Academia.eduAcademia.edu

Minimally and Noninvasive Approaches to Accelerate Tooth Movement

2017, Orthodontics: Current Principles and Techniques. 6th ed. In: Graber LW, Vanarsdall RL, Vig KWL, Huang GJ, editors. Elsevier.

Minimally and Non-Invasive Approaches to Accelerate Tooth Movement: Micro-osteoperforations. Patients are always attracted to decreasing the time it takes to complete orthodontic treatment. Recent advances in the understating of bone biology have been applied to a number of adjunctive techniques that in certain situations may reduce the time for certain tooth movements. In this new chapter, Ignacio Blasi looks at the use of micro-osteoperforations and the ability of these perforations to increase bone turnover rates, providing for increased speed of tooth movement. Studies have been done that demonstrate a localized positive effect on the speed of tooth movement. Mechanical Vibration. Dubravko Pavlin presents information on the influence of low level mechanical vibration on orthodontic treatment, a technique borrowed from orthopedic colleagues. Some of the animal and human studies have reported increased rates of tooth movement and an ability to reduce pain perception when low level vibration therapy is used. Still other studies report no clinical effectiveness. While the jury is still out on this technique, clinical and basic science research into adjuncts that can influence biologic factors, are likely to bear fruit in the future.

31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement Ignacio Blasi, Jr., and Dubravko Pavlin OUTLINE MICRO-OSTEOPERFORATIONS, by Ignacio Blasi, Jr., 913 Introduction, 913 Biological Mechanism, 913 Techniques and Indications, 914 Techniques, 914 Indications, 916 LOW-LEVEL MECHANICAL VIBRATIONS, by Dubravko Pavlin, 918 Introduction, 918 Clinical Studies, 918 Vibration and Treatment with Clear Aligners, 921 Biological Mechanism of Bone Response to Vibration, 921 MICRO-OSTEOPERFORATIONS* agents such as prostaglandins,22–25 Relaxin26–29 and platelet-rich plasma (PRP),30 decortication and related techniques (see Chapter 22),31,32 as well as distraction osteogenesis,33–35 corticision,36,37 osteoperforations (e.g., Propel, Propel Orthodontics, Ossining, NY),38 and low-level mechanical vibration (e.g., AcceleDent, OrthoAccel Technologies, Inc., Bellaire, TX).39–41 However, limited clinical and scientific evidence can be found for the effectiveness of most of these techniques.42,43 Performing micro-osteoperforations is a minimally invasive technique used to accelerate the rate of tooth movement by stimulating the patient’s own biologic response as an attempt to shorten treatment time. It can be also used to facilitate and accomplish certain difficult and challenging tooth movements in a more predictable manner. The concept is similar to other surgical techniques, such as alveolar decortication and variations, damaging or traumatizing the cortical alveolar bone to cause a localized inflammatory response and thereby increase the regular bone turnover (the regional accelerated phenomenon44,45 [RAP]) and increase the rate of tooth movement. Introduction Prolonged treatment time in orthodontics is an undesirable side effect for both the patient and the clinician. Usually, between 2 and 3 years of treatment are required for a case to be properly completed,1,2 which depends on a variety of factors including the biological response of each individual to orthodontic forces, the complexity of the case, skeletal discrepancies, the amount of dental camouflage of skeletal problems, treatment mechanics, and patient compliance. Regardless of the length of required treatment, it is important to emphasize that a clinician should provide to the patient the best treatment outcome possible. For example, in a case with an excessive overjet and lack of anterior guidance, coupling of the anterior segments should not be compromised because of a prolonged treatment time. The first of the two fundamental principles in minimizing the length of orthodontic treatment is a proper diagnosis and an individualized treatment plan that includes clear treatment objectives to correct a malocclusion and to provide optimal occlusion without trespassing on the anatomic boundaries and compromising aesthetics, while avoiding any harm to the adjacent tissues. The second principle is an understanding of orthodontic biomechanics, which allows the clinician to develop a sound mechanical plan and to select appropriate appliances to achieve the treatment goals specific for each patient. In addition to these two basic principles, several approaches have been proposed to accelerate orthodontic tooth movement. These include self-ligating brackets,3–5 robotic prefabricated wires (e.g., SureSmile, OraMetrix, Inc., Richardson, TX),6,7 indirect bonding technique,8–10 low-level laser therapy (e.g., OrthoPulse, Biolux Research Ltd., Vancouver, BC, Canada),11–15 electrical currents stimulation,16–19 pulsed electromagnetic fields,20 piezoelectricity,21 injections of pharmacologic *Ignacio Blasi Jr. Biological Mechanism Orthodontic tooth movement occurs in the presence of a mechanical stimulus sequenced by remodeling of the alveolar bone and the periodontal ligament (PDL). Orthodontic tooth movement consists of three phases: (1) initial phase, (2) lag phase, and (3) postlag phase.46 The initial phase consists of an immediate and rapid movement and occurs within 24 to 48 hours after the initial application of force to the tooth. The rate of movement is largely attributed to the displacement of the tooth in the PDL space, causing its compression and undermining bone resorption on the pressure side. Bone resorption occurs through osteoclastic activity by creating bone lacunae that will later be filled in by osteoblast cells. The lag phase lasts 20 to 30 days and displays relatively little to no tooth movement. This phase is marked by PDL hyalinization in the region of compression where the blood supply is cut off. No subsequent tooth movement occurs until the cells complete the removal of all of the necrotic tissues. Once the PDL regenerates, 913 914 CHAPTER 31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement tooth movement continues. The postlag phase follows the lag phase, during which the rate of movement increases.47,48 When tooth movement occurs, the fibers on the tension side are stretched and resist further movement. Light continuous tension causes elongation of fiber bundles and subsequent bone formation mediated by osteoblasts. Osteoblasts are differentiated from the local precursor cells, called mesenchymal stem cells. Mature osteoblasts form the osteoids, and the mineralization processes follow.49 In addition, endothelial nitric oxide synthase (eNOS) and enzyme profiles indicate bone formation in the tension area.50 Different cytokines and hormones are involved in the biological mechanism of tooth movement. Tumor necrosis factor–alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), prostaglandin E2 (PGE2), and other inflammatory cytokines can facilitate osteoclastic bone resorption