Background
Materials and methods
Reporting format
Population (P), intervention (I), comparison (C), outcomes (O), and study design (PICOS)
Search strategy
Electronic search
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The Cochrane Central Register of Controlled Trials (CENTRAL) (up to October 1st, 2020);
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MEDLINE (PubMed) (1946 to September Week 4, 2020);
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Ovid MEDLINE (in-process & other non-indexed citations, October 1st, 2020);
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Ovid Embase (1974 to October 1st, 2020);
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LILACS (1982 to October 1st, 2020)
Unpublished literature search
Manual search
Study selection
Data collection
Quality assessment
Data analysis
Heterogeneity
Assessment of reporting bias
Subgroup analyses/ sensitivity analysis
Unit of analysis issues
Results
Description of studies
Authors Study design | Study title | Sample size/sex/age | Health status/ drug intake | Type of orthodontic treatment | Observation period | Method of GCF collection | Tooth site of collection | Control group | Biomarker assessed |
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Castroflorio et al. 2017 [16] RCT/ Split mouth | Biochemical markers of bone metabolism during early orthodontic tooth movement with aligners | 10 (5 F, 5 M) Mean age 22.3 ± 3.3 years | No anti-inflammatory or antibiotic therapy in the previous 6 months | Aligners (Invisalign) | • 1 h before placement • 1 h after aligner placement • 7 days after • 21 days after | Periopaper strips | Distobuccal and mesiobuccal sites of second molar under distalization | Contralateral second molar | Osteopontin (OPN) |
Al Swafeeri et al. 2015 [17] RCT/ Split mouth | Crevicular alkaline phosphatase activity during the application of two patterns of orthodontic forces | 12 (7 F, 5 M) Mean age 17.5 ± 2.4 years | Healthy medical status/ drug intake not reported | Fixed appliances/ extraction of 1st premolar/ distalization of canine | Baseline (before the activation) and every week for 3 weeks after the initial activation | Paper strips | Constant orthodontic force 150cN for 3 weeks mesial side of maxillary canine and distal site of maxillary first molar | Increasing orthodontic force 50 cN throughout the first week, 100 cN throughout the second week and 150 cN the third week. | Alcaline phosphatase (ALP) |
Wahab et al. 2014 [18] RCT/ Split mouth | Enzyme activity profiles and ELISA analysis of biomarkers from human saliva and GCF during orthodontic tooth movement using self-ligating brackets | 19 (14 F, 5M) Between 16 and 28 years old | No drug intake during the study or 1 month before | Fixed appliances/ extraction of 1st premolar/ distalization of canine | Baseline and every week for 5 weeks after the initial application | Periopaper strips | 100-g force on tested canine | 150-g force on contralateral canine | Tartrate-resistant acid phosphatase (TRAP) Alkaline Phosphatase (ALP) |
Barbieri et al. 2013 [19] RCT/ Split mouth | Biochemical markers of bone metabolism in GCF during early orthodontic treatment | 10 (5 F, 5 M) Aged from 22–29 years | No anti-inflammatory or antibiotic therapy in the previous 6 months | Separators | • Baseline • 24 h • 7 days after the placement of separators | Periopaper strips | Mesiobuccal and distobuccal sides of tested molars | Mesiobuccal and mesiolingual of contralateral molars | Osteopontin (OPN) |
Kalha et al. 2010 [20] RCT | Redefining orthodontic space closure: sequential repetitive loading of the periodontal ligament—a clinical study | 10 (6 F, 4 M) Mean age 20.6 ± 3.2 years | Healthy medical status/ drug intake not reported | Fixed appliances/ extraction of 1st premolar/ distalization of canine | • 1 h before • 1 h after the activation • On days 7, 14, 21, and 28 | Sterile paper strips | Distogingival margin of the four canines (5 patients with hycon-screw) | Distogingival margin of the four canines (5 patients with active tie-backs) | Alcaline phosphatase (ALP) |
Bitra et al. 2017 [21] Prospective | Gingival crevicular fluid turnover markers in premenopausal vs. postmenopausal women receiving orthodontic treatment | 25 F Postmenopausal (mean age 57 years) | No drug intake 1 month before the study | Fixed appliances | • Baseline • 24 h | Periopaper strips | NA | 25 F Premenopausal (mean age > 30 years) | Osteopontin (OPN) |
