YIJOM-3938; No of Pages 12 Systematic Review and Meta-Analysis Pre-Implant Surgery Int. J. Oral Maxillofac. Surg. 2018; xxx: xxx–xxx https://doi.org/10.1016/j.ijom.2018.04.022, available online at https://www.sciencedirect.com Efficacy of stem cells in maxillary sinus floor augmentation: systematic review and meta-analysis T. C. Niño-Sandoval, B. C. Vasconcelos, S. L. D. Moraes, C. A. A. Lemos, E. P. Pellizzer: Efficacy of stem cells in maxillary sinus floor augmentation: systematic review and meta-analysis. Int. J. Oral Maxillofac. Surg. 2018; xxx: xxx–xxx. ã 2018 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. The aim of this review was to test the hypothesis of no difference in the efficacy of bone regeneration when using stem cells in maxillary sinus floor augmentation surgery in comparison to other grafts. Nine randomized clinical trials and one follow-up study involving human subjects were identified through a search of the PubMed/MEDLINE, Scopus, Cochrane, and Web of Science databases, supplemented by a hand search. No significant difference between groups was found for the implant survival rate, increase in bone height, marginal bone loss following implant placement, or new bone formation. With regard to the residual bone graft, an effect favouring the graft group at 3–4 months (P = 0.001) and favouring the stem cell group at 6 months (P = 0.01) was found. Analyses of the subgroup in which the BMAC system extraction method was used in combination with Bio-Oss, revealed no difference in new bone formation; however, the results for residual bone graft at 3 months favoured the control graft (Bio-Oss) (P = 0.01), but at 6 months favoured the stem cells (Bio-Oss + BMAC system) (P = 0.01). Based on all findings, the use of stem cells does not contribute significantly to greater implant survival rates or the efficacy of bone regeneration following sinus lift procedures. Please cite this article in press as: Niño-Sandoval TC, et al. Efficacy of stem cells in maxi review and meta-analysis, Int J Oral Maxillofac Surg (2018), https://doi.org/10.1016/j.ijo 0901-5027/000001+012 ã 2018 International Association of Oral and Maxillofacial Surge T. C. Niño-Sandoval1, B. C. Vasconcelos1, S. L. D. Moraes2, C. A. A. Lemos3, E. P. Pellizzer3 1Department of Oral and Maxillofacial Surgery, University of Pernambuco, Camaragibe, Pernambuco, Brazil; 2Department of Prosthodontics, University of Pernambuco, Recife, Pernambuco, Brazil; 3Department of Prosthodontics and Dental Materials, Araçatuba Dental School, São Paulo State University – UNESP, Araçatuba, São Paulo, Brazil Key words: stem cells; sinus augmentation; sinus lift; review. Accepted for publication 24 April 2018 The posterior region of the maxilla often requires work for the rehabilitation of edentulous patients. The main challenges in this region are low bone density and anatomical limitations due to alveolar resorption following tooth loss and close contact with the maxillary sinus1,2. It is essential to consider the recovery of bone volume for rehabilitation in this area. Maxillary sinus floor augmentation (sinus lift) is considered the most appropriate procedure in such cases. Autogenous grafts are regarded as one of the best materials for the repair of bone defects2–5. The most notable characteris- tics of these grafts have been described widely in the literature, in animal models and in human and in vitro studies3,6. The llary sinus floor augmentation: systematic m.2018.04.022 ons. Published by Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.ijom.2018.04.022 https://doi.org/10.1016/j.ijom.2018.04.022 https://doi.org/10.1016/j.ijom.2018.04.022 2 Niño-Sandoval et al. YIJOM-3938; No of Pages 12 osteoinductive, osteoconductive, and os- teogenic properties of autogenous grafts have been demonstrated7. This material is used to fill the area between the ele- vated Schneiderian (sinus) membrane and the posterior maxillary bone ridge. While autogenous bone grafts have prop- erties that enhance the quality of hard tissue recovery, morbidity at the donor site as well as the difficulties posed by the technique during the bone preparation process are important undesirable aspects to consider2–4,8. Continual advances have been made in the field of tissue engineering, offering effective options for the resolution of such problems and representing a solu- tion based partially on natural mecha- nisms of bone growth and development. One such option is the use of stem cells, which contribute to bone regeneration. Moreover, the acquisition of stem cells is often less traumatic than the acquisition of autogenous bone, which leads to a considerable reduction in donor site morbidity2,8–10. Stem cells have pluripotent character- istics and a mesenchymal origin, with the capacity to differentiate into specific tis- sues, depending on molecular stimuli9,10. In the case of sinus lift, the idea is to enhance the bone regeneration process through the differentiation of stem cells into osteogenic cells11. This process has demonstrated important bone recovery, as shown in histological and morphomet- ric analyses12–14. Studies involving ani- mals have demonstrated a positive response with regard to the effectiveness of bone repair in the maxillary sinus6. However, unlike animal studies, research involving humans is scarce and hetero- geneous. For this reason, no definitive method of cellular isolation, scaffold, and tissue of origin for mesenchymal stem cell collection have been estab- lished as the most effective for maxillary sinus lift procedures. This situation was observed in recent systematic reviews related to oral sur- gery5,15, in which the absence of a con- sensus about the use of stem cells associated with bone graft for maxillary sinus floor