processes51,52 through activation of the nuclear factor kappa B (RANK) and the nuclear factor kappa B ligand (RANKL). In addition, osteoblastic cells regulate osteoclastic differentiation by synthesizing RANKL.52,53 Different cytokiness such as TNF-α levels are increased at the gingival sulcus with orthodontic tooth movement.54,55 To assess the impact of tooth movement, studies blocking these factors have been conducted and have demonstrated less tooth movement when compared with the control group.56–59 In an animal study, mechanical forces were applied to tumor necrosis factor receptor (TNFR)-deficient mice to investigate the role of TNF signaling in orthodontic tooth movement. The experiment demonstrated that tooth movement was delayed 6 days after the application of the appliance in TNFR-deficient mice compared with wild-type mice. Therefore these results revealed certain roles of TNF in orthodontic movement, and the assumption that increasing the levels of these factors can accelerate tooth movement is a reasonable conclusion.60 In a study in which micro-osteoperforations were performed in combination with orthodontic tooth movement in a rat model, the expression of different inflammatory markers was observed to increase. It was hypothesized that these markers, caused by the micro-osteoperforations, led to increased osteoclast activity and to increased speed of tooth movement (Fig. 31-1, A).61 Cytokines such as IL-1, IL-6, IL-8, and TNF-α have been proven to be linked with bone remodeling during orthodontic movement.52 Alikhani and colleagues38 demonstrated that some chemokines (CCL-2, CCL-3, CCL-5, and IL-8) and cytokines (IL-1, TNF-α, and IL-6) had increased levels during orthodontic tooth movement and that osteoperforations significantly increased the expression of these factors. Their study suggested that the higher presence of these cytokines is related with more osteoclast activity and therefore increased tooth movement (Fig. 31-1, B). Techniques and Indications The key to success when performing micro-osteoperforations depends first of a proper diagnosis and case selection and second of an appropriate application of the technique. Micro-osteoperforations and decortication with bone grafting (see Chapter 22) employ the same biological and physiologic principles to accelerate tooth movement. Although both techniques accelerate the rate of tooth movement, they can be used for different treatment objectives. The objective for the first technique is the velocity of the tooth movement or achieving a complex movement; for the second technique, a periodontal benefit could be the principal objective and the acceleration of tooth movement a beneficial side effect. Therefore a careful periodontal evaluation should first be completed in each case. Micro-osteoperforations involve a less invasive approach than corticotomy. The perforations are performed through the gingival tissues, penetrating the cortical plate (Fig. 31-2). There is no need to raise a mucogingival flap, create any incisions or perform a tissue punch to access the cortical bone. The osteoperforations are performed with a bone screw, which is self-drilling and self-tapping, and no pilot hole is necessary. The Propel device (Propel Orthodontics, Ossining, NY) is a good example. The first-generation Propel device was a single-use, sterile, disposable manual perforator similar in size to a small handheld screwdriver. It had a light-emitting diode (LED) depth stop indicator that illuminated once the desired perforation depth was achieved. The second-generation Propel device has a heavier, balanced metal handle and disposable screw tips with marks to indicate the depth of the perforation. The third-generation consists of a disposable screw tip, an automatic electric torque driver and a contra-angle. The technique is performed by the orthodontist, requires no surgical instrumentation, and can be performed in a standard dental setting using a traditional aseptic protocol. Techniques Knowing and evaluating the anatomy surrounding the tissues of the site to be treated are important; the mandibular nerve and the maxillary sinuses should be located. Palpating and exploring the area for root proximity to ensure safety while performing the perforations are essential. A current panoramic or a cone-beam computed tomography (CBCT) x-ray image might be helpful tool a to verify the patient’s anatomy and root location. The oral cavity should be aseptic to diminish the bacterial count on the site to be treated. Either local infiltrative or topical anesthetic could be used to anesthetize the area. If topical anesthetic is chosen, then the compounded formulas are the best to be used.62 Profound gel (Steven’s Pharmacy, Costa Mesa, CA) is a mixture of 10% prilocaine, 10% lidocaine, and 4% tetracaine. The ingredients in the Baddest Topical in Town (BTT 12.5) (Woodland Hills Pharmacy, Woodland Hills, CA) are 12.5% lidocaine, 12.5% tetacaine, 3% prilocaine, and 3% phenylephrine gel. Before applying the topical anesthesia, the gingiva should be thoroughly dried with gauze to remove the saliva and salivary proteins that can act as a barrier to the medications within the compounded formula. The topical anesthetic should be in contact with the gingiva for at least 4 minutes or until the tissue gets a corrugated look. Local infiltration may be used to numb the patient in a more predictable manner and is definitely the choice for palatal perforations. The area should be tested to ensure numbness. The osteoperforations should penetrate through the cortical plate into the cancellous bone to ensure trauma to the alveolar bone and to achieve an inflammatory response greater than orthodontic forces alone. The depths of the perforations are dependent upon the soft tissue and bone thickness. A transgingival perforation with a periodontal probe is recommended to determine the soft tissue thickness. Katranji and colleagues63 reported that the buccal plate of the dentate maxilla and mandible ranged from 1.6 to 2.2 mm in thickness. The average cortical thickness in the maxilla is 2.23 mm in the molar, 1.62 mm in the premolar, and 1.59 mm in the anterior regions. In the mandible, the cortical thickness is 1.98 mm in the molar, 1.20 mm in the premolar, and 0.99 mm in the anterior regions. They found that the thinnest area is in the lower anterior region and the thickest area in the upper posterior region.63 Although the cortical thicknesses may vary among individuals, the soft tissue CHAPTER 31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement 915 A B FIGURE 31-1 A, Cascade of events occurs with the initiation of tooth movement. Cytokine chemical messengers mediate osteoblast and osteoclast communication to remodel bone. B, Schematic representation of bone remodeling. F, force g ; IL1-α, interleukin-1 alpha; TNF, tumor necrosis factor. (From Propel Orthodontics, Ossining, NY.) thickness should be assessed and accounted for when calculating the depth of the perforations. For example, if osteoperforations are to be performed in the premolar area with a soft