{'fraction_non_alphanumeric': 0.0327981750096845, 'fraction_numerical': 0.02246804114836655, 'mean_word_length': 5.083791568473423, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
The Protocol of Low-level Laser Therapy in Orthodontic Practice: A Scoping Review of Literature

ABSTRACT Low-level laser therapy (LLLT) has been widely investigated as an adjunct technique for orthodontic treatment due to photobiomodulation effect. LLLT appears to be supportive for an orthodontic practice in terms of tooth movement acceleration, pain relief, and root resorption management. The decrease in these adverse effects will enhance the compliance in orthodontic patients, which could positively impact treatment outcomes. However, there seemed to be inconsistency in the impact of LLLT as well as its laser and treatment parameters. This scoping review aimed to evaluate the impact of different irradiation parameters on tooth movement acceleration, pain relief, and root resorption as well as to construct a protocol of LLLT in orthodontic practice. The search was conducted across PubMed, Scopus, Web of Science, Embase, Google Scholar, and the reference lists of identified articles. The last search was conducted on October 10, 2021 to identify experiments in humans regarding the application of LLLT as noninvasive treatment in orthodontic practice published between 2010 and 2021. However, they were excluded if they were not clinical research, if they did not report the source of laser, or if they were not relevant to tooth movement, pain perception, and root resorption, or if they were not available in English or in full-text. Following the systematic search and selection process, 60 articles were included in this review. A majority of included articles were published in the past few years. The findings of this review supported the application of LLLT in orthodontic practice with purposes of tooth movement acceleration and pain reduction. The positive impact of LLLT on root resorption had not been clearly evident yet. As this review demonstrated heterogeneity of both laser and treatment parameters, further research should be required to ensure the effectiveness of its specific parameters in orthodontic practice.

the degree of root resorption. [3,4] Orthodontic pain is another unpleasant side effect, which seems to be one of the concerns among patients. Discomfort, dull pain, and hypersensitivity from orthodontic care are unavoidable, [5] which can lead to incompliance or early termination of treatment. [6] Consequently, research to minimize these adverse effects has currently been a focus of orthodontics, with the purpose of the enhancement in compliance and comfort among patients.
The application of noninvasive low-level laser therapy (LLLT) has been introduced in an orthodontic practice in order to favor the biomechanics of tooth movements. LLLT can be considered as an alternative approach in offering analgesic and anti-inflammatory effects. [7] It can have a positive impact on pain relief, tooth movement, and root resorption. [8][9][10] With a low energy output, LLLT should not raise the temperature of a targeted tissue to over normal body temperature, [11] to avoid negative thermal effects. There seems to be no significant adverse effect of LLLT, compared to drug usage, corticotomy, and electric simulation. [12] This leads to an increase in a number of studies of LLLT as a noninvasive approach in orthodontic practice with the expectation of promoting better experience in patients.
With a large number of studies in the use LLLT in orthodontic practice, there appears to be inconsistency in the impact of LLLT on pain relief, tooth movement, and root resorption. In addition, the variation of LLLT implementation in orthodontic practice was identified, in terms of irradiation (wavelength and radiant power) and treatment parameters (exposure duration and frequency of the therapy). The consistency of LLLT protocol should also be considered for orthodontic education, where its appropriate parameters could be delivered to residents. Therefore, the aims of this scoping review were to evaluate the clinical outcomes of different irradiation parameters on tooth movement acceleration, pain relief, and root resorption as well as to construct a protocol of LLLT in orthodontic practice.

Inclusion and exclusion criteria
All types of experimental studies with humans regarding the application of LLLT as noninvasive treatment in orthodontic practice published between 2010 and 2021 were included in this review. However, the identified articles were excluded if they were not clinical research (conducted using animal testing or in vitro methods), if they did not report the source of laser, or if their research outcomes were not relevant to tooth movement, pain perception, and root resorption. They were also excluded if they were not available in English or in full text.

Risk of bias assessment for included articles
The Cochrane Collaboration's tool was implemented to assess a risk of bias of all included articles. This tool was selected, as it could support the judgment in evaluating a risk of bias assessment of included studies whether their risk was "low," "high," or "unclear." [16] The six domains of bias were assessed including (1) selection bias, (2) performance bias, (3) detection bias, (4) attrition bias, (5) reporting bias, and (6) other bias. [16] The outcomes of the bias assessment would show whether or not the included articles provided reliable evidence, reflecting the quality in conducting and reporting their experimental designs.   . There were also five additional articles identified from Google Scholar and the reference lists of identified articles. Following the removal of 492 duplicates, 331 titles and abstracts were initially screened against the inclusion and exclusion criteria. One hundred and ninety-nine articles were excluded, as they were not experimental research with humans of LLLT in orthodontic practice. Finally, 134 full-texts were considered, and 74 of them were excluded: 36 articles were not conducted with an experimental design (e.g., case reports or reviews); eleven were animal research; ten did not report the source of laser; six were not the use of noninvasive LLLT in orthodontic practice (with purposes of tooth movement, pain reduction, or root resorption); eight were the use of light-emitting diode (LED); one was not available in full-text; and two were not available in English. Consequently, 60 articles were included in this scoping review. This article selection process was presented in Figure 1.

