Curriculum Vitae. Name: Ahmad Hammami Hawasli, BDS, MS. Contact information: Degree and Date to be conferred: M.S.

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1 Curriculum Vitae Name: Ahmad Hammami Hawasli, BDS, MS Contact information: Degree and Date to be conferred: M.S., 2015 Collegiate Institutions Attended: University of Maryland, Baltimore School of Dentistry M.S. in Biomedical Sciences Teshreen VA Hospital, Syria Certificate in Oral-Maxillo-Facial Surgery October 6 th University, Egypt School of Dentistry B.D.S Professional Positions Held: Resident University of Maryland, Baltimore School of Dentistry Current Committee Memberships: Dr. Mark Reynolds Dr. Mary-Elizabeth Aichelmann-Reidy Dr. Glen Minah

2 Title of thesis: The Effect and Predictability of Root Surface Biomodification on Periodontal Surgical Outcome: A Systematic Review Ahmad Hammami Hawasli, Master of Science, 2015 Thesis Directed by: Dr. Mary-Elizabeth Aichelmann-Reidy Recent systematic reviews concluded root surface bio-modifiers provide no benefit of clinical significance to root coverage and chronic periodontitis treatments. The purpose of this systematic review was to determine whether chemical root surface biomodification (CRSB) improves the predictability of attaining positive clinical results following chronic periodontitis treatment or root coverage procedures. Material and Methods: A literature search for all randomized controlled human clinical trials of periodontal surgical treatment with CRSB was performed. Mean change in clinical measurements and the mean coefficient of variability for treatment outcomes were analyzed. Results: 19 randomized controlled trials were identified. No significant differences were found between treatment groups with and without CRSB, regardless of treatment type. Conclusion: The addition of CRSB to treatment of chronic periodontitis or root coverage procedures produced no significant change in mean clinical outcomes and did not improve the predictability of periodontal surgical clinical outcomes.

3 The Effect and Predictability of Root Surface Biomodification on Periodontal Surgical Outcome: A Systematic Review By Ahmad Hammami Hawasli Thesis submitted to the Faculty of the Graduate School of the University of Maryland, Baltimore in partial fulfillment of the requirements for the degree of Master of Science 2015

4 Table of Contents Chapter...Page Introduction....1 I. Tetracycline..2 II. Citric acid..3 III. EDTA...4 IV: What are the most effective concentrations and ph of root biomodifiers?...5 V. Are there negative effects of citric acid on root surfaces?.. 7 Purpose...8 Materials and Methods.9 Search Protocol. 9 Selection Criteria Data Collection and Analysis.. 11 Results..14 Summary of findings Discussion Conclusions...28 References iii

5 List of Tables Table 1. The Basis for Strength of Recommendation from JEBDT...12 Table 2. The Basis for grading the quality of evidence from JEBDT...12 Table 3. List of Excluded Studies Table 4. Study Characteristics...18 Table 5. Means of clinical outcomes of different treatment modalities 21 iv

6 List of Figures Figure 1. Data flowchart depicting initial search results to final included studies.13 v

7 List of Abbreviations 1-PRT: Pocket Reduction Therapies 2-GTR: Guided Tissue Regeneration 3-RC: Root Coverage 4-PD: Pocket Depth 5-CAL: Clinical Attachment Loss 6-REC, GR: Gingival Recession 7-CA: Citric Acid 8-TC, TET: Tetracycline 9-EDTA: Ethylene-diamine tetra-acetic acid 10-CRSB: Chemical Root Surface Biomodifications 11-SD: Standard of Deviation: 12-CV: Coefficient of Variation 13-RCT: Randomized Clinical Trial 14: C: Control group 15: T: Test group vi

