photobiomodulation

Although visible light makes up 44 % of the total solar energy in our environment, its effect on cellular function and physiology are not fully established [14]. There is emerging in vitro mechanistic data demonstrating red light may be an effective treatment for skin fibrosis; however, there is a paucity of evidence for red light’s clinical effects. Visible light may represent a safer therapeutic modality compared to UV light as it does not generate DNA damage associated with skin cancer [14].

A potential mechanistic pathway demonstrating the cellular effects of red light photobiomodulation in skin fibrosis is diagrammed in Fig. 3. Key downstream targets for the modulation of skin fibrosis include reducing cellular fibroblast proliferation and migration speed, inhibiting pro-fibrotic cytokines and their related pathways such as the transforming growth factor-beta (TGF-beta) pathway, and decreasing synthesis and deposition of collagen.

Fig. 3

Theoretical mechanism of LED red light photobiomodulation. 1 Light has optimal tissue penetration when its wavelength is within the “optical window,” (600–1070 nm). Red light (620–750 nm) takes advantage

Mitochondrial Signaling

The molecular mechanism behind LED-RL’s photobiomodulatory effects appears to initiate in the mitochondria [28, 29]. Red light stimulates the copper/heme-iron centers on cytochrome C oxidase (CCO), an intramitochondrial component of the electron transport chain (Fig. 3) [15, 16]. CCO is a protein complex containing two copper and heme-iron groups that play a key role in the electron transport within the mitochondrial. LED-RL photostimulation of CCO directly influences reactive oxygen species (ROS) and adenosine triphosphate (ATP) production and results in increased ROS and ATP levels (Fig. 3).

Red light has also been shown to modulate a number of other mitochondrial functions, including increased intramitochondrial calcium concentration, and alterations in mitochondrial membrane potential, which may also play a role in mediating downstream effects (Fig. 3) [16]. Furthermore, while there is substantial data demonstrating the effects of redox mechanisms on cellular health and function, there is a paucity of data on how specific mitochondrial measures, such as calcium concentration, might lead to downstream cellular effects. The absence of precise mechanistic links between these other mitochondrial alterations has led many researchers to focus on studying the downstream cellular effects of LED-RL and investigating the role of visible light-associated alterations in ROS levels.

ROS-Related Intracellular Signaling and Transcriptional Changes

For instance, altering ROS levels can release TGF-beta 1 and TGF-beta 3 from their associated latency binding proteins (Fig. 3). The interaction of these cytokines with their associated receptors is critical in the pathogenesis or prevention of skin fibrosis. Altering the levels of TGF-beta 1 versus TGF-Beta 3 bound to the TGF-beta receptor complex modulates the pro-fibrotic cascade that leads to downstream activation of key signaling molecules called SMADs and numerous growth factors that ultimately result in fibroblast proliferation and collagen biosynthesis [17, 18, 21, 22].

It is believed that visible light-associated increases in ROS levels within the cell trigger redox-sensitive transcription factors such as AP-1, NF-kB, p53, and hypoxia inducible factor 1 (HIF-1) [30]. Cellular redox changes also modulate insulin-like growth factors (IGFs), Akt/PKB, and phosphoinositide 3-kinase (PI3K) pathways, and activate mammalian target of rapamycin (mTOR) [31]. ROS-initiated alterations in these pathways often contribute to the downstream effects on transcription, cellular proliferation, migration speed, and extracellular matrix production. This suggests that ROS may be the mechanistic link between the mitochondrial effects of LED-RL and the resulting downstream transcriptional and cellular effects.

In additional to these canonical transcriptional alterations, some researchers believe that alterations in microRNA levels also play a role in LED-RL photobiomodulation (Fig. 3). However, there is currently a paucity of data investigating the specific effects of LED-RL on microRNA levels. Interestingly, research has demonstrated that laser-generated visible red light leads to specific alterations in microRNA that are associated with skin fibrosis, including microRNA-7a, 21, 29, 133b, and 192 [31, 32]. Further research is warranted to investigate the role these microRNA play in causing LED-RL-associated downstream cellular effects.

Effects of Red Light on Cellular Functions Related to Fibrosis

Cellular Proliferation

Modulation of mitochondrial, intracellular, and nuclear processes ultimately alter downstream cellular processes involved in skin fibroblast proliferation. For instance, fibroblast proliferation is a key contributor to the initiation and maintenance of skin fibrosis, and control of fibroblast proliferation is a critical therapeutic strategy for addressing skin fibrosis [33]. Our group has found that LED-RL is capable of inhibiting fibroblast proliferation in a dose-dependent manner [34]. Furthermore, red light does not appear to affect fibroblast viability, with no increases in apoptosis or necrosis observed [34, 35••]. This suggests that visible red light is likely modulating fibroblast function through means other than direct cellular cytotoxicity, such as through modulation of the cell cycle or autophagy.

