The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing tissue damage has been known for almost forty years since the invention of lasers. Originally thought to be a peculiar property of laser light (soft or cold lasers), the subject has now broadened to include photobiomodulation and photobiostimulation using non-coherent light. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial. This likely is due to two main reasons; firstly the biochemical mechanisms underlying the positive effects are incompletely understood, and secondly the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. In particular a biphasic dose response has been frequently observed where low levels of light have a much better effect than higher levels. This introductory review will cover some of the proposed cellular chromophores responsible for the effect of visible light on mammalian cells, including cytochrome c oxidase (with absorption peaks in the near infrared) and photoactive porphyrins. Mitochondria are thought to be a likely site for the initial effects of light, leading to increased ATP production, modulation of reactive oxygen species and induction of transcription factors. These effects in turn lead to increased cell proliferation and migration (particularly by fibroblasts), modulation in levels of cytokines, growth factors and inflammatory mediators, and increased tissue oxygenation. The results of these biochemical and cellular changes in animals and patients include such benefits as increased healing in chronic wounds, improvements in sports injuries and carpal tunnel syndrome, pain reduction in arthritis and neuropathies, and amelioration of damage after heart attacks, stroke, nerve injury and retinal toxicity.

There have been numerous reports describing the phenomena of low-level light therapy (LLLT) within the clinic and its broad application to alleviate pain, enhance the rate of wound healing, including spinal cord injury, reduce inflammation, improve learning, bolster immunity and combat disease. Yet, despite the breadth of potential applications for which bio-stimulation may prove beneficial, there persists a dramatic ignorance in our understanding of the signal pathways that govern these effects. At the cellular level, there exist a variety of endogenous chromophores such as cytochrome C oxidase, NADPH, FAD, FMN and other factors intrinsic to the electron transport chain in mitochondria that absorb light of specific wavelength and will undoubtedly have their role in bio-stimulation, however the dose dependency of effect with regard to total light fluence and fluence rate, as well as the importance of specific subcellular targeting, remains elusive. Furthermore, the translation of cellular response(s) in vitro to in vivo needs to be expounded. Clearly, a rigorous examination of bio-stimulatory parameters as a function of cellular and tissue response is necessary if we are to attain optimized, reproducible protocols based on a true scientific rationale for using bio-stimulation as a therapeutic modality in clinic. This paper introduces a number of the challenges we now face for advancing the bio-stimulation phenomena into the scientific mainstream by highlighting our current knowledge in this field as well as some of the research that we are conducting using LLLT in combination with photodynamic therapy.

One of the most important factors in laser therapy is the dose. In the literature we find that the dose usually is defined as the amount of energy applied to 1 cm² of skin. In this presentation we will look closer on what we mean with "dose" and what happens to the energy brought into the tissue. What is the dose 1 cm down in tissue? Should the unit instead be joules per cm³, or, would it be better using joules per mm³. In a blood vessel under an illuminated square centimeter of skin, we might perhaps use joules per ml. The light gives both local effects on cells and tissue and systemic effects - which is the most dominating? The energy that we feed into the tissue will cause a three dimensional light intensity distribution with different values in different points. In a static situation we will have the same dose distribution growing linearly with exposure time. In the case of coherent light illumination, a three dimensional speckle field is created and locally the energy density is varying a lot from point to point, causing field gradients. In some points of the illuminated volume, the dose might be so high that retarding effects may occur while in other, the dose may be close to zero. The situation is different for in vitro situation, for treatment of open wounds, for entering the light via a fiber in a syringe, for using super pulsed light sources etc. For wavelengths with very low tissue penetration the situation is different.

The classification of the cellular effects of phototherapy into primary, secondary and tertiary types is an aid to understanding variation in the predictability of the events that follow its application. Primary effects are generally restricted to the absorption of photons by cytochromes and catalytic interactions with these and other intracellular molecules. If suprathreshold, they stimulate cell activity, initiating secondary anabolic effects in those cells affected by the photons. These events can also be initiated by nonphotonic stimuli. Some of the secondary effects, such as growth factor secretion, can produce effects in cells that did not absorb photons. It is proposed that this group of effects be classified as tertiary. Primary effects are strongly predictable, secondary effects less so, being dependent on cell sensitivity, while tertiary effects are the least predictable, being affected by variation in both the internal and external environment and by intercellular interactions. The investigation of primary and secondary effects of phototherapy can be used to determine which irradiation parameters are ineffective in vitro and therefore cannot be effective in vivo. Since tertiary effects predominate in vivo only clinical testing can demonstrate which parameters are most likely to be effective, and with what level of predictability. It is essential that all relevant exposure conditions be recorded and disseminated if experimental work is to be of clinical value. It is also essential that all relevant information about the target of phototherapy, be it molecule, organelle, cell, healthy volunteer or patient, be recorded and disseminated.