Smuthkochorn et al. 2017 [22] Prospective | Gingival crevicular fluid bone turnover biomarkers: how postmenopausal women respond to orthodontic activation | 16 F Postmenopausal (mean age 63 years) | No drug intake 1 month before the study | Fixed appliances | • Baseline • 24 h | Periopaper strips | 2 Anterior and 2 posterior teeth | 12 F Premenopausal (mean age 32 years) | Osteopontin (OPN) |
Yang et al. 2014 [23] Prospective | Preliminary study on the best-exerted force chance in the female menstrual cycle | 12 F Aged 18–28 years | Not reported | Fixed appliances/ extraction of 1st premolar/ distalization of canine | • Baseline • 15 days • 30 days • 45 days after | Paper strips | Distal site of canine that is distalized | NA | Osteocalcin (OC) |
Alfaqeeh et al. 2011 [24] Prospective | Osteocalcin and N-telopeptides of type I collagen marker levels in gingival crevicular fluid during different stages of orthodontic tooth movement | 20 (10 F, 10 M) Aged 15–25 years | No regimen or antibiotic therapy the last 3 months | Fixed appliances/ extraction of 1st premolar/ distalization of canine | • 1 h, 1 day, 7, 14, and 21 days after application | Periopaper strips | Buccal and palatal, mesial, and distal sites of tested canines | Contralateral canine with fixed appliance but not activated | Osteocalcin (OC) N-telopeptides (NTX) |
Batra et al. 2006 [25] Prospective | Alkaline phosphatase activity in gingival crevicular fluid during canine retraction | 10 F Aged 12–21 years | Healthy medical status/ drug intake not reported | Healthy medical status/ drug intake not reported | • Baseline (before the activation) • Immediately after • 1 day • 7 days • 14 days • 21 days after | Micropipettes of 1 μl capacity | Mesial and distal sites of tested canine | Contralateral canine (no forced applied) | Alcaline phosphatase (ALP) |
Isik et al. 2005 [26] Prospective | Bone marker levels in GCF during orthodontic intrusive tooth movement. A preliminary study. | 9 (5 F, 4 M) Mean age: 14.6 ± 2.08 years | Not reported | Fixed appliances/ intrusion of 1st premolar | • 1 h • 24 h • 168 h after 1st activation • 22nd day • 28th day after 2nd activation | Periopaper strips | Mesiobuccal, distobuccal, palatinal crevicular region of maxillary first premolars | NA | Deoxypyridinoline (DPD) Osteocalcin (OC) N-telopeptide (NTX) Bone alkaline phosphatase (BALP) |
Perinetti et al. 2004 [27] Prospective | Longitudinal monitoring of sub-gingival colonization by Actinobacilllus actinomycetemcomitans and crevicular alkaline phosphatase and asparate aminotransferase activities around orthodontically treated teeth | 21 (11 F, 10 M) Mean age 17.1 ± 3.3 years | No drug intake 1 month before the study | Fixed appliances/ extraction of 1st premolar/ distalization of canine | • Baseline • On day 28 | Standardized sterile paper strips | Mesial and distal sites of experimental canine | Mesial and distal sites of contralateral and antagonist canine | Alcaline phosphatase (ALP) |
Perinetti et al. 2002 [28] Prospective | Alkaline phosphatase activity in GCF during human orthodontic tooth movement | 16 (10 F, 6 M) Mean age 15.5 ± 3.5 years | No drug intake 1 month before the study | Fixed appliances/ distal retraction of 1st molar | • 1h after activation • 1, 2, 3, and 4 weeks after | Sterile paper strips | Mesial & distal sites of maxillary 1st molar | Contralateral molar with fixed appliance but not activated and antagonist molar without appliance | Alcaline phosphatase (ALP) |
Griffiths et al. 1998 [29] Prospective | Evaluation of osteocalcin and pyridinium crosslinks of bone turnover in gingival crevicular fluid during different stages of orthodontic treatment | 20 (12 F, 8 M) Mean age 13.5 years | Not reported | Fixed appliances/ extraction of 1st premolar/ distalization of canine | T1 prior to orthodontic appliance, T2 post appliance fit but prior to activation, T3 during active retraction, T4 during retention | Paper strips | Distal surface of maxillary canines | NA | Osteocalcin (OC) Pyridinoline (PYD) Deoxypyridinoline (DPD) |
Insoft et al. 1996 [30] Cross-sectional | The measurement of acid and alkaline phosphatase in GCF during orthodontic movement | 30 (sex NA) Aged 8–12 years | Not reported | 3 Groups: 1) Bionator 2) Headgear 3) Control group | One collection time point | Periopaper strips | Mesial and distal sites of 1st molars | Control group | Acid and alcaline phosphatase (ALP) |
Quality assessment
RCTs
