Evaluation of efficacy of non-resorbable membranes compared to resorbable membranes in patients undergoing guided bone regeneration

Abstract

Background

Replacement of missing teeth in patients with prolonged edentulism poses a challenge for clinicians. An extended period of edentulism results in severe atrophy of alveolar ridges rendering them unsatisfactory for rehabilitation using an implant-supported prosthesis. To overcome this difficulty, Guided Bone Regeneration (GBR) was introduced and constructed upon the principles of Guided Tissue Regeneration (GTR) procedures. Evidence suggests that GBR has proven to be a predictable treatment modality for treating vertical and horizontal ridge deficiencies.

Objective

The present systematic review aimed to evaluate the efficacy of non-resorbable (N-RES) membranes compared to resorbable (RES) membranes in patients undergoing GBR.

Methods

An electronic search of three databases, including PubMed, Web of Science, and Scopus, was conducted for articles published until March 2022. A supplementary manual search of references from these articles was performed to include any articles that may have been overlooked in the electronic search. Articles that evaluated the efficacy of RES membranes and N-RES membranes in GBR were included. Case reports, case series, commentaries, letters to the editor, narrative or systematic reviews were excluded. Articles in languages other than English were also excluded. The articles were assessed against risk of bias 2 tool for Randomized Control Trials (RCTs) and ROBINS-I tool for Non-Randomized Clinical Trials (N-RCTs). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment was followed based on the Cochrane Handbook for quality assessment. A summary of findings table was used to present the results.

Results

One hundred and fifty one articles were identified in an electronic search. Eight articles met the inclusion criteria and were included in the present systematic review. The studies were conducted on partially or completely edentulous patients with alveolar ridge deficiencies undergoing vertical or horizontal bone for subsequent implant placement. The majority of the studies reported similar results for bone gain in both RES and N-RES membrane groups.

Conclusion

The available evidence suggests that RES and N-RES membranes are equally effective in GBR. However, the evidence must be interpreted with caution due to its ‘low quality’ GRADE assessment.

Clinical implications

Further research focusing on human clinical trials with well-matched subjects with homogeneity in the type and method of GBR and method of assessment of new bone formation will derive conclusive results on the efficacy of RES and N-RES membranes in achieving new bone formation.

1. Introduction

The demand for dental implants to replace missing natural teeth has risen over the past two decades. Presently, over 1 million dental implants are placed every year [1]. Oral rehabilitation of missing teeth has shifted emphasis from mere functional replacement to a holistic approach involving prosthetics and phonetics to recreate natural aesthetics and function. The current philosophy advocates that implants should be placed in a prosthetically determined position rather than available bone [2,3]. Despite this, the available bone quality and quantity play a key role in determining implant-supported prosthesis's success. In practice, patients requiring rehabilitation present with deficient alveolar ridges [4,5]. The presence of teeth determines the volume of alveolar bone. Thus, patients with prolonged edentulism often present with severely atrophic alveolar ridges that complicate their rehabilitation [6]. A deficient alveolar bone impedes implant-supported prosthetic rehabilitation and poses an anatomic problem [7]. Vertical and horizontal ridge augmentation procedures overcome this hurdle.

Guided bone regeneration (GBR) is a regenerative technique for ridge augmentation. It is a surgical procedure that employs barrier membranes with bone grafts or substitutes to direct bone growth [[8], [9], [10]]. GBR aims to preferentially direct osteogenic cells to the bone defect site while excluding cells that may impede osteogenesis. Physical barrier membranes inhibit the fast-growing epithelial and connective tissue cells from occupying the area to be regenerated and allow the slow-growing cells of the periodontal ligament, the cementoblasts and osteoblasts, to repopulate the defect site [9,10].

GBR essentially isolates soft tissues, allowing bone to grow. Bone defects need to be isolated for 16–24 weeks to ensure bone growth [11]. GBR utilizes barrier membranes with or without bone grafts/substitutes to encourage osseous regeneration. It prevents other biological components such as connective tissue and epithelium from interfering by selective cell repopulation and enhances bone regeneration. Evidence suggests that a seal formed between the barrier and the host bone ensures cell occlusivity and creates a space for the migration of pluripotent osteogenic cells [[12], [13], [14], [15]]. Membrane barriers also reduce the risk of resorption [16,17].