augmentation is evident. Thus, the aim of the present study was to per- form a systematic review and meta-analy- sis to evaluate the effectiveness of stem cells in the bone repair process following maxillary sinus floor augmentation. The hypothesis considered was that no differ- ence would be found in comparison to other grafts in this procedure with regard to the efficacy of bone regeneration and the implant survival rate. Please cite this article in press as: Niño-San review and meta-analysis, Int J Oral Maxil Materials and methods Study design and registry This systematic review was conducted in compliance with the recommenda- tions found in the Cochrane Handbook for Systematic Reviews of Interven- tions16 and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)17. The guid- ing question was ‘‘Is the use of grafts with stem cells more efficacious with regard to bone regeneration in maxillary sinus floor augmentation surgery?’’ This study is registered in the PROSPERO database (number CRD42017064323). Eligibility criteria The search terms were established using the PICO system: P (patient), i.e. patients submitted to maxillary sinus floor aug- mentation surgery; I (intervention), i.e. the use of graft material with stem cells; C (comparison), i.e. comparison to the use of graft material without stem cells; and O (outcomes), i.e. outcomes corresponding to the efficacy of bone regeneration. The inclusion criteria were randomized clinical trials that demonstrated the use and effectiveness of grafts with stem cells for maxillary sinus floor augmentation procedures in humans, published in the English language, with no restriction im- posed regarding the year of publication. Studies involving animals, in vitro studies, ex vivo studies, case series, and reviews were excluded. Search strategy Searches were performed in the PubMed/ MEDLINE, Scopus, Cochrane, and Web of Science databases for articles published up to May 2, 2017 using the following terms: ‘‘stem cells and sinus floor aug- mentation OR stem cells and sinus aug- mentation OR stem cells and sinus elevation OR stem cells and sinus lift OR stem cells and sinus graft’’. The titles and abstracts were read by two indepen- dent, blinded researchers (T.N.-S. and C. L.) for the pre-selection of potential arti- cles. Divergences of opinion regarding the inclusion or exclusion of a study were resolved by consensus. If necessary, a third researcher (B.V.) was consulted for the final decision. Hand-searches were also performed in specialized periodicals: British Journal of Oral and Maxillofacial Surgery, In- ternational Journal of Oral and Maxil- lofacial Surgery, Journal of Dentistry, Medicine and Medical Sciences, Journal doval TC, et al. Efficacy of stem cells in maxil lofac Surg (2018), https://doi.org/10.1016/j.ijo of Cranio-Maxillo-Facial Surgery, Jour- nal of Oral and Maxillofacial Surgery, and Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology. The criteria for the pre-selection of articles through title and abstract reading included the use of mesenchymal stem cells with an osteogenic lineage regardless of their origin, without a control that includes other stem cell methods. A kappa test was used to determine the level of agreement between the researchers re- garding the article selection process18. Data collection process Based on the first reading of the articles, two evaluation tables were created for the extraction of the data. The first table con- tained the main identification data, demo- graphic aspects of the sample, and quantitative measurement data (clinical, imaging, and histomorphometric data). The second table contained the qualitative data (materials employed, exclusion crite- ria, initial bone height, and type of im- plant) to complement the information in the first table and enable a more in-depth analysis. Evaluation of risk of bias The risk of bias in the randomized clinical trials was evaluated using the tool proposed by Cochrane19 and the Review Manager 5.3 software program (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Summary measures A meta-analysis was performed with the quantitative data obtained from the ran- domized clinical trials using Review Manager 5.3, considering differences in mean and standard deviation values. The I2 statistic was used for the determination of heterogeneity (25% = low, 50% = moderate, and 75% = high). The in- verse variance method was employed to determine the most adequate model for the analysis. A random-effects model was used if heterogeneity was statistically significant (P < 0.10) and a fixed-effects model was used if a larger P-value was found20. The inverse variance method was used for the evaluation of the implant survival rate and the determination of the risk ratio (RR) with a fixed-effects model, considering the dichotomous nature of the data. lary sinus floor augmentation: systematic m.2018.04.022 https://doi.org/10.1016/j.ijom.2018.04.022 Stem cells in maxillary sinus floor augmentation 3 YIJOM-3938; No of Pages 12 Results Selection of studies A total of 590 articles were identified: 104 were found in PubMed, 205 were found in Scopus, 235 were found in Web of Science, 12 were found in the Cochrane database, and 34 were found through the hand search. After analysis of the titles and abstracts, 54 articles were pre-selected. Once duplicates had been removed, 20 articles were submit- ted to full-text analysis. The kappa coefficient after the selection of titles and abstracts was 0.87 for PubMed/ MEDLINE, 0.87 for Scopus, 0.93 for Web of Science, 1.0 for Cochrane, and 1.0 for the hand search. According to Landis and Koch18, these kappa coefficients demon- strate a high level of agreement. After the full-text analysis, 10 articles were excluded: one for using