It is likely that these alterations in proliferation are a result of alterations in the redox state of fibroblasts treated with LED-RL. While mild elevations in free radicals have been shown to increase proliferation, we have found that the dose-dependent decreases in fibroblast proliferation are associated with a dose-dependent sustained increase in ROS [35••, 36]. Therefore, it is likely that the sustained alterations in the redox state of fibroblasts treated with LED-RL and the subsequent redox-initiated alterations in the TGF-beta pathway and related pathways are contributing to the dose-dependent decrease in fibroblast proliferation.

Cellular Migration

Furthermore, some believe that cellular migration speed may play a role in the recruitment of fibroblasts to sites of increased collagen production [3, 4]. This finding is supported by the fact that fibroblasts derived from skin affected by skin fibrosis demonstrate increased motility when compared to fibroblasts derived from normal healthy skin [37, 38]. Few studies have sought to address this potential therapeutic avenue and so the clinical effect of decreasing fibroblast motility is still unclear.

Researchers have demonstrated that the PI3K/Akt and MAPK/ERK pathways play crucial roles in the regulation of fibroblast migration, and that visible light is capable of directly activating or inhibiting the phosphorylation state of these key cell signaling molecules [32, 3944]. Our group recently found that LED-RL increased ROS levels and decreased fibroblast migration speed in a dose-dependent manner (Fig. 3) [35••]. Additionally, we found that LED-RL also altered phospho-Akt levels (unpublished data by Jagdeo Lab). Furthermore, migration speed returned to control levels when ROS increases were blocked by the pretreatment of fibroblasts with the antioxidant resveratrol or when cells were pretreated with the PI3K/Akt inhibitor LY294002 [35••]. This suggests that LED-RL’s effects on migration may be largely mediated by increased ROS that lead to modulation of phospho-Akt levels and subsequent alterations in fibroblast migration speed. Further research is needed to investigate the role cellular migration speed plays in the pathogenesis of skin fibrosis and the clinical effects of therapeutically targeting fibroblast motility.

Collagen Production

Fundamentally, the pathogenesis of all forms of skin fibrosis involves an increased deposition of skin collagen [33]. Therefore, suppression of collagen production is a fundamental component of any effective anti-fibrotic therapy [33]. Several studies support that visible red light is capable of modulating collagen production in vitro. Our group has demonstrated that LED-RL is capable of suppressing collagen production in human skin fibroblast cultures. In this study, fibroblasts were treated with LED-RL, and then collagen was measured using the collagen stain, picrosirius red (unpublished data by Jagdeo Lab). LED-RL resulted in decreased collagen production in a dose-dependent manner (Fig. 3). Furthermore, procollagen 1A1 levels were found to be decreased following LED-RL treatment, suggesting that this decrease in collagen levels may be due in large part to decreases in collagen subunits.

Another study investigated the effect of visible red light generated by a diode laser on murine NIH/3T3 fibroblasts [45]. They found that red light treatment inhibited TGF-beta induced fibroblast to myofibroblast differentiation and decreased collagen 1 expression. Furthermore, they found that red light was capable of upregulating matrix metalloproteinases (MMP)-2 and MMP-9, while downregulating tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 [45]. This suggests that red light may not only decrease collagen production, but may also change overall extracellular matrix remodeling profile. Further studies are needed evaluating the effects of red light phototherapy on in vivo collagen content and homeostasis; however, these early in vitro findings are promising.

Limitations and Future Directions

However, red light phototherapy does possess several limitations. First, the current understanding of the biochemical mechanisms underlying visible light photobiomodulation is limited. More laboratory research is needed to characterize the key pathways involved in initiating the downstream cellular effects observed. Another limitation of the field of visible light phototherapy is that many in vitro studies are done on cultured skin fibroblasts. Fibroblast monocultures do not completely recapitulate the complex fibroblast phenotype or the extracellular milieu that contributes to skin fibrosis pathology. Thus, randomized clinical trials are needed to demonstrate visible red light’s effect on skin fibrosis.

Perhaps, one of the most critical challenges facing visible light phototherapy is the selection of appropriate dosimetry. Visible light does not have sufficient measures for evaluating the pharmacokinetics of light or its effect on in vivo tissue. Therefore, many dosing protocols are based upon observed effects. However, the fluence delivered depends on the duration of treatment, the power density of the light source, and the distance of the source from its target tissue. Differing any one variable can at times lead to different photobiomodulatory effects. For instance, while red light at fluences above 320 J/cm2 inhibit fibroblast proliferation, red light at fluences below 50 J/cm2 often promote fibroblast proliferation. Therefore, establishing standardized dosing ranges and thresholds for future basic science and clinical research studies may improve the comparability of different clinical studies.