Membranes used for GBR are broadly categorized based on their degradation characteristics into non-resorbable (N-RES) and resorbable (RES) membranes. N-RES membranes, including titanium meshes and Polytetrafluoroethylene (PTFE) membranes, deliver predictable and long-term results for GBR. N-RES membranes retain their shape and structure. They offer excellent space maintenance and act as an effective barrier membrane. The only drawbacks associated with N-RES membranes are the need for a second surgery for their removal and a higher risk of complications like membrane exposure [[18], [19], [20]].

RES membranes include natural or synthetic polymers such as xenogeneic native collagen membranes, polyglycolide, and polylactide polymers [21]. Unlike the N-RES membranes, RES membranes are degraded by the body, reducing patient morbidity by eliminating a second surgery. This was a critical reason for popularising RES membranes among clinicians and patients [22]. However, unpredictable resorption can cause the membrane to collapse. This hampers bone regeneration, as a physical barrier does not support the defect [23]. RES membranes can suffer from lowered tensile strength, risking lowering of available space [24].

Despite the abundance of literature on this subject, previous reviews have mostly merely presented the findings without a thorough analysis of the results [[25], [26], [27], [28]]. So far, no review has examined and analysed the efficacy of bone regeneration in one membrane type versus the other in a systematic manner. The present systematic review aimed to evaluate the evidence for the efficacy of N-RES membranes compared to RES membranes in patients undergoing GBR. The uniqueness of this study lies in its meticulously designed search strategy, which employed specific inclusion and exclusion criteria to identify relevant evidence and extract data to validate current practices in GBR. This process was carried out by a team of multiple reviewers.

2. Methodology for literature search and selection

2.1. Search strategy

The current systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [29]. Risk of bias within the studies was also analysed. A thorough electronic search of three standard databases was performed to identify articles published until February 2022 - Scopus, PubMed, and Web of Science, using the keywords: guided bone regeneration (GBR) AND “non-resorbable membranes” OR “Resorb” OR “Resorbability”.

2.2. Inclusion criteria

Randomized control trials (RCTs), clinical trials, and comparative evaluations originally published in English language that evaluated the efficacy of N-RES versus RES membranes in patients undergoing GBR, until February 2022 were included in the review.

2.3. Exclusion criteria

We excluded commentaries, letters to the editors, narrative or systematic reviews, case reports, case series, in-vitro and animal studies. Articles in languages other than English were excluded.

2.4. Selection of studies

Duplicates were eliminated. Primary screening of the titles and abstracts of all the studies identified in the electronic search was conducted by two authors independently (SB, MHB). Full-text records of the relevant articles were extracted for further assessment of eligibility. Two authors (MAG, KJA) independently carried out the secondary screening of the full-text documents for study design, interventions, outcome measures, results, and discussion. Moreover, a manual search of the bibliography of the selected articles was performed to include articles undiscovered from the primary databases. Disagreements were resolved through discussion with a third author (SGP) until a consensus was reached. Studies that met the Population, Intervention Comparators, Outcomes, and Study design (PICOS)-based inclusion criteria were subjected to validity assessment and data extraction.

2.5. Data collection

Two authors (MMA, DHA) independently carried out data collection, and a third author (MRT-P) verified the data for accuracy. The following variables were collected from the articles included in the review onto a customized template (Microsoft Word, Microsoft Inc, Redwood, CA, USA): author details, study design, sample size, types of intervention, primary and secondary outcomes, and results.

2.6. Risk of bias within studies (quality assessment)

Two reviewers (DHA, SGP) independently assessed the quality of the included studies based on the Cochrane Handbook for Systematic Reviews for Interventions [30]. The studies were evaluated against two assessment tools: risk of bias (RoB) 2 [31] for RCTs and ROBINS-I [32] for Non-Randomized Clinical Trials (N-RCTs). RoB 2 is a modified tool that assesses the validity of RCTs based on five specific domains. The domains included were bias in the randomization process, deviation from intended intervention, missing outcome, variable outcome measures, and selective reporting. Each response was evaluated as ‘low,’ ‘high,’ or ‘some concern.’ The ROBINS-I tool assessed the N-RCTs against seven domains for validity, including confounding factors, participant selection, interventions, deviations from interventions, outcome measurements, missing data, and selective reporting. The responses were recorded as ‘low,’ ‘moderate,’ ‘serious,’ or ‘critical,’ depending on the signaling questions for each domain. Agreement between the two reviewers was assessed overall using the kappa statistic (>0.75).

