Print version ISSN 0365-0596
An. Bras. Dermatol. vol.86 no.5 Rio de Janeiro Sept./Oct. 2011
Effect of low-level laser therapy on the initial stages of tissue repair: basic principles*
Juliana Aparecida de Almeida Chaves PivaI; Elizângela Márcia de Carvalho AbreuII; Vanessa dos Santos SilvaII; Renata Amadei NicolauIII
ISpecialist - M.Sc. student, Universidade do Vale do Paraiba - UNIVAP (University of Vale do Paraiba) - São Jose dos Campos (SP), Brazil
IIM.Sc. in Biomedical Engineering - Professor at Universidade Paulista - UNIP (Paulista University) - São Jose dos Campos (SP), Brazil
IIIM.Sc. and PhD in Biomedical Engineering and Ph.D. in Basic Medical Sciences - Professor at Universidade do Vale da Paraiba (UNIVAP) - São Jose dos Campos (SP), Brazil
O objetivo do estudo foi realizar uma revisão de literatura a respeito da terapia com laser de baixa potência e sua relação com as fases iniciais de reparo. Foram analisados 22 artigos, observou-se a utilização de diferentes doses e comprimentos de ondas (632,8 a 904 nm). Nos estudos in vitro foram utilizadas doses entre 2,2 e 16 J/cm2. A dose de 5 J/cm2 tem sido apontada como responsável por mudanças significativas in vitro, porém a dose de 16 J/cm2 promove efeito inibitório sobre o crescimento celular em culturas. Em estudos in vivo, envolvendo animais foram utilizadas doses entre 0,04 a 21 J/cm2. Para estudos em humanos foram utilizadas doses entre 1,8 a 16 J/cm2. Conclui-se que a terapia com laser de baixa potência exerce efeitos antiinflamatórios importantes nos processos iniciais da cicatrização: redução de mediadores químicos, de citocinas, do edema, diminuição da migração de células inflamatórias e incremento de fatores de crescimento contribuindo diretamente para o processo de reabilitação tecidual. Porém, a falta de padronização dificulta a escolha de parâmetros ideais.
Keywords: Fibroblast growth factors; Inflammation; Inflammation mediators; Laser therapy, Low-level; Lasers
Clinical practice with low-level laser therapy (LLLT) has been investigated and employed for about 20 years. The growing interest in the effects of this therapy has been demonstrated by the significant amount of scientific publications in the area. However, researchers and therapists have questioned the clinical benefits of laser therapy due to divergent results in the literature caused by lack of methodological standardization in studies as well as by its clinical applicability, especially when it comes to using this resource in the early stages of tissue repair. 1-4
The initial effects of laser interaction with biological tissue may cause the release of pre-forming substances such as histamine, serotonin, bradykinin and modify normal enzymatic reactions, accelerating or delaying these reactions and promoting an increase in ATP production. This leads to increased efficiency of the sodium-potassium pump; consequently, the difference in electric potential between the inside and outside of the cell is maintained with better results. 5
The first stage of tissue repair is inflammation, which is essential to preserve the integrity of the organism. It involves an interaction between inflammatory cells (neutrophils, lymphocytes, monocytes/macrophages) and vascular cells (endothelial cells and smooth muscle). Initially, the inflammatory cells migrate to the target tissue by chemotaxis, induced by chemical mediators (histamine, prostaglandins - PGE2, leukotrienes - LTD4, interleukins - IL-1 and IL-6, nitric oxide - NO) that bind endothelial and cell receptors, stimulating an inflammatory response. 2After that, there is activation of other mediators of lipid (eicosanoids) and peptide (cytokines, growth factors and neuropeptides) nature, externalization of adhesion proteins for leukocytes in endothelial cells on the surface of the membrane facing the lumen of the vessels. As a result of the trauma itself or cellular activation, the microenvironment has its physicochemical composition changed (low O2 tension, decreased pH, presence of reactive nitrogen and oxygen species), which is another form of signaling that activates the cells involved in the process. 6
LLLT has shown to be an anti-inflammatory alternative with effects similar to those observed in therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), inhibiting and/or decreasing the concentration of prostaglandin ES2 (PGE2), cyclooxygenase 2 (COX2) and histamine. 7-9
Mizutani et al. suggest that LLLT inhibits the arachidonic acid cascade in damaged tissue, leading to decreased production of PGE2. 10 Later, this phenomenon interferes with the production of bradykinin and many kinds of inflammatory cytokines. In addition, the increase in local blood flow improves acidosis and, simultaneously, promotes both the release and removal of substances related to pain.