Author/ year | Bias arising from the randomization process | Bias due to deviations from the intended interventions | Bias due to missing outcome data | Bias in measurement of the outcome | Bias in selection of the reported result | Overall bias | |
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1 | Castroflorio et al. 2017 [16] | Authors' judgement: high risk Support for judgement: no details provided about randomization and allocation concealment processes | Authors’ judgement: some concerns Support for judgement: carers and trial personnel aware of participants’ assigned intervention | Authors’ judgement: low risk Support for judgement: all outcome data available | Authors’ judgement: low risk Support for judgement: outcome assessors blinded | Authors’ judgement: low risk Support for judgement: reported outcome data unlikely to have been selected | Authors’ judgement: high risk |
2 | Alswafeeri et al. 2015 [17] | Authors’ judgement: some concerns Support for judgement: randomization process adequate but allocation concealment process not described | Authors’ judgement: some concerns Support for judgement: carers and trial personnel aware of participants’ assigned intervention | Authors’ judgement: low risk Support for judgement: all outcome data available | Authors’ judgement: high risk Support for judgement: outcome assessors not blinded | Authors’ judgement: low risk Support for judgement: reported outcome data unlikely to have been selected | Authors’ judgement: high risk |
3 | Wahab et al. 2014 [18] | Authors’ judgement: high risk Support for judgement: quasi-randomization process and allocation concealment process not described | Authors' judgement: some concerns Support for judgement: carers and trial personnel aware of participants’ assigned intervention | Authors’ judgement: low risk Support for judgement: all outcome data available | Authors’ judgement: high risk Support for judgement: outcome assessors not blinded | Authors’ judgement: low risk Support for judgement: reported outcome data unlikely to have been selected | Authors’ judgement: high risk |
4 | Barbieri et al. 2013 [19] | Authors’ judgement: high risk Support for judgement: no details provided about randomization and allocation concealment processes | Authors’ judgement: some concerns Support for judgement: carers and trial personnel aware of participants’ assigned intervention | Authors’ judgement: low risk Support for judgement: all outcome data available | Authors’ judgement: high risk Support for judgement: outcome assessors not blinded | Authors’ judgement: low risk Support for judgement: reported outcome data unlikely to have been selected | Authors’ judgement: high risk |
5 | Kalha et al. 2010 [20] | Authors’ judgement: high risk Support for judgement: no details provided about randomization and allocation concealment processes | Authors’ judgement: some concerns Support for judgement: carers and trial personnel aware of participants’ assigned intervention | Authors’ judgement: low risk Support for judgement: all outcome data available | Authors’ judgement: high risk Support for judgement: outcome assessors not blinded | Authors’ judgement: low risk Support for judgement: reported outcome data unlikely to have been selected | Authors’ judgement: high risk |
Non-RCTs
Author/year of publication | Bias due to confounding | Bias in selection of participants into the study | Bias in classification of interventions | Bias due to deviations from intended interventions | Bias due to missing data | Bias in measurement of outcomes | Bias in selection of the reported result | Overall |
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Bitra et al. 2017 [21] | Low risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Moderate risk |
Smuthkochorn et al. 2017 [22] | Low risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Moderate risk |
Yang et al. 2014 [23] | Serious risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Serious risk |
Alfaqeeh et al. 2011 [24] | Low risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Moderate risk |
Batra et al. 2006 [25] | Critical risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Critical risk |
Isik et al. 2005 [26] | Critical risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Critical risk |
Perinetti et al. 2004 [27] | Low risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Moderate risk |
Perinetti et al. 2002 [28] | Low risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Moderate risk |
Griffiths et al. 1998 [29] | Serious risk | Low risk | Low risk | Low risk | Low risk | Moderate risk | Low risk | Serious risk |