8 Introduction: The primary etiological factor in periodontal disease is bacterial plaque. This results in an inflammatory lesion in the gingival tissues leading to progressive destruction of the supporting periodontal tissues. Periodontitis-affected root surfaces are hypermineralized and contaminated with cytotoxic and other biologically active substances, such surfaces are not biocompatible with adjacent periodontal cells, the proliferation of which is pivotal for periodontal wound healing (18). The main objective of periodontal therapy includes tissue repair by producing a biocompatible root surface. Based on the concept that periodontal disease begins by the interaction of the microbiological challenge and the host response against this injury, the healing of periodontal tissues may depend on the type of planned periodontal therapy. Some authors believe that conservative therapy, which includes oral hygiene instructions and root planning, is enough to transform the root surface into a biocompatible one (13). However, other authors consider that the characteristics of the periodontitis-affected root surface facilitate bacterial colonization and make the elimination of the biofilm and respective toxins difficult(14).the use of root surface chemical conditioner agents, which act in association with mechanical root planning, has been the objective of many studies (13). Register and Burdick (72) reported that accelerated reattachment with cementogenesis to dentin may take place when root surfaces are demineralized in situ. This approach led others to evaluate pocket closure both clinically and histologically in patients treated with the demineralization procedure. A variety of surgical techniques have been attempted in efforts to regenerate the periodontium. The use of citric acid, and tetracycline to structurally and chemically modify the root surface has been used with the hope that it would enhance the regenerative potential of the periodontium 1

9 following surgery (1). Some authors suggest that root surface biomodification (RSB) with chemical agents, in conjunction with scaling and root planing, improves gingival attachment (2) These agents remove the smear layer, exposing collagen fibers on the dentin matrix and eliminating cytopathic substances that inhibit human gingival fibroblast growth. Citric acid (3,4,5,6) tetracycline, and ethylene-diamine tetra-acetic acid (EDTA) (7) are the main substances.(8,9) Tetracycline: Tetracyclines comprise a broad-spectrum antimicrobial agent, which is effective against many species of periodontal pathogens. Besides its antimicrobial effectiveness, this group of drugs has other special properties used in the management of periodontal disease. Included among these are its anti-inflammatory action, collagenase inhibition, bone resorption inhibition and its ability to improve fibroblast attachment. Tetracyclines are still used in combination with bone grafting and as conditioning agents for the root surface, to enhance periodontal tissue regeneration(15). Tetracycline s substantivity, another important property for periodontal therapy, allows the tetracycline to affix to a substrate and realize slow release, important for maintaining its antimicrobial and non-antimicrobial properties for an extended time, when the drug is locally applied (16). A Scanning electron microscopy (SEM) was used to evaluate root surface characteristics of human periodontitis following periodontal instrumentation and topical application of tetracycline HCl (TTC-HCl; ph 1.6; 4 min). Twenty-two single root periodontitis affected human teeth scheduled for extraction were selected. Mucoperiosteal flaps were raised, root surfaces were mechanically and chemically treated, Tetracycline solution was 2

10 applied with a cotton pellet. Flaps were repositioned and maintained in place for 20 min. Teeth then were extracted. Specimens were examined using Scanning electron microscopy SEM. Smear layer was successfully removed, exposing dentinal tubules; however, fibrin network formation in situ was not improved by application of TTC- HCl. (44) Citric Acid: Application of citric acid on dentin and cementum produces a demineralized zone consisting of exposed collagen fibrils. This demineralized zone could be biologically equivalent to predentin and cementoid, making the dentin and cementum compatible with the adjacent connective tissue, restricting resorption and facilitating the splicing of dental fibrils with adjacent connective tissue.(10) Acid application produces a four micron demineralized surface that exposed collagen fibers in the dentin matrix, thus providing a suitable nidus for splicing with new fibrils during the healing process.(9) Smith (39) in his study of the effectiveness of citric acid as an adjunct to surgical re-attachment procedures in humans found no added advantage in using citric acid during Modified Widman Flap (MWF) surgery in humans. Recession and pocket reduction were not enhanced or decreased following citric acid application. Finally, no clinical evidence of improved or accelerated healing was expected. Stahl & Froum (59) reported in their human study in 1977 that the application of citric acid on diseased root surface did not induce or accelerated cementogenesis; nor did it create an environment for new or accelerated attachment of functionally oriented collagen fibers at the root sites previously exposed to the oral environment in association with inflammatory, periodontal disease. Lafferty 1993 (43) in his comparative SEM study on the effect of acid etching with tetracycline HCL (TC) or citric acid (CA) on instrumented periodontally-involved human 3

