Background and Objective
Low-level laser/light therapy (LLLT) is a noninvasive, nonthermal approach to disorders requiring reduction of pain and inflammation and stimulation of healing and tissue regeneration. Within the last decade, LLLT started being investigated as an adjuvant to liposuction, for noninvasive body contouring, reduction of cellulite, and improvement of blood lipid profile. LLLT may also aid autologous fat transfer procedures by enhancing the viability of adipocytes. However the underlying mechanism of actions for such effects still seems to be unclear. It is important, therefore, to understand the potential efficacy and proposed mechanism of actions of this new procedure for fat reduction.
The concept of lipoplasty was introduced by Charles Dujarrier of France in the 1920s. In an attempt to remove subcutaneous tissue from a dancer's calves, Dujarrier ultimately caused gangrene and the death of his patient. Lipoplasty was reintroduced in 1974 by Dr. Giorgio Fischer, and his son who utilized oscillating blades within a cannula to cut away subcutaneous tissue. In 1983, Illouz reported his 5-year experience with a new lipoplasty technique utilizing cannulas as large as 10 cm and suction tubing to safely remove fat from different regions in the body. Figure 1 shows a graphical representation of this technique. This success ushered in the era of modern lipoplasty. Over the ensuing decades the concept of tumescent technique decreased blood loss and subsequent morbidity associated with liposuction and led to improved results. Ultrasound and laser lipoplasty methods have provided further advancement in the range of technical choices offered to the plastic surgeon however they all have limitations and carry certain risks. These limitations led to investigation of noninvasive alternative modalities for fat reduction such as cryolipolysis, radiofrequency, and low-level laser therapy.
Illustration of liposuction with a cannula. A cannula is inserted to the subcutaneous layer and the fat is suctioned with the aid of a suction tube in order to remove fat from different regions in the body.
LOW-LEVEL LASER/LIGHT THERAPY ( LLLT )
The first reports of LLLT were published by Endre Mester from the Semmelweiss University in Hungary. He originally noticed hair regrowth in mice exposed to a ruby laser (694 nm) and later used HeNe laser (632.8 nm) to stimulate wound healing in animal models and subsequently in clinical studies . Since those early days LLLT has become widely practiced by physical therapists and chiropractors, although it is still regarded with a degree of skepticism by the medical profession at large. LLLT is highly effective to relieve pain, inflammation, and edema in orthopedic injuries and degenerative disease, and is also used for nonhealing leg ulcers. LLLT has great potential to prevent tissue death and stimulate tissue regeneration in a wide variety of diseases in neurology, ophthalmology, cardiology, and otolaryngology. It was shown to be effective in reducing pain following breast augmentation surgery and in 2008, Erchonia EML, 630–640 nm (Erchonia Medical, Inc., McKinney, TX) received FDA market clearance for this purpose. Another important application is in prevention of oral mucositis as a side effect of cancer therapy. Although all the early studies used coherent lasers as the light source, it is now thought that noncoherent light emitting diodes are also effective. The mechanism is based on absorption of red and near-infrared photons by chromophores in the mitochondria (particular cytochrome c oxidase) leading to increases of mitochondrial membrane potential, oxygen consumption, adenosine triphosphate (ATP), a transient increase in reactive oxygen species (ROS), and a release of nitric oxide (NO). Transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) are activated leading to signaling pathways that promote cell survival, cell proliferation, and cell migration. Figure 2 shows the cell signaling and downstream effects caused by photon absorption in the mitochondria. In this article we will mainly focus on several studies that have been reported on LLLT's use in liposuction, noninvasive body contouring and fat reduction, reduction of cellulites, and reduction in serum cholesterol and triglyceride levels.
Possible mechanism of action of LLLT in reduction of fat. LLLT stimulates the cytochrome c found within the respiratory chain in the mitochondria in adipocytes. This stimulation in turn leads to a transient increase in reactive oxygen species (ROS), release of nitric oxide (NO) and cause increased levels of ATP synthesis with subsequent upregulation of cAMP.
LLLT ASSISTED LIPOSUCTION
In 2000 a new technique was introduced by Niera et al. which utilized LLLT as an adjunct to liposuction. They used a dose rate that caused no detectable temperature rise in the tissue and no macroscopic changes in the tissue structure were observed. This application of LLLT was derived from prior investigations of LLLT in wound healing, pain relief, and edema prevention . The development of LLLT was predicated on determining the optimum wavelength, and power necessary to augment lipoplasty without altering macroscopic structure of the tissue. Evidence existed that wavelengths between 630 and 640 nm were optimum for biomodulation and these wavelengths were therefore used for LLLT-assisted lipoplasty. Moreover, LLLT has been reported to reduce inflammatory response and pain , and promote wound healing which would all facilitate the post-surgical healing .