Cross-sectional studies
Author/year of publication | Selection | Comparability | Outcome | Overall | |||
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Representativeness of the sample | Nonrespondents | Ascertainment of the exposure | Assessment of the outcome | Statistical test | |||
Insoft el al. 1996 [30] | 1 star | - | 1 star | - | 2 stars | - | 4/7 stars |
Quantitative synthesis of the included studies
Authors Study design | Changes in GCF/time point biomarkers | Measurement unit | Biological consequence | Clinical significance |
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Castroflorio et al. 2017 [16] RCT/ Split mouth | OPN test sites: T0: 28.1 ± 15.5 T1: 35.6 ± 19.9 T2: 35.2 ± 18.5 T3: 46.0 ± 22.7 Control sites: T0: 31.2 ± 15.7 T1: 26.2 ± 13.6 T2: 32.9 ± 14.5 T3: 31.3 ± 14.7 | ng/μl | Invisalign aligners release an initial force of about 1 N on distalizing a maxillary molar. This force delivery produces an increased concentration of OPN at tension sites. | Not reported |
Al Swafeeri et al. 2015 [17] RCT/ Split mouth | Constant force group Canine A0 9.16 ± 5.22 A1 12.10 ± 7.86 A2 23.19 ± 9.83 A3 21.73 ± 12.16 Molar B0 7.19 ± 6.26 B1 9.32 ± 6.57 B2 21.23 ± 9.70 B3 13.95 ± 8.05 Gradually increasing force group Canine C0 10.66 ± 6.99 C1 19.50 ± 12.41 C2 35.73 ± 10.10 C3 20.22 ± 12.88 Molar D0 5.70 ± 6.39 D1 11.42 ± 5.05 D2 18.74 ± 5.48 D3 27.03 ± 9.32 | IU/μl | The use of a gradually increasing orthodontic force could induce an increase in osteoblastic activity during initial stage of orthodontic tooth movement compared with that induced by a relatively constant orthodontic force. | Gradually increasing force systems could be recommended for clinical use in orthodontics. |
Wahab et al. 2014 [18] RCT/ Split mouth | The LDH activity for 100 g of force exhibited significant differences at weeks 2 and 3, while the activities of AST and TRAP were significantly different from control values at week 5. For 150 g of force, there were significant differences in the LDH activities at weeks 3, 4, and 5 but no significant differences in the TRAP activities. | U/mg | The activity of LDH in the GCF increased significantly at 2 and 3 weeks for 100 g of force and at 1, 2, 3 weeks for 150 g of force. These findings showed that inflammation occurred earlier when 150 g of force was applied, which might induce a painful sensation that starts earlier and lasts longer. The 150-g force is a heavy force, and it produced significant AST-specific activity or necrosis earlier than the application of 100-g force. TRAP activity shows no differences for 150g of force throughout the treatment, this finding indicates that heavy force results in undermining resorption | The movements of the canines showed no significant differences between 100 and 150 g of force throughout the 5 weeks of treatment. LDH, TRAP, and AST from the GCF may be used as biomarkers for monitoring orthodontic tooth movement |
Barbieri et al. 2013 [19] RCT/ Split mouth | At the control sites there were no differences between the values recorded for buccal/palatal sites or between values recorded at different visits. In contrast, the concentration of OPG significantly decreased at the compression site by 24 h and the amount, and concentration of RANK differed significantly between control, compression, and tension sites after 7 days. A significant increase in absolute TGF-β1 levels was also detected at the compression site versus the control and tension sides after 7 days. | pg/ml or pg | Both increased expression of bone resorptive mediators (RANK, TGFβ1) and decreased expression of a bone-forming mediator (OPG) on the compression side were detected. | Bone metabolism is affected by application of force to the teeth by elastic separators. |
Kalha et al. 2010 [20] RCT | There was a 200% increase in the alkaline phosphatase level between days 21 and 28 in the active tie-back group at all sites, while that in the retraction screw group was more than 260%. | IU/l | Alkaline phosphatase levels increased more in the Hycon-screw group between 14 and 28 days. That can be explained by the fact that elastomeric modules generally lose 50–70% of their initial force after 3 weeks of loading. | Sequential repetitive loading of the periodontal ligament with small and controlled activations is effective for space closure as indicated by a significantly higher increase in the GCF alkaline phosphatase level if a retraction screw is used instead of active tie-backs. |
