Bacterial modulators of bone remodeling in the periodontal pocket.
Henderson Brian,Kaiser Frank
Periodontology 2000
The signaling network involved in the pathogenesis of periodontal disease is not yet fully understood. This review aims to describe possible mechanisms through which the bacterial modulators may be linked directly or indirectly to the process of alveolar bone loss in periodontitis. From the late 1970s to present, new paradigm shifts have been developed regarding our understanding of pathological bone remodeling in periodontal disease. Upcoming evidence suggests that in periodontal disease the local immune response is exacerbated and involves the existence of signaling pathways that have been shown to modulate bone-cell function leading to alveolar bone loss. Those complex signaling pathways have been observed not only between bacteria but also between bacteria and the gingival surface of the host. More specifically, it has been shown that bacteria, through their secretion molecules, may interact indirectly and directly with immune-type cells of the host, resulting in the production of osteolytic agents that enhance bone resorption. Further research is required to provide a clear understanding of the role of these molecules in the pathogenesis of periodontal disease, and the availability of new technologies, such as next-generation sequencing and metagenomic analysis, may be useful tools in achieving this.
10.1111/prd.12160
Personalized medicine: an update of salivary biomarkers for periodontal diseases.
Korte Dina L,Kinney Janet
Periodontology 2000
This article provides an up-to-date review of the more robust salivary biomarkers, as well as of panels of combinatorial markers and periodontal pathogens, that reveal high sensitivity and specificity for enhancing clinical decision-making in periodontal disease progression, risk and diagnosis. Periodontal diseases are complex and require an inflammatory response to bacterial pathogens in a susceptible host to stimulate tissue destruction. When used alone, traditional clinical assessments provide a diagnosis of periodontitis only after the biologic onset of the disease process, and are unable to substantiate disease activity or future risk. New technologies are becoming available that are capable of measuring combinations of inflammatory cytokines and proteinases for rapid chair-side testing. Utilizing saliva to identify and measure specific phenotypes and host-derived mediators will allow highly individualized diagnosis, prognosis and treatments for periodontal diseases. This personalized medicine approach will strengthen the power of the clinical oral examination and medical history assessments, providing patients with evidence-based, targeted risk care.
10.1111/prd.12103
Role of occlusion in periodontal disease.
Passanezi Euloir,Sant'Ana Adriana Campos Passanezi
Periodontology 2000
This article deals with establishing a new link between trauma from occlusion and periodontal pockets based on the know-how and background gradually developed. To provide a better understanding to the reader, a historical perspective is firstly presented. The main features on the controversy of the role played by trauma from occlusion on the physiologic behavior of the periodontal structures are shown, together with how deviations from the normal characteristics of this relationship itself affect the integrity of the periodontal tissues when or associated with dental biofilm in the presence or not of periodontal pockets have arisen. The literature provides evidence showing that the very first publication to establish a strong correlation between trauma from occlusion and periodontal pockets in humans was of Latin-American origin. However, subsequently, trauma from occlusion was mostly evaluated by an American group, followed by a Scandinavian group, yet with some contributions from the Latin-American group. Basically trauma from occlusion has been correlated with periodontal pockets in view of the fact that these would render the periodontal supporting tissues more amenable to the spread of inflammation of biofilm-related periodontal pockets. This would facilitate the fast deepening of periodontal pockets, influencing the generation of infrabony periodontal pockets or suprabony periodontal pockets that are deeper than in areas without trauma from occlusion. The factors related to these different behaviors are discussed. Several clinical cases are presented showing evidence that corroborates the possibility of an actual interrelationship between trauma from occlusion and periodontitis. Theoretical evaluations based on recent advances of the mechanisms involving molecular modulation in physiological and altered occlusal functions, as well as on research data, and evaluations from data of clinical cases, support the assumption that trauma from occlusion and periodontitis may embrace the unique pathologic condition of the associated lesion trauma from occlusion plus periodontitis or act independently even if both co-exist simultaneously in a particular case. The link between both conditions that was emphasized as definitively necessary in order for an associated lesion to develop is that both lesions, namely trauma from occlusion and periodontitis, occur in their destructive stage at exactly the same time. This involvement would explain why so many different data are presented in the literature and hopefully will shed some light for development of new methodologies of research. Clinical cases were selected to present a treatment philosophy on the subject.
10.1111/prd.12251
Targeting epigenetic mechanisms in periodontal diseases.
