A successful story of translational orthodontic research: Micro-osteoperforation-from experiments to clinical practice

Biology of orthodontic tooth movement

Biological response plays a central role in controlling orthodontic tooth movement.^[2] Force application on teeth induces an aseptic, acute inflammatory response that involves a series of molecular and cellular events, resulting in osteoclast formation and activation that initiates bone remodeling machinery and allows movement of teeth to occur. During the inflammatory response, a repertoire of chemokines and cytokines are activated thus inflammatory cells and osteoclast precursors are recruited into the area; in turn, more inflammatory markers are released which directly or indirectly activate RANK-RANKL pathway toward osteoclast differentiation and activation [Figure 3]. Therefore, the rate of tooth movement is determined by the rate of bone resorption in the direction of movement; meanwhile, the rate of bone resorption is determined by the rate of osteoclast formation. The positive correlation between the activities of inflammatory marker, osteoclast activation, and rate of tooth movement has been demonstrated in our previous study in rats and humans.^[3-5]

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Figure 3

Diagram of cellular events in the compression side in response to application of orthodontic force

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The importance of cytokines in controlling the rate of tooth movement can be appreciated from studies that block their effects. It has been shown that injection of interleukin-1 receptor antagonist or soluble tumor necrosis factor (TNF)-α receptor type I antagonist results in a 50% reduction in tooth velocity.^[6-8] Similarly, tooth movement in TNF receptor type II-deficient mice is reduced compared to wild-type mice.^[9] Animals deficient in CC chemokine receptor 2 (i.e., the receptor for chemokine ligand 2) or chemokine ligand 3 show a significant reduction in orthodontic tooth movement and the number of osteoclasts.^[10] Likewise, it is well known that nonsteroidal anti-inflammatory drugs can reduce the velocity of tooth movement by inhibiting prostaglandin synthesis.^[11,12] Inhibition of other derivatives of arachidonic acid, such as leukotrienes, also significantly decreases the rate of tooth movement.^[13]

These studies strongly support that the proinflammatory cytokines are essential mediators of orthodontic tooth movement. Such findings have compelled us to develop a simple method to amplify and titrate the patient’s normal biological response to safely accelerate orthodontic tooth movement.

Boosting the biological response to orthodontic force

Based on the understanding of normal biological events on the application of orthodontic force, it is logical to assume that increasing the amount of inflammatory mediators should increase the rate of tooth movement. Therefore, developing an approach to stimulate the body to produce an increased amount of inflammatory mediator is the fundamental drive during the R&D process of accelerated techniques.

One of the most intuitive and common measures among clinicians to conquer slow tooth movement is to increase the magnitude of orthodontic force. Our studies at CTOR demonstrated that increasing the magnitude of orthodontic force increases inflammatory marker levels, osteoclast recruitment and formation, alveolar bone resorption, and the rate of tooth movement. However, there is a force level above which we cannot stimulate these biological responses any further.^[3] Thus, the magnitude of cytokine release that can be induced by orthodontic forces has an upper limit and consequently the osteoclast activity initiated by orthodontic forces has a “biological saturation point.” While increasing the force magnitude does not overcome this limitation, it requires another methodology that can increase the osteoclast numbers in the area to enhance this biological response.

Some studies have attempted to inject prostaglandins^[14] or arachidonic acid derivatives^[15] locally or systemic application of PGE₁ analog^[16] to increase the rate of tooth movement. Although such measures do increase the rate of tooth movement, the short half-life and side effects such as hyperalgesia have limited its clinical application.

Another approach to increase the proinflammatory mediators is to stimulate the body to produce these factors at a higher level through its natural course. The advantage of such approach is a coordinated increase in the level of all inflammatory mediators. As discussed before, many cytokines participate in response to orthodontic forces. Injecting one cytokine does not mimic the normal inflammatory response, which is a balance of pro- and anti-inflammatory mediators. Imbalance of such reactions can lead to many side effects, thus it is unsafe to be utilized in daily clinical practice.

