Membranes for guided bone regeneration in dentistry : a review of human randomized blinded clinical trials

Objective: to review the literature currently available on membranes for guided bone regeneration in clinical dental practice. Material and Methods: a literature search was performed on PubMed, Web of Science and Scopus. The Jadad Scale was used for data collection and selection. The quality of the studies was evaluated through Cochrane Center Guidelines. Randomized and blinded clinical trials published in Portuguese, Spanish and English were included. Literature reviews of studies without randomization and blinding or when a percentage equal to or greater than 20% of the sample did not proceed with the study follow-up were excluded. We selected 27 studies that were categorized according to the findings. Results: the number of publications found limited the conclusions on the success of GBR in dentistry. Conclusion: the variety of techniques and membranes applied, as well as the small number of studies found are in need of well-designed studies in order to better evaluate the potential of GBR in patients submitted to these treatment approaches, as well as to determine accurate treatment protocols.


D
iseases, injuries or trauma may cause tissue loss or degeneration in the human body leading to the need for treatments that facilitate its repair, replacement or regeneration. 1The history of tissue repair goes back to prehistory and, over a long period of time, has occurred empirically, aiming the inertia, non-toxicity and tolerance of the biomaterial. 2issue engineering aims at regenerating injured tissue through the development and use of biological substitutes, 3 which act as a scaffold to regenerate, maintain, improve, or stimulate the formation of new tissues. 1The area is of interest to most dental specialties including periodontics, orthodontics, surgery, endodontics and dental implantology 1,4,5 with the need for materials capable of effective and rapid bone formation. 6everal methods have been developed to increase bone volume as well as to stimulate the formation of this tissue such as distraction osteogenesis, 7 osteoinduction, 8 osteoconduction 9 and guided bone regeneration (GBR). 10The concept of Guided Bone Regeneration (GBR) is attributed to the combination of bone substitutes and membranes commonly used to restore lost or defective bone. 11iterature shows that membranes would exclude non-osteogenic tissues from interfering with the healing process or bone repair. 12However, this hypothesis remains speculative given that the mechanisms of bone regeneration through the use of membranes were not accurately described, 11 having a need of better understanding of its chemical and biological processes. 13n order to be used for medical and dental purposes, membranes must follow certain criteria such as: biocompatibility, space creation, tissue integration and adequate handling, 14 biodegradability, architecture and satisfactory mechanical properties as well as the technology for its manufacture 1 .Although, promising solutions in animal models, an ideal membrane has not been established for clinical applications.Its selection should be based on a thorough understanding of its benefits and limitations in view of its specific clinical application. 15ccording to biodegradability, the membranes used for GBR are classified into two groups: non-absorbable and resorbable. 51][22][23][24][25][26][27][28][29][30][31] However, there is no 1."biocompatible materials" OR "biocompatible" AND "materials OR "biocompatible materials" OR "biomaterials AND "guided" AND "bone regeneration" OR "bone" AND "regeneration" OR "bone regeneration" AND "barrier" AND "membranes" OR "membranes" OR "membrane".Stipulated time: ┤10/12/2017.

PubMed
Web of Science Scopus Table 1.Search strategy months. 34Moreover, the lack of knowledge of the minimum time for regeneration with barrier membranes, in order to guarantee a safe period for bone formation and maturation, a minimum period of six months for evaluation of results was adopted.

Data Collection and Analysis
Data was extracted by two authors independently.Disagreements were resolved by discussion after a thorough review of the studies.The articles were identified and imported into Mendeley Desktop software version 1.17.11(Glyph & Cog, Petaluma, CA, USA) in which the duplicates were removed.Subsequently, titles and abstracts were selected by relevance, using the inclusion and exclusion criteria.
The articles were obtained in full text, and the eligible studies were included in this review.Review articles, clinical case reports, manuscripts in other languages, articles not available in full text, non-relevant publications, non-randomized and blinded or follow-up period of less than six months were removed.Eligible studies had their reference lists screened as well.