2.7. GRADE assessment

We assessed each outcome in the summary of findings table based on the recommendations mentioned in the Cochrane Handbook for Systematic Reviews of Interventions [30,33]. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was applied by one reviewer (DHA), and the ratings were applied after discussion with the other two reviewers (SGP, MRT-P). After a consensus was reached among the three review members, the final ratings were applied. To begin with, each outcome for RCTs was graded as ‘high’ quality. The evidence rating was subsequently downgraded by one level based on five parameters, i.e., the risk of bias, indirectness of evidence, imprecision of results, inconsistent results, and publication bias.

3. Results

A total of 151 articles were identified in the electronic search from the aforementioned databases. Duplicates were removed. The remaining 69 articles were screened based on their titles and abstracts. The 20 articles that cleared the preliminary screening were subjected to full-text analysis to determine their eligibility. Eight studies that met the inclusion criteria were included in this systematic review [[34], [35], [36], [37], [38], [39], [40], [41]]. Fig. 1 shows the PRISMA flow diagram. The agreement between the two authors on article screening was uniform (kappa = 0.922).

Fig. 1.

The PRISMA flow diagram summarising the literature searches. ‘n' represents the number of articles.

3.1. Characteristics of included studies

All eight studies included in the present systematic review were human clinical trials [[34], [35], [36], [37], [38], [39], [40], [41]]. Two hundred and sixty one patients were examined across eight studies. Six studies were RCTs [[36], [37], [38],40], and two were N-RCTs [39,41]. The studies were conducted predominantly across various countries in Europe, such as Italy [35,36,40] and Switzerland [38]. Two studies were conducted in Asia, one in India [41] and one in China [39], while one early study was conducted in the USA [34]. The studies were conducted on partially or completely edentulous patients with alveolar ridge deficiencies in the age group of 20–70 years. These patients required either vertical or horizontal bone augmentation to attain adequate bone width and height for subsequent implant placement. Table 1 summarizes the relevant characteristics of the included studies.

Table 1.

Summary of the characteristics of the selected studies.

Author, Year	Country	Sample size	Study design	Intervention	Control	Outcome measure	Outcome	Inference
Carpio et al. 2000	USA	48 patients	Grp A: e-PTFE (25) Grp B: Collagen membrane (23)	GBR with e-PTFE membrane	GBR with collagen membrane	Bone gain as reduction in defect size measured clinically	There were no statistically significant difference between the Grps (p > 0.05)	GBR is equally effective with resorbable and non-resorbable membranes
Cucchi et al. 2017	Italy	40 patients	Grp A: d-PTFE (20) Grp B: Collagen plus Ti-mesh (20)	GBR with d-PTFE membrane	GBR with collagen plus Ti-mesh membrane	Bone gain as difference between final peri-implant bone defect (FBD) and initial peri-implant bone defect (IBD)	There was no statistically significant differences between the Grps (p = 0.58)	GBR is equally effective with resorbable and non-resorbable membranes
Cucchi et al. 2019	Italy	40 patients	Grp A: Ti-PTFE (20) Grp B: Collagen plus Ti-mesh (20)	GBR with Ti-PTFE membrane	GBR with collagen plus Ti-mesh membrane	Bone gain as percentage of regenerated bone measured by histomorphological analysis	There was no statistical significance between both Grps in terms of native bone and regenerated bone (p = 0.05)	GBR using non-resorbable membranes and Ti-mesh with resorbable membranes in combination with autogenous bone and bone allograft provide similar histological and histomorphometric results
Atef et al. 2019	Egypt	20 patients	Grp 1: Native collagen membrane (10) Grp 2: Ti-mesh (10)	GBR with Ti-mesh	GBR with native collagen membrane	Bone gain as difference in horizontal bone width measured by CBCT	The mean bone gain of collagen Grp was 3.9 ± 0.9 mm comparedto 3.4 ± 1.2 in Ti-mesh Grp. This was statistically not significant (p = 0.214)	GBR using native collagen membrane and Ti-mesh as a barrier are comparable techniques of horizontal augmentation for deficient maxillary ridges
Naenni et al. 2021	Switzerland	27 patients	Grp 1: Resorbable collagen (9); Grp 2: ePTFE (11)	GBR with Ti-mesh	GBR with native collagen membrane	Bone gain as difference in horizontal bone thickness measured by CBCT	The horizontal bone thickness differed insignificantly between the two Grps at 5 years follow-up	GBR is equally effective with resorbable and non-resorbable membranes
Cucchi et al. 2021	Italy	30 patients	Grp A: Custom made Ti-mesh alone (15) Grp B: Ti-mesh + collagen membrane (15)	GBR with Ti-mesh alone	GBR with Ti-mesh + collagen membrane	Bone gain as difference in vertical bone height and bone volumes measured by CBCT	Bone gain was 803.27 mm3 and 843.13 mm3in Grps A and B respectively, (p = 0.44) i.e. not significant	The results showed that customized meshes alone do not appear to be inferior to customized meshes covered by cross-linked collagen membranes in terms of healing complication rates and regeneration rates
Li et al. 2021	China	40 patients; 65 sites	Grp 1: Resorbable collagen (20 patients/34 sites) Grp 2: Ti-mesh Grp (20 patients/31 sites)	GBR with membrane	GBR with membrane	Bone gain as difference in height and thickness of labial measured by CBCT	The vertical and horizontal bone gain was significantly higher in the Ti-mesh Grp (p < 0.05)	Both resorbable membrane and digital Ti-mesh in GBR were able to successfully reconstruct the bone defect, digital Ti-meshes were better at maintaining the hard tissue volume in the osteogenic space
Vaibhav et al. 2022	India	16 subjects, 32 sites	Grp A: e-PTFE (25) Grp B: Collagen membrane (23)	GBR with e-PTFE membrane	GBR with collagen membrane	Bone gain as percentage of regenerated bone measured radiographically	There was no statistically significant differences in the intergroup comparison (p > 0.05)	GBR is equally effective with resorbable and non-resorbable membranes