Viegas et al. suggest that LLLT promotes early activation of the inflammatory phase in the tissue repair process, thus causing exacerbation of its signs. 11 This activation was due to substantial vascular activation in the first 36 hours of the repair process.
According to Gavish et al, LLLT has shown to reduce inflammation in a variety of clinical situations. 12 Their studies have shown that LLLT modifies some fundamental aortic aneurysm processes, progressively increasing matrix protein and smooth muscle cell proliferation, as well as secretion and expression of matrix metalloproteinase. Inhibition of gene expression of proinflammatory cytokine interleukin-1 β from these cells was also observed.
Rocha Jr. et al. observed a greater amount of fibroblasts in irradiated cells, showing a significant increase in fibroblast proliferation and decreased inflammatory infiltrate, concluding that LLLT accelerates the process of tissue repair. 13
Thus, LLLT seems to be able to modulate inflammation in various tissues. Also, it has advantages, since it is a noninvasive, nonpharmacologic method with a low rate of side effects. 3,7,8 Therefore, this study aims to review the publications of the last 14 years in order to provide scientific foundation for the use of low-power laser radiation in processes that assist tissue healing in the initial phase.
MATERIALS AND METHODS
The material used was obtained by researching scientific papers in databases such as Medline, Lilacs and Scielo. We selected publications dating from 1995 to 2009. In order to perform the search, we used a combination of the following keywords: low-level laser, inflammation, chemical mediators, growth factors.
We analyzed 22 articles, according to the data shown in table 1. We observed that the areas studied varied a lot, no matter whether the studies were in vitro or in vivo (animal or human). We found relevant differences regarding the area of study and irradiation parameters (wavelength and dose used). The objects of study varied from cells such as monocytes, macrophages and fibroblasts to membranes, mucosa, diabetic and skin wounds, cartilage, tendons, muscles, fluids such as human blood, organs and arteries.
Graphs 1 and 2 show that in vivo studies correpond to approximately 74% of the total. Of this percentage, 76.5% were conducted in animals (5.9% rabbits, 70.6% rats) and only 23.5% were conducted in humans. As for in vitro studies, they correspond to 26% of the studies surveyed.
Among the studies analyzed, we found that different wavelengths (no. = 12) ranging from 632.8 to 904 nm were used. The most widely used wavelength was 830 nm, when compared separately. As for spectral range, the most used was that between 632.8 and 685 nm, lasers in the red range of the electromagnetic spectrum.
The effects found were slightly different, varying according to the area studied, model and wavelength. The effect was classified as positive (+), negative (-) or null. Positive effect corresponds to antiinflammatory action, negative effect corresponds to proinflammatory action and null effect corresponds to no change or significant effect. Among the main positive (+) effects presented in Table 1 are reduction of pro-inflammatory cytokines (TNF-α, IL-6, IL-2) and chemical mediators such as PGE2 and increase in growth factors (bFGF, IGF-1).
Doses of 2.2, 5.0, 6.32 and 16 J/cm2 were used in in vitro studies, and the dose of 5 J/cm2 did not cause any significant changes. However, when diabetic wounds and wound cells were irradiated with 16 J/cm2, they suffered an inhibitory effect, presenting significant decrease in cell proliferation. Studies involving rats presented a greater variety of doses (0.04 to 21 J/cm2), with the dose of 7.5 J/cm2 being the most employed. For studies in humans, doses of 1.8, 5.0, 8.7 and 16 J/cm2 were used. For doses of 8.7 and 16 J/cm2, the results were null. It was observed that different doses produced similar physiological results. The positive effect was evident, i.e., the anti-inflammatory effect of LLLT in the early stages of tissue repair. However, the wide variety of doses used demonstrates the lack of standardization of the studies and, consequently, the difficulty in comparing the results obtained.