Selected Studies
The 27 studies found in the bibliographic search were categorized as evidence related to: preservation of alveolar bone in surgical procedures (n=6); application of barrier membranes in endodontics (n=2); application of membranes in dental implants (n=5); use of membranes in furcation and intraosseous lesions (n=14).
Based on these findings, we determined the following features for critical analysis: synthesis of the results and characteristics of the studies according to the categories.Limitations of the study as well as its implications for clinical practice are presented in order to have a better understanding of its findings considering the design of this review.

Synthesis of Results
For this literature review, the initial search resulted in a total of 919 records found in the electronic databases: PubMed (n = 319), Web of Science (n = 88) and Scopus (n = 512).363 studies were excluded for duplication and the remaining 556 studies were selected as potentially relevant.393 publications were excluded after reading their titles and abstracts according to the Oxford Quality Scale Scoring System. 33The remaining 163 studies were then obtained in full text and evaluated for eligibility, taking into account the inclusion and exclusion criteria as well as the quality assessment of the studies through the recommendations of the Cochrane Center. 35Finally, 27 manuscripts were selected, no study from the reference lists was added (Figure 1).

Characteristics of the Studies
The studies were categorized according to the following results: membranes for preservation of alveolar bone, membranes for endodontic application, membranes with application in dental implants, and membranes for furcation and intraosseous lesions.Information was recorded for each study, including authorship and year of publication, study design, sample size and age, follow-up period, surgical treatment, evaluation method, results and study considerations.

GBR Membranes Used for Alveolar Bone Preservation
According to the proposed methodology, six publications were identified, which are presented in table 3.These studies correspond to randomized blinded [36][37][38][39] and blinded splitmouth trials. 17,18,40  The study compared the use of PRP, PRP + CS and a CM in the treatment of apicomarginal defects.Clinical and radiographic measurements were determined at baseline and every 3 months after surgery up to 1 year.The cases were defined as healed when there were no clinical signs or symptoms, and the radiographs showed complete or incomplete (scar tissue) healing of previous radiolucencies.
All three treatments had highly significant reductions (P <0.05) in periodontal pocket depth, clinical insertion level, at the position of the gingival margin; in the periapical lesion size, in the percentage reduction of periapical rarefaction and periapical healing.There were no significant differences between the three groups for these parameters (P> 0.05).
Platelet-rich plasma or platelet-rich plasma + collagen sponge leads to improvements in clinical outcomes of apical margins in terms of periapical healing, clinical insertion level, periodontal pocket depth reduction.PRP may be an alternative treatment to the collagen membrane in AM treatment.Some studies suggest that the treatment of the alveolar bone with membranes after surgical procedures constitutes a valuable approach to preserve and prevent defects after dental extractions 17 , improving the clinical attachment and bone levels in the region 36 through supporting bone formation. 37Thus, the treatment of these defects with membranes could exert significant benefit to the patients. 38owever, there is evidence that GBR membranes exerted a partial effect on the preservation of bone width and height, 25 without additional clinical benefit to the bone repair process when compared to treatment approaches such as platelet-rich plasma 37 or grafts alone. 38 also observed different approaches and membranes for GBR, such as absorbable membrane of glycolic and lactic polymers, 18,38 resorbable collagen membranes 35,37,38 and ribose cross-linked membranes. 39Thus, the results should be interpreted with caution due to the risk of bias.