Barros Silvana P,Hefni Eman,Nepomuceno Rafael,Offenbacher Steven,North Kari
Periodontology 2000
Epigenetic factors are heritable genome modifications that potentially impact gene transcription, contributing to disease states. Epigenetic marks play an important role in chronic inflammatory conditions, as observed in periodontal diseases, by allowing microbial persistence or by permitting microbial insult to play a role in the so-called 'hit-and-run' infectious mechanism, leading to lasting pathogen interference with the host genome. Epigenetics also affects the health sciences by providing a dynamic mechanistic framework to explain the way in which environmental and behavioral factors interact with the genome to alter disease risk. In this article we review current knowledge of epigenome regulation in light of the multifactorial nature of periodontal diseases. We discuss epigenetic tagging in identified genes, and consider the potential implications of epigenetic changes on host-microbiome dynamics in chronic inflammatory states and in response to environmental stressors. The most recent advances in genomic technologies have placed us in a position to analyze interaction effects (eg, between periodontal disease and type 2 diabetes mellitus), which can be investigated through epigenome-wide association analysis. Finally, because of the individualized traits of epigenetic biomarkers, pharmacoepigenomic perspectives are also considered as potentially novel therapeutic approaches for improving periodontal disease status.
10.1111/prd.12231
Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data.
Nature communications
Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.
10.1038/s41467-019-10630-1
Gingival solitary chemosensory cells are immune sentinels for periodontitis.
Zheng Xin,Tizzano Marco,Redding Kevin,He Jinzhi,Peng Xian,Jiang Peihua,Xu Xin,Zhou Xuedong,Margolskee Robert F
Nature communications
Solitary chemosensory cells (SCCs) are epithelial sentinels that utilize bitter Tas2r receptors and coupled taste transduction elements to detect pathogenic bacterial metabolites, triggering host defenses to control the infection. Here we report that SCCs are present in mouse gingival junctional epithelium, where they express several Tas2rs and the taste signaling components α-gustducin (Gnat3), TrpM5, and Plcβ2. Gnat3 mice have altered commensal oral microbiota and accelerated naturally occurring alveolar bone loss. In ligature-induced periodontitis, knockout of taste signaling molecules or genetic absence of gingival SCCs (gSCCs) increases the bacterial load, reduces bacterial diversity, and renders the microbiota more pathogenic, leading to greater alveolar bone loss. Topical treatment with bitter denatonium to activate gSCCs upregulates the expression of antimicrobial peptides and ameliorates ligature-induced periodontitis in wild-type but not in Gnat3 mice. We conclude that gSCCs may provide a promising target for treating periodontitis by harnessing innate immunity to regulate the oral microbiome.
10.1038/s41467-019-12505-x
Dual Corona Vesicles with Intrinsic Antibacterial and Enhanced Antibiotic Delivery Capabilities for Effective Treatment of Biofilm-Induced Periodontitis.
Xi Yuejing,Wang Yue,Gao Jingyi,Xiao Yufen,Du Jianzhong
ACS nano
Periodontitis is a common disease caused by plaque biofilms, which are important pathogenic factors of many diseases and may be eradicated by antibiotic therapy. However, low-dose antibiotic therapy is a complicated challenge for eradicating biofilms as hundreds (even thousands) of times higher concentrations of antibiotics are needed than killing planktonic bacteria. Polymer vesicles may solve these problems effective antibiotic delivery into biofilms, but traditional single corona vesicles lack the multifunctionalities essential for biofilm eradication. In this paper, we aim to effectively treat biofilm-induced periodontitis using much lower concentrations of antibiotics than traditional antibiotic therapy by designing a multifunctional dual corona vesicle with intrinsic antibacterial and enhanced antibiotic delivery capabilities. This vesicle is co-assembled from two block copolymers, poly(ε-caprolactone)--poly(lysine--phenylalanine) [PCL--P(Lys--Phe)] and poly(ethylene oxide)--poly(ε-caprolactone) [PEO--PCL]. Both PEO and P(Lys--Phe) coronas have their specific functions: PEO endows vesicles with protein repelling ability to penetrate extracellular polymeric substances in biofilms ("stealthy" coronas), whereas P(Lys--Phe) provides vesicles with positive charges and broad spectrum intrinsic antibacterial activity. As a result, the dosage of antibiotics can be reduced by 50% when encapsulated in the dual corona vesicles to eradicate or biofilms. Furthermore, effective treatment has been achieved from a rat periodontitis model, as confirmed by significantly reduced dental plaque, and alleviated inflammation. Overall, this "stealthy" and antibacterial dual corona vesicle demonstrates a fresh insight for improving the antibiofilm efficiency of antibiotics and combating the serious threat of biofilm-associated diseases.