Characteristics of included low-level laser therapy
As expected, there appeared to be various parameters of LLLT used in orthodontic practice, especially when considering the laser parameters. A couple of laser sources were used including GaAlAs, GaAs, InGaAlP, He-Ne, InAlAs, Nd:YAG, and InGaAs. GaAlAs, was used as a laser diode in a majority of experiments, whereas six articles reported just the model and registered trademark without reporting the chemical elements. [34,40,41,54,63,67] The wavelength of laser ranged from 630 to 1064 nm, which 810-980 nm appeared to be the common parameters used        for LLLT in orthodontic practice. The selection of LLLT operating mode seemed to be consistent, as nearly all of the included articles considered the use of continuous wave, rather than a pulsed mode.
According to the treatment parameters, there were several points to be considered such as exposure duration, frequency of laser therapy, and application techniques (irradiation points). The exposure durations were varied from 10 to 480 s, depending on the area exposed to the irradiation. The frequency of LLLT seemed to be very varied, and most studies employed LLLT immediately after the application of orthodontic force. In case that the multiple sessions were designed, LLLT appeared to be more frequently applied in the initial phase (the first 2 weeks). The irradiation points were mostly applied on both buccal and palatal/lingual surfaces, with the common techniques being 6-8 points for a tooth. A couple of studies applied LLLT by moving a laser tip along the root of a tooth on buccal and/or lingual surfaces, rather than as a point.

Overview of low-level laser therapy research on tooth movement
The outcome of LLLT on tooth movement acceleration was evaluated in 25 articles [ Table 1]. The acceleration of tooth movement could be evaluated by measuring the moving distance during the canine retraction or the duration of complete treatment for decrowding. The tooth movement could be measured in an oral cavity, [19,26] on dental casts [17,18,[20][21][22][23]25,27,28,[30][31][32][33]35,39] or digital models [24,[36][37][38]40,41] by using a digital caliper or stereomicroscope with appropriate reference points. Irregularity index representing horizontal overlapping or crowding can also be used for the evaluation. [22] Six experiments additionally collected gingival crevicular fluid (GCF) to analyze tooth movement-related substance, including IL-1β, TGF-β1, PGE 2 , MMP-9, OPG, OPN, and RANKL. [19,25,29,33,34,41] The impact of low-level laser therapy on tooth movement acceleration LLLT was found to be effective in accelerating tooth movement, as positive outcomes were shown in 21 from 25 articles [ Table 1]. According to the four studies reporting no positive outcomes, [20,21,31,36] one experiment evaluated the effect of LLLT as supplementary to corticotomy. [31] This might result in no significant difference between LLLT and non-LLLT groups, as corticotomy had already accelerated the tooth movement.

The parameters of low-level laser therapy for a purpose of tooth movement acceleration
GaAlAs appeared to be the most common laser diode used for accelerating tooth movement, which was used in 20 from 25 articles [ Table 1]. Other laser diodes included ArGaA and InAlAs. The wavelength was ranging from 658 nm to 980 nm, with the most common protocol seemed to be 810 nm. The average radiant power was very varied, ranging from 0.25 to 2000 mW, which was likely to depend on the size of laser tip.
In terms of clinical application, a majority of research applied LLLT immediately after the force application followed by Days 3, 7, and 14 for the first month and then every 15 days. The irradiation points for each tooth were varied from two to ten, which the 10-point protocol appeared to be the most common. All experiments applied LLLT on both buccal and lingual surfaces; however, one of them moved the laser tip along the root area, rather than a points technique. [26] The exposure time was varied from 10 to 300 s, leading to the variation of irradiation target from 2.25 to 25 J/cm 2 .