GBR Membranes Used for Endodontic Application
The literature research reported only two randomized and blinded clinical studies 41,42  The measures evaluated were implant failures, complications, pink aesthetics, patient satisfaction and marginal peri-implant bone levels.
After implant placement, mean bone levels were -0.21 mm in GBR + BS and -1.92 mm GBR, while at 1 year after loading were -1.04 and -1.76, respectively.When comparing the two groups, GBR + BS implants showed 0.70 mm more peri-implant marginal bone than GBR implants.Aesthetics was statistically significantly better for the GBR + BS.In a one-year evaluation study, Garret et al. 41 with 26 patients between 24 and 67 years of age, found that there was no statistically significant difference between bone healing in cases where a polylactic acid-based resorbable membrane was or was not used in periapical surgeries.It suggests that the use of this membrane would not have an additional beneficial effect in relation to the bone formation.Therefore, not justifying the additional expense for the patient.
Goyal et al., 42 30 patients were compared of the use of platelet-rich plasma in a combination with collagen sponge and a collagen membrane for the treatment of apical-marginal defects.It was observed that all treatment modalities presented significant reductions, with no significant differences be-tween the three groups in relation to periapical healing.
It is important to highlight that, even when applying similar methodologies in both studies, the results should not be extrapolated due to the different treatments and membranes used, as well as the limited number of available publications identified according to the methodology used in this literature review.

GBR Membranes Applied in Dental Implants
Five studies regarding the use of membranes for guided bone regeneration with dental implant application (Table 5) were found.Four blinded randomized clinical trials [43][44][45][46] and one blinded and randomized multicenter clinical study. 47 Merli, Migani and Esposito 43 evaluated a resorbable and a non-resorbable membrane and both treatments were effective in bone augmentation for dental implants.However, the membranes employed were associated with complications.The authors emphasize that the risks and benefits when considering the use of GBR membranes should be carefully balanced.

ABG = Autogenous
Comparing resorbable and polyethylene glycol membranes, Jung et al. 44 found that polyethylene glycol membranes presented simplified clinical handling and enhanced bone gain results.This corroborates with Ramel et al., 45 whose study compared the clinical performance of a polyethylene glycol and a collagen resorbable membrane and it was found a statistically significant evidence that the polyethylene glycol membrane present better results than the collagen membrane in the treatment of bone dehiscence around dental implants.
Gassling et al. 46 evaluated a platelet-rich plasma membrane and a collagen membrane and found that the two resorbable membranes resulted in a satisfactory and similar amount of bone formation.The use of resorbable collagen membranes has also been associated with a better aesthetic gain around dental implants. 47

GBR Membranes Used for the Treatment of Furcation and Intraosseous Defects
Table 6 shows the main characteristics of the 14 studies included on membranes for bone regeneration in furcation and intraosseous defects according to: authorship, type of study, follow-up period, sample, methodology, results and considerations.[61] Membranes for guided bone regeneration in dentistry: a review of human randomized blinded clinical trials Author The reduction of the PD (mean ± SD) for EG and CG was 4.3 ± 0.5 and 3.0 ± 1.3 mm; The CAL was 2.9 ± 0.8 and 1.7 ± 1.5 mm; and the increase in the level of bone was 2.9 ± 1.4 and 1.2 ± 1.2 mm, respectively.Clinical improvements were significantly different from surgery for both groups (P <0.01).There were no significant differences between the groups in the reduction of PD and CAL.The bone level increase was significantly higher in the demineralized bovine bone + CSM group compared to CG (P <0.05).The study evaluated the effect of PRP on the healing of deep ID treated with IBMB and GBR with a NRM (ePTFE).24P with advanced chronic periodontal disease and IO were randomly treated with a combination of PRP + IBMB + GBR or IBMB + GBR.They were evaluated at the beginning and 1 year after treatment: plaque index, gingival index, bleeding probing, PD, gingival recession and CAL.
No differences were observed in any of the parameters studied at the baseline between the groups.PRP + IBMB + GBR showed a reduction in mean PD of 8.6 -1.7 mm to 3.1 -1.3 mm (P <0.001) and a change in CAL, mean of 10.3-1.4 mm to 5.7-1.6 mm (P <0.001).In the group treated with IBMB + GBR, mean PD was reduced from 8.8 -1.7 mm to 3.1 -1.0 mm (P <0.001) and mean CAL changed from 10.4-2.6 mm to 5.9-1.8mm (P <0.001).In both groups, all sites gained ‡ 3 mm CAL.No statistically significant differences were observed in any of the parameters studied between the two groups.Significant and positive gains in bone attachment levels can be obtained with the use of GBR membranes in furcation and intraosseous lesions with lower complications and morbidity for the patient. 48Eickholz et al. 58 analyzed the clinical performance of two resorbable membranes and observed a reduction in plaque index and probing depth, thus recommending their use for the treatment of furcation and intraosseous defects.
There is evidence of greater bone filling in regions where treatment with bone regeneration was employed alone 57,60 or in combination with bovine bone 51,52 hydroxyapatite 55 , bone substitute 58 or autogenous bone. 56It also produced additional clinical benefits such as minimizing the post-surgery recession compared to single surgical flap techniques. 54Polylactic acid or polyglactin-910 membranes also demonstrated similar favorable results in bone regeneration of intraosseous defects. 58hen compared to surgical flap techniques, the use of calcium sulfate membranes in combination with demineralized bovine bone resulted in reduced probing depth and improved clinical attachment levels.It was also observed that the bone gain evaluated in deep periodontal pockets was greater compared with only surgical flap techniques. 49assibag-Berkman et al. 53 evaluated the platelet-rich plasma in combination with collagen-resorbable membranes in the treatment of anterior interproximal intraosseous defects and found that all treatment options were effective and that the addition of plasma platelet-rich combination did not add any additional clinical benefit when in combination with the GBR treatment.