Bitra et al. 2017 [21] Prospective | OPN: Baseline: Premenopausal 241.52 pg/μl and postmenopausal 317.15 pg/μl 24 h after: Premenopausal 540.97 pg/μl and postmenopausal 492.73 pg/μl | pg/μl | No difference is observed in GCF levels of OPN while comparing the mean premenopausal and postmenopausal women. | Orthodontic treatment appears to be equally safer for both premenopausal and postmenopausal subjects. |
Smuthkochorn et al. 2017 [22] Prospective | OPN Premenopausal T0 238.92 ± 66.88 T1 531.72 ± 465.98 Postmenopausal T0 323.26 ± 157.27 T1 489.61 ± 280.38 | pg/μl | There are OPN baseline differences in GCF bone turnover markers in premenopausal vs. postmenopausal groups. | Reactions to orthodontic activation are not significantly different between the groups. |
Yang et al. 2014 [23] Prospective | The OCN levels were significantly higher in the ovulation period group than in the menstrual period group (P < 0.05). | pg/nl | The OCN levels affected from the menstrual period | Exerted force on teeth during the menstrual period may promote rapid tooth movement. |
Alfaqeeh et al. 2011 [24] Prospective | At the experiment sites, the GCF NTX level steadily increased from day 7 to day 21. The control side did not show any statistically significant variation throughout the observation period. The OC levels in the GCF showed no difference at the control site. At the experimental site where pressure was applied, the levels of OC showed higher values on day 7 and onward. | nmol of bone collagen equivalents per litre (nmol BCE/L) | Statistically significant changes in NTX and OC levels on days 7, 14, and 21 when we compared the experimental and control sides. The peak in all activity of the variables occurred on day 14 after retraction. | The GCF NTX and OC markers showed statistically significant increases in the levels on days 14 and 21 at the side that had orthodontic tooth movement. |
Batra et al. 2006 [25] Prospective | Significant changes on ALP activity on 7, 14, and 21 days at mesial & distal sides compared with experimental and control teeth | IU/l | The peak in enzyme activity occurred on the 14th day of initiation of retraction followed by a significant fall in activity. | ALP activity could possibly be a biological indicator of the activity in the periodontium and orthodontic tooth movement. |
Isik et al. 2005 [26] Prospective | OC: Initial 500.22 ± 360.67 1 h 500.22 ± 360.67 1 day 451.86 ± 330.07 7 days 505.85 ± 236.15 22 days 326.98 ± 240.58 28 days 309.22 ± 173.85 BALP: Initial 102.08 ± 63.62 1 h 91.82 ± 65.07 1 day 57.39 ± 33.48 7 days 75.14 ± 49.56 22 days 44.60 ± 24.17 28 days 52.35 ± 27.10 DPD: Initial 1.54 ± 0.57 1 h 1.16 ± 0.66 1 day 0.95 ± 0.56 7 days 0.85 ± 0.50 22 days 0.52 ± 0.12 28 days 0.75 ± 0.48 NTX: Not detectable | pmol/mg | DPD, OC, and BALP values decrease with force application. | The applied forces may have caused the hyalinization process and decrease of bone turnover. |
Perinetti et al. 2004 [27] Prospective | ALP: Test tooth: Mesial • T0 60 ± 36 • 28 days 159 ± 83 Distal • T0 52 ± 18 • 28 days 102 ± 43 Contralateral tooth: Mesial • T0 59 ± 33 • 28 days 80 ± 31 Distal • T0 61 ± 23 • 28 days 81 ± 26 Antagonist tooth: Mesial • T0 46 ± 26 • 28 days 47 ± 24 Distal • T0 43 ± 19 • 28 days 44 ± 24 | mU/sample | GCF ALP is sensitive in distinguishing between tension and compression sites on day 28. | Factors as clinical condition changes may affect the enzymatic activities. GCF ALP should be considered as a reliable biomarker of tissue responses to orthodontic treatment only when oral hygiene is kept under control. |
Perinetti et al. 2002 [28] Prospective | Distalized molar: Baseline 60 ± 33 1 h 79 ± 53 7 days 138 ± 95 14 days 160 ± 82 21 days 147 ± 101 28 days 153 ± 84 Contralateral molar: Baseline 43 ± 25 1 h 69 ± 52 7 days 74 ± 44 14 days 90 ± 52 21 days 73 ± 43 28 days 75 ± 38 Antagonist molar: Baseline 50 ± 24 1 h 46 ± 30 7 days 45 ± 18 14 days 50 ± 15 21 days 37 ± 21 28 days 46 ± 23 | mU/sample | High levels of ALP activity have been described after 7 days when bone deposition begins, greater in dental sites of tension than in sites of compression. | Increased ALP activity in teeth-bearing orthodontic appliances might be due to gingival inflammation independently of clinically detectable movement. |