11 root surfaces found that the surfaces of both acid-treated sets of specimens (tetracycline HCL or citric acid) differed considerably from specimens treated with root planing alone, regardless of root planning. Treatments with tetracycline HCL (TC) and citric acid (CA) exhibited removal of the smear layer and the dentinal tubules were open with exposed collagen fibrils. Ethylene-diamine tetra-acetic acid / EDTA: Studies have shown that a chelating agent (EDTA) working at neutral ph appears preferable with respect to preserving the integrity of exposed collagen fibers, early cell colonization, and periodontal wound healing (20-22). Gamal 2003 (45) showed that EDTA gel exposure for 2 minutes following scaling and root planning resulted in removal of the smear layer and a marked exposure of round to oval dentinal tubule orifices. The root surfaces after the 4 minute EDTA gel application had a fibrillar texture associated with a marked decrease in the number and increased diameter of the exposed dentinal tubules. With respect to PDL cell adhesion, 2 minute EDTA gel conditioned non-instrumented samples failed to demonstrate cell adherence to diseased root surfaces while 2 minute EDTA application after SRP showed a significant increase in the number of flat and round adherent cells. The 4 minute treated samples showed a significant increase in the number of flat cells when compared to the 2 minute samples. Thus, greater cell attachment followed 4 minute EDTA gel conditioning, producing the most desirable root surface to which maximum PDL cells can adhere and grow (19). Blomlöf in1996 studied the efficacy of subgingival application of an EDTA gel preparation following non-surgical periodontal therapy. EDTA gel preparation in conjunction with non-surgical root planning removed the smear layer and exposed collagen fibers. However, etching with an EDTA gel preparation without root planing 4

12 was insufficient for subgingival plaque removal, at least following short (2 minutes) exposure time. When compared to citric acid (low PH), which may necrotize the surrounding periodontal tissue cells and jeopardize the healing potential, etching with EDTA provides an alternative to the adverse effects of low ph etching. Root planing and EDTA etching do not necrotize the periodontal membrane or flap in surgical therapy as seen with citric or phosphoric acid (20). Application of EDTA results in surfaces virtually free of debris and with numerous collagen fibers exposed on the surface, however, EDTA causes a morphologic change to the collagen fibers. (11) Of note, when combined with application of biologic mediator, Kasaj in 2013 (12) found that the addition of 24% EDTA for root surface conditioning prior to EMD application provided no synergistic effects in terms of early root surface colonization by PDL fibroblasts. Oliveira and Muncinelli in a 2012 systematic review (46) of the efficacy of root surface biomodification for root coverage treatment concluded the use of root surface biomodification (RSB) agents did not improve root coverage outcomes. Depending on the protocol adopted, RSB can even worsen the results of treatment. Thus, the use of any modality of RSB associated with root coverage should be reconsidered. What are the most effective concentrations and ph of root biomodifiers? Root surface conditioning studies present great variability in their results due to a variety of factors, including the degree of root surface mineralization. The duration of root surface exposure to the oral environment affects the degree of mineralization (24). A hypermineralized root surface is harder to demineralize and decontaminate than a less mineralized one. The demineralizing action of citric acid is dependent on its 5