Grp: Group.

e-PTFE: Expanded Polytetrafluoroethylene.

d-PTFE: Dense Polytetrafluoroethylene.

Ti-PTFE: Titanium reinforced Polytetrafluoroethylene.

Ti-mesh: Titanium mesh.

GBR: Guided bone regeneration.

CBCT: Cone beam computed tomography.

3.2. Characteristics of interventions

The study groups in the present review received GBR using a RES membrane, such as a collagen membrane, or an N-RES membrane, such as a titanium mesh, or a combination thereof. Full-thickness mucoperiosteal flaps were reflected to expose the bone defects. Most of the studies used native collagen in the control group, however it was layered with a titanium mesh in two studies [36,40]. Four out of eight studies used ePTFE (expanded polytetrafluoroethylene), a popular N-RES synthetic fluoropolymer [[34], [35], [36],41], while the other four studies used titanium meshes as the intervention [[37], [38], [39], [40]].

The bone grafts used for GBR varied among the studies. Two studies utilized autogenous bone [36,40], another two used xenogeneic bone material [38,39], while one used a combination of autogenous bone scrapings with a xenogeneic bone graft material [37]. The remaining studies used a pre-formed titanium mesh for GBR [37,39,40]. Moreover, the placement of the membranes varied between the studies. The membranes were secured underneath the flap, and complete wound closure was achieved. N-RES PTFE membrane sutures were placed in a tension-free manner. Three out of five studies secured the membranes with titanium mini-screws or tac pins [36,37,40], whereas two did not use any additional fixations [38,39].

3.3. Characteristics of outcome measures

All studies measured bone gain following GBR as the primary outcome. Bone gain refers to new bone formation in the defect site, including horizontal, vertical, or an overall increase in the volume of new bone formation. Only one out of eight studies reported an overall increase in the volume of regenerated bone. On the other hand, two studies reported horizontal bone gain (increase in bone width), and two other studies reported horizontal and vertical changes in dimension (increase in bone width and bone height). Cone Beam Computed Tomography was used to determine the dimensional changes in four out of five studies [[37], [38], [39], [40]], while one study used histomorphological analysis for the same [36]. Seven studies reported postoperative complications, including dehiscence, fenestrations, and premature exposure of membranes [[34], [35], [36], [37], [38], [39], [40]]. However, only four studies measured membrane exposure as secondary outcomes [34,35,39,40].

3.4. Characteristics of outcomes

Of the eight studies included in this systematic review, seven reported a null effect for both the test and control groups. The studies found that bone gain was similar when using a RES or N-RES membrane [[34], [35], [36], [37], [38],40,42]. However, one study dissented with this view and reported significant differences in bone gain with N-RES membranes. In this case, sites treated with a titanium mesh showed a higher horizontal and vertical bone gain (p<0.05) [39]. This was attributed to better space maintenance property of the digital titanium meshes compared to RES membranes. As a result, bone regeneration was more stable in the titanium mesh group.