tissue thickness of 3 mm, then the selected length of the screw should be no less than 5 mm. In addition, the clinician may feel less resistance once the cortical plate is penetrated. Once the depth is calculated, the perforations can be performed through the gingiva in the selected area. The perforations can be made either on the attached keratinized tissue or on the free gingival mucosa. Ideally, three micro-osteoperforations in each interdental space of the area selected should be buccally and/or lingually performed. However, the practitioner may perform as many osteoperforations as desired. The perforations can be made in a linear or triangular distribution (Fig. 31-3). In the areas where performing three or more perforations is anatomically not possible as a result of root proximity, one or two may be sufficient. A patient could receive either a single micro-osteoperforation application or repeated multiple applications at different times to maximize the benefits of the biological stimulation. Studies have reported that an aggressive technique triggers higher osteoclastic activity and/or lower alveolar bone density, which in turn accelerates orthodontic tooth movement.30 Therefore one can assume that a series of osteoperforations performed at periodic intervals will maintain a high level of inflammation. Further research is still needed to determine the exact number of perforations and frequency that is adequate to achieve the desired biological response. Minor bleeding may occur after performing the procedure, especially in the alveolar mucosa. In general, minor discomfort is reported. However, some patients may experience some level of pain around the treatment site. If any discomfort is present, then it should be treated with acetaminophen (Tylenol). Nonsteroidal 916 CHAPTER 31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement anti-inflammatory drugs (NSAIDs), such as ibuprofen (Advil), should be completely avoided. NSAIDs may diminish the effect created by the inflammation to accelerate the tooth movement. Alikhani and colleagues38 evaluated the effect of microosteoperforations on the rate of tooth movement. In this randomized, single-blinded clinical trial, the rate of canine retraction with and without perforations was studied. This trial also evaluated the stimulation of inflammatory markers and the discomfort of the patients during treatment. The sample of 20 patients (ages ranging between 19.5 and 33.1 years) was divided in two groups. The control group consisted of three men and seven women, and the experimental group consisted of five men and five women. Both groups had similar malocclusions (Class II, Division II) and were treated with maxillary first premolar extractions. The retraction mechanics of the maxillary canines consisted of nickel-titanium closing-coil springs activated from a temporary anchorage device (TAD) to a power FIGURE 31-2 This diagram illustrates the micro-osteoperforation into the alveolar bone. The insertion is performed flapless through the gingiva to reach the alveolar bone. (From Propel Orthodontic, Ossining, NY.) A arm on the canine bracket close to the center of resistance of the tooth. Its activation was delayed 6 months to minimize any inflammatory effect from the extraction procedure. The canines were checked for any occlusal interference that could affect the movement. The experimental group received three microosteoperforations distal to the canine on one side only, whereas the control group did not receive any perforations. The rate of canine retraction, measured at 28 days after activation, was a statistically significant (2.3-fold) increase in the experimental side when compared with the control side. Gingival crevicular fluid samples were collected from the canines to evaluate for inflammatory markers. The protein analysis was performed in different time points—before retraction and 24 hours, 7 days, and 28 days after activation. Increases in the levels of cytokines and chemokines analyzed 24 hours in both groups were significant, compared with their baseline values (before retraction). The differences between the two groups were also significantly different, with the experimental group higher than the control group. At day 28, only interluekin-1 was still significantly elevated in the control group and in the experimental group. The difference between the two groups was not statistically significant. Although the patients in this study reported local tolerable discomfort at the experimental site, it did not require additional medication. Indications Orthodontic tooth movement depends on a multitude of factors, including skeletal pattern of the patient, musculature, occlusal forces, anatomic characteristics of the jaws, and mechanical orthodontic forces. One important factor is the alveolar bone shape and its density. Lekholm described a classification system of bone and divided it in four categories: type 1 to type 4 (from dense cortical bone to low-density trabecular bone).64 The mandible generally has denser corticated bone than the maxillae, and in both arches, the thickness of the cortical plate decreases and trabecular space porosity increases moving posteriorly. As the bone density is reduced, the rate of tooth movement increases. For this reason, maxillary molars present a lower degree of B C FIGURE 31-3 A 64-year-old woman with minimal tooth movement. A, Micro-osteoperforations can be performed in a linear or triangular shape distribution, depending on anatomic limitations. B, Note the vertically angulated upper incisors and the torquing auxiliary to upright the root over the alveolar bone. C, Cone-beam computed tomography (CBCT) sagittal cut at the level of the upper central incisors shows minimal buccal plate present. Note the root position of the incisor against the cortical plate that may have had an impact on decreasing the rate of tooth movement. In this case, micro-osteoperforations can be buccally performed between the interdental spaces in combination with palatal perforations to accelerate the bone turnover. CHAPTER 31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement anchorage when compared with mandibular molars. A remark supporting this concept is the observation of higher tooth movement in children when compared with adults.65 Therefore the micro-osteoperforation technique may help surpass these physiologic and anatomic barriers. A B FIGURE 31-4 A, Three micro-osteoperforations were performed between the second premolar and the mesially inclined first molar in the leveling initial phase of treatment. B, The molar was uprighted after one visit. Note healing of the soft tissues. Orthodontic tooth movement may be problematic when the alveolar width between the buccal and lingual cortical plates is not appropriate to accommodate the complete anatomic dimension of the roots. Consequently, tooth movement through the cortical plate may be reduced and buccal and/or lingual bone dehiscences and/or fenestrations might develop.66 Therefore a proper periodontal evaluation is crucial (see Chapter 22). Bone