13 concentration (25). According to Fontanari (26) ), root surface conditioning when compared with different agents (1%and 25% citric acid, 24% EDTA and 50 mg/ml tetracycline hydrochloride) on impacted teeth and roots exposed to the oral environment, 24% EDTA and 25% citric acid were effective, while 50 mg/ ml tetracycline hydrochloride and 1% citric acid inadequately demineralized hyper-mineralized dental surfaces. However, less mineralized dental surfaces from impacted teeth were readily demineralized. Isik et al (47) using different tetracycline HCl concentrations of 0, 10, 25, 50, 75, 100, 125 and 150 mg/ml for root conditioning found that concentration between 50 mg/ml and 150 mg/ml showed a statistically significant opening of dentinal tubules. Mittal 2014 showed that tetracycline hydrochloride at a concentration 100 mg/ml effectively removed the smear layer and enlarged the dentinal tubules. Another study by Nada 2014 (17) using EDTA (10% with ph 4.7) and tetracycline HCl (10% with ph 2.2) on 40 specimens showed efficacy in removal of smear layer in both groups (10% EDTA and 10% tetracycline HCl). Tetracycline HCl resulted in a higher number and patency of dentinal tubules as compared to EDTA. This difference was probably due to a lower ph of tetracycline HCl (ph = 2.2) compared to EDTA (ph = 4.7). EDTA was more efficient in opening dentinal tubules diameter as compared to tetracycline HCl. Although tetracycline HCl has lower ph as compared to EDTA, EDTA was found to be much more effective root conditioning agent because it enlarged the diameter of dentinal tubules more than that of tetracycline HCl. Further, Grover 2011 (48) they studied the application of citric acid (ph 1), EDTA (24%, ph 7.4) and tetracycline hydrochloride (50 mg/ml, ph 1.8), they found that the number of patent tubules present in the citric acid and EDTA test groups was significantly higher than those in the tetracycline hydrochloride test group. They 6

14 concluded that all three agents are equally effective root biomodification agents. In clinical practice, EDTA might be more useful and produce less tissue damage owing to its neutral ph. Are there negative effects of citric acid on root surface? Valenza (49) found morphological changes of the gingiva treated for 5 minutes with citric acid when compared with untreated controls. Diffuse edema with cytologic alterations, both cytoplasmatic and nuclear with reduced number of desmosomes was noted. After 10 minutes of application, there were alterations in all layers, more marked in the basal and prickle layers, where most of the cells were affected by karyolysis and vacuolization. Thus, the findings showed that citric acid affects not only the cementum, but also the gingival epithelium, where it causes marked alterations. It is likely that the alterations in the gingival epithelium contribute in some way to the prevention of the long JE attachment. On other hand, Nilveus (50) showed that acid application did not seem to have an adverse effect on healing of gingival soft tissues, which have been in direct contact with the acid. It should be realized that this study was not carried out in human teeth, nor had the teeth been involved in chronic periodontal disease prior to experimentation. The pulp does not appear affected by citric acid as an adjunct in reconstructive periodontal surgery. In vitro research and animals experiments suggest great promise in the use of chemical root modifiers, but numerous human histologic and clinical studies have not been able to corroborate the periodontal regeneration observed in basic or animal research(1). 7

15 Purpose of this study: Root surface modification has not demonstrated clinical benefits when added to therapeutic periodontal procedures. (1, 46) The purpose of this study was to determine whether use of root surface biomodifiers will improve the predictability of attaining positive clinical results following periodontal pocket reduction therapies, regenerative and root coverage procedures. 8

