Minimally Invasive Techniques to Accelerate the Orthodontic Tooth Movement: A Systematic Review of Animal Studies

Objective. To evaluate various noninvasive and minimally invasive procedures for the enhancement of orthodontic tooth movement in animals. Materials and Methods. Literature was searched using NCBI (PubMed, PubMed Central, and PubMed Health), MedPilot (Medline, Catalogue ZB MED, Catalogue Medicine Health, and Excerpta Medica Database (EMBASE)), and Google Scholar from January 2009 till 31 December 2014. We included original articles related to noninvasive and minimally invasive procedures to enhance orthodontic tooth movement in animals. Extraction of data and quality assessments were carried out by two observers independently. Results. The total number of hits was 9195 out of which just 11 fulfilled the inclusion criteria. Nine articles were good and 5 articles were moderate in quality. Low level laser therapy (LLLT) was among the most common noninvasive techniques whereas flapless corticision using various instruments was among the commonest minimally invasive procedures to enhance velocity of tooth movement. Conclusions. LLLT, low intensity pulsed ultrasound (LIPUS), mechanical vibration, and flapless corticision are emerging noninvasive and minimally invasive techniques which need further researches to establish protocols to use them clinically with conviction.


Introduction
The major concern of most of the patients going for orthodontic treatment is to improve their dentofacial esthetics while oral health benefits are secondary concerns [1]. However like other interventions orthodontic treatment with fixed appliances also poses some inherent complications and risks. These undesirable outcomes of the treatment are either due to excessive force exerted on the tooth in order to achieve movement or with difficulty in brushing and plaque accumulation around brackets [2,3]. Irrespective of the reason, adverse effects of treatment are directly proportionate to the duration of treatment. Currently the duration of orthodontic treatment with fixed braces is 2 to 3 years on average [4,5]; however the patient does not want more than 1.5 years [6]. Prolonged treatment duration is also detrimental to the productivity of a national healthcare system and private practices [7]; therefore accelerating the tooth movement and shortening the treatment duration have always been an issue of concern for patients as well as for orthodontists [8].
There are two basic ways to reduce the treatment duration (Table 1). One approach is by making the treatment mechanics more efficient, for example, use of low friction and selfligating brackets [9,10], preformed robotic archwires [11,12], and use of microimplants [13,14].
Another approach involves interventions to increase the velocity of orthodontic tooth movement by enhancing the bone remodeling. This intervention can be classified into three categories: (1) use of certain biochemical, (2) mechanical or physical stimulation of the alveolar bone which 2 BioMed Research International  includes the use of cyclic vibration [15], magnets [16], or direct electrical current [16], and (3) surgical interventions to accelerate tooth movement [17].
Surgical procedures that enhance tooth movement involve alveolar corticotomies, rapid canine retraction, or dental distraction. These are highly invasive procedures associated with postoperative morbidity and harmful effects on periodontal tissues; thus the patient's acceptance of the procedure is low [23].
Hence the researchers are always looking for minimally invasive methods that enhance the orthodontic tooth movement and are also well accepted by the patients because of minimal side effects and low cost. Low level laser therapy [24] has shown some evidence of being effective in acceleration of tooth movement in humans and also been reviewed systematically [25]. However the need is to bring the researcher's attention towards all other techniques used in animal based researches on the subject so that there is further progress in the development of minimally invasive/noninvasive techniques. Therefore the objective of this systematic review is to review all recently published animal studies involving noninvasive as well as minimally invasive procedures for acceleration of orthodontic tooth movement.

Eligibility Criteria.
Publications included in this study comprised research articles from the past six years, that is, from January 2009 till 31 December 2014. Eligibility criteria for inclusion were original in vivo researches on the noninvasive/minimally invasive modalities to enhance orthodontic tooth movement in animals. Randomized clinical trials and human based researches were excluded from the systematic review. Articles dealing with role of biochemical (iii) Google Scholar.
The main keyword used to search the literature was "orthodontic tooth movement", which was searched in combination with the following terms: (i) Concerning enhancement of movement: accelerate, rapid, velocity.

Data Extraction and Quality Assessment.
Two authors independently searched the literature, selected the studies, extracted the data, and assessed the risk of bias of the studies using ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines [26]. Interobserver disagreements were resolved with discussions. The quality assessment of the included studies was performed by using ARRIVE guidelines [26]. Maximum score of 20 was attributed to each study. Studies were evaluated and categorized as good (≥75%), moderate (56% to 74%), or poor (≤55%) quality based on the total score attained ( Studies included in quantitative synthesis (meta-analysis) (n = 0)  [60]. For more information, visit http://www.prisma-statement.org/.