Study Limitations
Although this review was carried out on randomized clinical trials, the difficulty of categorizing and standardizing the data presented an important limitation.However, the results offer a certain confidence since the selection and quality evaluation of the studies were strictly followed, reducing possible flaws in this process.It was emphasized that the adoption of strict inclusion and exclusion criteria had a significant impact on the results found as well as its applicability.
Another possible limitation of this systematic review was the use of only three electronic databases (PubMed, Web of Science and Scopus), not including the gray literature.However, the three included databases indexes a large amount of manuscripts that offer good quality of scientific evidence in the medical and dental area.Data meta-analysis was not performed and may also be considered a limitation of this study.However, an accurate synthesis with deep critical assessments of these studies prevailed in order to make this review more informative and reliable.
In view of the number of studies that were disregarded for analysis due to the proposed methodology, it would be plausible to conduct a study that contemplated a holistic view of the use of membranes for guided bone regeneration in dentistry, with different follow-up intervals.A review based on clinical cases could favor a more comprehensive view of this issue.
The number of studies that met the inclusion criteria on GBR membranes with application in endodontics (n=2), dental implants (n=6), and preservation of alveolar bone in surgical cases (n=6) were observed.This number may suggest the need for future controlled and randomized clinical trials, duly designed to better assess the potential of GBR use in patients undergoing this treatment approach, especially involving endodontic procedures.

Implications for Clinical Practice
The present literature review included different types of membranes and approaches combined with or without bone substitutes that guided bone regeneration in dentistry.Most of these studies showed significant differences between the membranes used considering the investigated parameters.It was seen to contribute to the role of GBR membranes in the preservation of the alveolar bone or bone gain in procedures for dental and periodontal procedures.However, in specific cases such as GBR membrane for endodontics, it was not possible to provide further considerations due to the lack of available clinical evidence.Randomized and blinded clinical studies are need in order to provide more reliable results with a minimum bias in its approach.
Regarding the treatment of furcation or intraosseous defects, these findings showed that guided bone regeneration through membranes was effective for resolution of cases when compared with flap surgery alone.These data corroborate a systematic review, meta-analysis, 30 and a systematic review 23 which demonstrated that GBR is more effective in gain of clinical attachment and reduction of probing depth in the treatment of intraosseous as well as furcation defects.
It is not fully explained in the scientific literature if the combination of barrier membranes and graft materials can contribute to the guided bone regeneration process when comparing membranes or graft materials alone.However, the combination therapies presented better results than the PEDROSA MS et al.
isolated therapies, with small additional benefits. 22,28he small number of studies that met the inclusion criteria of this literature review limited the conclusions about GBR's success in certain dentistry areas.The diversity of techniques and membranes employed show the need for controlled clinical trials to support predictable and successful treatment protocols using membranes for guided bone regeneration.
Although most of the results corroborates with satisfactory clinical results, they should not be extrapolated, since there is a probability that there will be a continuous disagreement about clinical recommendations, techniques and membranes that should be used when considering its application.Therefore, the decision to conduct guided bone regeneration therapy using barrier membranes requires caution and individual assessment of each patient.The decision-making process, whether or not to consider the use of GBR membranes should be based on the available scientific evidence combined with the clinical experience of the professional.