16 Material and Methods: A systematic review was performed of all clinical trials identified following a literature search of all available English language human randomized controlled clinical trials of periodontal procedures with chemical root conditioning agents. SEARCH PROTOCOL: Electronic searches were conducted using University of Maryland library electronic database, EMBASE, Medline(PubMed). All databases were searched up to February 17, Search terms: The search terms used are as follows: Terms with the following fields were searched using the operator or and terms between fields used the operator and. Field 1: Root surface modification, root surface biomodification, root surface treatment, chemical root surface modification, root surface biomodifications, citric acid, tetracycline, and ethylene-diamine tetra-acetic acid, EDTA. Field 2: Flap surgery, apically positioned flap, replaced flap, osseous surgery, bone graft, bone replacement graft, autogenous, autogenous bone graft, bone matrix, allogenic, allogenic bone graft, osseous autograft, osseous graft, osseous grafting, osseous composite grafting, allograft, bone allograft, osseous allograft, cancellous bone allograft, freeze-dried bone, demineralized freeze-dried bone, bovine bone, Bio-Oss, synthetic graft, polymer, calcium carbonate, ceramic, bioglass, bioactive glass, Perioglass, Biogran, Unigraft, hydroxyapatite, hydroxylapatite, porous HA, HA, durapatite, coralline calcium carbonate, calcium carbonate, polymethylmethacrylate, hydroxyethylmethacrylate, calcium polymer, betatricalcium phosphate, tri-calcium phosphate, tricalcium phosphate, TCP graft(s), HTR polymer, Periograf, periodontal regeneration, periodontal defect, intra-bony, 9

17 intrabony, infra-bony, infrabony, intraosseous, intraosseous, vertical defect, vertical lesion, furcation, furcations, furcation lesion(s), furcation invasion, complication, surgical complications, postoperative complications, surgical wound infection, guided tissue regeneration, guided-tissue-regeneration, GTR, periodontal regeneration, gingival recession, root coverage. Field 3. Human Randomized clinical trials and studies. Hand searches included complete searches of the Journal of Clinical Periodontology, Journal of Periodontology, Journal of Periodontal Research up to February 2015 as well as bibliographies of all relevant papers and review articles. Selection Criteria: Once identified, abstracts and titles were reviewed based on the following criteria: Inclusion criteria: Randomized and clinical studies evaluating the effects of citric acid, tetracycline, or EDTA on root surfaces of patients with chronic periodontitis were considered for inclusion. Study types were human studies with a patient population diagnosed with chronic periodontitis or gingival recession. Exclusion criteria: Animal studies, histologic studies and any study evaluating extracellular matrix proteins (e.g., fibronectin), enamel matrix proteins (e.g., amelogenins), or other proteins or growth factors applied to the root surface were not included. Articles without standard deviations SD or without any reported clinical measurements of PD,CAL, REC were not included. Clinical trials without controls and case reports were excluded. Interventions The principal intervention was chemical root surface biomodification (CRSB) and it was applied to the following: 1) scaling and root planing; 2) flap surgery; 3) bone replacement grafts; 4) guided tissue regeneration; and 5) surgery to treat gingival recession. 10

18 Outcomes Outcomes measures included changes in clinical attachment levels (CAL), probing depths (PD), and gingival recession (GR). Data Collection and Analysis An independent reviewer screened titles and abstracts to identify eligible studies and reviewed full text of the studies included in the systematic review database. A data extraction sheet was used to collect information and entered into a database. Evidence tables were constructed. The chemical root surface modifier, protocol, number of subjects, periodontal defects, type of intervention, primary outcomes, and manuscript quality appraisal were identified. Weighted mean differences across studies were used for continuous data for primary variables (clinical attachment levels, probing depths, and recession). The coefficient of variation was determined for each outcome measure. Quality Assessment of Evidence: The protocol for grading the level of evidence of included studies was based on the strength of recommendation taxonomy (SORT) from the Journal of Evidence- Based Dental Practice (71). Assessment was based on Strength-of-Recommendation (Table 1) and Quality of Evidence (Table 2). While other assessment systems are available, the JEBDT was used because it is clear, easy to use, and thorough in evaluating evidence. (71) 11

19 Table 1. The Basis for Strength of Recommendation from JEBDT. (71) Table 2. The Basis for grading the quality of evidence from JEBDT. (71) 12