An alternative treatment modality for diabetic wound healing includes low level laser therapy (LLLT). Biostimulation of such wounds may be of benefit to patients by reducing healing time. Structural, cellular and genetic events in diabetic wounded human skin fibroblasts (WS1) were evaluated after exposing cells in culture to a Helium-Neon (632.8nm), a Diode laser (830nm) and a Nd:YAG (Neodynium:Yttrium-Allumina-Gallium) laser (1064nm) at either 5J/cm² or 16J/cm². Cells were exposed twice a week and left 24 hours post-irradiation prior to measuring effects. Structural changes were evaluated by assessing colony formation, haptotaxis and chemotaxis. Cellular changes were evaluated using cell viability, (adenosine-triphosphate, ATP production), and proliferation, (alkaline phosphatase, ALP and basic fibroblast growth factor, bFGF expression), while the Comet assay evaluated DNA damage and cytotoxicity was determined assessing membrane permeability for lactate dehydrogenase (LDH). Caspase 3/7 activity was used as an estimate of apoptosis as a result of irradiation. The irradiated diabetic wounded cells showed structural, cellular as well as molecular resilience comparable to that of unwounded normal skin fibroblast cells. With regards to fluence, 5J/cm² elicit positive cellular and structural responses while 16J/cm² increases cellular and genetic damage and cellular morphology is altered. Different wavelengths of LLLT influences the beneficial outcomes of diabetic wounded cells and although all three wavelengths elicit cellular effects, the penetration depth of 830nm plays a significant role in the healing of diabetic wounded human fibroblast cells. Results from this study validate the contribution of LLLT to wound healing and elucidate the biochemical effects at a cellular level while highlighting the role of different dosages and wavelengths in LLLT.

Laser produces a monochormatic collimated and coherent radiation. In dentistry, diode lasers have been used predominantly for application which are broadly termed "Low level laser therapy (LLLT) or biostimulation (L.J. Walch 1997)". Periodontal ligament fibroblast (PDLF) have a key function in periodontal regeneration. Stimulatory effects on the proliferation of these cells could therefore be beneficial for the reestablishment of connective tissue attachment. The aim of this in vitro study was to evaluate the potential stimulatory effect of low level laser irradiation on the proliferation of PDLF.

When cells are irradiated with visible and near-infrared wavelengths a variety of stimulatory effects are observed in their metabolism. To explain the observed light effects, researchers try to identify the chromophores that are involved in the processes. However, the mechanism of light absorption by a chromophore does not explain many of the experimental observations and therefore the primary mechanism for cellular light responses remains unproven. In addition to the ability of photons to produce electronic excitation in chromophores, light induces an alternating electric field in a medium that is able to interact with polar structures and produce dipole transitions. The effect of the light induced electric field in enzymatic molecules is analyzed in the present article, and it will be described how enzymatic activity is enhanced by this mechanism.

One of the feasible explanations for long-term treatment effects of laser therapy of diseases connected with tissue ischemia and altered blood circulation is activation of angiogenesis after low level laser irradiation. The aim of the current study was to investigate if laser irradiation can enhance vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (FGF) induced angiogenesis in vitro. The study was conducted on rat thoracic aortal rings. Samples of group 1 served as control, samples of groups 2 and 3 were incubated with VEGF or FGF, group 4 samples were irradiated with laser (660 nm, 20 mW) during 10 min, samples of groups 5 and 6 were incubated with VEGF or FGF accordingly and received 10 min of laser irradiation. In the control group no noticeable angiogenesis occurred. The application of VEGF activated angiogenesis: the area covered by new vessels was 1,3±0,24 mm² and the maximal length of vessels was 0,93±0,11 mm. Laser light irradiation (group 4) activated angiogenesis (1,9±0,29 mm² and 0,75±0,10 mm). The combined influence of laser light and VEGF on angiogenesis (group 5) was significantly stronger (p <0,001), than each of the factors separately (6,98±0,88 mm2 and 1,7±0,23 mm). Application of FGF also activated angiogenesis: the area covered by new vessels was 2,76±0,22 mm² and the maximal length of vessels was 1,19±0,12 mm. Combined influence of laser light and FGF on angiogenesis (group 6) was again significantly stronger (p <0,001), than each of the factors separately (5,43±0,28 mm² and 1,99±0,10 mm). Studies show that laser irradiation can intensify effects of growth factors in vitro.