10.1021/acsnano.9b03237
DEL-1 promotes macrophage efferocytosis and clearance of inflammation.
Kourtzelis Ioannis,Li Xiaofei,Mitroulis Ioannis,Grosser Daniel,Kajikawa Tetsuhiro,Wang Baomei,Grzybek Michal,von Renesse Janusz,Czogalla Aleksander,Troullinaki Maria,Ferreira Anaisa,Doreth Christian,Ruppova Klara,Chen Lan-Sun,Hosur Kavita,Lim Jong-Hyung,Chung Kyoung-Jin,Grossklaus Sylvia,Tausche Anne Kathrin,Joosten Leo A B,Moutsopoulos Niki M,Wielockx Ben,Castrillo Antonio,Korostoff Jonathan M,Coskun Ünal,Hajishengallis George,Chavakis Triantafyllos
Nature immunology
Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.
10.1038/s41590-018-0249-1
Host defense against oral microbiota by bone-damaging T cells.
Tsukasaki Masayuki,Komatsu Noriko,Nagashima Kazuki,Nitta Takeshi,Pluemsakunthai Warunee,Shukunami Chisa,Iwakura Yoichiro,Nakashima Tomoki,Okamoto Kazuo,Takayanagi Hiroshi
Nature communications
The immune system evolved to efficiently eradicate invading bacteria and terminate inflammation through balancing inflammatory and regulatory T-cell responses. In autoimmune arthritis, pathogenic T17 cells induce bone destruction and autoimmune inflammation. However, whether a beneficial function of T-cell-induced bone damage exists is unclear. Here, we show that bone-damaging T cells have a critical function in the eradication of bacteria in a mouse model of periodontitis, which is the most common infectious disease. Bacterial invasion leads to the generation of specialized T17 cells that protect against bacteria by evoking mucosal immune responses as well as inducing bone damage, the latter of which also inhibits infection by removing the tooth. Thus, bone-damaging T cells, which may have developed to stop local infection by inducing tooth loss, function as a double-edged sword by protecting against pathogens while also inducing skeletal tissue degradation.
10.1038/s41467-018-03147-6
Periodontitis: from microbial immune subversion to systemic inflammation.
Hajishengallis George
Nature reviews. Immunology
Periodontitis is a dysbiotic inflammatory disease with an adverse impact on systemic health. Recent studies have provided insights into the emergence and persistence of dysbiotic oral microbial communities that can mediate inflammatory pathology at local as well as distant sites. This Review discusses the mechanisms of microbial immune subversion that tip the balance from homeostasis to disease in oral or extra-oral sites.
10.1038/nri3785
Prophylactic supplement with melatonin successfully suppresses the pathogenesis of periodontitis through normalizing RANKL/OPG ratio and depressing the TLR4/MyD88 signaling pathway.
Renn Ting-Yi,Huang Yung-Kai,Feng Sheng-Wei,Wang Hsiao-Wei,Lee Wei-Fang,Lin Che-Tong,Burnouf Thierry,Chen Li-You,Kao Pan-Fu,Chang Hung-Ming
Journal of pineal research
Periodontitis (PD) is an inflammatory disease characterized by gingival inflammation and resorption of alveolar bone. Impaired receptor activator of nuclear factor-kappa B ligand/osteoprotegerin (RANKL/OPG) signaling caused by enhanced production of pro-inflammatory cytokines plays an essential role in the pathogenesis of PD. Considering melatonin possesses significant anti-inflammatory property, this study aimed to determine whether prophylactic treatment with melatonin would effectively normalize RANKL/OPG signaling, depress toll-like receptor 4/myeloid differentiation factor 88 (TLR4/MyD88)-mediated pro-inflammatory cytokine activation, and successfully suppress the pathogenesis of PD. PD was induced in adult rats by placing the ligature at molar subgingival regions. Fourteen days before PD induction, 10, 50, or 100 mg/kg of melatonin was intraperitoneally injected for consecutive 28 days. Biochemical and enzyme-linked immunosorbent assay were used to detect TLR4/MyD88 activity, RANKL, OPG, interleukin 1β, interleukin 6, and tumor necrosis factor-α levels, respectively. The extent of bone loss, bone mineral intensity, and calcium intensity was further evaluated by scanning electron microscopy, micro-computed tomography, and energy-dispersive X-ray spectroscopy. Results indicated that high RANKL/OPG ratio, TLR4/MyD88 activity, and pro-inflammatory cytokine levels were detected following PD. Impaired biochemical findings paralleled well with severe bone loss and reduced calcium intensity. However, in rats pretreated with melatonin, all above parameters were successfully returned to nearly normal levels with maximal change observed in rats receiving 100 mg/kg. As prophylactic treatment with melatonin effectively normalizes RANKL/OPG signaling by depressing TLR4/MyD88-mediated pro-inflammatory cytokine production, dietary supplement with melatonin may serve as an advanced strategy to strengthen oral health to counteract PD-induced destructive damage.
