References
Low level light therapy (LLLT) for the treatment and management of dental and oral diseases
From Volume 41, Issue 9, November 2014 | Pages 763-772
Article
In 1967, Dr Endre Mester at Semmelweis Medical University in Budapest, Hungary, attempted to determine if the newly developed laser (Light Amplification by Stimulated Emission of Radiation) ‘ray of light’ caused cancer. In his studies, he shaved the hair from the backs of mice and subsequently exposed one group of animals to a low-powered ruby laser while the other unexposed group was used as the control. Instead of the treatment group developing cancer, as he had predicted, the hair on the treated mice grew back more rapidly than in the unexposed animals. This effect was subsequently described as ‘laser biostimulation’ and this work has subsequently underpinned thousands of research papers, and generated significant interest from NASA and the US Navy. At present, this field is generally termed Low Level Laser (or Light) Therapy (LLLT), phototherapy or photobiomodulation. The published data currently aims to describe its mechanism of action, the downstream physiological effects and its clinical benefits as demonstrated in both randomized clinical trials and in systematic reviews.1,2,3
The therapeutic effect of light in treating a wide range of diseases has been recognized for many centuries. Indeed, in the early part of the 20th century, exposure to sun and other natural light was commonly used to treat systemic diseases, ranging from dementia and tuberculosis to skin diseases such as lupus vulgaris and acne. More recently, within the last century, UV light therapies have been developed and are used to treat patients suffering from rickets (vitamin D deficiency), neo-natal jaundice, pain and a variety of dermatological disorders.1,4
Unlike many other applications in healthcare, the light or lasers used in LLLT are neither ablating nor do they provide a heat-based therapy, indeed their action is more analogous to photosynthesis in plants in the way that light exerts its effect (cellular and molecular transduction of light are discussed below). Today LLLT utilizes low power lasers or light emitting diodes (LEDs) of less than 500 mW in the red to near infrared (NIR) spectrum (600–1100 nm) (Figure 1), which emit minimal heat to promote tissue healing, reduce inflammation, and relieve pain.5 A large number of animal models and clinical studies have now demonstrated the beneficial healing effects of LLLT in a variety of both chronic and acute diseases and injuries. Recent studies have demonstrated that this non-invasive approach is beneficial in treating diseases of the joints, connective tissue, neuronal tissue, bone, skin, muscle and the vasculature (Figure 2a).1,2
Cellular-and tissue-associated therapeutic effects
Anti-inflammatory
The anti-inflammatory action of LLLT most likely occurs due to its ability to regulate the master transcriptional regulator NF-κB, which leads to a reduction in proinflammatory mediator activity. Several studies have shown the ability of LLLT to decrease cytokine levels in a variety of experimental and animal models, as well as human disease situations, indicating its utility in treating chronic and acute inflammatory disorders.6
Analgesia
The mechanism(s) of action which underlie the analgesic effects of LLLT remain unclear, however, evidence indicates that LLLT may have significant neuropharmacological effects relating to the synthesis, release and metabolism of a range of key neurochemicals, such as serotonin, acetylcholine, histamine and prostaglandin. In addition, the effect of LLLT on pain relief may also be explained by the ability to enhance synthesis of endorphins, as well as modulating nociceptor responses via c-fibre activity and bradykinin levels.7
Angiogenesis
Another important tissue process activated by LLLT is its capacity to promote neovascularization and angiogenic events and this may relate to its ability to increase cellular and tissue levels of pro-angiogenic mediators, including growth factors and nitric oxide (NO) (discussed below). These molecules subsequently act to promote endothelial cell and vascular responses via direct and indirect interactions.2,3
Wound repair
Within tissues, studies have shown that LLLT can promote cell growth, viability, cytoprotection, adhesion, migration, differentiation and hard and soft tissue formation (Figure 2b). Notably, these effects have been demonstrated in a range of cell types including stem cells, immune/blood cells, vascular cells, skin cells and many other hard and soft tissue-derived cells.2,3,8
Combined, these tissue and cellular responses promoted by LLLT enable its successful application for disease treatment and wound repair at many sites within the body (Figure 2a).