Micro-osteoperforation – Evidence from rats to humans

The concept of MOP originated from the attempt of boosting normal inflammatory responses, during which pro-inflammatory mediators are stimulated then followed by an appropriate recovery/repair process. Our animal study that was first published in Journal of Dental Research has shown that introducing small perforations in the alveolar bone (micro-osteoperforation) during orthodontic tooth movement can significantly stimulate the expression of inflammatory mediators. While the application of orthodontic force beyond the saturation point does not elevate the expression and activation of inflammatory mediators beyond certain levels,^[3] adding MOP to the area of tooth movement increases the level of inflammatory mediators.^[5] This response is accompanied by a significant increase in the osteoclast number, bone resorption and localized osteopenia around all adjacent teeth, which could explain the increase in the rate of tooth movement.

Similarly, our human clinical trial using a canine retraction model demonstrated that MOP can amplify the catabolic response to orthodontic forces. Canine retraction in the presence of MOP results in twice as much distalization compared with patients receiving similar orthodontic forces without MOP. This acceleration in tooth movement is accompanied by an increase in the level of inflammatory mediators.^[17]

In addition, our clinical studies demonstrated that increasing the number of MOP significantly increases expression of inflammatory mediators and the magnitude of tooth movement.^[18] Therefore, one should expect procedures such as orthognathic surgery, corticotomies, or piezocision to significantly increase the levels of inflammatory cytokines beyond those induced by MOP. Although increase in cytokine release by these methods is accompanied with a higher rate of tooth movement, the increase in the expression of inflammatory mediators is not sustained for a long time, unfortunately. A significant decrease in cytokine activity is observed 2–3 months after any of these treatments. As a result, each of these procedures would need to be repeated during orthodontic treatment, which renders some of the above-mentioned modalities impractical.

Application of micro-osteoperforation in edentulous ridge and extensive sinus pneumatization

A simplified description of biphasic theory is that activation of osteoblasts by osteoclasts is observed during tooth movement where the bone resorption phase of tooth movement (catabolic phase) is followed by a bone formation phase (anabolic phase) to prevent bone loss during tooth movement. A similar phenomenon can be stimulated during movement of a tooth into an area of alveolar bone loss. These areas usually are occupied with a thick cortical bone that is short in height and narrow in width. Moving a tooth in this area is usually extremely slow, can cause root resorption and usually results in tilting the crown into the edentulous space without significant root movement. Applying MOP in this edentulous area harnesses the catabolic phase of orthodontic treatment to decrease the bone density. This allows faster tooth movement into the area with less possibility of root resorption and greater bodily movement rather than tipping. This osteoclast activity then increases osteoblast activity significantly, which couples catabolism-dependent tooth movement with anabolism-dependent remodeling that restores the bone height and width in the previously edentulous site. Such phenomenon can be utilized for implant site development or tooth movement into maxillary edentulous areas that have extensive sinus pneumatization.^[19]

Micro-osteoperforation-generated cortical drift

Alveolar cortical bone sets the physical and physiological limits of orthodontic tooth movement. While a tooth can be driven through the cortical plate if the orthodontic force applied to it has sufficient magnitude, direction and duration, the speed of cortical bone remodeling is slow enough that appropriately directed forces rarely place any tooth in danger of breaching the physical limit set by the cortical bone. However, orthodontists face a conundrum when they have a borderline extraction case where expansion would provide the ideal space needed to unravel the crowding, but the alveolar boundary conditions are not robust enough to tolerate the expansion. Therefore, it would be beneficial for orthodontists to manipulate these boundary conditions by increasing bone formation at the surface of the cortical bone. Application of MOP in the opposite direction of orthodontic tooth movement can stimulate osteoclasts that will first decrease the bone density of cortical bone, and second stimulate osteoblast activity in the direction of movement. This treatment results in the drifting of the cortical plate into a new position with significant bone formation in the direction of tooth movement. This is especially important during movement of teeth toward the cortical boundaries, for example, during expansion in adults or retraction of lower anterior teeth during correction of severe class III patients.^[19]