stem cells in the control group21, one for not presenting quantitative outcome data4, seven for be- ing case series9,12,13,22–25, and one for being a compilation of four previously published studies26. Figure 1 displays the article selection process. Thus, 10 articles were selected for the qualitative and quantitative analyses: nine randomized clinical trials2,7,10,11,14,27–30 and one follow-up study of a randomized clinical trial offeringadditional information that completed the evaluation table8. Of the nine randomized clinical trials selected for review, three had a partial split-mouth de- sign14,28,30. In one of these studies, all max- illary sinuses were randomized and a partial split-mouth cross-over design was employed28. In the other two studies, the split-mouth design was performed for bi- lateral treatment and the remaining patients were included in the stem cell group14,30. Three studies employed a complete split- mouth design2,27,29. Three other studies Please cite this article in press as: Niño-San review and meta-analysis, Int J Oral Maxil Fig. 1. Article selection process. employed a design in which half of the sinuses were randomly allocated to the control group and half to the stem cell group7,10,11. One hundred and thirty-six patients were included in the studies. Their mean age was 56.46 years (range 49.1– 60.8 years). Table 1 displays the number of patients and maxillary sinuses submitted to stem cell treatment and control treatment (graft without stem cells), as well as a description of the clinical cases. Implant survival rate The difference in implant survival rate was not significant when comparing con- trol grafts and grafts with stem cells (P = 0.06; Risk ratio (RR) of 4.28, (95% CI 0.95–19.38)) (Fig. 2). Imaging characteristics All studies involved severe bone defects. The initial alveolar height did not surpass 11.6 mm and most heights were less than 5 mm (Table 2). The increase in bone height (mm) was evaluated on radiographs at 4–5 months in two studies11,30, and no difference was found between the stem cell and control groups (P = 0.57; mean difference (MD) �0.38, 95% CI �1.68 to 0.92) (Fig. 3). Two studies evaluated the increase in bone height using computed tomography at a similar postoperative evaluation time11,28. Once again, stem cells were found to have no significant influence on bone gain (cm3) (P = 0.24; MD 0.23, 95% CI �0.15 to 0.62) (Fig. 4). Two studies evaluated marginal bone loss following implant placement8,10. No significant difference was found between the groups (P = 0. 42; MD �0.27, 95% CI �0.93 to 0.39) (Fig. 5). doval TC, et al. Efficacy of stem cells in maxi lofac Surg (2018), https://doi.org/10.1016/j.ijo Histomorphometric characteristics In the majority of randomized clinical trials that involved a histomorphometric analysis, biopsy samples were obtained 3–4 months after maxillary sinus floor augmentation surgery2,14,27–29. No signif- icant difference between the stem cell group and the control group (graft without stem cells) was found with regard to the formation of new bone (P = 0.41; MD 2.21, 95% CI �3.09 to 7.51) (Fig. 6A). The same was true for the formation of new bone in samples obtained 6 months after surgery (P = 0.10; MD 4.29, 95% CI �0.80 to 9.38) (Fig. 6B)7,27,29,30. As can be observed in Table 2, four studies used the same extraction and cellu- lar isolation method2,7,27,28, in which Bio- Oss was used as a control and stem cells were isolated with the BMAC method and subsequently were installed in Bio-Oss. This allowed an analysis of subgroups to be performed with regard to new bone formation and residual graft content. In the subgroup analysis, no significant difference in new bone formation was found between the stem cell group (Bio- Oss + BMAC system) and the control group (Bio-Oss) at 3–4 months (P = 0.86; MD �0.42, 95% CI �5.04 to 4.20) (Fig. 7A). Moreover, no significant difference was found between the stem cell group (Bio-Oss + BMAC system) and the control group (Bio-Oss) at 6 months (P = 0.36; MD 12.94, 95% CI �14.72 to 40.60) (Fig. 7B). In studies that determined the influence of treatment on the residual graft, the control group (graft without stem cells) demonstrated better results in comparison to the stem cell group in the evaluations performed at 3–4 months (P = 0.001; MD 9.96, 95% CI 3.92 to 16.01) (Fig. 8A), whereas a significant difference favouring the stem cell group was found at the 6- month evaluation (P = 0.01; MD �5.52, 95% CI �9.87 to �1.17) (Fig. 8B). In the subgroup analysis of residual graft content, a difference in favour of the control group (Bio-Oss) was found at 3–4 months (P = 0.01; MD 8.13, 95% CI 1.73 to 14.52) (Fig. 9A). At the 6-month evaluation, the results favoured the stem cell group (Bio-Oss + BMAC system) over Bio-Oss (P = 0.01; MD �8.76, 95% CI �15.65 to �1.87) (Fig. 9B). The final histomorphometric measure investigated in this review was the marrow space, which was evaluated in two studies2,28. In both studies, the control group was Bio-Oss bovine bone mineral + autogenous graft. As seen in Fig. 10, more marrow space was found in the control llary sinus floor augmentation: systematic m.2018.04.022 https://doi.org/10.1016/j.ijom.2018.04.022 4 N iñ o -S a n d o va l et a l. Y IJO M -3 93 8 ; N o o f P ag es 1 2 P lease cite th is article in p ress as: N iñ o -S an d o v al T C , et al. E ffi cacy o f stem cells in m ax illary sin u s fl o o r au g m en tatio n : sy stem atic rev iew an d m eta-an aly sis, In t J O ra l M a x illo fa c S u rg (2 0 1 8 ), h ttp s://d o i.o rg /1 0 .1 0 1 6 /j.ijo m .2 0 1 8 .0 4 .0 2 2 Table 1. Characteristics of studies selected; T, test group; C, control group. Author Patients Sinusesa Follow-up after surgery New bone formation (mean, %) Presence/residual graft content (biomaterial) (%) Marrow space Increase in bone height (mean, mm) Increase in bone (mean, cm3) Bone loss after implant placement (mean, mm) Healing time (months) Implant survival rate Gonshor et al. 201114 14 7 BIL (7T, 7C) 7 UNI (7T) Total: 21 (14T, 7C) 3–4 months 3–4 months C: 18.3 � 10.6 T: 32.5 � 6.8 3–4 months C: 4.9 � 2.4 T: 25.8 � 13.44 – – – – T: 3.7 � 0.6 – Rickert et al. 20112 11 11 BIL (11T, 11C) Total: 22 3–4 months 3–4 months C: 13.08 � 6.2 T: 18.86 � 7.36 3–4 months C: 26.47 � 7.3 T: 28.96 � 9.73 3–4 months C: 54.07 � 7.6 T: 52.4 � 5.9 – – – 3.25–4 (13–16 weeks) – Rickert et al. 20148 (Follow-up of Rickert et al. 20112) 12 12 BIL (12T, 12C) Total: 24 12 months – – – – – 12 months C: 0.41 � 0.25 T: 0.47 � 0.31 – C: 100% T: 91% Sauerbier et al. 201128 26 7 UNI (6T, 1C) 9 BIL (18T) 10 BIL (10T, 10C) Total: 45 (34T, 11C) 3–4 months 3–4 months C: 14.3 � 1.8 T: 12.6 � 1.7 3–4 months C: 19.3 � 2.5 T: 31.3 � 2.7 3–4 months C: 57.7 � 2.3 T: 54.4 � 2.2 – 3–4 months C: 1.33 � 0.62 (11 samples) T: 1.74 � 0.69 (28 samples) – Total: 3.41 � 0.39 C: 3.34 � 0.42 T: 3.46 � 0.43 – Hermund et al. 201210 19 19 UNI (9T, 10C) Total: 19 2.5 years – – – – 2.5 years C: 1.88 � 0.37 T: 1.27 � 0.23 4 C: (20/20) 100% T: (15/18) 83% Wildburger et al. 201327 7 7 BIL (7T, 7C) Total: 14 6 months 3 months C: 11.89 � 6.24 T: 7.46 � 4.14 3 months C: 34.99 � 11.89 T: 42.67 � 3.57 – – – – – – 6 months C: 13.95 � 8.57 T: 13.53 � 5.47 6 months C: 39.51 � 9.3 T: 36.27 � 7.87 Payer et al. 201429 6 6 BIL (6T, 6C) Total: 12 6 months 3 months C: 9.45 � 4.15 T: 10.36 � 11.83 3 months C: 16.40 � 18.59 T: 15.06 � 12.52 – – – – – (44/44) 100% 6 months C: 10.41 � 5.25 T: 14.17 � 3.59 6 months C: 20.26 � 11.32 T: 17.89 � 9.63 Kaigler et al. 201511 23 23 UNI (11T, 12C) Total: 23 12 months – – – 4 months C: 12.8 � 2.8 T: 12.2 � 3.3 4 months C: 2.1 � 0.9 T: 1.8 � 1.0 – – C: (20/20) 100% T: (18/19) 94.73% Pasquali et al. 20157 8 8 BIL (8T, 8C) Total: 16 6 months 6 months C: 27.30 � 5.55 T: 55.15 � 20.91 6 months C: 22.79 � 9.60 T: 6.32 � 12.03 – – – – – – https://doi.org/10.1016/j.ijom.2018.04.022 S tem cells in m a xilla ry sin u s fl o o r a u g m en ta tio n 5 Y IJO M -3 93 8 ; N o o f P ag es 1 2 P lease cite th is article in p ress as: N iñ o -S an d o v al T C , et al. E ffi cacy o f stem cells in m ax illary sin u s fl o o r au g m en tatio n : sy stem atic rev iew an d m eta-an aly sis, In t J O ra l M a x illo fa c S u rg (2 0 1 8 ), h ttp s://d o i.o rg /1 0 .1 0 1 6 /j.ijo m .2 0 1 8 .0 4 .0 2 2 Prins et al. 201630 10 6 BIL (6T: 3 BCP, 3 b-TCP; 6C: 3 BCP, 3 b-TCP) 4 UNI (4T: 2 BCP, 2 b-TCP) Total: 16 (10T, 6C) �3 years 6 months C (b-TCP): 12.0 � 2.6 (MBV) T (b-TCP): 16.4 � 5.2 (MBV) 6 months C (b-TCP): 29.6 � 8.2 T (b-TCP): 17.4 � 9.4 – 5 months C (b-TCP): 10.2 � 1.5 T (b-TCP): 9.9 � 1.3 – – – C: (16/16) 100% T: (27/28) 96.42% 6 months C (BCP): 14.7 � 3.2 (MBV) T (BCP): 15.1 � 2.3 (MBV) 6 months C (BCP): 19.1 � 5.9 T (BCP): 18.5 � 3.7 5 months C (BCP): 12.4 � 1.6 T (BCP): 12.1 � 1.6 BCP, biphasic calcium phosphate; b-TCP, beta-tricalcium phosphate; MBV, mineralized bone volume. a BIL, bilateral; UNI, unilateral. https://doi.org/10.1016/j.ijom.2018.04.022 6 Niño-Sandoval et al. YIJOM-3938; No of Pages 12 Fig. 2. Implant survival rate: graft vs. graft + stem cells. group than in the stem cell group (P < 0.0001; MD �3.19, 95% CI �4.68 to �1.69). Assessment of risk of bias Figure 11 displays the results of the meth- odological quality appraisal of the ran- domized clinical trials. Discussion In this systematic review, the efficacy of bone regeneration was evaluated using histomorphometric aspects (new bone for- mation, residual graft, and marrow space). No significant difference in the new bone formation rate was found with the use of stem cells in comparison to bone grafts alone for maxillary sinus lift, regardless of the follow-up period. These findings are in disagreement with those of previous reviews, which have reported promising results when stem cells are used in maxil- lary sinus lift procedures3,31. This differ- ence may be explained by the inclusion of only randomized clinical trials in the pres- ent review in an attempt to offer better scientific evidence. Stem cells may be favourable in maxil- lary sinus lift procedures, as the results for bone regeneration were similar to those achieved with bone grafts, such as Bio- Oss. The literature reports that these mate- rials achieve favourable bone regeneration results that are often similar to the ‘gold standard’ (autogenous bone)32,33. To reduce as much variation in the results as possible, a subgroup analysis of studies using the same extraction meth- od was considered. The BMAC method combined with Bio-Oss was used in four studies2,7,27,28 (Fig. 7). In this analysis, the difference remained non-significant, even though each article showed an important gain in bone formation with stem cells. Considering the absence of a benefit from the use of stem cells, the advantages do not outweigh the disadvantages of performing Please cite this article in press as: Niño-San review and meta-analysis, Int J Oral Maxil an extra procedure or the costs needed to associate stem cells with the graft8. Among the studies included in the meta- analysis, Gonshor et al. reported better new bone formation results in the stem cell group in comparison to the control group14. This difference may be related to the use of homologous bone in the control group and, to some extent, the use of stem cells contributes to better bone formation compared to bone graft alone. In contrast, higher residual bone graft content was found in the stem cell group in that study, which contributed to the significant differ- ence favouring the control group at the 3–4-month