We believe the use of commercially available LEDs as a visible light source is an exciting avenue of future research. LED-RL devices are safe, economic, and portable, and we believe are the optimal devices for future research and clinical use of visible red light.

Conclusions

Visible light phototherapy is an emerging therapeutic modality for treatment of skin fibrosis. There is a growing body of evidence demonstrating that visible red light is capable of modulating key cellular characteristic associated with skin fibrosis. We believe that further laboratory research may elucidate the underlying mechanisms and effects involved in visible light photobiomodulation. LED-based devices are the optimal devices for red visible light phototherapy. There is a current lack of clinical trials investigating the efficacy of LED-RL to treat skin fibrosis. Randomized clinical trials are needed to demonstrate visible red light’s clinical efficacy on different types of skin fibrosis.

Acknowledgments

This study was funded by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR000002 and linked awards TL1 TR000133 and KL2 TR000134.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Disclaimer

The contents herein do not represent the views of the US Department of Veterans Affairs or the US Government. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

This article is part of the Topical Collection on Laser Therapy

References

 Papers of particular interest, published recently, have been highlighted as: ••?Of major importance
1. Bayat A, McGrouther DA, Ferguson MW. Skin scarring. BMJ. 2003;326:88–92. doi: 10.1136/bmj.326.7380.88. [PMC free article] [PubMed] [Cross Ref]
2. Lim AF, Weintraub J, Kaplan EN, et al. The embrace device significantly decreases scarring following scar revision surgery in a randomized controlled trial. Plast Reconstr Surg. 2014;133:398–405. doi: 10.1097/01.prs.0000436526.64046.d0. [PMC free article] [PubMed] [Cross Ref]
3. Mamalis AD, Lev-Tov H, Nguyen DH, et al. Laser and light-based treatment of keloids—a review. J Eur Acad Dermatol Venereol. 2013;28(6):689–99. doi: 10.1111/jdv.12253. [PMC free article] [PubMed][Cross Ref]
4. Vitiello M, Abuchar A, Santana N, et al. An update on the treatment of the cutaneous manifestations of systemic sclerosis: the dermatologist’s point of view. J Clin Aesthet Dermatol. 2012;5:33–43.[PMC free article] [PubMed]
5. Tran KT, Prather HB, Cockerell CJ, et al. UV-A1 therapy for nephrogenic systemic fibrosis. Arch Dermatol. 2009;145:1170–4. doi: 10.1001/archdermatol.2009.245. [PubMed] [Cross Ref]
6. Connolly KL, Griffith JL, McEvoy M, et al. Ultraviolet A1 phototherapy beyond morphea: experience in 83 patients. Photodermatol Photoimmunol Photomed. 2015;31:289–95. doi: 10.1111/phpp.12185. [PubMed] [Cross Ref]
7. Sunderkotter C, Kuhn A, Hunzelmann N, et al. Phototherapy: a promising treatment option for skin sclerosis in scleroderma? Rheumatology (Oxford) 2006;45(Suppl 3):iii52–iii4. [PubMed]
8. Berking C, Takemoto R, Satyamoorthy K, et al. Induction of melanoma phenotypes in human skin by growth factors and ultraviolet B. Cancer Res. 2004;64:807–11. doi: 10.1158/0008-5472.CAN-03-3438.[PubMed] [Cross Ref]
9. Cleaver JE, Crowley E. UV damage, DNA repair and skin carcinogenesis. Front Biosci. 2002;7:d1024–43. doi: 10.2741/cleaver. [PubMed] [Cross Ref]
10. Matsumura Y, Ananthaswamy HN. Short-term and long-term cellular and molecular events following UV irradiation of skin: implications for molecular medicine. Expert Rev Mol Med. 2002;4:1–22. doi: 10.1017/S146239940200532X. [PubMed] [Cross Ref]
11. Koek MB, Sigurdsson V, van Weelden H, et al. Cost effectiveness of home ultraviolet B phototherapy for psoriasis: economic evaluation of a randomised controlled trial (PLUTO study) BMJ. 2010;340:c1490. doi: 10.1136/bmj.c1490. [PMC free article] [PubMed] [Cross Ref]