Study
Selection. PRISMA guidelines were followed to scrutinize the articles as detailed in Table 4 and Figure 1. The total number of hits was 9195 in the databases: 8873 in Google Scholar, 43 in MedPilot, and 279 in NCBI search resources. After adjusting the duplicates, 3450 hits were scrutinized for inclusion in the study. The majority of them were excluded as they did not match the inclusion criteria, leaving 73 publications. After excluding randomized clinical trials, patents, case reports, and hypothetical articles, just 11 original articles were remained which were included in this systematic review. Interobserver reliability for 20 criteria was 0.54 which is a moderate level of agreement. Cohen's kappa for the majority of the criteria from A to T showed absolute agreement except four criteria which showed moderate-to-good level of interrater agreement:

Study Characteristics.
The selected articles could be categorized in two major categories: (A) studies focusing on noninvasive modalities and (B) studies involving minimally invasive modalities. Noninvasive procedures included 5 articles and studies based on minimally invasive techniques were 5. One article combined both invasive and noninvasive procedure to enhance orthodontic tooth movement.
In noninvasive modalities 2 researches were based on the use of low level laser therapy (LLLT) for acceleration of Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators 4 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made

Risk of bias in individual studies 12
Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level) and how this information is to be used in any data synthesis    4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Score Altan et al. [40] 2012 Shirazi et al. [39] 2013 Xue et al. [45] 2013 Al-Daghreer et al. [46] 2014 Kim et al. [61] 2013 Safavi et al. [59] 2012 Flapless bur decortication Dibart et al. [55] 2013 Ruso et al. [56] 2013 orthodontic tooth movement, 1 article evaluated mechanical vibration, and 2 involved low intensity pulsed ultrasound (LIPUS). One article studied the effect of LLLT with piezocision on velocity of tooth movement in animal model. In minimally invasive group, all researches involved flapless corticision with slightly different approaches. Three researchers used piezoelectric knife, 1 author used laser assisted corticision, and 1 research evaluated flapless corticotomy using burs.

Quality Assessment and Risk of Bias.
The quality of the studies was assessed by ARRIVE guidelines. Table 5 shows the assessment of the included studies. The quality of most of the studies was good and none of the studies were categorized as poor quality (Table 3). Low level laser therapy was the most common among noninvasive modalities (2 articles) as it was also used along with corticision in an article. However flapless piezocision was among the commonest minimally invasive procedures to enhance orthodontic tooth movement (3 studies).

Low Level Laser Therapy. Low level laser therapy (LLLT)
is also known as photobiomodulation or biostimulation that involves the use of near infrared or low levels of red light to treat a variety of ailments. It does not raise local tissue temperature by more than 1 ∘ C and therefore is referred to as "cold laser" or "low level laser" [8,28]. Although the exact mechanism of therapeutic effects of LLLT is not well established yet, it has been observed that it has effects at the molecular, cellular, and tissue levels. At the cellular level, there is strong evidence that LLLT acts on mitochondria [29] which results in increase in adenosine triphosphate (ATP) production [30] and the induction of transcription factors [31]. These transcription factors trigger protein synthesis leading to cell proliferation and migration. It also modulates the levels of cytokines, inflammatory mediators, and growth factors [32]. Since LLLT accelerate bone regeneration and remodeling by increasing vascularization, promoting trabecular osteoid tissue formation, and enhancing tissue metabolism [33], therefore it was thought to be beneficial also in acceleration of orthodontic tooth movement. In vitro studies involving rat osteoclast precursor cells and osteoclasts have shown that laser irradiation induces differentiation and activation of osteoclasts [34][35][36][37][38] through expression of RANK, MMP-9, cathepsin K, and (v) 3 integrin.
In all of the articles included in this systematic review, diode laser was the source of LLLT including the one which combined LLLT with corticision; however the wavelength, frequency, energy input, and hence the results were slightly different (Table 6) [39,40]. Shirazi et al. [39] in their research concluded that LLLT can increase the velocity of tooth movement 2.3-fold and the laser light does not reflect to the contralateral side as they found no difference in the movement on the contralateral side compared with the control group. However Altan et al. [40] reported no difference between laser and control groups after application of high energy density. The reason for insignificant results could be the use of higher energy density (54 J) used by Altan in his study, because the most effective range of LLLT for biomodulation is reported to be 0.5-4 J/cm 2 [41].
Kim et al. applied high energy density laser therapy and found it equally effective in accelerating tooth movement as corticision [42]. But the difference in their research from other reviewed articles was the pulsed mode of laser therapy rather than the continuous mode. When both the procedures (LLLT and corticision) were performed on the same site, there was decrease in the velocity of tooth movement. Although the article was good in quality assessment, the sample size ( = 6 premolars in each group) was too small to reach any conclusion.