evaluation. On the other hand, in the analysis of the stem cells obtained using the BMAC method combined with Bio-Oss, the resid- ual bone graft content was significantly lower in the control graft (Bio-Oss) at 3–4 months (Fig. 9A). However, at 6 months, less residual bone graft was found in the stem cell group (Fig. 9B). Similar results were also found for the overall residual graft content (Fig. 8). Thus, it is possible that a healing period of 3–4 months is insufficient to perform the implant installation procedure. None- theless this premise can only be proved with the inclusion of new randomized clinical trials. The final histomorphometric measure investigated in this review was the marrow space, which was evaluated in two studies and was found to be significantly greater in the control group (without stem cells)2,28. This finding is important, since this space will be replaced with bone marrow and blood vessels, favouring the blood flow necessary for bone develop- ment2,28. Both studies reported greater residual bone graft at the 3-month evalua- tion, which implies incomplete maturation of the grafts when combined with stem cells in comparison to autogenous bone grafts. This may have been one of the factors contributing to the high implant failure rate in one of the studies evaluat- ed8. However, no difference in implant doval TC, et al. Efficacy of stem cells in maxil lofac Surg (2018), https://doi.org/10.1016/j.ijo survival rate was found in the comparison of maxillary sinus lift procedures with stem cells and those with bone graft alone. Such results are likely due to the lack of a difference in new bone formation between the two groups. Another clinical characteristic consid- ered for evaluation in the present review was the healing time, since, in theory, the use of stem cells leads to a shorter healing time and enables earlier implant place- ment2,4,8,13,14,24,30. However, only Sauerb- ier et al. provided a detailed description of this comparison between the groups28. Thus, it was not possible to determine the efficacy of stem cells in terms of this outcome. Several limitations were found in the present review, one of the most important being the heterogeneity of the materials used and different stem cell sources. In most cases, the stem cells were obtained through an aspiration puncture of the pelvic bone latero-caudally in the upper superior–posterior region of the iliac crest with a bone marrow biopsy nee- dle2,7,11,27,28. However, other sources were also used. Payer et al. obtained stem cells from the bone marrow of the medial condyle on the proximal surface of the tibia29, although one should consider the possibility that cell concentrations for relevant effects on bone regeneration may be lower in this region in comparison to other sources. Prins et al. obtained adipose tissue cells through liposuction of the abdominal wall30. Although such cells have an adequate volume with os- teogenic capacity, there are problems re- garding the standardization of the process, such as the concentration, due to the fact that the implementation of this technique on humans is relatively recent. Obtaining stem cells is minimally trau- matic for the patient and does not require general anaesthesia or sedation, which is an advantage in relation to aspiration tech- niques involving the iliac crest, tibial con- dyle, or abdominal wall. In the study by Hermund et al., cells were obtained from lary sinus floor augmentation: systematic m.2018.04.022 https://doi.org/10.1016/j.ijom.2018.04.022 S tem cells in m a xilla ry sin u s fl o o r a u g m en ta tio n 7 Y IJO M -3 93 8 ; N o o f P ag es 1 2 P lease cite th is article in p ress as: N iñ o -S an d o v al T C , et al. E ffi cacy o f stem cells in m ax illary sin u s fl o o r au g m en tatio n : sy stem atic rev iew an d m eta-an aly sis, In t J O ra l M a x illo fa c S u rg (2 0 1 8 ), h ttp s://d o i.o rg /1 0 .1 0 1 6 /j.ijo m .2 0 1 8 .0 4 .0 2 2 Table 2. Qualitative characteristics of studies selected. Author Control grafta Mesenchymal stem cells (MSCs)a Initial alveolar height, mmb Type of implanta Gonshor et al. 201114 Cancellous particulate allograft (AlloOss) Allograft cellular bone graft material (Osteocel) (from cadavers within 24 h of death) <5 NR Rickert et al. 20112 Rickert et al. 20148 (follow-up of Rickert et al. 20112) BBM (Bio-Oss) + autogenous bone BBM (Bio-Oss) + iliac crest MSCs: BMAC system (superior–posterior iliac spine) Left side: 2.2 � 0.6 Right side: 2.1 � 0.3 12 mm length, 4.1 mm diameter; endosseous implants (Straumann standard SLA implants) Sauerbier et al. 201128 BBM (Bio-Oss) + autogenous bone BBM (Bio-Oss) + superior–posterior iliac spine MSCs: BMAC system <4 NR Hermund et al. 201210 Composite graft of 1 cm3 of autogenous bone harvested with a scraper (SafeScraper) from the lateral side of the maxilla and 1 cm3 of DBBM (Bio-Oss) MSCs (atrophic tuberosity region) + composite graft of 1 cm3 of autogenous bone harvested with a scraper (SafeScraper) from the lateral side of the maxilla and 1 cm3 of DBBM (Bio-Oss) <3 10–12 mm length, 4.1 mm diameter; Wide Neck/Plus Straumann SLA dental implants Wildburger et al. 201327 BBM (Bio-Oss) BBM (Bio-Oss) + BMAC system (superior–posterior iliac crest) <3 XiVE implants Payer et al. 201429 Bio-Oss 0.25–1 mm Bone marrow (proximal medial tibia condyle) + Bio-Oss 0.25–1 mm <3 XiVE implants Kaigler et al. 201511 b-TCP scaffold Stem cell therapy (bone marrow from posterior iliac crest) (Ixmyelocel-T) + b-TCP scaffold Control: 5.0 (2.5–6.2) MSCs: 3.5 (2.1–6.1) 10–14 mm length, 3.3–4.8 mm diameter; Straumann oral implants Pasquali et al. 20157 Xenogeneic bone from bovine hydroxyapatite (1–2 mm Bio-Oss) Bio-Oss, BMAC system (superior– posterior iliac crest) �4 Black-Fix implants Prins