augmentation procedures designed to increase the alveolar width in combination with orthodontic treatment are suggested to prevent these undesirable consequences.67 Micro-osteoperforations do not change the basal bone and/ or alveolar bone. They do not expand the limits of the envelope of discrepancy for the maxillary and mandibular arches; tooth movement is still limited by anatomic alveolar boundaries. Primary indications are to (1) accelerate the rate of tooth movement to shorten the treatment time, (2) facilitate the tooth movement for challenging movements, and (3) modify anchorage. The technique is contraindicated in systemically compromised patients (American Society of Anesthesiology (ASA) Class III), patients requiring chronic NSAID or steroid prescriptions, and patients in treatment with bisphosphonates. The technique is minimally invasive; however, potential disadvantages include damage to surrounding tissues, root perforation, and potential patient discomfort. Micro-osteoperforations can be used in many different situations, depending on what is needed for each individual case. The clinician might decide to use this approach in simple cases where crowding and rotations are difficult movements to correct or simply to shorten the treatment time. It could be used during the initial stages of treatment for faster leveling and alignment (Fig. 31-4), during the working stages of space closure (Fig. 31-5), for single or multiple intrusions or extrusions (e.g., to correct a deep bite by intrusion of the lower incisors or to correct an open bite by intrusion of the posterior segments), for protraction (Fig. 31-6) of the dentition to be achieved in A B 917 C FIGURE 31-5 A, Micro-osteoperforations were performed in a lineal distribution on the open space to accelerate the rate of tooth movement. B, C, Two weeks after the procedure, the tissue is healing within normal limits, and forward movement is being achieved. The beneficial effects of the osteoperforations are accelerating the tooth movement and minimal root resorption of this temporary tooth. 918 CHAPTER 31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement A A B B FIGURE 31-6 A, B, Six micro-osteoperforations are made in a triangular shape for protraction on the mandibular segment for faster tooth movement. a more predictable way, and/or for distalization (Fig. 31-7) or mesialization of a single tooth or a whole segment (e.g., a Class II [see Fig. 31-7] or Class III correction). Micro-osteoperforations could be used for any limited treatment or adjunct orthodontics such as molar uprighting. It can be hypothesized that it could diminish the amount of external tooth resorption as a result of the decrease in orthodontic treatment time.68,69 In cases where this procedure may facilitate a specific challenging movement, the practitioner should prepare the teeth to get the maximum benefit from the biologic response of the osteoperforations. In summary, the micro-osteoperforation technique is a clinical approach that can be performed to generally accelerate tooth movement or to achieve a particular movement that is needed in a particular area. Frequent repeated applications (approximately every 4 to 6 weeks until the desired movement is completed) should decrease the treatment time by maintaining a high level of the inflammatory markers that stimulates the osteoblast and osteoclast activity. Although finishing a case is subjective, there are standards that must be met in every case. Treatment time is an important consideration in orthodontics, but quality should not be compromised for speed. LOW-LEVEL MECHANICAL VIBRATIONS† Introduction A plethora of evidence from orthopedic research suggests that low-level mechanical oscillatory signals (vibrations) have †Dubravko Pavlin FIGURE 31-7 A 16-year-old female adolescent with unilateral Class II malocclusion and upper midline discrepancy. A, Microosteoperforations were performed in each interdental space on the posterior segment to maximize the inflammation effects for the challenging movement. B, Progress 4.5 months later, with two sessions of osteoperforations. The use of a temporary anchorage device and extraction of the 3rd molar also facilitated the distalization in a more predictable manner. a positive effect on bone metabolism, increasing the rate of remodeling in long bones during adaptation to mechanical loading.70 This type of mechanical stimulation is currently used as a nonpharmacologic intervention in the prevention of osteoporosis.71 Results from multiple clinical trials demonstrate that the application of low-magnitude, high-frequency mechanical stimulation causes in an increase in bone density and a decrease in bone loss in postmenopausal women.72 In addition to clinical trials, animal studies have provided evidence from the cranial suture model73,74 and long bone periosteum,75 suggesting that dynamic loading can substantially improve bone formation. Results from a study using a rodent model showed that dynamic vibrational loading increased the rate of orthodontic tooth movement, with no negative side effects on the periodontium and surrounding tissues of the alveolar bone.76 Loading with a pulsating force for 1.5 hours per day over 3 weeks resulted in approximately 1.3 to 1.4 times greater tooth movement than loading with a static force. However, until recently, clinical evidence concerning the effect of vibratory loading on orthodontic tooth movement was lacking, which prompted several clinical studies discussed in this section. Clinical Studies Based on an increasing body of evidence that low-level mechanical cyclic loading results in an anabolic effect on bone metabolism and stimulates remodeling in long bones, vertebrae, and cranial sutures, and that orthodontic tooth movement in rodents is also stimulated by this type of loading, a clinical trial was conducted at the Department of Orthodontics in San Antonio, Texas, to test the effect of vibrations on tooth movement in patients undergoing orthodontic treatment.77 The objective of this study was to test the hypothesis that low-level mechanical vibration, as an adjunct to standard orthodontic CHAPTER 31 A Minimally and Noninvasive Approaches to Accelerate Tooth Movement 919 B FIGURE 31-8 A, AcceleDent Aura. B, Patient wears the AcceleDent for 20 minutes per day by lightly biting on the mouthpiece. (Courtesy of OrthoAccel Technologies, Inc., Bellaire, TX.) treatment, has a stimulatory effect on the rate of tooth movement in orthodontic patients treated for 20 minutes per day by the AcceleDent device (OrthoAccel Technologies, Inc., Bellaire, TX), which delivers a vibrational force of 0.25 newton (N) (25 grams) with a frequency of 30 Hertz (Hz) (Fig. 31-8). This study was preceded by a pilot study78 and followed by two other clinical studies addressing similar topics, which are discussed later in this chapter. The San Antonio study conducted at the Department of Orthodontics was a prospective, randomized, controlled, double-blind, parallel group clinical trial (described in detail elsewhere)77; a brief summary of its protocol