Acupuncture is frequently used to treat pain. Although human pain quantification is difficult and often subjective, in rodent models the tail-flick test provides a well-established and objective assessment of analgesia. This test measures the time taken before a rat withdraws its tail from a heat source. Needle and electroacupuncture at the acupuncture point Spleen-6, located at the tibia's posterior margin above the medial malleolus, has been found to increase tail-flick time in rats. The aim of the current study was to determine if laser acupuncture had a similar effect. A 550 μm diameter optic fiber was used to irradiate Spleen-6 for 2 minutes (690 nm, 130 mW) in female Sprague-Dawley rats. In addition, control experiments were performed in which rats were subjected to sham treatment (restraint but no irradiation) or irradiation of an non-acupuncture point (the tail's dorsal surface, 1cm from the base) using the same laser parameters. The baseline tail-flick time was measured and 15 minutes later the laser acupuncture or the control protocols were performed and tail-flick time re-measured 10 minutes after treatment. Additional experiments were done in which the opioid-blocker naloxone (20 mg/kg, intraperitoneal injection) was administered one hour before laser acupuncture. Tailflick time increased after laser acupuncture (P = 0.0002), but returned to baseline values one hour later. In contrast, no increase was found after either sham treatment or tail irradiation. Pretreatment with naloxone attenuated the increase in tail-flick time. In summary, laser acupuncture exerts a transient analgesic effect which may act via an opioid-mediated mechanism.

It has been known for many years that low levels of laser or non-coherent light (LLLT) accelerate some phases of wound healing. LLLT can stimulate fibroblast and keratinocyte proliferation and migration. It is thought to work via light absorption by mitochondrial chromophores leading to an increase in ATP, reactive oxygen species and consequent gene transcription. However, despite many reports about the positive effects of LLLT on wound healing, its use remains controversial. Our laboratory has developed a model of a full thickness excisional wound in mice that allows quantitative and reproducible light dose healing response curves to be generated. We have found a biphasic dose response curve with a maximum positive effect at 2 J/cm² of 635-nm light and successively lower beneficial effects from 3-25 J/cm², the effect is diminished at doses below 2J/cm² and gradually reaches control healing levels. At light doses above 25 J/cm² healing is actually worse than controls. The two most effective wavelengths of light were found to be 635 and 820-nm. We found no difference between filtered 635±15-nm light from a lamp and 633-nm light from a HeNe laser. The strain and age of the mouse affected the magnitude of the effect. Light treated wounds start to contract after illumination while control wounds initially expand for the first 24 hours. Our hypothesis is that a single brief light exposure soon after wounding affects fibroblast cells in the margins of the wound. Cells may be induced to proliferate, migrate and assume a myofibroblast phenotype. Our future work will be focused on understanding the mechanisms underlying effects of light on wound healing processes.