Conclusion
The small number of studies that met the inclusion criteria limited the conclusions on the success of membranes for guided bone regeneration in specific dentistry areas.However, there is a strong evidence of the important role of the use of GBR membranes in procedures involving dental implants in aesthetic areas as well as in treatment of intraosseous or furcation defects, which suggests their indication in these cases.
It has not been showed to what extent the use of membranes combined with or without graft materials can contribute to the process of bone regeneration.The variety of techniques and membranes employed as well as the small number of studies surveyed show the need for properly controlled clinical trials designed to determine predictable and successful treatment protocols when considering GBR as a treatment approach.
The use of bone substitute (Endobon) with resorbable collagen membrane (OsseoGuard) in bone dehiscence around the Intraosseous Defect improves the aesthetic result.
the clinical response of Class II furcation lesions with GBR.CERT (n = 30) was compared to the FS (n = 30).The CERT was a combination of absorbable hydroxyapatite and tetracycline (3: 1), an NRM and FS.Plaque index, bleeding probing, gingival recession, PD, CAL, loss of horizontal clinical insertion vertical clinical insertion loss, vertical furcation height, horizontal furcation depth and the amount of tissue under the NRM.Both treatments resulted in improvements in all clinical variables evaluated.Reduction in DP of 3.65 -0.6 mm and 0.60 -1.0 mm; Vertical gains of 3.05 -0.6 mm and 0.65 -0.6 mm and horizontal gains of 3.45 -1.3 mm and 0.55 -0.7 mm in CERT and SF, respectively.In the CERT, significant positive correlations were found between initial PD and reduction of PD, and the initial vertical furcation height correlated positively with the reduction of PD and horizontal height gain.The horizontal furcation depth and the amount of tissue formed under the NRM were positively correlated with the reduction of the PD and the horizontal furcation height and vertical furcation height gains.For the FS group, the initial PD correlated positively with the reduction of PD and the gains of furcation vertical height and horizontal furcation height and correlated negatively with the gingival recession.The initial vertical furcation height correlated positively with reductions of PD.Experimental combined regenerative therapy presented significantly better clinical results, with greater reduction of depth of probing, vertical furcation height gains and horizontal furcation height, and greater frequency of furcate closure compared to surgical flap, and it was shown to be promising as a treatment technique regenerative.

Table 3 .
Characteristics of the studies on alveolar bone preservation displayed in chronological order (n = 6)

Table 4 .
Characteristics of the studies on GBR with endodontic application displayed in chronological order (n = 2) on membrane applications for guided bone regeneration in endodontics, published in 2002 and 2011 (Table4).The results of the bibliographic research are conflicting.

Table 5 .
Characteristics of the studies on GBR used in dental implants displayed in chronological order (n = 5)

Table 6 .
Characteristics of the studies on GBR in intraosseous and furcation defects in chronological order (n = 14) PEDROSA MS et al.

Membranes for guided bone regeneration in dentistry: a review of human randomized blinded clinical trials
PEDROSA MS et al.