et al. 201630 BCP BCP + autologous adipose-derived SVF (from abdominal wall) 4–8 10–12 mm length, 4.1 mm diameter, Straumann dental implants b-TCP b-TCP + autologous adipose-derived SVF (from abdominal wall) BBM, bovine bone mineral; BCP, biphasic calcium phosphate; BMAC, Bone Marrow Aspirate Concentrate; b-TCP, beta-tricalcium phosphate; DBBM, deproteinized bovine bone mineral; NR, not reported; SVF, stromal vascular fraction. a AlloOss (ACE Surgical Supply Co., Inc. Brockton, MA, USA); Osteocel1 (NuVasive1, Inc. by ACE Surgical Supply Co., Inc. Brockton, MA, USA); Bio-Oss (Geistlich Biomaterials, Wolhusen, Switzerland); BMAC system (Harvest Technologies Corporation, Plymouth, MA, USA); SafeScraper (Meta, Reggio Emilia, Italy); Ixmyelocel-T (Vericel Corporation, Cambridge, MA, USA); Cerasorb (Curasan AG, Germany); Straumann implants (Institut Straumann AG, Basel, Switzerland); XiVE implants (Dentsply-Friadent, Mannheim, Germany); Black-Fix (AS Technology, São José dos Campos, Brazil). b Data are shown as the mean � standard deviation, or median (range). https://doi.org/10.1016/j.ijom.2018.04.022 8 Niño-Sandoval et al. YIJOM-3938; No of Pages 12 Please cite this article in press as: Niño-Sandoval TC, et al. Efficacy of stem cells in maxillary sinus floor augmentation: systematic review and meta-analysis, Int J Oral Maxillofac Surg (2018), https://doi.org/10.1016/j.ijom.2018.04.022 Fig. 3. Postoperative increase in bone height (mm): graft vs. graft + stem cells. Fig. 4. Postoperative bone volume increase (cm3): graft vs. graft + stem cells. Fig. 5. Marginal bone loss (mm): graft vs. graft + stem cells. Fig. 6. Overall new bone formation (%): graft vs. graft + stem cells. (A) At 3–4 months. (B) At 6 months. https://doi.org/10.1016/j.ijom.2018.04.022 Stem cells in maxillary sinus floor augmentation 9 YIJOM-3938; No of Pages 12 Fig. 7. New bone formation (%) according to subgroup: Bio-Oss vs. Bio-Oss + BMAC. (A) At 3–4 months. (B) At 6 months. Fig. 8. Overall residual graft content (%): graft vs. graft + stem cells. (A) At 3–4 months. (B) At 6 months. the region of atrophic tuberosity, which has osteoprogenitor cells and mature osteoblasts10; however, the authors only reported results with regard to marginal bone loss following implant placement. Among the studies analyzed herein, only Gonshor et al. used a commercial allograft prepared from tissue obtained from cada- vers within 24 hours after death, reporting important new bone content14. In such cases, however, the selective immunode- pletion process must be rigorous to avoid rejection of the graft. Another limitation was the lack of standardization among the studies in terms of the analysis of graft success. It is more feasible and recommendable to analyze success outcomes as a com- Please cite this article in press as: Niño-San review and meta-analysis, Int J Oral Maxil plete process with at least 1 year of fol- low-up. This is to take into consideration not only the histomorphometric and im- aging aspects, but also the clinical aspects that involve the implant and its rehabilitation, since the graft must resist the loads that may be presented. In this review, Rickert et al. presented the most complete analysis in terms of success2,8. Another problem related to standardiza- tion was the absence of information on different conditions (respiratory disease and/or sinusitis)2,8,11,23,25,27–30, the inclu- sion of smokers, since smoking can exert a negative impact on bone regeneration9– 11,14,23–25,27, and the implant survival rate8. Moreover, the small number of patients did not enable more objective doval TC, et al. Efficacy of stem cells in maxi lofac Surg (2018), https://doi.org/10.1016/j.ijo conclusions. Thus, the findings may be subject to speculation27,29. Finally, many of the results are highly influenced by the lack of a balance in the sample. For example, in the study by Sauerbier et al., the large difference be- tween the test and control groups was reflected in the weight of the meta-analy- sis28. Only the study by Hermund et al. had an acceptable sample size calculation10. Kaigler et al. reported that the selection of the sample was based more on viability than statistical precision11. However, the greater bone marrow space with Bio-Oss compared to stem cells was conclusive. Despite difficulties in obtaining clear responses, this article can serve as a start- ing point for the design of randomized llary sinus floor augmentation: systematic m.2018.04.022 https://doi.org/10.1016/j.ijom.2018.04.022 10 Niño-Sandoval et al. YIJOM-3938; No of Pages 12 Please cite this article in press as: Niño-Sandoval TC, et al. Efficacy of stem cells in maxillary sinus floor augmentation: systematic review and meta-analysis, Int J Oral Maxillofac Surg (2018), https://doi.org/10.1016/j.ijom.2018.04.022 Fig. 9. Residual graft content (%) according to subgroup: Bio-Oss vs. Bio-Oss + BMAC. (A) At 3–4 months. (B) At 6 months. Fig. 10. Bone marrow space (%): Bio-Oss + autogenous bone vs. Bio-Oss + BMAC. Fig. 11. Risk of bias of the randomized clinical trials. https://doi.org/10.1016/j.ijom.2018.04.022 Stem cells in maxillary sinus floor augmentation 11 YIJOM-3938; No of Pages 12 clinical trials addressing this and similar topics that could improve the analyses presented. Long-term studies should eval- uate the efficacy of stem cells in different steps, taking into consideration clinical, imaging, and histomorphometric aspects. Thus, further randomized clinical trials with better characteristics in terms of the design and a longer follow-up period are needed to draw firm conclusions. In conclusion, despite the limitations of the present study, the meta-analysis revealed that the inclusion of stem cells did not contribute significantly to improvements in the implant survival rate or the efficacy of bone regeneration. Funding No source of funding. Competing interests No competing interests. Ethical approval Not applicable. Patient consent Not applicable. Acknowledgements. The authors are grate- ful to the Brazilian fostering agency Coor- denação de Aperfeiçoamento de Pessoal de Nı́vel Superior (CAPES) and Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq). References 1. Scharager-Lewin D, Arraño-Scharager DP, Biotti-Picand J. Biomaterials in maxillary sinus lift for dental implants. Rev Clin Period- oncia Implantol Rehabil Oral 2017;10:20–5. In Spanish. 