Objective: Concomitant use of multiple therapies is common in musculoskeletal and airway disorders. Low level laser therapy (LLLT) is considered a promising therapy in arthritis, tendinopathies and rhinitis. We designed two animal studies to assess if the expected anti-inflammatory effect LLLT could be affected by resection of the adrenal gland or concomitant use of the cortisol antagonist mifepristone. Methods: Two studies were performed, with 40 male Wistar rats and with 40 Balb C male mice respectively.. In both studies, four groups received carrageenan and one control group received saline. At 1, 2, and 3 hours after injections, LLLT irradiation was performed with a dose of 7.5 J/cm². In the rat study, two of the carrageenan groups had the adrenal gland dissected. In the mice study, two of the carrageenan-injected groups were in addition pre-treated with orally administered mifepristone. Results: In the rat paw study, LLLT reduced edema significantly compared to the carrageenan only group (1.5 vs 0.9 ml, p< 0.05), but LLLT failed to inhibit edema formation in the group which had the adrenal gland resected. In carrageenan-induced pleurisy, LLLT significantly reduced the number of leukocyte cells ( p<0.0001, Mean 34.5 [95%CI: 32.8 - 36.2] versus 87.7 [95%CI: 81.0 - 94.4]), and that the effect of LLLT could be totally blocked by adding the cortisol antagonist mifepristone ( p<0.0001, Mean 34.5 [95%CI: 32.1 - 36.9] versus 82.9 [95%CI: 70.5 - 95.3]). Conclusion: Steroid therapy should not be used concomitantly with LLLT, as the anti-inflammatory effect of LLLT is lost if cortisol receptors are downregulated.

This is a clinical presentation on the use of laser therapy in a private dental practice using a 810nm diode. A wide range of conditions involving pain management, treatment and as an adjunct to procedures to enhance patient comfort and experience. This will include cases treated for TMD (Temporo mandibular dysfunction), apthous ulcers, angular chelitis, cold sores, gingival retraction, periodontal treatment and management of failing dental implants. The case presentation will include the protocols used and some long term reviews. The results have been very positive and will be shared to enable this form of treatment to be used more frequently and with confidence within dental practice.

Recently, there has been significant improvement in the process of research and application of Low Intensity Laser Therapy (LILT). Despite this positive direction, a wide discrepancy between the research component and clinical understanding of the technology remains. In our efforts to achieve better clinical results and more fully comprehend the mechanisms of interaction between light and cells, further studies are required. The clinical results presented in this paper are extrapolated from a wide range of musculoskeletal problems including degenerative osteoarthritis, repetitive motion injuries, sports injuries, etc. The paper includes three separate clinical studies comprising 151, 286 and 576 consecutive patient discharges at our clinic. Each patient studied received a specific course of treatment that was designed for that individual and was modified on a continuing basis as the healing process advanced. On each visit, clinical status correlation with the duration, dosage and other parameters was carried out. The essentials of the treatment consisted of a three stage approach. This involved a photon stream emanating from a number of specified gallium-aluminum-arsenide diodes; stage one, red light array, stage two consisting of an array of infrared diodes and stage three consisting of the application of an infrared laser diode probe. On average, each of these groups required less than 10 treatments per patient and resulted in a significant improvement / cure rate greater than 90% in all conditions treated. This report clearly demonstrates the benefits of LILT, indicating that it should be more widely adapted in all medical therapeutic settings.

Objective: Low level laser therapy (LLLT) has been forwarded as therapy for osteoarthritis and tendinopathy. Results in animal and cell studies suggest that LLLT may act through a biological mechanism of inflammatory modulation. The current study was designed to investigate if LLLT has an anti-inflammatory effect on activated tendinitis of the Achilles tendon. Methods: Seven patients with bilateral Achilles tendonitis (14 tendons) who had aggravated symptoms by pain-inducing activity immediately prior to the study. LLLT (1.8 Joules for each of three points along the Achilles tendon with 904nm infrared laser) and placebo LLLT were administered to either Achilles tendons in a random order to which patients and therapist were blinded. Inflammation was examined by 1) mini-invasive microdialysis for measuring the concentration of inflammatory marker PGE₂ in the peritendinous tissue, 2) ultrasound with Doppler measurement of peri- and intratendinous blood flow, 3) pressure pain algometry and 4) single hop test. Results: PGE_2- levels were significantly reduced at 75, 90 and 105 minutes after active LLLT compared both to pre-treatment levels (p=0.026) and to placebo LLLT (p=0.009). Changes in pressure pain threshold (PPT) were significantly different (P=0.012) between groups. PPT increased by a mean value of 0.19 kg/cm² [95%CI:0.04 to 0.34] after treatment in the active LLLT group, while pressure pain threshold was reduced by -0.20 kg/cm² [95%CI:-0.45 to 0.05] after placebo LLLT. Conclusion: LLLT can be used to reduce inflammatory musculskeletal pain as it reduces inflammation and increases pressure pain threshold levels in activity-induced pain episodes of Achilles tendinopathy.