20 Statistical Analysis Descriptive statistics were expressed as mean and standard of deviations. A repeated measures analysis of variance (ANOVA) was used to detect intergroup differences of PD, CAL, and REC in pocket reduction flap surgeries, guided tissue regeneration, and root coverage. A Wilcoxon rank sum test was used to test the change between test and control groups at baseline and at end of study for PD, CAL, REC and for each treatment modality separately (PRT, GTR, RC). The paired t test was used to compare the mean difference of PD, CAL, REC between control (without CRSB) and test groups (with CRSB). A significance level of 0.05 was used in all statistical comparisons. Fig 1. Data flowchart depicting initial search results to final included studies 13

21 Results According to the flow chart shown in Fig. 1, our search provided 4996 articles articles were clearly not relevant to the review because they addressed completely different research questions, involved animal research only, in vitro studies, or they were review articles after screening titles and abstracts. 36 articles were retrieved for detailed evaluation after reviewing the abstract and were relevant to our study question. However, 15 articles were then excluded because they were either histological studies lacking clinical measurements or were case reports, or using different method for physical root surface treatment such as Laser application. After reviewing the full text of 21 remaining articles. One article was excluded because it lacked standard of deviations (SD) in its statistic results, and 1 additional article was excluded because it lacked PD, CAL or REC measurements. 14

22 Reference Albair et al (56) Alger et al.1990 (66) Gamal Y.2013 (45) Abitbol T 1996 (54). Bertrand and Dunlap 1988 (5) Cole et al. 1980(55) Common & McFall.1983 (60) Dilsiz A 2010 (53) Frank et al.1983 (57) Froum et al.1983 (65) Ibbot et al.1985 (61) Kashani et al.1984 (58) Liu and Solt.1980 (62) Renvert et al.1985 (63) Shiloah.1980 (64) Rationale For Exclusion* Histological study. Histological study. In vivo scanning electron microscopy study, no clinical measurements. Scanning electron microscopy study, no clinical measurements. Lack of PD and CAL measurements. Case report and histological study. Histological study. Used Nd:YAG laser as root surface biomodification. Histological study. Case report and histological study. Lack of SD in the study. Histological study. Case report. Case report. Case report 15

23 Stahl & Froum 1977(59) Singh J. (51) Histological study. Case report. Table 3. List of Excluded Studies (* More than one exclusion criterion may apply.) The search strategy yielded a combined total of 36 articles, which were screened to meet inclusion criteria. Of the articles that met the inclusion criteria, 17 were eliminated based on the exclusion criteria (table 3), leaving 19 articles for this review. 16

24 Table 4. Study Characteristics 17

25 Table 4. Study Characteristics 18

26 Table 5 Comparison of weighted PD mean between treatment with or without CRSB. (P>0.05) 19

27 Table 5. Comparison of weighted CAL mean between treatment with or without CRSB. (P>0.05) 20

28 Table 5. Comparison of weighted REC mean between treatment with or without CRSB (P>0.05) 21

29 Summary of Findings: Of the included studies, there were 19 randomized clinical trials. Characteristics of Participants: The ages of participants of the included studies ranged from (Table 4). Some trials failed to report the mean age (17 studies) (7,29,32,33,40,35,34,30,36,10,22,31,42,28,37,38,39) while others failed to report a range of the ages of participants (9 studies) (7,29,18,33,35,30,22,37,39). The number of males and females were not specified in 12 trials(29,18,33,40,35,34,30,31,42,28,37,38,). Sample Size: The sample size ranged from 6 to 91 subjects (Table 4). The duration of root surface biomodification application to the root surfaces ranged from 1 to 5 minutes and the study duration was between 2 and 12 months Articles were categorized according to treatment modalities (PRT, GTR, RC) as shown in (Table 5). Pocket reduction therapy / flap surgery (PRT): 12 articles included under (PRT), for a total of 195 control sites and 199 test sites (using RSB). The weighted means of pre-treatment measures and post treatment changes for pocket depth (PD), clinical attachment loss (CAL) and gingival recession (REC) were evaluated and no statistic differences were found between the two groups (P>0.05). (Table 5) Guided tissue regeneration (GTR): 4 articles were included under (GTR), for a total of 50 control sites and 48 test sites (using RSB). The weighted means of pre-treatment measures and post-treatment changes for pocket depth (PD), clinical attachment loss (CAL) and gingival recession (REC) were evaluated and found no statistic differences between the two groups (P>0.05). (Table 5) Root surface coverage (RC): 3 articles were included under (RC), for a total of 39 sites control sites and 39 sites in the test group (using RSB). The weighted means of pre-treatment measures and 22