2. Rickert D, Sauerbier S, Nagursky H, Menne D, Vissink A, Raghoebar GM. Maxillary sinus floor elevation with bovine bone mineral com- bined with either autogenous bone or autoge- nous stem cells: a prospective randomized clinical trial. Clin Oral Implants Res 2011;22:251–8. 3. Mangano FG, Colombo M, Veronesi G, Caprioglio A, Mangano C. Mesenchymal stem cells in maxillary sinus augmentation: a systematic review with meta-analysis. World J Stem Cells 2015;7:976–91. 4. Bertolai R, Catelani C, Aversa A, Rossi A, Giannini D, Bani D. Bone graft and mesen- chymal stem cells: clinical observations and histological analysis. Clin Cases Miner Bone Metab 2015;12:183–7. Please cite this article in press as: Niño-San review and meta-analysis, Int J Oral Maxil 5. Ceccarelli G, Presta R, Benedetti L, Cusella De Angelis MG, Lupi SM, Rodriguez Y, Baena R. Emerging perspectives in scaffold for tissue engineering in oral surgery. Stem Cells Int 2017;2017:4585401. 6. Park JB. Use of cell-based approaches in maxillary sinus augmentation procedures. J Craniofac Surg 2010;21:557–60. 7. Pasquali PJ, Teixeira ML, Oliveira TA, de Macedo LG, Aloise AC, Pelegrine AA. Max- illary sinus augmentation combining Bio-Oss with the bone marrow aspirate concentrate: a histomorphometric study in humans. Int J Biomater 2015;2015:1–7. 8. Rickert D, Vissink A, Slot WJ, Sauerbier S, Meijer HJ, Raghoebar GM. Maxillary sinus floor elevation surgery with Bio-Oss mixed with a bone marrow concentrate or autoge- nous bone: test of principle on implant sur- vival and clinical performance. Int J Oral Maxillofac Surg 2014;43:243–7. 9. Shayesteh YS, Khojasteh A, Soleimani M, Alikhasi M, Khoshzaban A, Ahmadbeigi N. Sinus augmentation using human mesenchy- mal stem cells loaded into a beta-tricalcium phosphate/hydroxyapatite scaffold. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:203–9. 10. Hermund NU, Donatsky O, Nielsen H, Clau- sen C, Holmstrup P. Long-term changes in graft height after sinus floor augmentation with mesenchymal stem cells in a random- ised clinical trial: radiographic evaluation with a minimum follow up of 2.5 years. J Dent Med Med Sci 2012;2:5–14. 11. Kaigler D, Avila-Ortiz G, Travan S, Taut AD, Padial-Molina M, Rudek I, Wang F, Lanis A, Giannobile WV. Bone engineering of maxillary sinus bone deficiencies using enriched CD90+ stem cell therapy: a ran- domized clinical trial. J Bone Miner Res 2015;30:1206–16. 12. Smiler D, Soltan M, Lee JW. A histomor- phogenic analysis of bone grafts augmented with adult stem cells. Implant Dent 2007;16:42–53. 13. McAllister BS, Haghighat K, Gonshor A. Histologic evaluation of a stem cell-based sinus-augmentation procedure. J Periodon- tol 2009;80:679–86. 14. Gonshor A, McAllister BS, Wallace SS, Prasad H. Histologic and histomorphometric evaluation of an allograft stem cell-based matrix sinus augmentation procedure. Int J Oral Maxillofac Implants 2011;26:123– 1310. 15. Cristalli MP, Marini R. Performance of mes- enchymal cell-scaffold constructs in human oral reconstructive surgery: a systematic re- view. J Biotechnol Biomater 2016;6:1–9. 16. Higgins J, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane Collaboration; 2011. 17. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA, PRISMA-P Group. Preferred reporting items for systematic review and meta-analy- doval TC, et al. Efficacy of stem cells in maxi lofac Surg (2018), https://doi.org/10.1016/j.ijo sis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2015;350:g7647. 18. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Bio- metrics 1977;33:159–74. 19. Carvalho A, Silva V, Grande A. Avaliação do risco de viés de ensaios clı́nicos randomizados pela ferramenta da colaboração Cochrane. Diagn Tratamento 2013;18:38–44. 20. Chrcanovic BR, Albrektsson T, Wennerberg A. Immediately loaded non-submerged versus delayed loaded submerged dental implants: a meta-analysis. Int J Oral Max- illofac Surg 2015;44:493–506. 21. Duttenhoefer F, Hieber SF, Stricker A, Schmelzeisen R, Gutwald R, Sauerbier S. Follow-up of implant survival comparing Ficoll and bone marrow aspirate concentrate methods for hard tissue regeneration with mesenchymal stem cells in humans. Biores Open Access 2014;3:75–6. 22. Ueda M, Yamada Y, Ozawa R, Okazaki Y. Clinical case reports of injectable tissue-engi- neered bone for alveolar augmentation with simultaneous implant placement. Int J Peri- odontics Restorative Dent 2005;25:129–37. 23. Yamada Y, Nakamura S, Ito K, Kohgo T, Hibi H, Nagasaka T, Ueda M. Injectable tissue-engineered bone using autogenous bone marrow-derived stromal cells for max- illary sinus augmentation: clinical applica- tion report from a 2–6-year follow-up. Tissue Eng Part A 2008;14:1699–707. 24. Ueda M, Yamada Y, Kagami H, Hibi H. Injectable bone applied for ridge augmenta- tion and dental implant placement: human progress study. Implant Dent 2008;17:82– 90. 25. Yamada Y, Nakamura S, Ueda M, Ito K. Osteotome technique with injectable tis- sue-engineered bone and simultaneous im- plant placement by cell therapy. Clin Oral Implants Res 2013;24:468–74. 