12. NPF. National Psoriasis Foundation policy brief: phototherapy copayments impact access to treatment 2010 [cited 2015 10-10-2015]. Available from: http://www.psoriasis.org/document.doc?id=1387.
13. Jagdeo JR, Adams LE, Brody NI, et al. Transcranial red and near infrared light transmission in a cadaveric model. PLoS One. 2012;7:e47460. doi: 10.1371/journal.pone.0047460. [PMC free article][PubMed] [Cross Ref]
14. Liebel F, Kaur S, Ruvolo E, et al. Irradiation of skin with visible light induces reactive oxygen species and matrix-degrading enzymes. J Investig Dermatol. 2012;132:1901–7. doi: 10.1038/jid.2011.476. [PubMed][Cross Ref]
15. Chung H, Dai T, Sharma SK, et al. The nuts and bolts of low-level laser (light) therapy. Ann Biomed Eng. 2012;40:516–33. doi: 10.1007/s10439-011-0454-7. [PMC free article] [PubMed] [Cross Ref]
16. Karu TI. Mitochondrial signaling in mammalian cells activated by red and near-IR radiation. Photochem Photobiol. 2008;84:1091–9. doi: 10.1111/j.1751-1097.2008.00394.x. [PubMed] [Cross Ref]
17. Barcellos-Hoff MH, Dix TA. Redox-mediated activation of latent transforming growth factor-beta 1. Mol Endocrinol. 1996;10:1077–83. [PubMed]
18. Jobling MF, Mott JD, Finnegan MT, et al. Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species. Radiat Res. 2006;166:839–48. doi: 10.1667/RR0695.1.[PubMed] [Cross Ref]
19. Lorda-Diez CI, Montero JA, Garcia-Porrero JA, et al. Tgfbeta2 and 3 are coexpressed with their extracellular regulator Ltbp1 in the early limb bud and modulate mesodermal outgrowth and BMP signaling in chicken embryos. BMC Dev Biol. 2010;10:69. doi: 10.1186/1471-213X-10-69. [PMC free article][PubMed] [Cross Ref]
20. Waynant R, Tata D, Arany P. Photobiomodulation by low power laser irradiation involves activation of latent TGF-?1. Proceedings of light-activated tissue regeneration and therapy conference. Lecture notes in electrical engineering. 12: Springer US; 2008. p. 207–12.
21. Massague J. TGFbeta signaling: receptors, transducers, and Mad proteins. Cell. 1996;85:947–50. doi: 10.1016/S0092-8674(00)81296-9. [PubMed] [Cross Ref]
22. Chin GS, Liu W, Peled Z, et al. Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg. 2001;108:423–9. doi: 10.1097/00006534-200108000-00022. [PubMed] [Cross Ref]
23. Yan X, Liu Z, Chen Y. Regulation of TGF-beta signaling by Smad7. Acta Biochim Biophys Sin Shanghai. 2009;41:263–72. doi: 10.1093/abbs/gmp018. [PubMed] [Cross Ref]
24. Penn JW, Grobbelaar AO, Rolfe KJ. The role of the TGF-beta family in wound healing, burns and scarring: a review. Int J Burns Trauma. 2012;2:18–28. [PMC free article] [PubMed]
25. Khoo YT, Ong CT, Mukhopadhyay A, et al. Upregulation of secretory connective tissue growth factor (CTGF) in keratinocyte-fibroblast coculture contributes to keloid pathogenesis. J Cell Physiol.2006;208:336–43. doi: 10.1002/jcp.20668. [PubMed] [Cross Ref]
26. Cutroneo KR. TGF-beta-induced fibrosis and SMAD signaling: oligo decoys as natural therapeutics for inhibition of tissue fibrosis and scarring. Wound Repair Regen. 2007;15(Suppl 1):S54–60. doi: 10.1111/j.1524-475X.2007.00226.x. [PubMed] [Cross Ref]
27. Ghahary A, Tredget EE, Ghahary A, et al. Cell proliferating effect of latent transforming growth factor-beta1 is cell membrane dependent. Wound Repair Regen. 2002;10:328–35. doi: 10.1046/j.1524-475X.2002.10509.x. [PubMed] [Cross Ref]
28. Greco M, Guida G, Perlino E, et al. Increase in RNA and protein synthesis by mitochondria irradiated with helium-neon laser. Biochem Biophys Res Commun. 1989;163:1428–34. doi: 10.1016/0006-291X(89)91138-8. [PubMed] [Cross Ref]
29. Karu TI, Pyatibrat LV, Kalendo GS. Photobiological modulation of cell attachment via cytochrome c oxidase. Photochem Photobiol Sci. 2004;3:211–6. doi: 10.1039/b306126d. [PubMed] [Cross Ref]