and results is provided. The study fully adheres to the CONSORT guidelines and CONSORT 2010 checklist79 for conducting and reporting randomized clinical trials (RCTs). The power analysis required a minimum sample size of 32, but the final total sample was increased to 45 subjects. Subjects were randomly assigned to a vibration group (n=23, vibration applied using the AcceleDent device) or to a control group (n=22, using a device in which vibration was internally disabled). A third-party vendor provided a computer-generated randomization schedule. One subject inclusion criterion was that the treatment plan required the extraction of the upper bicuspids. All subjects were treated by orthodontic residents under the supervision of one of the principal investigators. In both groups, a routine set of initial orthodontic records, including study models, photographs, and radiographs, were obtained. All subjects were bonded with a 0.022- × 0.028-inch prescription edgewise MBT Appliance System with twin brackets (3M Unitek, St. Paul, MN). Compliance with the device was assessed using a logbook with a daily record form, requiring the subjects to enter the times of initiation and cessation of device use. In both groups, the use of AcceleDent was prescribed for 20 minutes per day from the start of the treatment. After the initial alignment, a mini-implant TAD (Tomas [temporary orthodontic micro anchorage system] anchorage pin, Dentaurum GmbH & Co., Ispringen, Germany), 1.6 mm in diameter and 9 mm in length, was inserted into the interdental bone between the roots of the maxillary second premolar and the first molar and immediately loaded using a nickel-titanium closing-coil spring stretched between the mini-implant and the hook on the canine bracket to provide a force of approximately 180 grams (Fig. 31-9). To determine the amount of canine movement, the distance between the canine and the TAD was measured before each closing-coil spring activation using a digital caliper placed parallel to the occlusal plane. The analysis of the intent-to-treat (ITT) sample (n=45) reported that the rate of tooth movement in the treatment group (1.16 mm/month) was higher than in the control group (0.79 mm/month).77 The rate of movement of the retracting cuspids in the per protocol (PP) sample (the patients in which treatment was finished according to the protocol n=39) was also faster when vibration was applied. Interpretation of the results is more meaningful by focusing on the ITT sample, since after enrollment and randomization, some subjects (6) were withdrawn from the group for various reasons (pregnancy, small extraction space after alignment, loose TADs), which could result in a bias in the remaining PP group. The secondary outcome of this RCT was to determine the effect of AcceleDent-induced vibration on the rate of initial alignment of lower anterior teeth. This analysis was conducted by measuring the change in the arch perimeter before and after alignment on the plaster models of the lower arch. Because the arch perimeter measurement is not suitable in nonextraction cases, only the patients with extractions were analyzed, which reduced the sample size. Despite that limitation, initial findings indicate that the rate of alignment was increased by approximately 51% in the subjects exposed to vibration. Results from other outcomes of this RCT were related to patients’ safety, comfort, and ease of use of the AcceleDent device. The most significant safety outcome was to determine whether the low-level vibration increases the risk of external apical root resorption (EARR) during orthodontic treatment. Both cementum and bone are the mineralized tissues of the periodontium that can undergo resorption when exposed to a compressive stress during mechanical loading by orthodontic forces.80,81 The anabolic effect on bone produced by vibratory (cyclic) loading reflects the increased rates of bone resorption and bone formation, thus raising the concern that tooth cementum could be subject to a higher level of resorption when exposed to concomitant stresses from orthodontic forces and vibrations. The root 920 CHAPTER 31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement A B a b FIGURE 31-9 A, Orthodontic appliance for separate canine retraction. C, Canine being retracted; T, temporary anchorage device (TAD) (Tomas [temporary orthodontic micro-anchorage system] anchorage pin, Dentaurum, GmbH & Co., Ispringen, Germany), 1.6 mm in diameter and 9 mm in length was inserted between the maxillary second premolar and the first molar, under local anesthetic, and immediately loaded; F, retraction force of 180 g of force, measured by Dontrix gauge (American Orthodontics, Sheboygan, WI) was applied by a nickel-titanium closing-coil spring activated between the TAD and the canine bracket; d, distance measured parallel to the occlusal plane using a digital caliper before each closing-coil spring activation or reactivation. An average value from two measurements was entered at each visit; visits were approximately 4 weeks apart. The spring was truncated as needed and re-tied to deliver 180 g of force. B, Representative example of retraction mechanics for space closure. a, The activated closing-coil spring is in place at the beginning of space closure. b, One month later, the space opened mesial to the canine. length analysis was conducted using panoramic radiographs from the subjects participating in the RCT, which were taken in the same laboratory before the start of treatment, at the end of space closure, and at the end of treatment in both the vibration and control groups. Total tooth length was measured using the digital ruler in the Medicor Imaging Picture Archive Communication System (MiPACS, Medicor Imaging, Charlotte, NC). Included were all the teeth from first molar to first molar, except for the first bicuspids because of the variability of root shape. The canines appeared to move predominantly by translation, based on the direction of the reversal lines in alveolar bone adjacent to the root, which represent the areas of the onset of the new bone formation on the tension side of the periodontium. The initial analysis of total tooth length showed no significant difference in this parameter between the AcceleDent device and the sham group at either the end of space closure or the end of treatment, indicating that mechanical vibration as an adjunct to orthodontic loading did not increase the risk of EARR in orthodontic patients. Several outcomes of this RCT related to the patients’ comfort and ease of using the AcceleDent device. The subjects were assessed at each study visit using a visual analog scale (VAS) to evaluate the following parameters: discomfort, hygiene, drooling, schedule disruption, reliability, ease of use, noise, cleanliness and maintenance, and overall satisfaction with the device. The VAS was based on a 100point scale, and the scores from the control and AcceleDent groups were compared. The initial assessments are showing very similar VAS scores for both groups, indicating that the patients are very