Purpose: To examine factors that affect penetration of phototherapy. Methods: Age, sex, height, and weight were recorded; skin color, skinfold thickness, and light transmission through a skinfold were measured over biceps and triceps muscles, and at the anterior waistline. Light was generated using two 23-diode LED arrays at 840 nm and 660 nm with surface area of 7 cm². Photon irradiation was measured using an Optical Power Meter consisting of a 1x1-cm² light detector placed in the centre of the illuminated 7 cm² spot. Transmission was measured using three skin-diode coupling conditions. Results: Penetration of LED irradiation increased when diodes were coupled to skin with pressure. Red light attenuated more rapidly than infrared light and the attenuation of red light increased as skin color darkened. Penetration of red and infrared light decreased as the amount of subcutaneous fat increased. There were gender effects on penetration of infrared light at normal and low BMI values. Conclusions: When using divergent light sources for phototherapy, radiant exposure should take into account individual physical characteristics, irradiation wavelength and diode configuration of the laser therapy system.

During the past 20 years, several researchers have found varying results in the effect of lasers on neural growth or function. The mechanisms of influence of laser light interaction with nerve tissues have not been clarified so far. Agrin should be considered as a possible mediator of light effects on nerve tissues. This meta-analysis hypothesizes that functional changes of agrin by light may explain these variable results in previous laser experiments. Agrin is one of the main regulating mechanisms in neural function and growth. Effective interactions between cells and their environment often rely on the creation, maintenance, and regulation of specialized membrane domains. Such domains are typically comprised of selected cytoskeletal, signaling, and adhesion molecules. How are such domain-specific specializations formed and maintained? A large body of work has established that the neuromuscular junction is induced by the secretion of agrin from the nerve terminal.

Purpose: To determine the effect of low intensity laser therapy (LILT) on healing of infected skin wounds in the rat. Methods: Wounds on the dorsum of Sprague-Dawley rats (14 per group) were inoculated or sham-inoculated with P. aeruginosa. Wounds were irradiated or sham-irradiated three times weekly from Day 1-19 using 635nm or 808nm diode lasers at radiant exposure of 1 or 20 J/cm² delivered in continuous wave (CW) or at an intensity modulation frequency of 3800Hz. Wound area and bacterial growth were evaluated three times weekly. Results: CW 808 nm (1 and 20 J/cm²) irradiation generally delayed healing in acute wounds. However, from Day 10 onwards CW 808 nm (1 J/cm² and 20 J/cm²) and 808 nm 3800 Hz (1 J/cm²) irradiation improved healing in inoculated wounds. Healing in acute wounds improved using 635 nm irradiation at low radiant exposure (1 J/cm²); however, using 635 nm irradiation at high radiant exposure (20 J/cm²) delayed healing. Bacterial balance in wounds was significantly altered using 635 nm (20 J/cm²) and CW 808 nm irradiation (1 and 20 J/cm²). Conclusion: Clearing wounds of normal flora was not associated with improved healing. Proliferation of staphylococcal species in wounds was associated with delayed healing.

The use of light and laser in the treatment of diabetes has been under research and some controversy. The following paper explores some of the mechanisms involved in glucose level regulation in connection to light. Several researchers have found that laser irradiation can activate ATP production, influence redox values within cells, and have other effects which can (in)directly activate AMP-activated protein kinase (AMPK). The activation of AMPK plays an important, albeit not an exclusive, role in the induction of GLUT4 recruitment to the plasma membrane. In addition, there is some demonstration that AMPK may regulate glucose transport through GLUT1. Increased glucose uptake will result in an increase in glycolysis and ATP production.

The questions concerning the mechanism of action of a low-energy electromagnetic radiation of the extremely high frequency range (EMR EHF) are considered. Also the features of biological effects are considered in their application as therapeutic actions. As an example the advantages of EHF treatment of patients with chronic brucellosis are shown, the algorithm of a choice of the scheme of treatment using EMR EHF is offered.