30. Chen AC, Arany PR, Huang YY, et al. Low-level laser therapy activates NF-kB via generation of reactive oxygen species in mouse embryonic fibroblasts. PLoS One. 2011;6:e22453. doi: 10.1371/journal.pone.0022453. [PMC free article] [PubMed] [Cross Ref]
31. Shroff A, Mamalis A, Jagdeo J. Oxidative stress and skin fibrosis. Curr Pathobiol Rep. 2014;2:257–67. doi: 10.1007/s40139-014-0062-y. [PMC free article] [PubMed] [Cross Ref]
32. Choi H, Lim W, Kim I, et al. Inflammatory cytokines are suppressed by light-emitting diode irradiation of P. gingivalis LPS-treated human gingival fibroblasts: inflammatory cytokine changes by LED irradiation.Lasers Med Sci. 2012;27:459–67. doi: 10.1007/s10103-011-0971-5. [PubMed] [Cross Ref]
33. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med.2012;18:1028–40. doi: 10.1038/nm.2807. [PMC free article] [PubMed] [Cross Ref]
34. Lev-Tov H, Mamalis A, Brody N, et al. Inhibition of fibroblast proliferation in vitro using red light-emitting diodes. Dermatol Surg. 2013;39:1167–70. doi: 10.1111/dsu.12212. [PubMed] [Cross Ref]
35.••. Mamalis A, Koo E, Isseroff RR, et al. Resveratrol prevents high fluence red light-emitting diode reactive oxygen species-mediated photoinhibition of human skin fibroblast migration. PLoS One.2015;10:e0140628. doi: 10.1371/journal.pone.0140628. [PMC free article] [PubMed] [Cross Ref]
36. Sarsour EH, Kumar MG, Chaudhuri L, et al. Redox control of the cell cycle in health and disease.Antioxid Redox Signal. 2009;11:2985–3011. doi: 10.1089/ars.2009.2513. [PMC free article] [PubMed][Cross Ref]
37. Ashcroft KJ, Syed F, Bayat A. Site-specific keloid fibroblasts alter the behaviour of normal skin and normal scar fibroblasts through paracrine signalling. PLoS One. 2013;8:e75600. doi: 10.1371/journal.pone.0075600. [PMC free article] [PubMed] [Cross Ref]
38. Wu CS, Wu PH, Fang AH, et al. FK506 inhibits the enhancing effects of transforming growth factor (TGF)-beta1 on collagen expression and TGF-beta/Smad signalling in keloid fibroblasts: implication for new therapeutic approach. Br J Dermatol. 2012;167:532–41. doi: 10.1111/j.1365-2133.2012.11023.x. [PubMed][Cross Ref]
39. Guo A, Song B, Reid B, et al. Effects of physiological electric fields on migration of human dermal fibroblasts. J Investig Dermatol. 2010;130:2320–7. doi: 10.1038/jid.2010.96. [PMC free article] [PubMed][Cross Ref]
40. Huang C, Jacobson K, Schaller MD. MAP kinases and cell migration. J Cell Sci. 2004;117:4619–28. doi: 10.1242/jcs.01481. [PubMed] [Cross Ref]
41. Kanazawa S, Fujiwara T, Matsuzaki S, et al. bFGF regulates PI3-kinase-Rac1-JNK pathway and promotes fibroblast migration in wound healing. PLoS One. 2010;5:e12228. doi: 10.1371/journal.pone.0012228. [PMC free article] [PubMed] [Cross Ref]
42. Li W, Fan J, Chen M, et al. Mechanism of human dermal fibroblast migration driven by type I collagen and platelet-derived growth factor-BB. Mol Biol Cell. 2004;15:294–309. doi: 10.1091/mbc.E03-05-0352.[PMC free article] [PubMed] [Cross Ref]
43. Sepe L, Ferrari MC, Cantarella C, et al. Ras activated ERK and PI3K pathways differentially affect directional movement of cultured fibroblasts. Cell Physiol Biochem. 2013;31:123–42. doi: 10.1159/000343355. [PubMed] [Cross Ref]
44. Ong WK, Chen HF, Tsai CT, et al. The activation of directional stem cell motility by green light-emitting diode irradiation. Biomaterials. 2013;34:1911–20. doi: 10.1016/j.biomaterials.2012.11.065. [PubMed][Cross Ref]
45. Sassoli C, Chellini F, Squecco R, et al. Low intensity 635 nm diode laser irradiation inhibits fibroblast-myofibroblast transition reducing TRPC1 channel expression/activity: new perspectives for tissue fibrosis treatment. Lasers Surg Med. 2015;48(3):318–32. doi: 10.1002/lsm.22441. [PubMed] [Cross Ref]
Dermatol Surg. 2016 Mar 15. [Epub ahead of print]