To investigate the mechanism of action of laser on experimental edema (carrageenan), Albertini et al. conducted studies in rats with intact adrenal glands and in adrenalectomized rats, treated with diclofenac sodium and LLLT. 14 The doses that produced anti-inflammatory effect were 1 and 2.5 J/cm2, reducing edema by 27% and 45.4%, respectively. The best result in terms of edema reduction was that obtained with irradiation 1 hour after inflammation induction. The energy density of 2.5 J/cm2 produced anti-inflammatory effects similar to those produced by diclofenac sodium at a dose of 1 mg/kg. In adrenalectomized animals, LLLT failed to inhibit the edema, suggesting that lowlevel laser irradiation possibly exerts its anti-inflammatory effects, stimulating the release of adrenal corticosteroid hormones. In another study, Albertini et al. demonstrated that the edema was significantly smaller in the groups treated with LLLT, compared to the control group. 2 The percentage was 65.3% for the group treated with a wavelength of 660 nm and 54.5% for the 684-nm group compared with the control group 4 hours after induction of inflammation by carrageenan. A significant reduction of inflammatory cells in the irradiated groups was also demonstrated.
In their studies, Zhevago and Samoilova concluded that one of the major mechanisms responsible for the anti-inflammatory effects of LLLT is the decrease in the plasma level of proinflammatory cytokines (TNF-α, IL-6 and IL-2). 15
Studies by Saygun et al. suggest that the biomodulation effects of LLLT may be associated with an increased production of growth factors such as bFGF and IGF-1. 16 These studies confirm the findings observed in Table 1, according to which the action of LLLT and its anti-inflammatory effects are directly related to reduction of pro-inflammatory cytokines, as well as the amount of chemical mediators. Other relevant items demonstrated by Albertini et al. were observed, such as decreased TNFα, IL-1 β and IL-6 mRNA expression after laser therapy, both with wavelengths of 660 nm and 684 nm. 17 These results indicate that LLLT induces an inflammatory reaction that may modulate transcription factors linked to mRNA expression of proinflammatory cytokines. These data are corroborated by previous studies conducted by Nomura, Yamaguchi and Abiko, which suggest that laser therapy can reduce the production of inflammatory mediators and events that contribute to the inhibition of IL-1 β . Studies by Aimbire et al. confirm these findings as they show that LLLT significantly reduced the levels of TNFαcompared with the control group. 7 The authors suggest that the therapeutic potential of LLLT regarding the suppression of TNFαis necessary in various inflammatory diseases in internal medicine. They also highlight that it is important to note that this effect is highly dependent on the dose used.
Fukuda and Malfatti reported that one of the most relevant aspects and main divergence is the dose. 19 A dose may be defined as the amount of radiation given to the tissue. Also, according to the authors, the ideal dose to be used should be based on the literature describing successful laboratory practices, in which it is estimated in accordance with the tissue to be irradiated, the energy absorbed for each tissue, irradiation time and size of the affected area. This data confirm a study by Qadri et al. in which it was observed that there were no changes in IL-1 or elastase, probably because more appropriate parameters were not used, as stated by the authors. 20 Still, with regard to dose, Correa et al. demonstrated that the best results with LLLT were obtained using a dose of 3J/cm2, 24 hours after induction of inflammation by lipopolysaccharide (LPS) in the peritoneum of rats, with a reduction of 77% in neutrophils and 49% in leukocytes. 8
LLLT also exerts a stimulatory effect on TGF- β and PDGF. It should be noted that stimulation of these growth factors is directly related to the repair process. In a study by Numata et al., specific aspects of wound healing were evaluated, which refer to macrophage infiltration, keratinocyte migration, angiogenesis, fibroblast and growth factor (bFGF), under the effect of histamine. 21 The authors found that, clinically, it is important to reduce the area of the lesion as quickly as possible in order to relieve stress and reduce the possibility of infection. Specifically, skin wound healing is a complex process, involving a series of overlapping events that include leukocyte recruitment, matrix deposition, epithelialization and, finally, resolution of the inflammation with formation of a mature scar. Normal wound repair includes a vigorous angiogenic response that delivers nutrients to the inflammatory cells and damaged tissue.