10.1111/jpi.12464
Point-of-Care Periodontitis Testing: Biomarkers, Current Technologies, and Perspectives.
He Wanghong,You Minli,Wan Wanting,Xu Feng,Li Fei,Li Ang
Trends in biotechnology
Periodontitis has become one of the most universal chronic inflammatory diseases worldwide. Subclinical symptom progression, ultimately leading to permanent damage, calls for early diagnosis and long-term monitoring. However, traditional clinical diagnostic methods are complex and expensive, and cannot meet these requirements. Recently, with more biomarkers and the development of new technologies, various point-of-care testing (POCT) platforms have been developed for periodontitis diagnosis and monitoring. These are easy to perform, rapid, low-cost, and are perfectly suited for high-frequency diagnosis of periodontitis at the point-of-care (POC). We summarize existing biomarkers of different periodontitis stages and recent developed POCT platforms (including lab-on-a-chip, paper-based platforms, and chairside tests), discuss their existing challenges and future potential, and provide some inspiration and guidelines for future POC periodontitis testing.
10.1016/j.tibtech.2018.05.013
Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response.
Hajishengallis George
Trends in immunology
Recent studies have uncovered novel mechanisms underlying the breakdown of periodontal host-microbe homeostasis, which can precipitate dysbiosis and periodontitis in susceptible hosts. Dysbiotic microbial communities of keystone pathogens and pathobionts are thought to exhibit synergistic virulence whereby not only can they endure the host response but can also thrive by exploiting tissue-destructive inflammation, which fuels a self-feeding cycle of escalating dysbiosis and inflammatory bone loss, potentially leading to tooth loss and systemic complications. Here, I discuss new paradigms in our understanding of periodontitis, which may shed light into other polymicrobial inflammatory disorders. In addition, I highlight gaps in knowledge required for an integrated picture of the interplay between microbes and innate and adaptive immune elements that initiate and propagate chronic periodontal inflammation.
10.1016/j.it.2013.09.001
A dysbiotic microbiome triggers T17 cells to mediate oral mucosal immunopathology in mice and humans.
Dutzan Nicolas,Kajikawa Tetsuhiro,Abusleme Loreto,Greenwell-Wild Teresa,Zuazo Carlos E,Ikeuchi Tomoko,Brenchley Laurie,Abe Toshiharu,Hurabielle Charlotte,Martin Daniel,Morell Robert J,Freeman Alexandra F,Lazarevic Vanja,Trinchieri Giorgio,Diaz Patricia I,Holland Steven M,Belkaid Yasmine,Hajishengallis George,Moutsopoulos Niki M
Science translational medicine
Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, we demonstrate an expansion of resident memory T helper 17 (T17) cells in human periodontitis. Phenocopying humans, T17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral T17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)-dependent manner, periodontitis-associated expansion of T17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. T17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of T17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in T17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human T17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Our study highlights distinct functions of T17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.
10.1126/scitranslmed.aat0797
Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
Moutsopoulos Niki M,Konkel Joanne,Sarmadi Mojgan,Eskan Mehmet A,Wild Teresa,Dutzan Nicolas,Abusleme Loreto,Zenobia Camille,Hosur Kavita B,Abe Toshiharu,Uzel Gulbu,Chen Wanjun,Chavakis Triantafyllos,Holland Steven M,Hajishengallis George
Science translational medicine
Leukocyte adhesion deficiency type I (LAD-I), a disease syndrome associated with frequent microbial infections, is caused by mutations on the CD18 subunit of β₂ integrins. LAD-I is invariably associated with severe periodontal bone loss, which historically has been attributed to the lack of neutrophil surveillance of the periodontal infection. We provide an alternative mechanism by showing that the cytokine interleukin-17 (IL-17) plays a major role in the oral pathology of LAD-I. Defective neutrophil recruitment in LAD-I patients or in LFA-1 (CD11a/CD18)-deficient mice--which exhibit the LAD-I periodontal phenotype--was associated with excessive production of predominantly T cell-derived IL-17 in the periodontal tissue, although innate lymphoid cells also contributed to pathological IL-17 elevation in the LFA-1-deficient mice. Local treatment with antibodies to IL-17 or IL-23 in LFA-1-deficient mice not only blocked inflammatory periodontal bone loss but also caused a reduction in the total bacterial burden, suggesting that the IL-17-driven pathogenesis of LAD-I periodontitis leads to dysbiosis. Therefore, our findings support an IL-17-targeted therapy for periodontitis in LAD-I patients.