Prevention of Thyroidectomy Scars in Asian Adults With Low-Level Light Therapy.

Park YJ1, Kim SJ, Song HS, Kim SK, Lee J, Soh EY, Kim YC.

Author information

  • 1Departments of *Dermatology, and †Surgery, Ajou University School of Medicine, Suwon, South Korea.

Abstract

BACKGROUND:

Abnormal wound-healing after thyroidectomy with a resulting scar is a common dermatologic consultation. Despite many medical and surgical approaches, prevention of postoperative scars is challenging.

OBJECTIVE:

This study validated the efficacy and safety of low-level light therapy (LLLT) using an 830/590 nm light-emitting diode (LED)-based device for prevention of thyroidectomy scars.

METHODS AND MATERIALS:

Thirty-five patients with linear surgical suture lines after thyroidectomy were treated with 830/590 nm LED-LLLT. Daily application of 60 J/cm (11 minutes) for 1 week starting on postoperative day 1 was followed by treatment 3 times per week for 3 additional weeks. The control group (n = 15) remained untreated. Scar-prevention effects were evaluated 1 and 3 months after thyroidectomy with colorimetric evaluation using a tristimulus-color analyzer. The Vancouver Scar Scale (VSS) score, global assessment, and a subjective satisfaction score (range: 1-4) were also determined.

RESULTS:

Lightness (L*) and chrome values (a*) decreased significantly at the 3-month follow-up visit in the treatment group compared with those of controls. The average VSS and GAS scores were lower in the treatment group, whereas the subjective score was not significantly different.

CONCLUSION:

Light-emitting diode based LLLT treatment suppressed the formation of scars after thyroidectomy and could be safely used without noticeable adverse effects.

J Cosmet Laser Ther.  2013 Feb 5. [Epub ahead of print]

Evaluation of low-level laser therapy in rabbit oral mucosa after soft tissue graft application: A pilot study.

Kara C, Demir T, Ozbek E.

Source

Department of Periodontology, Faculty of Dentistry, Ordu University , Ordu , Turkey.

Abstract

The aim of the present study was to assess the histopathological effects of low-level laser therapy (LLLT) on healing of the oral mucosa after soft tissue graft operations. The alterations at the end of healing in normal and LLLT-applied oral mucosa were studied in two healthy adult New Zealand white rabbits by taking specimens for light microscopic inspection. There was no adverse event reported in the study and no post-operative complications, such as swelling, bleeding, or edema, were observed in the rabbits. Complete wound healing was faster in the LLLT-applied rabbit. Compared to the normal rabbit oral mucosa, thickening of the stratum corneum (hyperkeratosis) was found in the epithelia of the rabbits. A significant increase in the epithelial thickness was found in the samples of rabbits, suggesting increased scar tissue following the wound repair. Additionally, many mitotic figures were present in the epithelia of the LLLT-applied rabbit, indicating epithelial cell hyperplasia. Long and irregular connective tissue protrusions projecting into the undersurface of the epithelium and mononuclear cell infiltrations were noted in the rabbits. The results suggest that LLLT used for soft tissue operations provides better and faster wound healing and that LLLT enhances epithelization.

Lasers Surg Med. 2010 Aug;42(6):597-601.

Prophylactic low-level light therapy for the treatment of hypertrophic scars and keloids: a case series.

Barolet D, Boucher A.

RoseLab Skin Optics Research Laboratory, Montreal, Quebec, Canada. daniel.barolet@mcgill.ca

Abstract

BACKGROUND AND OBJECTIVES: Hypertrophic and keloid scars result from alterations in the wound healing process. Treating abnormal scars remains an important challenge. The aim of this case series was to investigate the effectiveness of near infrared (NIR) light emitting diode (LED) treatment as a prophylactic method to alter the wound healing process in order to avoid or attenuate the formation of hypertrophic scars or keloids.

STUDY DESIGN/PATIENTS AND METHODS: Three patients (age 27-57) of phototypes I-III with hypertrophic scars or keloids due to acne or surgery participated in this case series. Following scar revision by surgery or CO(2) laser ablation on bilateral areas, one scar was treated daily by the patient at home with non-thermal, non-ablative NIR LED (805 nm at 30 mW/cm(2)) for 30 days. Efficacy assessments, conducted up to a year post-treatment, included the Vancouver Scar scale (VSS), clinical global assessment of digital photographs, and quantitative profilometry analysis using PRIMOS. Safety was documented by adverse effects monitoring.

RESULTS: Significant improvements on the NIR-treated versus the control scar were seen in all efficacy measures. No significant treatment-related adverse effects were reported.

CONCLUSION: Possible mechanisms involved are inhibition of TGF-beta I expression. Further studies in larger group of patients are needed to evaluate this promising technique.

J Cosmet Laser Ther. 2010 Jul 14. [Epub ahead of print]

Low-level laser therapy for the treatment of epidermolysis bullosa: A case report.

Minicucci EM, Barraviera SR, Miot H, Almeida-Lopes L.