Use of light energy in dentistry
The application of light is routinely used by dentists, for example, in the curing (photopolymerization) of light-activated, resin-based restorations, caries detection and, more recently, ablative lasers, which have been used for calculus removal, osseous surgery and soft-tissue management.9,10 Current developments have now seen the use of cold diffuse lasers in photo-activated disinfection (PAD) or photodynamic therapy (PDT). This approach utilizes light indirectly to trigger photosensitive dyes to release antibacterial reactive oxygen species, which reduces the microbial load. PDT is now regarded as a useful adjunctive tool for treating infections in oral surgery, endodontics and periodontitis (eg Periowave™).11
The application of LLLT in dentistry is not well documented (in the UK, in particular), compared with many other areas of medicine. However, there now appears to be increased interest and evidence of its utility.8,9,10,12 Indeed, data is now emerging in favour of the therapeutic application of LLLT in a wide range of oral hard and soft tissues areas, covering many key dental specialties, including: endodontics, periodontics, orthodontics, oral medicine and oral surgery (Table 1, Figure 3).
| SPECIALTY | INDICATION | LLLT EFFECT | REFERENCES |
|---|---|---|---|
| Conservative Dentistry | Dentine hypersensitivity |
|
Gerschman et al, 1994;13 |
| Cavity preparation |
|
Kreisler et al, 2004;16 |
|
| Pulp therapy |
|
Shigetani et al, 2011;18 Matsui et al, 200719 | |
| Periodontal Disease | Chronic gingivitis |
|
Igic et al, 2012;20 Mârţu et al, 2012;21 Igic et al, 201222 |
| Periodontitis |
|
Makhlouf et al, 2012;23 |
|
| Titanium implants |
|
Khadra et al, 2004;27 Boldrini et al, 2013;28 Omasa et al, 2012;29 Naka and Yokose, 201230 | |
| Oral Medicine | Burning mouth syndrome |
|
Yang and Huang, 2011;31 Kato et al, 2010;32 dos Santos Lde et al, 201133 |
| Herpes simplex virus |
|
Muñoz Sanchez et al, 2012;34 Schindl and Neumann, 1999;35 de Carvalho et al, 201036 | |
| Lichen planus |
|
Jajarm et al, 2011;37 Agha-Hosseini et al, 2012;38 Cafaro et al 201039 | |
| Oral mucositis |
|
Bjordal et al 2011;40 Gautam et al 2012;41 Bensadoun and Nair, 201242 | |
| Dry mouth |
|
Lončar et al, 2011;43 Vidović et al, 2010;44 Pavlic, 201245 | |
| Denture stomatitis |
|
Maver-Biscanin et al 2005;46 |
|
| Oral Surgery | Post-operative healing |
|
Igic et al, 2012;49 Pejcic et al, 2010;50 Amorim et al, 200651 |
| Nerve paraesthesia |
|
Ozen et al, 2006;52 Khullar et al, 199653; Khullar et al 199654 | |
| Post third molar extraction |
|
Markovic and Todorovic, 2006;55 Aras and Gungormus, 2009;56 Markovic and Todorovic, 200757 | |
| Temporo-mandibular joint disorder |
|
Salmos-Brito et al, 2013;58 Marini et al, 2010;59 Mazzetto et al, 201060 | |
| Post-mandibular fracture |
|
Rochkind et al, 200461 | |
| Bisphosphonate-related osteonecrosis of the jaw (BRONJ) |
|
Scoletta et al, 2010;62 Vescovi et al, 2012;63 Vescovi et al, 201264 | |
| Mandibular distraction |
|
Miloro et al, 2007;65 Abtahi et al, 2012;66 Freddo et al, 201267 | |
| Orthodontics | Tooth movement |
|
Kim et al, 2013;68 Genc et al, 2013;69 Doshi-Mehta and Bhad-Patil, 201270 |
| Orthodontic treatment-associated pain |
|
Artes-Ribas et al, 2013;71 Habib et al, 201072 |