Overview of low-level laser therapy research on pain relief
Pain relief seemed to be the most common outcome of LLLT research. There were 40 experimental studies reporting the outcomes of LLLT on pain relief [ Table  2]. The level of pain was typically measured at leveling and canine retraction phases as well as at the period of separator placement. A couple of methods were designed to assess level of pain in orthodontic patients. Visual analog scales (VASs) appeared to be the most popular tool to gather self-perceived pain, which was used in 29 articles. [18,20,23,37,38,[42][43][44][45][46][47][48][49][50][51][52][53]56,58,59,[61][62][63][64][65][66]69,70,72] Eight articles employed numerical rating scales (NRS). [24,39,54,55,57,60,67,68] The Wong-Baker faces pain rating scale, used in three articles, could also be applied to collect self-reported pain. [21,28,71] Three studies GCF to measure painrelated substance, including prostaglandin E 2 (PGE 2 ), substance P, and pro-inflammatory factors. [42,66,70] The impact of low-level laser therapy on pain relief LLLT appeared to have a positive impact on the reduction of orthodontic treatment-related pain. There were 32 experimental researches reporting the positive impact of LLLT on pain relief, compared with conventional or other techniques [ Table 2]. There was an experiment comparing the impact of LLLT on pain reduction with anesthetic gel and transcutaneous electrical nerve stimulation, which the laser method appeared to be more effective. [69] Only eight articles reported no positive impact of LLLT on pain reduction.

The parameters of low-level laser therapy for a purpose of pain relief
When considering the laser parameters, GaAlAs was the most popular laser diode for pain relief, as reported in 30 from 40 articles [ Table 2]. Other laser diode included He-Ne, GaAs, InGaAlP, Nd:YAG, and ArGaA. The wavelength was ranging from 630 to 1064 nm, where 830 nm seemed to be the most common wavelength (reported in ten experiments) followed by 810 (eight articles) and 940 nm (five articles). The average radiant power was very varied, ranging from 0.7 to 800 mW.
Similar to the clinical application for tooth movement acceleration, nearly all experiments applied LLLT immediately after the force application. In case more than a session of LLLT was applied, the application tended to be more frequent during the first week (Days 0, 3, and 7). There were also three articles reporting the LLLT use before the force application. [42,61,62] The irradiation points for each tooth were varied from 2 to 16, which 6 and 10 points appeared to be the common instruction. They were typically applied on both buccal and palatal (lingual) sides. Four experiments reported the use of different technique, where the laser tip was moved along the root of tooth (both buccal and lingual surfaces), showing the positive outcome on pain relief. [45,50,68,70] The exposure time was varied from 20 to 480 s, leading to the variation of energy density from 1 to 35.4 J/cm 2 .

Overview of low-level laser therapy research on root resorption
The impact of LLLT on root resorption seemed to be a new research topic, which four from five studies were published over the past few years [ Table 3]. A study conducted in 2021 evaluated this impact by measuring the root on the periapical radiograph from the gingival edge of the orthodontic bracket to the root apex at different periods. [17] Following the advanced technology, three articles published between 2018-2020 evaluated the root resorption using microcomputed tomography (micro-CT) [73][74][75] An experiment published in 2021 enhanced the accuracy of root resorption analysis by using a non-contact three-dimensional optical profilometer. [76] The impact of low-level laser therapy on a reduction of root resorption The positive impact of LLLT on root resorption had not been clearly evident. Although four experiments found no positive outcome on root resorption, [17,[73][74][75] one study supported the use of LLLT based on the analysis with the optical profilometer. [76] The parameters of low-level laser therapy for a purpose of a reduction of root resorption AlGaAs and InGaAs appeared to be a laser diode used for decreasing induced inflammatory root resorption, with wavelength ranging from 660 nm to 980 nm [ Table  3]. The research applying AlGaAs found no positive outcome on a reduction of root resorption. The average radiant power was ranging from 20 to 360 mW, which 100-mw irradiation could be sufficient to offer a positive impact on root reduction.
The clinical application of LLLT for root resorption seemed to be less varied than the other two outcomes. The exposure duration of low-level laser at each point ranged from 72 to 120 s for continuous wave, and one study applied pulsed wave for 36 s. [74] All studies conducted LLLT for a period with the purpose of root resorption, with approximately three to six sessions per month. Similar to the use of LLT for other purposes, LLLT was applied more frequently in the first week. The energy density was ranging from 5 to 8 J/cm 2 . Based on the included studies, eight to ten irradiation points were applied for each tooth, divided equally for both buccal and lingual sides.