Department of Dermatology and Radiotherapy, Botucatu School of Medicine of São Paulo State University – UNESP, Brazil.

Abstract

Abstract Epidermolysis bullosa (EB) is a rare group of diseases characterized by skin fragility. There is no specific treatment, short of protection from trauma, currently available for these patients. Low-level laser therapy (LLLT) was effective as an analgesic and in accelerating cutaneous wound healing after six sessions of therapy in a child with dystrophic EB with cutaneous scarring and blisters on the limbs and trunk.

Photomed Laser Surg.  2010 Jun;28(3):417-22.

Effects of low-level laser therapy on pain and scar formation after inguinal herniation surgery: a randomized controlled single-blind study.

Carvalho RL, Alcântara PS, Kamamoto F, Cressoni MD, Casarotto RA.

Source

Postgraduate Program in Rehabilitation Sciences, University of São Paulo, São Paulo, Brazil.

Abstract

OBJECTIVE:

The aim of this study was to investigate the efficacy of an infrared GaAlAs laser operating with a wavelength of 830 nm in the postsurgical scarring process after inguinal-hernia surgery.

BACKGROUND:

Low-level laser therapy (LLLT) has been shown to be beneficial in the tissue-repair process, as previously demonstrated in tissue culture and animal experiments. However, there is lack of studies on the effects of LLLT on postsurgical scarring of incisions in humans using an infrared 830-nm GaAlAs laser.

METHOD:

Twenty-eight patients who underwent surgery for inguinal hernias were randomly divided into an experimental group (G1) and a control group (G2). G1 received LLLT, with the first application performed 24 h after surgery and then on days 3, 5, and 7. The incisions were irradiated with an 830-nm diode laser operating with a continuous power output of 40 mW, a spot-size aperture of 0.08 cm(2) for 26 s, energy per point of 1.04 J, and an energy density of 13 J/cm(2). Ten points per scar were irradiated. Six months after surgery, both groups were reevaluated using the Vancouver Scar Scale (VSS), the Visual Analog Scale, and measurement of the scar thickness.

RESULTS:

G1 showed significantly better results in the VSS totals (2.14 +/- 1.51) compared with G2 (4.85 +/- 1.87); in the thickness measurements (0.11 cm) compared with G2 (0.19 cm); and in the malleability (0.14) compared with G2 (1.07). The pain score was also around 50% higher in G2.

CONCLUSION:

Infra-red LLLT (830 nm) applied after inguinal-hernia surgery was effective in preventing the formation of keloids. In addition, LLLT resulted in better scar appearance and quality 6 mo postsurgery.

Photomed Laser Surg. 2009 Oct 12. [Epub ahead of print]

Effects of Low-Level Laser Therapy on Pain and Scar Formation after Inguinal Herniation Surgery: A Randomized Controlled Single-Blind Study.

de Paiva Carvalho RL, Alcântara PS, Kamamoto F, Cressoni MD, Casarotto RA.

1 Postgraduate Program in Rehabilitation Sciences , University of São Paulo, São Paulo, Brazil .

Abstract Objective: The aim of this study was to investigate the efficacy of an infrared GaAlAs laser operating with a wavelength of 830 nm in the postsurgical scarring process after inguinal-hernia surgery. Background: Low-level laser therapy (LLLT) has been shown to be beneficial in the tissue-repair process, as previously demonstrated in tissue culture and animal experiments. However, there is lack of studies on the effects of LLLT on postsurgical scarring of incisions in humans using an infrared 830-nm GaAlAs laser. Method: Twenty-eight patients who underwent surgery for inguinal hernias were randomly divided into an experimental group (G1) and a control group (G2). G1 received LLLT, with the first application performed 24 h after surgery and then on days 3, 5, and 7. The incisions were irradiated with an 830-nm diode laser operating with a continuous power output of 40 mW, a spot-size aperture of 0.08 cm(2) for 26 s, energy per point of 1.04 J, and an energy density of 13 J/cm(2). Ten points per scar were irradiated. Six months after surgery, both groups were reevaluated using the Vancouver Scar Scale (VSS), the Visual Analog Scale, and measurement of the scar thickness. Results: G1 showed significantly better results in the VSS totals (2.14 +/- 1.51) compared with G2 (4.85 +/- 1.87); in the thickness measurements (0.11 cm) compared with G2 (0.19 cm); and in the malleability (0.14) compared with G2 (1.07). The pain score was also around 50% higher in G2. Conclusion: Infra-red LLLT (830 nm) applied after inguinal-hernia surgery was effective in preventing the formation of keloids. In addition, LLLT resulted in better scar appearance and quality 6 mo postsurgery.

Lasers Surg Med. 2004;34(5):451-7.