In the field of conservative dentistry and endodontics, studies have indicated that LLLT may be efficacious in several areas relating to both pain management and induction of dental tissue repair. While the exact therapeutic mechanisms are not known, dentinal hypersensitivity in response to tactile and thermal stimuli has been shown to be reduced in patients receiving LLLT. Potentially, the therapeutic effects may relate to the analgesic, anti-inflammatory or repair inductive effects following LLLT application. Similarly, LLLT has been shown to reduce discomfort in patients following cavity preparation and this effect may also relate to the induction of cellular protective and analgesic mechanisms in response to restorative placements. Recently, both in our own laboratory studies and work performed in animal models has shown that LLLT can increase pulp cell repair and dental developmental responses, indicating the potential for its clinical application.8
For periodontal diseases, LLLT has been shown to exert anti-inflammatory effects and decrease tissue swelling in both chronic gingivitis and periodontitis. Subsequently, it has been proposed as a potentially useful adjunctive therapy in conjunction with scaling, root planing, curettage and surgical treatment (Table 1). In addition, it has been demonstrated to exert oral healing effects within both the hard and soft tissues, as is demonstrated by reduced pocket depth and arrested bone loss deterioration in periodontitis patients receiving LLLT. Similarly, following implant placement, enhanced osseo-integration and improved healing within the surrounding hard and soft tissue interfaces has been observed following adjunctive application of LLLT (Table 1).
In the oral medicine area, a range of different diseases and clinical conditions, generally involving the soft tissues, have been proposed to respond favourably to LLLT (Table 1). These conditions, which occur due to infectious agents, side-effects from other treatments or are of unknown aetiology, potentially benefit mostly from the anti-inflammatory properties of LLLT. In addition, and as a result of arrest of disease and promotion of beneficial cellular responses, enhanced healing is also often evident in many of the disorders treated (Table 1). LLLT application may also benefit several areas of oral surgery, in particular the post-operative healing phases for both the hard and soft tissues (Table 1). Furthermore, the analgesic properties of LLLT may offer clinical benefit in providing relief to the debilitating temporo-mandibular joint disorder (TMJD). While pain relief is likely to be important for TMJD treatment in the short-term (Table 1), it is also likely that the effect of LLLT on muscle function is central to its long-term successful treatment outcome. Interestingly, it is potentially the anti-apoptotic and cellular protective properties activated by LLLT which may provide the clinical benefit in bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Table 1). In fact, LLLT for BRONJ has been shown to arrest the hard and soft tissue loss (Table 1). It is probable that the activation of the cells involved in alveolar bone and/or periodontal ligament remodelling is key to the ability of LLLT to enhance outcomes in mandibular distraction and orthodontic tooth movement. Notably, the safety profile and lack of identifiable side-effects of LLLT (discussed below) make its use appropriate in many areas of paediatric dentistry.