10.1126/scitranslmed.3007696
Undetected Dysglycemia Is an Important Risk Factor for Two Common Diseases, Myocardial Infarction and Periodontitis: A Report From the PAROKRANK Study.
Norhammar Anna,Kjellström Barbro,Habib Natalie,Gustafsson Anders,Klinge Björn,Nygren Åke,Näsman Per,Svenungsson Elisabet,Rydén Lars
Diabetes care
OBJECTIVE:Information on the relationship among dysglycemia (prediabetes or diabetes), myocardial infarction (MI), and periodontitis (PD) is limited. This study tests the hypothesis that undetected dysglycemia is associated with both conditions. RESEARCH DESIGN AND METHODS:The PAROKRANK (Periodontitis and Its Relation to Coronary Artery Disease) study included 805 patients with a first MI and 805 matched control subjects. All participants without diabetes (91%) were examined with an oral glucose tolerance test. Abnormal glucose tolerance (AGT) (impaired glucose tolerance or diabetes) was categorized according to the World Health Organization. Periodontal status was categorized from dental X-rays as healthy (≥80% remaining alveolar bone height), moderate (79-66%), or severe (<66%) PD. Odds ratios (ORs) and 95% CIs were calculated by logistic regression and were adjusted for age, sex, smoking, education, marital status, and explored associated risks of dysglycemia to PD and MI, respectively. RESULTS:AGT was more common in patients than in control subjects (32% vs. 19%; < 0.001) and was associated with MI (OR 2.03; 95% CI 1.58-2.60). Undetected diabetes was associated with severe PD (2.50; 1.36-4.63) and more strongly in patients (2.35; 1.15-4.80) than in control subjects (1.80; 0.48-6.78), but not when categorized as AGT (total cohort: 1.07; 0.67-1.72). Severe PD was most frequent in subjects with undetected diabetes, and reversely undetected diabetes was most frequent in patients with severe PD. CONCLUSIONS:In this large case-control study previously undetected dysglycemia was independently associated to both MI and severe PD. In principal, it doubled the risk of a first MI and of severe PD. This supports the hypothesis that dysglycemia drives two common diseases, MI and PD.
10.2337/dc19-0018
Periodontal diseases.
Kinane Denis F,Stathopoulou Panagiota G,Papapanou Panos N
Nature reviews. Disease primers
Periodontal diseases comprise a wide range of inflammatory conditions that affect the supporting structures of the teeth (the gingiva, bone and periodontal ligament), which could lead to tooth loss and contribute to systemic inflammation. Chronic periodontitis predominantly affects adults, but aggressive periodontitis may occasionally occur in children. Periodontal disease initiation and propagation is through a dysbiosis of the commensal oral microbiota (dental plaque), which then interacts with the immune defences of the host, leading to inflammation and disease. This pathophysiological situation persists through bouts of activity and quiescence, until the affected tooth is extracted or the microbial biofilm is therapeutically removed and the inflammation subsides. The severity of the periodontal disease depends on environmental and host risk factors, both modifiable (for example, smoking) and non-modifiable (for example, genetic susceptibility). Prevention is achieved with daily self-performed oral hygiene and professional removal of the microbial biofilm on a quarterly or bi-annual basis. New treatment modalities that are actively explored include antimicrobial therapy, host modulation therapy, laser therapy and tissue engineering for tissue repair and regeneration.
10.1038/nrdp.2017.38
Effect of orthodontic treatment on the periodontal tissues.
Antoun Joseph S,Mei Li,Gibbs Kelsi,Farella Mauro
Periodontology 2000
Reduced periodontal support is a challenge that clinicians often face during rehabilitation of compromised dentition. The close and intricate relationship between the periodontal tissues and the processes of tooth movement suggest that adjunct orthodontic therapy may play an important role in overcoming these problems. On the other hand, excessive movement of teeth beyond the anatomic boundaries of the alveolar process is commonly believed to contribute to further destruction of the periodontal tissues. This review evaluates the clinical effects of various orthodontic tooth movements on the surrounding periodontal soft tissues and alveolar bone. Another objective was to identify possible patient and treatment-related factors that may influence the response of periodontal tissue to specific orthodontic treatments. Particular emphasis is placed on specific tooth movements, such as extrusion, intrusion, space closure and arch expansion. Limitations of current research are also highlighted and discussed.
10.1111/prd.12194