These findings prompted the development of a device, the EML Laser (Erchonia Medical, Inc.) that emits 14 mW of 635-nm light (Figure 3). It was applied to the surface of the skin before liposuction, with the intent to emulsify the fat thereby softening the area prior to aspiration. A placebo-controlled, randomized, double-blind, multicentered clinical study was performed to evaluate the clinical utility of this application as an adjunct to liposuction and the results suggested that laser therapy decreased operating room times, increased the volume of fat extracted, less force was required by the physician to breakup fat, and the recovery for patients was significantly improved. Based on the findings of this study the FDA issued 510k clearance for the EML device in 2001 for use as an adjunctive therapy to liposuction.
Examples of LLLT devices. This figure shows four of the light source devices that either been approved or clinically applied for fat reduction. A: The EML low-level laser for laser assisted liposuction from Erchonia Medical, Inc. B: The Zerona LipoLaser for noninvasive body contouring from Erchonia Medical, Inc. C: The NovoThor LED canopy for weight loss from Thor Photomedicine (Chesham, Bucks, UK). D: The SmoothShapes system for cellulite reduction from Eleme Medical.
Niera et al. studied samples of human adipose tissue from 12 lipectomy patients who were operated with and without tumescent technique and externally irradiated with a 635-nm, 10 mW diode laser with total energy values of 1.2–3.6 J/cm2 for 0–6 minutes. The group found out that the tumescent technique had synergistic effects, facilitated laser light penetration, and intensity, thus improved fat liquefaction. While after 4 minutes of laser exposure 80% of the fat was released from the adipose cells, after 6 minutes of laser exposure almost all of the fat was released from the adipocyte. When no tumescent solution was applied and adipose tissue was exposed to laser beam for 4 and 6 minutes, scanning electron microscope (SEM) and transmission electron microscope (TEM) images after 6 minutes laser exposure in samples taken without tumescent solution corresponded to those observed in samples exposed to 4 minutes of laser irradiation with equal parameters and the tumescent solution. Without laser exposure and only tumescent technique, the adipose tissue remained intact and adipocytes maintained their original spherical structure.
It should be noted that there is another procedure termed “laser assisted liposuction. In 2012, Chia and Theodorou reported 1,000 consecutive cases of laser-assisted liposuction and suction-assisted lipectomy managed with local anesthesia. This procedured used a high power Nd:YAG laser at either 1,064-nm (pulsed at 40 Hz) or a dual wavelength device at 1,064/1,320-nm pulsed at 25 Hz. After injection of tumescent solution containing local anesthetic, a fiber optic was inserted via a cannula into the deep and intermediate subcutaneous spaces moving at a rate of at least 1 cm/second. The applied power setting ranged from 7 to 38 W, with a total fluence ranging from 2,000 to 64,000 J per site. Suction-assisted lipolysis was then performed using standard manual Mercedes-style-tip liposuction cannulas. Even though results were satisfactory, burn and hematoma were possible complications of this procedure.
MECHANISM OF ACTION OF LLLT FOR FAT REMOVAL
The mechanism of action of LLLT on fat remains somewhat controversial. In Neira's first article the effects of LLLT on adipocytes were attributed to formation of transitory micropores which were visualized on SEM (Figure 4). These pores were proposed to allow the release of intracellular lipids from adipocytes. Based on these data it was proposed that up to 99% of fat could be released from the adipocytes via application of 635 nm, 10 mW intensity LLLT for a period of 6 minutes. One possible explanation might be that, increased ROS levels following LLLT initiate a process known as lipid peroxidation where ROS reacts with lipids found within the cellular membranes, and temporarily damages them by creating pores. However, in an attempt to replicate Neira et al.'s data , Brown et al. failed to visualize any transitory micropores. In another study, Medrado et al. investigated the action of different fluences (9 mW, 670 nm, 4, 8, 12, and 16 J/cm2 for 31, 62, 124, and 248 seconds, respectively) from a gallium–aluminum arsenide laser which was applied through the intact skin to the dorsal fat pad of rats. LLLT caused brown adipose fat droplets to coalesce and fuse, apparently transforming them into yellow fat but had only negligible effect on yellow fat itself. Increased vascular proliferation, mitochondria, and congestion were evident findings in the laser irradiated brown fat. Considering most changes were restricted to the brown fatty tissue only and yellow tissue always preserved its appearance with no signs of lipolysis observed, results from this study were not in accordance with Niera et al.'s study. However, it is worthwhile to mention that experimental parameters used in these studies were not the same. Another possible mechanism of action for release of lipids was proposed to be through activation of the complement cascade which could cause induction of adipocyte apoptosis and subsequent release of lipids. To investigate the complement activation theory, Caruso-Davis et al. exposed differentiated human adipocytes to plasma. With and without irradiation there was noted to be no difference in complement induced lysis of adipocytes. Although no enzymatic assays were done to determine levels of complement within the plasma, the group concluded that laser does not activate complement. Lastly, unlike Niera et al.'s findings, the external cell membrane preserved its normal appearance in electron microscopy, presenting no ruptures nor pores, in spite of the disposition of its fused fatty vacuoles, and no other signs of lipolysis were observed. An additional paper called into question the ability of red light (635 nm) to penetrate effectively below the skin surface and into the subdermal tissues. In a supportive commentary Peter Fodor stated; "One could postulate that the presence of the black dots on SEM images on the surface of fat cells reported by Neira et al. could represent an artifact".