satisfied with treatment and the device is easy to use without disruption of their daily activities. In addition to the RCT focusing on cuspid retraction discussed previously, the increased interest in accelerated tooth movement has resulted in several recent studies that focused on the effect of supplemental vibratory loading during the initial alignment/leveling stage of treatment. Miles and colleagues conducted a randomized trial with 66 patients, using the Tooth Masseuse device82. They found no effect on the rate of reduction of irregularity during anterior alignment. They also did not find any difference in alleviation of pain. Three other studies have been published on the AcceleDent device. The most recent, by Woodhouse and colleagues, was a three-armed randomized trial, comparing AcceleDent with fixed appliances, sham AcceleDent with fixed appliances, and CHAPTER 31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement 921 A FIGURE 31-10 Invisalign case, courtesy of Dr. Sam Daher. Number of aligners: 52; refinement aligners: 7; total: 59 aligners. Normal treatment time: 59 × 2 weeks = 118 weeks (2 years and 3 months). Treated with AcceleDent: aligners changed as follows: 7 days for initial 52 aligners and every 5 days for the 7 refinement aligners. Total treatment time (actual) was 1 year, 1 month. A: Initial, B: Progress, C: Final. fixed appliances only83. The authors reported no difference in the time to reach initial or final tooth alignment among the three groups. Bowman in a retrospective study, reported a faster rate of alignment in an AcceleDent group, but also stated that the difference was not statistically different84. Bowman did report a significantly faster rate of leveling in the AcceleDent group. In addition, Kau and colleagues reported on a group of 14 patients (case series) all treated with fixed appliances and the AcceleDent device. Although there was no comparison group, the authors reported that the rate of tooth movement seen in their study was 2-3 times faster than conventional tooth movement (estimated to be about 1 mm per month)78 . Vibration and Treatment with Clear Aligners The use of the AcceleDent device as an adjunct to treatment with Invisalign is becoming increasingly popular among the clinicians in the United States and in other parts of the world. Although no clinical studies have been published on this subject, numerous personal reports of practitioners indicate that the treatment time can be cut by 50% or more when the AcceleDent device is used during treatment with Invisalign. The proponents of this approach report that the time for wearing each aligner can be cut down from the prescribed 2 weeks to 1 week or less when vibration is applied. Studies are needed to determine the mechanics underlying such a sharp decrease in treatment time. The fact that the tight contact of the aligner with the entire tooth surface allows a more efficient transmission of vibration to the root and surrounding bone is a logical speculation. Figure 31-10 shows a representative patient with Invisalign aligner trays whose treatment time was reduced by more than 50% with the adjunctive use of the AcceleDent device. Biological Mechanism of Bone Response to Vibration The biological mechanism underlying the anabolic effect of cyclic loading on bone metabolism is not fully understood. Several signaling pathways have been implied in the response of bone cells to mechanical loading,85,86 and further studies are needed to determine which of these pathways is activated by low-level vibrations. Since oscillatory forces, even at the extremely low levels used in this study, are readily transmitted beyond the bone surface and into the deep compartments of bone, the speculation that the initial response occurs in the cells embedded in bone matrix, such as osteocytes, is reasonable. 922 CHAPTER 31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement B C FIGURE 31-10, cont’d CHAPTER 31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement Our group and others have previously identified osteocytes as the early mechanoresponsive cells in the alveolar bone during orthodontic tooth movement.87 As early as 6 hours after the onset of mechanical loading, a surge in the expression of genes for osteocalcin and dentin matrix protein was detected in the alveolar osteocytes. These mechanically induced signaling pathways could be triggered by fluid shear stress in osteocyte lacunae and canaliculi or by piezoelectric potentials induced by bone bending, all of which can occur during vibrations. In addition, bone microfractures, at the level similar to or lower than those exerted by physical activity, may be a contributing factor in the early response to oscillatory loading. Further studies showed that these early mechanoresponsive events in osteocytes are followed by increased differentiation of osteoblasts88 and stimulation of bone characteristic genes (alkaline phosphatase, type I collagen) in these cells after 24 hours and up to 5 days.89–90 Because similar signaling and gene regulatory events are most likely involved in response to orthodontic loading of bone with and without vibrations, one of the key questions to be addressed in future studies is whether cyclic loading superimposed on the force systems from an orthodontic appliance produces a faster and quantitatively higher levels of the same types of early anabolic signals or if completely different pathways of signaling and genetic responses are initiated that result in stimulation of bone remodeling and faster tooth movement. REFERENCES References for Micro-Osteoperforations 1. Fink DF, Smith RJ. The duration of orthodontic treatment. Am J Orthod Dentofacial Orthop. 1992;102(1):45–51. 2. Fisher MA, Wenger RM, Hans MG. Pretreatment characteristics associated with orthodontic treatment duration. Am J Orthod Dentofacial Orthop. 2010;137(2):178–186. 3. Budd S, Daskalogiannakis J, Tompson BD. A study of the frictional characteristics of four commercially available self-ligating bracket systems. Eur J Orthod. 2008;30(6):645–653. 4. Chen SS, Greenlee GM, Kim JE, et al. Systematic review of self-ligating brackets. Am J Orthod Dentofacial Orthop. 2010;137(6): 726.e721–726, e718; discussion 726–727. 5. Henao SP, Kusy RP. Frictional evaluations of dental typodont models using four self-ligating designs and a conventional design. Angle Orthod. 2005;75(1):75–85. 6. Alford TJ, Roberts WE, Hartsfield Jr JK, et al. Clinical outcomes for patients finished with the SureSmile™ method compared with conventional fixed orthodontic therapy. Angle Orthod. 2011;81(3):383–388. 7. Saxe AK, Louie LJ, Mah J. Efficiency and effectiveness of SureSmile. World J Orthod. 2010;11(1):16–22. 8. Grauer D, Wiechmann D, Heymann GC, et al. Computer-aided design/ computer-aided manufacturing technology in customized orthodontic appliances. J Esthet Restor Dent. 2012;24(1):3–9. 9. Koo BC, Chung CH, Vanarsdall RL. Comparison of the accuracy of bracket placement between direct and indirect bonding techniques. Am J Orthod Dentofacial Orthop. 1999;116(3):346–351. 