For Houreld and Abrahamse, the use of lasers to stimulate in vivo and in vitro healing of diabetic wounds and diabetic wound cells promoted cell migration and proliferation, stimulation of cytokine (IL-6) and fibroblasts (WS1). 22 The aim of the study was to determine the importance of proteases and growth factors in the regulation and equilibrium of the tissue repair process, which, according to the authors, if interrupted, may delay healing and lead to degradation, which is a characteristic of chronic wounds. Also according to the authors, cytokines are involved in all of the wound phases, from migration, proliferation, differentiation and cell metabolism to healing. In this study, the authors report that proper fluence of phototherapy stimulates IL-6 expression, cell proliferation and migration in cells of diabetic wounds. A fluence of 5 J/cm2 stimulates the healing of diabetic wounds in vitro, whereas a fluence of 16 J/cm2 is inhibitory. The authors believe that laser parameters can be optimized and standardized and the underlying mechanisms better understood. According to them, phototherapy can become a safe alternative for the treatment and healing of wounds of slow evolution, such as those in patients with diabetes.
In their studies, Bortone et al. used laser on experimental edema (carrageenan) to promote an inflammatory process in the subplantar muscle of rats. After laser therapy, they found that there was a decrease in B2 kinin receptors mRNA expression when using both wavelengths of 660 nm and 684 nm. Their results suggest that the expression of both kinin receptors is modulated by LLLT, possibly contributing to its anti-inflammatory effect.23
Barbosa et al. reports the effect of LLLT on the formation of edema and leukocyte influx caused by the venom of the jararacussu snake (Bothrops jararacussu) in rats. The site of injury was irradiated with a wavelength of 685nm and a dose of 4.2J/cm2. A combined therapy including LLLT and serum was also studied. The results showed that LLLT significantly reduced edema formation by 53% and 64% in 3 and 24 hours, respectively, and in reduced accumulation of neutrophils (P <0.05). The combined therapy was more effective than the therapy used separately. In conclusion, LLLT significantly reduced edema and leukocyte influx in the muscle being studied, suggesting that LLLT should be considered as a potential therapeutic approach for the treatment of local effects of the Bothrops species. 24
Boschi et al. investigated the possible effects of LLLT in the modulation of pro-inflammatory and antiinflammatory mediators in rats with pleurisy. Inflammation was induced by carrageenan injected into the pleural cavity. A continuous wave (20 mW) of laser diode with a wavelength of 660 nm was used in four groups employing different doses and forms of treatment 1, 2 and 3 hours after inflammation induction. A group received a single dose of 2.1 J, and other three groups received a total energy of 0.9, 2.1 and 4.2 J. Subsequently, the volume of exudate, differential and total leucocytes, concentration of protein, NO, IL6, IL-10, TNF-alpha and MCP-1 were measured from the aspirated liquid. The results showed that LLLT in a wavelength of 660 nm significantly reduced the volume of exudate, inducing an anti-inflammatory effect characterized by differential or total inhibition of leukocyte influx, exudation, total proteins, NO, IL-6, MCP-1, IL-10 and TNF-alpha in a dose-dependent mode. That is, laser treatment with 2.1 J was more effective than 0.9 and 4.2 J 25
The effect of LLLT on the gene expression of mediators in the mucosal tissues and gingiva of rats was investigated by Safavi et al. Of the two groups studied, one group received irradiation twice with an interval of 24 hours, while the inflamed tissues in the other group were irradiated three times with He-Ne laser with a wavelength of 632.8 nm and dose of 7,5 J/cm2 for 300s. It was noted that the gene expression of IL-1beta and IFN-gamma was significantly inhibited in both groups, while the gene expression of PDGF and TGF-beta significantly increased. These findings suggest that LLLT decreases the amount of inflammation and accelerates the wound healing process, altering the expression of genes responsible for the production of inflammatory cytokines. 26