Furthermore, there were appreciable differences in the efficacy of the GBR membranes. N-RES membranes showed slower resorption rates and prevented soft tissue ingress into the defect sites, while the RES membranes lost their barrier function relatively early and allowed soft tissue ingrowth. The soft tissue thickness partially compensated for the hard tissue changes observed over a long period, resulting in stable bone regeneration [38].

Of the four studies that reported on membrane exposure as a secondary outcome, three reported a greater incidence associated with N-RES membranes such as titanium meshes [37,38,40]. One study reported higher rates of membrane exposure in the titanium mesh group (N-RES membranes) [39]. In contrast, two studies reported a significantly higher exposure rate in the group treated with RES membranes [40,42]. The higher rates of membrane exposure with RES membranes can be attributed to their stiffness. The stiffness makes the membranes less malleable and less adaptable to defect sites [43,44]. The resultant early or premature exposure of the membrane (within the first postoperative month) can significantly affect the new bone formation [[45], [46], [47]]. The corresponding exposures in RES membranes are usually late exposures that do not considerably affect new bone formation, albeit some may also occur early [[47], [48], [49], [50]]. Only one study reported that the rate of membrane exposure was equivalent in both groups [35].

3.5. Risk of bias within the studies

Using the RoB 2 tool, five out of six RCTs showed a ‘high’ risk of bias [[34], [35], [36], [37], [38]]. The ‘high’ risk of bias judgment was mainly owing to attrition bias due to missing outcome data. One study lacked relevant information regarding the randomization procedure and showed deviation from the intended intervention [34]. This could skew the effect estimates. Two studies also showed some concern regarding the blinding of outcome assessors [37,38]. Since the five studies had one or more critical domains at a high risk of bias, the overall judgment was evaluated as ‘high’ [[36], [37], [38]]. However, one study showed a low risk of bias [40].

Based on ROBINS-I, two N-RCTs showed a moderate risk of bias [39,41]. The judgment was based on the wide age bracket of the included participants, which resulted in confounding bias. Fig. 2, Fig. 3 depict the risk of bias for the included studies.

Fig. 2.

Summary of the risk of bias for randomized studies.

Fig. 3.

Summary of the risk of bias for non-randomized studies.

3.6. Grade assessment

The present systematic review included eight articles involving 261 patients. The quality of evidence for bone gain was ‘low’ as per the GRADE assessment. The quality of evidence was downgraded by one level to reflect the high risk of bias primarily due to attrition (missing outcome data) in the included studies. The majority of the studies in the present review reported a null effect for the primary outcome. Table 2 depicts the summary of findings using the GRADE system.

Table 2.

Summary of findings table.

	Quality Assessment					Summary of findings
Outcome	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Impact	Number of participants (Studies)	Certainty of evidence (GRADE)
Bone gain	Seriousa	Not serious	Not serious	Seriousb	Not serious	Our confidence in the effect estimate is limited	261 (8)	Low ⊕⊕

GRADE: Grading of Recommendations Assessment, Development and Evaluation.

^aFour studies showed serious concern due to missing outcome data, one study showed concern regarding randomization process and two studies showed concern regarding outcome measurement.

^bSeven studies showed null effect for outcome.

Overall, the studies included in the review were clinical trials that included six randomized clinical trials [[36], [37], [38],40], and two N-RCTs [39,41]. The results appear equivocal and suggest that RES and N-RES membranes appear equally effective in achieving bone gain during GBR. However, the evidence must be interpreted with caution due to its ‘low quality’ GRADE assessment.

4. Discussion

The quality and volume of bone in the implant area affect stability, shape recovery, and success of the implant restoration. Reconstruction of alveolar bone in the operative area for the implant placement is crucial to success. GBR aims to regenerate bone and limit other biological components, such as connective tissue and epithelium, from interfering by selective cell repopulation. The present systematic review evaluates the evidence for the efficacy of N-RES membranes compared to RES membranes in patients undergoing GBR. The results from this systematic review are based on eight articles that include six RCTs and two non-randomized studies. All eight studies included in this review examined the extent of new bone formation in partially or completely edentulous patients with alveolar ridge deficiencies undergoing GBR.