10. Silverman E, Cohen M, Gianelly AA, et al. A universal direct bonding system for both metal and plastic brackets. Am J Orthod. 1972;62(3):236–244. 11. Cruz DR, Kohara EK, Ribeiro MS, Wetter Nu. Effects of low-intensity laser therapy on the orthodontic movement velocity of human teeth: a preliminary study. Lasers Surg Med. 2004;35(2):117–120. 12. Yamaguchi M, Hayashi M, Fujita S, et al. Low-energy laser irradiation facilitates the velocity of tooth movement and the expressions of matrix metalloproteinase-9, cathepsin k, and alpha(v) beta(3) integrin in rats. Eur J Orthod. 2010;32(2):131–139. 923 13. Campanha BP, Gallina C, Geremia T, et al. Low-level laser therapy for implants without initial stability. Photomed Laser Surg. 2010;28(3): 365–369. 14. Altan BA, Sokucu O, Ozkut MM, Inan S. Metrical and histological investigation of the effects of low-level laser therapy on orthodontic tooth movement. Lasers Med Sci. 2012;27(1):131–140. 15. Fujita S, Yamaguchi M, Utsunomiya T, et al. Low-energy laser stimulates tooth movement velocity via expression of RANK and RANKL. Orthod Craniofac Res. 2008;11(3):143–155. 16. Beeson DC, Johnston LE, Wisotzky J. Effect of constant currents on orthodontic tooth movement in the cat. J Dent Res. 1975;54(2):251–254. 17. Davidovitch Z, Finkelson MD, Steigman S, Shanfeld JL. Electric currents, bone remodeling, and orthodontic tooth movement. I. The effect of electric currents on periodontal cyclic nucleotides. Am J Orthod. 1980;77(1):14–32. 18. Davidovitch Z, Finkelson MD, Steigman S, Shanfeld JL. Electric currents, bone remodeling, and orthodontic tooth movement. II. Increase in rate of tooth movement and periodontal cyclic nucleotide levels by combined force and electric current. Am J Orthod. 1980;77(1):33–47. 19. Kim DH, Park YG, Kang SG. The effects of electrical current from a micro-electrical device on tooth movement. Korean J Orthod. 2008;38(5):337–346. 20. Showkatbakhsh R, Jamilian A, Showkatbakhsh M. The effect of pulsed electromagnetic fields on the acceleration of tooth movement. World J Orthod. 2010;11(4):e52–e56. 21. Shapiro E, Roeber FW, Klempner LS. Orthodontic movement using pulsating force-induced piezoelectricity. Am J Orthod. 1979;76(1): 59–66. 22. Garlet TP, Coelho U, Silva JS, Garlet GP. Cytokine expression pattern in compression and tension sides of the periodontal ligament during orthodontic tooth movement in humans. Eur J Oral Sci. 2007;115(5): 355–362. 23. Lee KJ, Park YC, Yu HS, et al. Effects of continuous and interrupted orthodontic force on interleukin-1beta and prostaglandin E2 production in gingival crevicular fluid. Am J Orthod Dentofacial Orthop. 2004;125(2):168–177. 24. Leiker BJ, Nanda RS, Currier GF, et al. The effects of exogenous prostaglandins on orthodontic tooth movement in rats. Am J Orthod Dentofacial Orthop. 1995;108(4):380–388. 25. Yamasaki K, Miura F, Suda T. Prostaglandin as a mediator of bone resorption induced by experimental tooth movement in rats. J Dent Res. 1980;59(10):1635–1642. 26. Liu ZJ, King GJ, Gu GM, et al. Does human relaxin accelerate orthodontic tooth movement in rats? Ann N Y Acad Sci. 2005;1041:388–394. 27. Madan MS, Liu ZJ, Gu GM, King GJ. Effects of human relaxin on orthodontic tooth movement and periodontal ligaments in rats. Am J Orthod Dentofacial Orthop. 2007;131(1):8.e1–8.e10. 28. McGorray SP, Dolce C, Kramer S, et al. A randomized, placebo-controlled clinical trial on the effects of recombinant human relaxin on tooth movement and short-term stability. Am J Orthod Dentofacial Orthop. 2012;141(2): 196–203. 29. Stewart DR, Sherick P, Kramer S, Breining P. Use of relaxin in orthodontics. Ann N Y Acad Sci. 2005;1041:379–387. 30. Liou EJ. Accelerated orthodontic tooth movement. In: Miles PG, Rinchuse DJ, Rinchuse DJ, eds. Evidence-Based Clinical Orthodontics. Chicago: Quintessence Publishing Company; 2012:179–199. 31. Wilcko WM, Wilcko T, Bouquot JE, Ferguson DJ. Rapid orthodontics with alveolar reshaping: two case reports of decrowding. Int J Periodontics Restorative Dent. 2001;21(1):9–19. 32. Hoogeveen EJ, Jansma J, Ren Y. Surgically facilitated orthodontic treatment: a systematic review. Am J Orthod Dentofacial Orthop. 2014;145(4 Suppl):S51–S64. 33. Iseri H, Kisnisci R, Bzizi N, Tüz H. Rapid canine retraction and orthodontic treatment with dentoalveolar distraction osteogenesis. Am J Orthod Dentofacial Orthop. 2005;127(5):533–541; quiz 625. 34. Liou EJ, Figueroa AA, Polley JW. Rapid orthodontic tooth movement into newly distracted bone after mandibular distraction osteogenesis in a canine model. Am J Orthod Dentofacial Orthop. 2000;117(4):391–398. 924 CHAPTER 31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement 35. Liou EJ, Huang CS. Rapid canine retraction through distraction of the periodontal ligament. Am J Orthod Dentofacial Orthop. 1998;114(4):372–382. 36. Kim SJ, Park YG, Kang SG. Effects of corticision on paradental remodeling in orthodontic tooth movement. Angle Orthod. 2009;79(2):284–291. 37. Murphy CA, Chandhoke T, Kalajzic Z, et al. Effect of corticision and different force magnitudes on orthodontic tooth movement in a rat model. Am J Orthod Dentofacial Orthop. 2014;146(1):55–66. 38. Alikhani M, Raptis M, Zoldan B, et al. Effect of micro-osteoperforations on the rate of tooth movement. Am J Orthod Dentofacial Orthop. 2013;144(5):639–648. 39. Alikhani M, Khoo E, Alyami B, et al. Osteogenic effect of high-frequency acceleration on alveolar bone. J Dent Res. 2012;91(4):413–419. 40. Nishimura M, Chiba M, Ohashi T, et al. Periodontal tissue activation by vibration: intermittent stimulation by resonance vibration accelerates experimental tooth movement in rats. Am J Orthod Dentofacial Orthop. 2008;133(4):572–583. 41. Pavlin D, Anthony R, Raj V, Gakunga PT. Cyclic loading (vibration) accelerates tooth movement in orthodontic patients: a double-blind, randomized controlled trial. Semin Orthod. 2015;21(3):187–194. 42. Gkantidis N, Mistakidis I, Kouskoura T, Pandis N. Effectiveness of non-conventional methods for accelerated orthodontic tooth movement: a systematic review and meta-analysis. J Dent. 2014;42(10):1300–1319. 43. Long H, Pyakurel U, Wang Y, et al. Interventions for accelerating orthodontic tooth movement: a systematic review. Angle Orthod. 2013;83(1):164–171. 44. Frost HM. The biology of fracture healing. an overview for clinicians. Part I. Clin Orthop Relat Res. 1989;248:283–293. 45. Frost HM. The biology of fracture healing. an overview for clinicians. Part II. Clin Orthop Relat Res. 1989;248:294–309. 46. Burstone CJ. The biomechanics of tooth movement. In: Kraus BS, Riedel RA, eds. Vistas in Orthodontics. Philadelphia: Lea & Febiger; 1962:197–213. 47. Krishnan V, Davidovitch Z. Cellular, molecular, and tissue-level reactions to orthodontic force. Am J Orthod Dentofacial Orthop. 2006;129(4):469. e1–469.e32. 48. Reitan K. Tissue behavior during orthodontic tooth movement. Am J Orthod. 1960;46:881–900. 49. Sprogar S, Vaupotic T, Cör A, et al. The endothelin system mediates bone modeling in the late stage of orthodontic tooth movement in rats. Bone. 2008;43(4):740–747. 