Griffiths et al. 1998 [29] Prospective | PYD, DPD not detected OC showed variation between subjects and within subject at different stages | pg/ml or pg | OC has been shown to be present in the GCF of adolescents, but there was a wide variation between subjects in the amount and concentration. | GCF volume is the most sensitive indicator of gingival inflammation. |
Insoft et al. 1996 [30] Cross-sectional | Acid phosphatase activities were constantly higher in all groups. There was a substantial peak in acid phosphatase at month 11, followed by a smaller second peak at month 16, and an even smaller at month 19. ALP demonstrated a large first peak at month 15 and a second smaller at month 17.5. | sigma units/min | Changes in GCF phosphatase activities during orthodontic tooth movement may reflect bone remodeling. | ALP in GCF is partly influenced by gingival inflammation. |
Outcomes | Quality of the evidence (GRADE) | No. of participants (studies) | Comments |
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Alcaline phosphatase (ALP) | ⊕OOO Very low a Due to inconsistency and indirectness | 118 (6) | |
Osteopontin (OPN) | ⊕OOO Very low b Due to indirectness | 20 (2) | 2 studies were excluded because they had different comparison groups |
Osteocalcin (OC) | ⊕OOO Very low c Due to indirectness | 32 (2) | 2 studies excluded due to the lack of comparison group |
N-telopeptides (NTX) | ⊕⊕OO Low d | 20 (1) | One study was excluded due to the lack of comparison group |
Tartate-resistant acid phosphatase (TRAP) | ⊕OOO Very low e | 19 (1) |
Qualitative synthesis of the included studies
Type of orthodontic intervention
Biomarkers assessed
Discussion
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Isolation of the sites of GCF collection (most often with cotton rolls),
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Method of GCF collection (paper strips, micropipettes),
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Depth insertion of paper strips,
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One single or repeated measurements,
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Time that paper strips remain inside the gingival sulcus (e.g. 30 or 60 s),
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Time slot of the day for the collection,
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Incubation solution which was used for the GCF sample (e.g. phosphate-buffered saline),
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Biochemical assay used for the analysis of biomarkers (e.g. Elisa, Western blot).
Strengths & limitations
Implications for research
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The diversity in expressing the released quantities and the use of different units hindered this review. To allow unequivocal interpretation and comparison between different studies, it is recommended to express quantitative release data in standardized units. The use of internationally agreed decision limits and target values for these markers requires that measurements are universally comparable. Standardization and establishment of a reference system for the BTMs is the route to achieve this [36, 37].
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The limits for detection/quantification of each analyzed eluate are essential for the interpretation of the results, and should therefore always be mentioned. Compounds that could not be detected, may still have been released, but in concentrations below the detection limit. It would thus not be correct to assume that they are not released in the GCF.
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Contamination may lead to false-positive detection of compounds, and great care should be taken to avoid any contamination. All studies should report if the necessary measures were taken in order for contamination from saliva to be avoided.
Implications for clinical practice
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Too often, the materials and methods failed to mention necessary information about the GCF collection procedure. Information such as the volume of incubation solution, the percentage of solvent in case of dilutions, the pH of the solution, and the brand of paper strips should be always stated.
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As BTMs may show significant responses to the orthodontic treatment, their response to treatment may allow the best choice of a possible future chemical or pharmacological agent. They may also help with the proof of principle and help establish the mechanism of action. This could potentially alter the actual orthodontic treatment modalities.