In another study, Bjordal et al. investigated the effects of LLLT in a group of seven individuals with Achilles tendinitis; a total of 14 tendons were studied. The individuals had their symptoms deliberately aggravated before starting treatment. The treatment was performed in two stages. First, they were treated with LLLT with a wavelength of 904 nm and 5.4 J per site, with a power density of 20 mW/cm2 and then placebo LLLT (0 J) was administered to both Achilles tendons. After treatment, the authors observed that the concentrations of prostaglandin E2 were significantly reduced 75, 90 and 105 minutes after active LLLT, compared with the concentrations before treatment (p = 0.026) and after treatment with placebo LLLT (p = 0.009). According to patients' reports, pressure pain threshold had increased significantly (p = 0.012) after active LLLT compared to placebo LLLT: the mean difference in terms of change between the groups was 0.40 kg/cm2 (95% confidence interval, 0.10 to 0.70). The authors suggest that the therapeutic potential of LLLT at a dose of 5.4 J per site can reduce acute pain and inflammation of Achilles tendinitis. They conclude that LLLT has a great potential in the treatment of diseases with an inflammatory component. 27
In order to evaluate the effectiveness of LLLT in microcirculation and collateral circulation of a clogged blood vessel, Ihsan treated 34 rabbits with a wavelength of 904 nm and power of 10 mW and compared the findings with those of two rabbits in a control group. An incision was performed on the medial part of the thigh of each rabbit, and the femoral artery was exposed and ligated. The blood samples collected from the femoral artery were examined to determine the levels of growth hormones, adenosine and fibroblast growth factor. Tissue samples of the site of operation, i.e., the artery and its surrounding muscle fibers, were sent for histopathological examination to determine the fiber/capillary ratio (F/C) and capillary diameter. The results indicated that collateral circulation was accelerated and that microcirculation was enhanced with the use of LLLT. Moreover, the author concluded that there was normalization of the functional characteristics of the injured area. 28
For Sakurai et al., the use of LLLT stimulated the production of prostaglandin E2 and cyclooxygenase-2 in human gingival fibroblasts. The aim of this study was to determine the effect of laser irradiation on the production of PGE2, cyclooxygenase (COX) -1 and COX-2, and gene expression from stimulation of LPS (lipopolysaccharide) in in vitro cells of human gingival fibroblasts (HGF). HGF cells were prepared from healthy gingival tissues and stimulated with LPS. Diode laser (Ga-Al-As) was irradiated at a wavelength of 830 nm on the HGF cells. Irradiation with LLLT significantly inhibited PGE2 production in a dosedependent way, which led to a reduction of COX-2 mRNA levels. In conclusion, a low level of laser irradiation inhibited PGE2 by LPS on the HGF cells by reducing COX-2 mRNA level. The findings suggest that LLLT can be a beneficial therapy against the aggravation of gingivitis and periodontitis by bacterial infection. 29
In short, LLLT has shown to be able to modulate inflammation in various tissues and presents some advantages such as its noninvasive, non-pharmacologic nature and low rate of side effects, both in diabetic and healthy individuals. 1,3,4,7,8
After investigating the literature, it is possible to conclude that LLLT exerts important anti-inflammatory effects early in the wound healing process. For instance, it reduces chemical mediators (PGE2, histamine), cytokines (IL-1, IL-2, IL-6, IL -10, TNFa), migration of inflammatory cells (leukocytes, neutrophils) and edema and increases the amount of growth factors (FCF, bFGF, IGF-1, IGFBP3), thus contributing directly to the process of tissue rehabilitation. However, the lack of standardization complicates the choice of parameters to be used in its application.
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Mailing address: Received on 10.08.2010. * Work conducted at the Institute for Research and Development, Universidade Vale do Paraiba (IP & D - UNIVAP) - São Jose dos Campos (SP), Brazil.
Juliana Aparecida de Almeida Chaves Piva
Av. Shishima Hifumi, 2911- Urbanova
12244 000 São José dos Campos - SP, Brazil
Phone.: (12) 3947-1000
Approved by the Advisory Board and accepted for publication on 30.11.2010.
Financial Support: Fellowship Program of Coordination for the Improvement of Higher Education Personnel - CAPES.
Conflict of interest: None
Received on 10.08.2010.
* Work conducted at the Institute for Research and Development, Universidade Vale do Paraiba (IP & D - UNIVAP) - São Jose dos Campos (SP), Brazil.