Molecular signalling in LLLT
While it has been proposed that cell activation by light is a natural process acquired and preserved through evolution, the exact mechanism by which it works is not yet fully elucidated.73,74 Cells are, however, known to respond to LLLT by increasing their metabolism, viability, mitochondrial activity, growth, movement and other wound healing associated processes (Figure 2b).2 Increases in molecules, such as growth factors, nitric oxide (NO), reactive oxygen species (ROS), ATP, RNA and DNA, have all been detected following light irradiation of cells and tissues.75,76 While imperceptible temperature changes in response to light are acknowledged, the ‘photodissociation theory’ is proposed to explain the body's positive response to LLLT.2 It is proposed that light absorption at appropriate wavelengths by mitochondria results in the production of energy which drives the observed positive cellular responses (Figure 4). The photodissociation theory proposes that light energy is absorbed by, and activates, the mitochondrial enzyme cytochrome C oxidase (COX) which subsequently releases its bound NO. The release of NO allows oxygen to re-bind with COX and subsequently enables the cellular respiration cycle to be resumed, leading to generation of energy in the form of ATP.2 It is notable that owing to the inflammation and cell stress which occur in response to disease, there is an increase in NO levels which bind and impede COX activity. It is believed that decreased COX activity limits tissue repair, which can occur while the disease processes are ensuing.76 The release of NO, ATP or growth factors from cells directly activated by light may subsequently result in molecular messages being sent to adjacent or even distant cells and tissues. This process results in a so-called ‘bystander effect’, which results in activation of tissue repair processes in recipient cells and tissues.2,3,76
Delivery and clinical application of LLLT
Whilst many clinical LLLT devices utilize specific wavelengths in the 600–1000 nm spectrum (~660 nm and 810–830 nm are frequently used), successful treatment outcomes are also dependent on the parameters of the applied irradiation which include ‘dose’ (fluence, or radiant exposure measured in J.m -2), ‘intensity’ (properly termed, irradiance, W.m -2), treatment/irradiation time (s), treatment frequency, treatment intervals, total number of treatments, number of treatment target points and target area coverage. Different clinical applications will clearly require specific therapeutic regimes owing to the depth of penetration needed to irradiate the target cells as a consequence of light reflection, absorption, refraction and scattering through the tissue. The tissue composition affects how the irradiation penetrates, as light energy is transmitted more easily through mucosa and fat compared with bone, dental hard tissue and muscle. In addition to pigments, such as melanin, haemoglobin, lipids and water are significant absorbers of light and therefore can also limit transmission through tissue. In general, the deeper the penetration required, the longer the wavelength required (up to ~980 nm, the peak absorbance wavelength of water).1 Notably, while incorrect LLLT application is unlikely to be harmful, it may be ineffective, and subsequently the lack of standardization of treatment parameters within the literature has resulted in a lack of consistency in findings and generated significant controversy within the field.1,2,3
Common clinical targets for LLLT are:
The treatment times per therapeutic point are typically in the range of 30–60 seconds and as little as one, or up to 15 treatment target points may be irradiated, depending on the complexity of the disorder77 (Figure 3).
There is relatively minimal risk associated with the application of LLLT, and any potential hazards are mostly ocular rather than representing any risk from excessive temperature rises within the recipient tissue. Indeed, most LLLT devices are class 3B lasers or LEDs, although some are defocused class IV lasers. In most cases, LLLT devices emit divergent beams (not collimated), so the ocular risk decreases over distance (in the range of several metres) and manufacturers are subsequently obliged to provide the nominal ocular hazard distance (NOHD) for users. Furthermore, protective goggles, specific for the wavelength used, must be worn by both the patient and the therapist when applying LLLT. In general, international regulatory standards help ensure minimal risk is associated with LLLT devices.77
Conclusions
While light therapies are standardly used in several medical areas, such as in the treatment of neonatal jaundice and rickets, the direct application of light as a therapeutic intervention within the oral maxillofacial region has thus far received minimal clinical attention. However, data now indicates that LLLT may provide a relatively safe (no known side-effects, non-invasive and non-pharmaceutical), simple and inexpensive therapeutic approach, which can be used separately or as an adjunct to conventional treatments and can be applied in the clinical setting or by patients independently. In addition, it may provide a therapeutic approach to treat diseases and disorders where there is currently minimal successful clinical intervention possible and/or which are refractory to existing treatments. Nowadays, it is increasingly considered beneficial for the patient's long-term well-being that their own cellular defence and repair responses are activated to enable tissue regeneration. The ability of LLLT to activate many cell types, including stem cells locally, by promoting their proliferation, migration and differentiation, is also clearly desirable. Subsequently, optimized LLLT approaches may obviate the need for stem cell therapeutic applications, which require cell isolation, expansion and subsequent implantation for patient treatment. However, further fundamental basic science and clinical studies are critical in order to identify the optimal parameters relevant for the use of LLLT accurately in treating distinct oral and dental diseases.