30 post treatment changes for pocket depth (PD), clinical attachment loss (CAL) and gingival recession (REC) were evaluated and found no statistic differences between the two groups (P>0.05). (Table 5) Overall, for the comparison of post-treatment outcomes, there were no significant differences for pocket depth reduction, CAL gain or increase between treatment groups. RSB does not improve the mean of clinical outcome. No significant differences were found between treatment groups for RSB regardless of treatment type: Flap debridement (FD), Guided tissue regeneration (GTR) or Root coverage (RC). The mean CV for each treatment modality (FD, GTR, REC) with or without RSB was submitted to paired t test (p 0.05). The variance between the groups was not significantly different regardless of treatment modalities. Therefore, no reduction in variability of the mean clinical outcome measures was noted for root surface biomodification. RSB does not improve the predictability of clinical outcomes. 23

31 Discussion: This systematic review assessed the results of available randomized controlled trials where root surface biomodifiers were used before pocket reduction flap surgeries, periodontal regeneration and root coverage; strict inclusion criteria were imposed to enable an unbiased analysis and a conclusion regarding the impact of this practice on treatment results. Pocket reduction periodontal flap surgeries: According to this systematic review, using CRSB does not improve the predictability of pocket reduction flap surgical outcomes. None of the included studies showed any difference or benefits for using RSB with any of periodontal treatment modality. Blomlöf (18,29) reported that inclusion of EDTA root conditioning in the treatment protocol of periodontitis did not alter the clinical outcomes (clinical attachment gain or probing depth reduction) of either nonsurgical or surgical (open flap debridement) therapy. Thus, EDTA etching of root surfaces did not contribute to the elimination of periodontal pockets or increase clinical attachment when combined with conventional nonsurgical or surgical periodontal therapy. Patients with a small attachment loss at baseline responded better to treatment than patients severe periodontitis. (18). Smith (39) showed that the use of citric acid as a root conditioner in conjunction with modified Widman flap surgery provided no significant differences for clinical probing attachment levels. Both citric acid and non-citric acid treated quadrants showed comparable clinical results as measured by attachment level, probing depth and recession. 24

32 Erdic (41), showed that no additional effect of tetracycline root conditioning in improving tissue attachment (assessed by attachment level changes) to periodontally diseased root surfaces. However, tetracycline-treated sites displayed significantly better gingival index score 2 and 4 weeks after surgery. Periodontal Regeneration: According to this systematic review, using CRSB did not improve the predictability of periodontal regeneration surgical outcomes. A variety of surgical techniques have been attempted in efforts to regenerate the periodontium. The use of citric acid, tetracycline or ethylene di-amine tetra acetic acid EDTA to structurally and chemically modify the root surface has been used in the hope that it would enhance the regenerative potential of the periodontium following surgery. The use of chemical root modifiers has been particularly attractive to the clinician since they were relatively quick and easy to apply to exposed roots as well as being an inexpensive means to regenerate the periodontium. (1) However, recent studies showed there is no significant difference in clinical outcomes when applying RSB in periodontal regeneration. Parashi (28) found that omission of the EDTA treatment resulted in no differences in clinical or radiographic outcomes following (EMD) therapy in treatment of infrabony defects. Root conditioning or biomodification protocol lacks clinical effect in the treatment of either intrabony or recession defects (1). Blomlöf (18) reported that inclusion of EDTA root conditioning in the treatment protocol of periodontitis did not alter the clinical outcomes (clinical attachment gain or probing depth reduction) of either nonsurgical or surgical (open flap debridement) therapy. Thus, EDTA etching of root surfaces did not contribute to the elimination of periodontal pockets or increase clinical attachment when combined with conventional nonsurgical or surgical periodontal therapy. 25