Evaluation of the use of low level laser and photosensitizer drugs in healing.

Silva JC, Lacava ZG, Kuckelhaus S, Silva LP, Neto LF, Sauro EE, Tedesco AC.

IP&D, Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba, Av. Shishima Hifumi, 2911, Urbanova, 12244-000, Sao Josedos Campos, SP, Brasil.

BACKGROUND AND OBJECTIVES: In the last decade, many different kinds of therapies have emerged as a consequence of advances in the field of applied technology. It is known that low level laser therapy contributes to tissue healing; however, the use of photodynamic therapy (PDT) in healing and the scar formation processes has not been fully explored. The present study analyses the effect of low level laser InGaAIP (685 nm), radiation, either alone or combined with a phthalocyanine-derived photosensitizer (PS) in a gel base delivery (GB) system, on the healing process of cutaneous wounds in rats. STUDY DESIGN/MATERIALS AND METHODS: The rats were divided into six groups: control (untreated) (CG), gel base (GB), photosensitizer (PS), laser (LG), laser+photosensitizer (LPS), and laser+photosensitizer in a GB (LPSG). Standardized circular wounds were made on the dorsum of each rat with a skin punch biopsy instrument. After wounding, treatment was performed once daily and the animals were killed at day 8. Tissue specimens containing the whole wound area were removed and processed for histological analysis using conventional techniques. Serial cross-sections were analyzed to evaluate the organization of the dermis and epidermis as well as collagen deposition. RESULTS: The animals of groups LG, PS, LPS, and LPSG presented higher collagen content and enhanced re-epithelialization as compared to CG (control) and GB rats. Connective tissue remodeling was more evident in groups LPS and LPSG. CONCLUSIONS: The results clearly indicated a synergetic effect of light+photosensitizer+delivery drug on tissue healing. PDT did not cause any healing inhibition or tissue damage during the healing process. Copyright 2004 Wiley-Liss, Inc.

J Photochem Photobiol B. 2003 Apr;70(1):39-44.

The effect of 880 nm low level laser energy on human fibroblast cell numbers: a possible role in hypertrophic wound healing.

Webb C, Dyson M.

Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong. rscwebb@inet.polyu.edu.hk

Low level lasers (LLLs) have been shown to induce therapeutic effects in wound healing. However, there have been few LLL studies on burn wounds which may become unsightly, hypertrophic and impair function. Inhibitory effects on the healing of fibrotic wounds, prone to hypertrophy may be expected to reasonably reduce the problems accompanying hypertrophic scarring. The effects of LLL wavelengths and treatment parameters on wound healing cells in vitro often demonstrate meaningful results and without concurrent ethical difficulties of clinical trials. This experiment investigated the effect of an 880 nm, 16 mW GaAlAs diode at 2.4 and 4 J/cm(2) on cell numbers of two human fibroblast cell lines, derived from hypertrophic scar (HF) and normal dermal explants (NF), respectively. After irradiation by 880 nm LLL, cell numbers were measured utilising methylene blue bioassay and read by the spectrophotometer in the same microculture plates. HF and NF exhibited decreased cell numbers as compared to sham-irradiated controls. HF cell number, after 2.4 J/cm(2), was significantly lower on day 5 (P<0.05). The NF cell numbers were significantly lower on day 4 and/or day 5 (P<0.05). The results have implications on hypertrophic wound healing and further studies are required.

Lasers Surg Med. 1998;22(5):294-301.

Stimulatory effect of 660 nm low level laser energy on hypertrophic scar-derived fibroblasts: possible mechanisms for increase in cell counts.

Webb C, Dyson M, Lewis WH.

Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong.

BACKGROUND AND OBJECTIVE: Varying effects of red light wavelengths on in vitro cells have been reported. Low level lasers (LLL) are employed to assist wound healing especially for indolent ulcers. On healing, burn wounds may become hypertrophic, resulting in excessive wound contraction, poor cosmesis, and functional impairment. This study enquired whether 660 nm LLL affected hypertrophic scar-derived fibroblasts. STUDY DESIGN/MATERIALS AND METHODS: The experiments investigated the effect of a 660 nm, 17 mW laser diode at dosages of 2.4 J/cm2 and 4 J/cm2 on cell counts of two human fibroblast cell lines, derived from hypertrophic scar tissue (HSF) and normal dermal (NDF) tissue explants, respectively. The protocol avoided transfer of postirradiated cells. Estimation of fibroblasts utilized the methylene blue bioassay. RESULTS/CONCLUSION: The post-660 nm-irradiated HSFs exhibited very significantly higher cell counts than controls P < 0.01 on days 1-4 (Mann-Whitney U-test), and P < 0.01 on days 1-3 for similarly irradiated NDFs.