The majority of the studies included in this review reported equivocal outcomes for bone gain, irrespective of the type of membrane used. A growing body of evidence corroborates the results implying that both RES and N-RES membranes show similar results in the long-term [51,52]. Jung et al. conducted a longitudinal study with a follow-up of twelve years. The study assessed the radiographic changes in marginal bone levels. The authors reported similar results with both collagen membrane and e-PTFE groups over a prolonged period of time [52]. However, there was significant heterogeneity in terms of the materials used for the GBR procedures.

RES collagen membranes, including native collagen and synthetic polymers such as polyglycolide, polylactide, and polyesters, are most commonly used in guided tissue regeneration (GTR). Five articles included in this review reported utilizing native collagen membranes in their interventions. Of the five studies, one study reported a better outcome with the use of a native collagen membrane compared to N-RES membranes. This can be attributed to the fact that RES membranes undergo spontaneous degradation in the body with the help of collagenases and proteases. A RES membrane reduces the need for a second surgery to remove the membrane, limiting further tissue damage and reducing patient morbidity [53]. Collagen membranes also show better biocompatibility, tissue integration, and fewer postoperative complications [54,55]. A study conducted by Calciolari et al. on the degradation patterns of porcine collagen membranes proposes that such membranes maintain their structural integrity and mechanical stability during the initial period of wound healing [56]. The signs of degradation, such as a drastic decrease in thickness, usually appear a month after the surgery when most of the wound healing has already taken place. At thirty days post-operatively, the collagen membrane shows dense infiltration of leucocytes and fibroblast-like cells with a vast network of blood vessels penetrating throughout the membrane. These results are consistent with the findings of Moses et al., which advocate the ability of collagen membranes to act as a scaffold and provide the optimum environment for bone regeneration [57]. The properties of collagen membranes mentioned above suggest that these RES membranes can support and improve the bone formation process despite their degradability.

PTFE membranes, e-PTFE membranes, titanium meshes, and titanium reinforced PTFE membranes constitute the N-RES membranes commercially available for GTR. The results of the present systematic review are inconsistent with the studies conducted by Roccuzzo et al., Corinaldesi et al., and Degidi et al. [19,58,59]. The present review reported comparable outcomes among both groups in the majority of the studies. However, the disparity in results could be an outcome of the prolonged follow-up period in most of the articles included in the present review. The authors have reported that N-RES membranes show excellent results in GBR in their respective studies [19,58,59]. A plausible explanation for these results could be the macroporosity and rigidity of the commercially available N-RES membranes. The rigidity of N-RES titanium meshes improves the stabilization of the bone graft material and prevents its displacement. The membrane also allows for extensive and long-term space maintenance, a prerequisite, especially in vast horizontal and vertical ridge augmentations [18]. Macroporosity plays a central role in regulating blood supply to the grafted site. It also increases wound stability and acts as a semi-permeable membrane for the diffusion of extracellular components. The attachment of soft tissues to a N-RES membrane stabilizes the membrane and restricts epithelial migration. In conclusion, titanium mesh ensures predictable results for tissue regeneration [60,61].

The majority of the studies included in the review showed higher rates of complications associated with N-RES membranes in GBR. The stiffness of titanium meshes, albeit beneficial in long-term space maintenance, predisposes to early membrane exposure. The sharp edges due to manipulation of the titanium meshes are likely to cause soft tissue irritation and trauma [43,44].

On the other hand, evidence suggests a higher rate of infections in RES membranes due to their spongy architecture [48]. In contrast to the rough surface of resorbable collagen membranes, the smooth surface of titanium membranes reduces the likelihood of contamination [44,62]. This has been supported by several studies, which have demonstrated that titanium meshes possess superior mechanical and osteogenic properties [[63], [64], [65]].

4.1. Overall completeness and applicability of evidence

All the studies included in the present systematic review were human clinical studies. All eight studies included in the review reported on bone gain. However, horizontal and peri-implant bone regeneration may not be the only important aspect to be compared between the types of membranes. The complications regarding exposure of the mesh itself or loss of bone are important parameters that need to be reported. None of the studies reported on patient-related outcomes of pain and discomfort. Patient choices could be affected by effectiveness, safety, and morbidity associated with the intervention. Future studies should include this as an important outcome to be examined as this information can augment the applicability of one membrane over the other.