33 Root coverage: According to this systematic review, using RSB did not improve the predictability of periodontal root coverage surgical outcomes. Studies have suggested that the smear layer may serve as a barrier to the development of a connective tissue attachment to the root surface.(14) The hypothesis of using RSB in removal of the smear layer and exposure of collagen fibers to increase new connective tissue attachment can only be verified in animal models. (14) Bittencourt (7) indicated that EDTA negatively affected root coverage with (Semi-lunar coronally re-positioned flap) SCRF. The (Semi-lunar coronally re-positioned flap with EDTA) SCRF-E group had lower percentages of root coverage (70.2%) and complete soft tissue root coverage (40.0%) compared to the SCRF group (90.1% and 66.7%, respectively). This may have been due to the use of SCRF, a more sensitive technique that dispenses with sutures and depends more on clot formation and stabilization. EDTA might have inhibited blood element adsorption and adhesion to the dentin surface because of a possible incomplete removal of the gel from the root surface. In addition, EDTA is a calcium chelator; therefore, its residues may have inhibited or retarded coagulation events.(67) Although citric acid conditioning of roots has been advocated as a means of increasing soft tissue reattachment, no advantage was demonstrated when it was used with a lateral position flap or free gingival graft to cover denuded roots in human subjects with disease-produced gingival recession. (6, 61) Based on a systematic review (8), it is evident that the use of RSB agents does not improve root coverage outcomes. Depending on the protocol adopted, RSB can even worsen the results of treatment. Thus, the use of any modality of RSB associated with root coverage should be reconsidered as no evidence of its efficacy is available in the literature unless new randomized controlled trials with well-designed methods present different conclusions. 26

34 However, although root surface conditioning showed significant promising results histologically, it did not improve the outcome of various periodontal surgeries clinically. One explanation for this discrepancy may be the animal model used with evaluation following a relatively short healing period of 8 weeks in the investigation by Blomlöf (69). It has been shown that results observed in animal studies are not necessarily reproducible in humans. One example of this is the histologic evidence in dogs of new connective tissue following citric acid demineralization of root surfaces (70). Although some histologic evidence was also provided in human biopsies controlled clinical trials in humans did not predictably result in improved healing, indicating that citric acid root conditioning does not seem to provide any adjunctive clinically observed effects (31,35,38,39). Furthermore, healing following EDTA root conditioning of periodontitis affected teeth, which may exhibit varying degrees of hyper-mineralization cannot directly be compared to the healing of the dehiscence defects in monkeys. There may be a reduced demineralizing effect on periodontitis affected cementum (22). Additionally, in the animal model there were no attempts to control plaque accumulation, while in all clinical human studies chlorhexidine was prescribed followed by maintenance of adequate oral hygiene during the healing period. These differences in clinical conditions created different healing environments in the monkeys and in the humans. (22) In this systematic review, only three human clinical trial studies were available for comparison which mainly contributed to insignificant results of predictability of using root surface biomodifications during various periodontal surgical and nonsurgical treatments. 27

35 Conclusion: The addition of CRSB to PRT, GTR or RC treatment produced no significant change in mean clinical outcomes for PD, CAL and GR. Furthermore, the variance in attaining the clinical outcomes was not significantly altered by the root surface treatment. The variation in treatment response for each therapy was not significantly different. CRSB does not improve the predictability of PRT, GTR and RC clinical outcomes. 28

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