The long-term effects of low level laser therapy can involve mechanisms connected with activation of migration of stem cells towards damaged areas. Stromal cell-derived factor-1 alpha (SDF-1) plays a critical role in stem cell migration towards areas of tissue injury and hypoxia. This study examines the influence of laser light on migration of stem cells (FDCP-mix stem cell line) in absence and in presence of SDF-1, using Transwell system with 2 connected chambers separated by a filter. The first chamber contained medium and stem cells, second chamber contained medium with or without SDF. Group 1 cells served as a control. Cells of groups 2 and 5 were irradiated by red diode laser (660 nm, 20 mW, 15 min). Cells of groups 3 and 6 received infrared (IR) diode laser (958 nm, 36 mW, 15 min). Group 4 was SDF-1 control. Stem cells were seeded into first chamber of the Transwell system, and filters were placed into the wells containing medium with 150 ng/ml SDF-1 (groups 4, 5, 6) or without SDF-1 (groups 1, 2, 3). After incubation cells were collected and counted. The count of spontaneously migrated cells was 1496,5±409 (100%) in case of control. Red and IR laser light increased motility of stem cells up to 1892±283 (126%) and 2255,5±510 (151%) accordingly. Influence of SDF-1 caused directed migration of 3365,5±489 cells (225%). Combined effects of light irradiation and SDF-1 were significantly stronger (p<0,05): 5813±1199 (388%) for SDF-1 and red laser , 6391,5±540 (427%) for SDF-1 and IR laser. Study shows that laser radiation can up-regulate stem cell migration towards higher SDF-1 gradient.

Spectral study of light dosimetry for clinical LLT based on a simplified one-dimensional model of a two-layered medium analyzed within the limits of Kubelka-Munk approximation is presented. The relationship between the surface irradiance and the fluence rate seeing by a target at a given depth in tissues is studied for various irradiating wavelengths. The behavior of the fluence rate is also examined as a function of a blood volume fraction in tissues. Strong dependence of the fluence rate in skin on irradiating wavelengths has found in visible spectrum from about 600nm to about 800nm. In contrast, the fluence rate does not change much over the near infrared region from 800nm t0 1,300nm. Spectral dosimetry in blood content muscles exhibits progressive increase of the fluence rate over visible and near infrared ranges. It has shown that blood perfusion of tissues differently affects the fluence rate at various wavelengths. The discussed model allows estimation of the surface irradiance required to provide the therapeutic value of the fluence rate at a target.

Dental hypersensitivity has been studied for several years and it is reported as a strikingly painful condition originating from the exposition of dentinal tubuli . The exposed area is subjected to several kinds of stimuli, resulting in a rapid sharp acute pain. LLLT has been shown to have antiinflammatory, analgesic and cellular effects in both hyperemia and inflammation of the dental pulp. Our previous histological study showed that irradiated animals presented an increased production of dentine and shutting of dentinal tubuli. On the other hand, non-irradiated subjects still showed signals of intense inflammatory reaction and even necrosis at the same experimental times. Irradiated teeth did not show cell degeneration. The LLLT was shown to be efficient in the stimulation of odontoblast cells, producing reparative dentin and closing dentin tubuli. Our clinical studies with 660nm, 790nm and 830nm diode laser, and the total dose per tooth of 4J/cm was shown effective in treating dentinal hypersensitivity as it quickly reduces pain and maintains a prolonged painless status in 91.27 % to 97% of the cases. In a recent study our team observed that significant levels of dentinal desensitization were only found in patients belonging to the 25-35 age group. In conclusion, the results demonstrated indeed that LLLT, when based on the use of correct irradiations parameters is effective in treating hypersensitivity, but the age of patients is one of the factors that may alter the success of treatment due to dentinal sclerosis, which makes the penetration of light more difficult.

Laser devices in clinical applications must eventually be tested via clinical trials. An essential component in clinical trials is the double-blind study whereby the patient and the treating physician have no knowledge as to whether a given treatment is active or placebo. In pharmaceuticals, the problem is easily addressed. With laser therapy this can be very challenging. For some optical therapies, laser heating of tissue, by even as little as a few degrees can indicate to the patient and/or the physician that the device is active, un-blinding the study. This problem has been analyzed for a specific laser therapy using a combination of clinical data, analytical methods, finite element modeling, and laboratory testing. The methods used arrived at a solution, but not necessarily one that could have been predicted easily. This paper will present a model of tissue heating and the methods used to mask the effects from the laser in an effort to make active treatment and placebo indistinguishable.