Moreover, the thickness and porosity of the titanium meshes employed were not uniform across the studies. These key factors can affect mechanical properties. Pore size can affect tissue ingrowth into barriers, while mesh thickness may affect bone formation [66]. Currently, PTFE materials enjoy immense popularity as membrane and graft materials owing to their unique properties and performance. However, PTFE materials, while not directly regulated at this time, may be impacted by future investigations into its health risk, cytotoxicity, and bioaccumulation. Due to heterogeneity in the materials and procedures used for GBR in the studies, a meta-analysis could not be performed.

4.2. Quality of evidence

The evidence primarily consisted of RCTs, except for two N-RCTs. The majority of the studies reported significant attrition bias. This was primarily due to missing outcome data stemming from the removal of cases associated with complications or loss to follow-up of the participants. Some studies lacked relevant information regarding the randomization procedure or had concerns regarding the blinding of assessors. One study reported deviations from the intended intervention. Therefore, there was a significant imprecision in the quality of evidence owing to the disparity in the primary outcomes of the studies included in the present systematic review.

The quality of the evidence for the primary outcome, i.e., bone gain, and the secondary outcome, i.e., membrane exposure, was low based on the GRADE assessment. This limits our confidence in the effect estimates, suggesting that the true estimate and effect estimate may vary considerably. A high dropout and deviation from the intended intervention rate may skew the intervention effect and is the primary reason for a low assessment of the available evidence. Seven studies out of eight reported a null impact on bone gain (primary treatment outcome). Conversely, one study reported a null effect, and another reported a negative effect for membrane exposure (secondary outcome). This suggests an imprecision in the certainty of the effect of treatment that cannot be explained [67,68]. For the reasons mentioned above, the quality of evidence for the present systematic review was assessed as ‘low’. Overall, the methodological flaws within the studies lead to significant bias.

The strengths of our study include a comprehensive electronic search of three databases with a supplementary manual search of references from relevant articles to identify pertinent articles. The eligibility of the studies was determined by multiple reviewers adhering to a well-planned inclusion criterion. Despite the best efforts from the authors, this review is not without limitations. The present systematic review only included articles originally published in English, since translated articles may lack veracity. This may have inadvertently led to publication bias.

The future of bone regeneration involves further research in tissue engineering and three-dimensional printed scaffolds [39,40,69]. Understanding the strengths and shortcomings of the membranes will further facilitate research in this field. Future research should be aimed at conducting human clinical trials with a large well-matched patient population. Homogeneity in the type and method of GBR and method of assessment of new bone formation will derive conclusive results on the efficacy of RES and N-RES membranes in achieving new bone formation. Long-term follow-ups are essential to understand the behavior of RES and N-RES membranes over an extended period.

5. Conclusion

Based on the limited available evidence, RES and N-RES membranes appear equally effective in achieving bone gain during GBR. However, the evidence must be interpreted with caution due to its ‘low quality’ GRADE assessment. The limitations in the design and conduct of the included studies render their applicability to wider populations uncertain. Further research focusing on human clinical trials with well-matched patients with homogeneity in the type and method of GBR and method of assessment of new bone formation will have an effect on this estimation. Future research is needed to determine the safety and health risk of PTFE materials used for membranes for achieving new bone formation.

Funding statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability statement

Data included in article/supp. material/referenced in article.

Declaration of interest's statement

The authors declare no conflicts of interest. Marcos Roberto Tovani-Palone is one of the section editors of Heliyon, however the article will not be assigned to him or any of his colleagues.

Author contribution statement

Concept/Design: Shankargouda Patil (SGP), Marcos Roberto Tovani-Palone (MRT-P), Khalid J. Alzahrani (KJA).

Data collection: Shilpa Bhandi (SB), Mohammed Mousa H. Bakri (MHB), Mohammad S. Al-Ghamdi (MAG), Mrim M. Alnfiai (MMA).

Data analysis/interpretation: Dhalia H. Albar (DHA), Shankargouda Patil (SGP), Marcos Roberto Tovani-Palone (MRT-P).

Drafting article: Shankargouda Patil (SGP), Marcos Roberto Tovani-Palone (MRT-P), Dhalia H. Albar (DHA), Mohammad S. Al-Ghamdi (MAG).

Critical revision of the article: Shankargouda Patil (SGP), Marcos Roberto Tovani-Palone (MRT-P), Mrim M. Alnfiai (MMA).

Statistics: Shilpa Bhandi (SB), Mohammed Mousa H. Bakri (MHB).