dIscussIon
There seems to be an increasing use of LLLT in orthodontic practice, as implied from the trend of research in this topic. There were 48 articles published between 2018 and 2021, compared to 33 publications over the 8-year period (2010-2017). More than ten articles were published in a year from 2018 to 2020. The emphasis of LLLT research has also moved to tooth movement acceleration, in which 18 of 22 articles in this topic were made available in the past 5 years. According to the impact of LLLT on root resorption, four of five articles were published since 2018.
LLLT appeared to have positive outcomes in orthodontic practice. There seemed to be a significant impact on pain relief, tooth movement, and root resorption, as evident by the results retrieved from the included articles. These findings were consistent with previous literature, which LLLT was likely to have a positive effect on healing, nerve regeneration, inflammatory process, pain reduction, proliferation of osteoblasts, bone remodeling, root resorption, and tooth movement. [77][78][79][80] Therefore, LLLT can be considered as significantly supportive for an orthodontic practice.
The reduction of orthodontic pain could be considered as one of the significant outcomes of LLLT. Pain could be considered as an important concern in orthodontic practice, as it may discourage patients from the treatment. [6,7] In addition, orthodontic pain appears to be unavoidable, as it is induced from tooth movement during the treatment. Although analgesics appear to be an effective method for pain control, pharmacological actions and adverse effects should be concerned. [81] LLLT could be considered as an alternative option for the non-pharmacological management of pain. These reasons might lead to a popularity of research in the impact of LLLT on the orthodontic pain.
The duration of orthodontic management can be another factor to discourage patients from the treatment. Not only there can be a reduction of patient compliance throughout the long treatment duration, but also the risk of root resorption, alveolar bone resorption, dental caries, and gingivitis seems to be increasing. [2] Tooth movement acceleration, therefore, has become an important topic in orthodontic practice. A great number of studies emphasized on tooth movement acceleration as well as how to measure it. [82,83] Several techniques have been used to accelerate tooth movement, such as biological approaches (e.g., cytokines, prostaglandin, or parathyroid hormone injection), device-assisted techniques, surgical methods (e.g., corticotomy, interseptal alveolar surgery, osteotomy), and LLLT. [82] Although surgical techniques have been proved to enhance tooth movement acceleration, [84] it could be considered more aggressive than other methods. Consequently, LLLT appeared to be one of the most preferable noninvasive approaches for tooth movement acceleration without systemic adverse effects.
External apical root resorption is another major concern in orthodontic practice. It was likely to be one of the most common adverse effects of orthodontic treatment. [85,86] There is evidence reporting a correlation between root resorption and the duration of orthodontic treatment. [87,88] As orthodontically induced inflammatory root resorption seems to be an unavoidable complication, [89] a number of studies aimed to explore its influential factors. [90] One of the expectations is to prevent this adverse effect. However, the evidence of LLLT on the reduction of root resorption was not clear, as only the latest research showed the positive outcome.
This scoping review showed the heterogeneity in both laser and treatment parameters, for example, laser diodes, wavelength, average radiant power, energy density, exposure duration, frequency of LLLT applications, and points of irradiation. Although a number of studies showed no positive outcomes of LLLT in orthodontic practice, there was no clear evidence to suggest whether there were any inappropriate laser parameters for the use in orthodontic practice, as the LLLT parameters of no positive outcomes were found to effective in other research.
The findings retrieved from most of the included studies showed a positive impact of LLLT in orthodontic practice, at least for tooth movement acceleration and pain reduction, with non-significant adverse effects; however, there are limitations and restriction for its implementation. With the laser safety concern, protective equipment such as laser-protection eyeglasses is required for both patients and operators. Another concern of LLLT is its sensitive technique, requiring professional use to obtain the optimal dose of laser. There could be no positive biological impact if too low dose is used; however, too high dose may lead to a biosuppressive effect. [91] Orthodontic patients, therefore, are required to receive LLLT at a dental office which could be inconvenient for them. In addition, the cost of laser device is quite high, although it is currently less expensive than the past. [72] LED can be considered as alternative photobiomodulation therapy with similar purposes to LLLT, [92,93] as LED device can be used at home without laser safety considerations. [94] Therefore, the impact of LED, especially with a comparison with LLLT, in orthodontic practice should be required to confirm their effectiveness.
There were a few limitations in conducting this scoping review. The data extracted for the analysis included both laser and treatment parameters; however, there were a number of the LLLT parameters that could not be identified in a number of articles. In addition, there were some difficulties in comparing these studies due to parameter variability. As discussed, there were a couple of articles reporting no positive outcomes although their laser and treatment parameters were also similarly used in other studies which supported LLLT in orthodontic practice. Furthermore, the details of research design in a number of articles were not clearly confidently defined, and they were evaluated as "high" or "unclear" risk of bias. Most of the experiments with high risk of bias had a limitation in blinding operators or assessors, so only the patient side was blinded. One of the strengths of this scoping review was the inclusion of all available experimental evidence whether it was evaluated as high, low, or unclear risk of bias, offering the promising opportunities in developing a robust and rigorous systematic review or meta-analysis. Although this review provides available options for the effective use in orthodontic practice, further clinical research with robust design should be required to assure the positive impact of LLLT on the specific parameters in orthodontic practice.

conclusIon
This scoping review supports the use of LLLT in orthodontic practice, as the available evidence tended to reveal its positive impacts on tooth movement acceleration and pain relief. However, there were a number of studies reporting no positive impact of LLLT. In addition, the impact of LLLT on a reduction of root resorption had not been yet clearly evident. As there were little inconsistency of orthodontic impact as well as heterogeneity of both laser and treatment parameters, further research should be required to ensure the effectiveness of its specific parameters in orthodontic practice.