50. Tan SD, Xie R, Klein-Nulend J, et al. Orthodontic force stimulates eNOS and iNOS in rat osteocytes. J Dent Res. 2009;88(3):255–260. 51. Pacios S, Kang J, Galicia J, et al. Diabetes aggravates periodontitis by limiting repair through enhanced inflammation. FASEB J. 2012;26(4): 1423–1430. 52. Masella RS, Meister M. Current concepts in the biology of orthodontic tooth movement. Am J Orthod Dentofacial Orthop. 2006;129(4):458–468. 53. Karsenty G. The complexities of skeletal biology. Nature. 2003;423(6937): 316–318. 54. Uematsu S, Mogi M, Deguchi T. Interleukin (IL)-1 beta, IL-6, tumor necrosis factor-alpha, epidermal growth factor, and beta 2-microglobulin levels are elevated in gingival crevicular fluid during human orthodontic tooth movement. J Dent Res. 1996;75(1):562–567. 55. Lowney JJ, Norton LA, Shafer DM, Rossomando EF. Orthodontic forces increase tumor necrosis factor alpha in the human gingival sulcus. Am J Orthod Dentofacial Orthop. 1995;108(5):519–524. 56. Jäger A, Zhang D, Kawarizadeh A, et al. Soluble cytokine receptor treatment in experimental orthodontic tooth movement in the rat. Eur J Orthod. 2005;27(1):1–11. 57. Chae HS, Park HJ, Hwang HR, et al. The effect of antioxidants on the production of pro-inflammatory cytokines and orthodontic tooth movement. Mol Cells. 2011;32(2):189–196. 58. Knop LA, Shintcovsk RL, Retamoso LB, et al. Non-steroidal and steroidal anti-inflammatory use in the context of orthodontic movement. Eur J Orthod. 2012;34(5):531–535. 59. Iwasaki LR, Haack JE, Nickel JC, et al. Human interleukin-1 beta and interleukin-1 receptor antagonist secretion and velocity of tooth movement. Arch Oral Biol. 2001;46(2):185–189. 60. Yoshimatsu M, Shibata Y, Kitaura H, et al. Experimental model of tooth movement by orthodontic force in mice and its application to tumor necrosis factor receptor-deficient mice. J Bone Miner Metab. 2006;24(1): 20–27. 61. Teixeira CC, Khoo E, Tran J, et al. Cytokine expression and accelerated tooth movement. J Dent Res. 2010;89(10):1135–1141. 62. Kravitz ND. The use of compound topical anesthetics: a review. J Am Dent Assoc. 2007;138(10):1333–1339; quiz 1382. 63. Katranji A, Misch K, Wang HL. Cortical bone thickness in dentate and edentulous human cadavers. J Periodontol. 2007;78(5):874–878. 64. Lekholm U, Zarb GA. Patient selection and preparation. In: Branemark PI, Zarb GA, Albrektsson T, eds. Tissue Integrated Prostheses: Osseointegration in Clinical Dentistry. Chicago: Quintessence Publishing Company; 1985:199–209. 65. Roberts WE. Bone physiology, metabolism, and biomechanics in orthodontic practice. In: Graber TM, Vanarsdall RL, Vig KW, eds. Orthodontics: Current Principles and Techniques. 4th ed. St. Louis: Mosby; 2005:221–292. 66. Köle H. Corticalisschwächung zur Unterstützung bei der kieferorthopädischen Behand-lung. Fortschr KieferGesichtschir. 1958;4:161–166. 67. Diedrich PR. Guided tissue regeneration associated with orthodontic therapy. Semin Orthod. 1996;2(1):39–45. 68. Fox N. Longer orthodontic treatment may result in greater external apical root resorption. Evid Based Dent. 2005;6(1):21. 69. Segal GR, Schiffman PH, Tuncay OC. Meta analysis of the treatmentrelated factors of external apical root resorption. Orthod Craniofac Res. 2004;7(2):71–78. References for Low-Level Mechanical Vibrations 70. Rubin C, Turner AS, Müller R, et al. Quantity and quality of trabecular bone in the femur are enhanced by a strongly anabolic, noninvasive mechanical intervention. J Bone Miner Res. 2002;17(2):349–357. 71. Rubin C, Judex S, Qin YX. Low-level mechanical signals and their potential as a non-pharmacological intervention for osteoporosis. Age Ageing. 2006;35(Suppl 2):ii32–ii36. 72. Rubin C, Recker R, Cullen D, et al. Prevention of postmenopausal bone loss by a low-magnitude, high-frequency mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety. J Bone Miner Res. 2004;19(3):343–351. 73. Kopher RA, Mao JJ. Suture growth modulated by the oscillatory component of micromechanical strain. J Bone Miner Res. 2003;18(3):521–528. 74. Kopher RA, Nudera JA, Wang X, et al. Expression of in vivo mechanical strain upon different wave forms of exogenous forces in rabbit craniofacial sutures. Ann Biomed Eng. 2003;31(9):1125–1131. 75. Peptan AI, Lopez A, Kopher RA, Mao JJ. Responses of intramembranous bone and sutures upon in vivo cyclic tensile and compressive loading. Bone. 2008;42(2):432–438. 76. Nishimura M, Chiba M, Ohashi T, et al. Periodontal tissue activation by vibration: intermittent stimulation by resonance vibration accelerates experimental tooth movement in rats. Am J Orthod Dentofacial Orthop. 2008;133(4):572–583. 77. Pavlin D, Anthony R, Raj V, Gakunga PT. Cyclic loading (vibration) accelerates tooth movement in orthodontic patients: a double-blind, randomized controlled trial. Semin Orthod. 2015;21(3):187–194. 78. Kau CH, Nguyen JT, English JD. The clinical evaluation of a novel cyclical force generating device in orthodontics. Orthod Prac. 2010;1:1–4. 79. Schulz KF, Altman DG, Moher D. CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332. 80. Segal GR, Schiffman PH, Tuncay OC. Meta analysis of the treatmentrelated factors of external apical root resorption. Orthod Craniofac Res. 2004;7(2):71–78. 81. Weltman B, Vig KW, Fields HW, et al. Root resorption associated with orthodontic tooth movement: a systematic review. Am J Orthod Dentofacial Orthop. 2010;137(4):462–476; discussion 412A. 82. Miles P, Smith H, Weyant R, Rinchuse DJ. The effects of a vibrational appliance on tooth movement and patient discomfort: a prospective randomised clinical trial. Aust Orthod J. 2012;28(2):213–218. CHAPTER 31 Minimally and Noninvasive Approaches to Accelerate Tooth Movement 83. Woodhouse NR, DiBiase AT, et al. Supplemental vibrational force during orthodontic alignment: a randomized trial. J Dent Res. 2015;94(5):682– 689. 84. Bowman SJ. The effect of vibration on the rate of leveling and alignment. J Clin Orthod. 2014;48(11):678–688. 85. Rubin J, Rubin C, Jacobs CR. Molecular pathways mediating mechanical signaling in bone. Gene. 2006;367:1–16. 86. Pavlin D, Gluhak-Heinrich J. Effect of mechanical loading on periodontal cells. Crit Rev Oral Biol Med. 2001;12(5):414–424. 87. Gluhak-Heinrich J, Ye L, Bonewald LF, et al. Mechanical loading stimulates dentin matrix protein 1 (DMP1) expression in osteocytes in vivo. J Bone Miner Res. 2003;18(5):807–817. 925 88. Pavlin D, Goldman ES, Gluhak-Heinrich J, et al. Orthodontically stressed periodontium of transgenic mouse as a model for studying mechanical response in bone: the effect on the number of osteoblasts. Clin Orthod Res. 2000;3(2):55–66. 89. Pavlin D, Dove SB, Zadro R, et al. Mechanical loading stimulates differentiation of periodontal osteoblasts in a mouse osteoinduction model: effect on type I collagen and alkaline phosphatase genes. Calcif Tissue Int. 2000;67(2):163–172. 90. Pavlin D, Zadro R, Gluhak-Heinrich J. Temporal pattern of stimulation of osteoblast-associated genes during mechanically-induced osteogenesis in vivo: early responses of osteocalcin and type I collagen. Connect Tissue Res. 2001;42(2):135–148.