Low Intensity Pulsed Ultrasound.
Ultrasound is a sound wave having frequency above the limit of human ear perception, which can be transmitted into biological tissues. It is widely used in the field of medicine for diagnostic as well as therapeutic purpose [43]. LIPUS stimulation is being utilized effectively as therapeutic modality for bone regeneration and fracture healing; therefore it has been approved by the U.S. Food and Drug Administration (FDA) for healing of fractured bone [8].
Although very limited studies have been conducted on the effects of LIPUS on tooth movement, in vitro studies have shown that LIPUS has anabolic effects on growth factors and other signaling factors production that results in differentiation of osteogenic cells and extracellular matrix [44]. In a very recent study involving rat model, LIPUS accelerated orthodontic tooth movement by 45% and promoted alveolar bone remodeling by stimulating the HGF/Runx2/BMP-2 signaling pathway and RANKL expression [45]. In this systematic review, 2 animal studies related to the role of LIPUS on orthodontic tooth movement were reviewed ( Table 7). The outcome of both the researches was different in spite of using the same specification of LIPUS. Xue et al. reported 55%, 37%, and 45% acceleration in tooth movement after application of LIPUS for 5, 7, and 14 days, respectively; however Al-Daghreer et al. found no difference in tooth movement even after application for 4 weeks [45,46].

Mechanical Vibration.
Low level mechanical vibration has profound effect on musculoskeletal morphology [47]. Mechanical vibration signals can promote bone healing, enhance bone strength, and reduce the negative effect of catabolic process [48]. It was hypothesized that mechanical vibration may reduce the lag phase (hyalinization) of orthodontic tooth movement and can result in painless and rapid movement [49].
In this review just 1 article in relation to the use of mechanical vibration for orthodontic tooth movement was reviewed [50]. Shirazi et al. [39] used animal model to assess the effect of mechanical vibration on incisor's movement and reported favorable results but because of vague methodology, indistinct selection criteria, and moderate quality scores, it was difficult for us to give remarks on the effect of mechanical vibration on orthodontic tooth movement.

Minimally Invasive Techniques.
Osteotomy and corticotomy to accelerate tooth movement is not new in orthodontics, introduced by Köle in 1959 [51]. His concept was to segment the teeth containing alveolar bone with lingual and labial osteotomy and move the whole segmented alveolus with orthodontic forces. The technique was effective but required buccal as well as lingual full-thickness flaps followed by massive decortication of alveolar bone on buccal and lingual sides making the procedure very invasive and painful [52]. Thus the acceptance of the procedure was low and researchers were always looking for less invasive methods. Since the rapid movement in the procedure is not due to en bloc movement of alveolus rather there is a mechanism of accelerated soft tissue and hard tissue remodeling "Regional Acceleratory Phenomenon (RAP)" associated directly with the severity of surgical procedure [53]. Osteoperforations placed even far from the tooth to be moved can increase the rate of tooth movement, by increasing the level of inflammatory cytokine expression and extensive osteoporotic changes [54]. This led to the incessant development of less invasive approaches.
In this systematic review, five animal studies in relation to the minimally invasive technique to accelerate orthodontic tooth movement were reviewed. Mucoperiosteal flap was not reflected in any of the researches and there was no massive decortication of cortical bone, which made the procedures less invasive. In two studies, piezosurgery unit was used to perform cuts on the buccal alveolar bone, mesial and distal to the tooth to be moved [55,56]. However Xue et al. used ultrasonic piezotome to create multiple holes buccally and lingually [45]. Since the velocity of tooth movement is in direct proportion to the amount of surgical insult, Ruso et al. [56] found acceleration only by 135% which was though significantly greater than the conventional group but lesser than the corticotomy induced acceleration reported earlier [57]. This was in accordance with the ultrasonic piezopuncture method used by Xue et al. [45] who suggested repeated application at regular intervals to overcome the deficient RAP phase associated. On the other hand Teixeira et al. [54] concluded that greater increase in velocity of tooth movement can be obtained if mechanical stimulation of alveolar bone is maintained through constant orthodontic force, along with piezosurgery. Seifi et al. [58] used Er,Cr;YSGG laser device with the energy range of 300 mJ and pulse rates of 20 Hz for corticotomy. They found twofold acceleration in tooth movement, without any adverse effects on periodontal health on the experimental side. Safavi et al. [59] used tungsten carbide bur in high torque slow speed surgical handpiece to make holes in the buccal cortical plate. They found accelerated tooth movement in the first month of the experiment followed by lesser amount of movement in the third month of experiment. The reason could be the formation of more mature lamellar bone after bur decortication as compared to the control group (Table 8).

Conclusion
It can be concluded from the study that LLLT and flapless corticotomy have some evidence of accelerating effect on orthodontic tooth movement; however there is no set protocol found for the procedures yet. LIPUS and mechanical vibrations are also emerging noninvasive modalities but due to fewer studies, no evidence based conclusion can be drawn.

Abbreviations
LLLT: Low level laser therapy LIPUS: Low intensity pulsed ultrasound.