Scanning electron microscopy (SEM) images of transitory pores formed in cell membrane of adipocytes following LLLT.
It is also possible that LLLT stimulates the mitochondria in adipocytes that in turn leads to an increase ATP synthesis with subsequent upregulation of cAMP; the increased cAMP could activate protein kinase which could stimulate cytoplasmic lipase, an enzyme that converts triglycerides into fatty acids and glycerol, which can both pass through pores formed in the cell membrane may cause a shrinkage in adipocytes (Figure 5). However, Caruso-Davis et al. findings from in vitro studies on human fat cells obtained from subcutaneous fat, irradiated with 635–680 nm LLLT for 10 minutes demonstrated no increase of glycerol and fatty acids suggesting that fat loss from the adipocytes in response to laser treatment was not due to a stimulation of lipolysis, however they did detect increased triglyceride levels which further supported the formation of pores in adipocytes. Figure 6 graphically illustrates many of the proposed mechanisms that have been devised to explain the use of LLLT for fat removal.
Scanning electron microscopy (SEM) images of adipocytes following LLLT
A schematic illustration of lipolysis pathway. The binding of the ligand adenylate cyclase (AC) to its receptor-β-adrenergic receptor (β-AR) via protein G (Gs) elevates the levels of cyclic adenosine monophosphate (cAMP) which in turn activates protein kinase (PKA). PKA phosphorylates hormone sensitive lipase (HSL) that in turn causes degradation of triglycerides (TG) and diglycerides (DG) to monoglycerides (MG). With the help of monoglyceride lipase (MGL) monoglycerides are further degragated to fatty acid and glycerol.
LLLT FOR NONINVASIVE BODY CONTOURING
The Zerona LipoLaser (Erchonia Medical, Inc.) is a device with five rotating independent diode laser heads each emitting 17 mW of 635 nm laser light (Fig 3B). It was the first noninvasive aesthetic device to receive FDA market clearance in the US for circumferential reduction of the waist, hips, and thighs following completion of a placebo-controlled, randomized, double-blind, multisite clinical investigation evaluating 67 study participants. The results obtained from that study demonstrated an average reduction of 3.51 inches across patient's waist, hips, and thighs in as little as 2 weeks. The clinical trial, absence of diet restrictions, exercise requirements, or any other adjunctive components properly illustrated the clinical utility of the Zerona and set the precedent on how aesthetic devices should be evaluated.
In a randomized study, Caruso-Davis used 635–680 nm LLLT device (Meridian LAPEX 2000 LipoLaser System, Meridian Medical Inc. Anyang, Korea) for 30 minutes twice a week for 4 weeks on 40 healthy young men and women and subjects were asked not to change their diet nor exercise habits. Results demonstrated that LLLT achieved safe and significant girth loss at the end of the treatment period. However it is worthwhile to note that this device is currently approved by the FDA for hand and wrist pain associated with carpal tunnel syndrome only. Another study by Jackson et al. demonstrated a significant reduction (overall mean reduction of 5.17 inches across all measurement points) in circumferential measurements across waist, hips, and thighs of 689 patients following LLLT with Zerona LipoLaser (Erchonia Medical, Inc.). Treatment period was for two consecutive weeks, with each patient receiving three treatments per week every other day for a total of 40 minutes. The authors also noted that circumferential reduction exhibited following LLLT was not attributable to fluid nor fat relocation since all the measurement points including nontreated regions reported an inch loss. Moreover, a double-blind, controlled, randomized study designed to assess the efficacy of 635 nm LLLT (3.94 J/cm2, 17 mW) in reducing upper arm circumference, LLLT group (n = 20) demonstrated a significant progressive and cumulative treatment effect compared to sham treated group (n = 20) following six treatments with no side effects.
A recent study investigated the efficacy of LLLT –635 nm device that consists of 5 diodes generating an output intensity of ~0.95 J/cm2 each and the group demonstrated an average of 2.99 inches reduction in waist, hips, and thigh at the end of the treatment period. However, the study had several limitations such as lack of control group as well as administration of dietary supplements (niacin, niacinamide, l-carnitine, omega-3 fish oil, ginko biloba, and decaffeinated green tea) in the study subjects.
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