26. Hibi H, Yamada Y, Ueda M, Schmelzeisen R. Tissue-engineered osteogenic materials for dental implants:clinical results fromGermany and Japan. Int Med J 2005;12:243–5. 27. Wildburger A, Payer M, Jakse N, Strunk D, Etchard-Liechtenstein N, Sauerbier S. Im- pact of autogenous concentrated bone mar- row aspirate on bone regeneration after sinus floor augmentation with a bovine bone sub- stitute—a split-mouth pilot study. Clin Oral Implants Res 2014;25:1175–81. 28. Sauerbier S, Rickert D, Gutwald R, Nagursky H, Oshima T, Xavier SP, Christ- mann J, Kurz P, Menne D, Vissink A, Raghoebar G, Schmelzeisen R, Wagner W, Koch FP. Bone marrow concentrate and bovine bone mineral for sinus floor augmen- tation: a controlled, randomized, single- blinded clinical and histological trial—per- protocol analysis. Tissue Eng Part A 2011;17:2187–97. 29. Payer M, Lohberger B, Strunk D, Reich KM, Acham S, Jakse N. Effects of directly auto- transplanted tibial bone marrow aspirates on llary sinus floor augmentation: systematic m.2018.04.022 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0005 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0005 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0005 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0005 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0005 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0010 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0010 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0010 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0010 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0010 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0010 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0010 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0015 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0015 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http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0095 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0095 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0095 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0095 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0100 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0100 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0100 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0100 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0100 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0105 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0105 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0105 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0105 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0105 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0105 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0105 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0110 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0110 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0110 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0110 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0110 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0115 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0115 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0115 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0115 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0115 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0115 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0115 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0120 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0120 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0120 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0120 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0120 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0125 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0125 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0125 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0125 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0125 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0130 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0130 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0130 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0130 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0135 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0135 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0135 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0135 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0135 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0135 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0135 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0140 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0140 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0140 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0140 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0140 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0140 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0140 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0140 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0140 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0140 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0145 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0145 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0145 https://doi.org/10.1016/j.ijom.2018.04.022 12 Niño-Sandoval et al. YIJOM-3938; No of Pages 12 bone regeneration and osseointegration of dental implants. Clin Oral Implants Res 2014;25:468–74. 30. Prins HJ, Schulten EA, Ten Bruggenkate CM, Klein-Nulend J, Helder MN. Bone re- generation using the freshly isolated autolo- gous stromal vascular fraction of adipose tissue in combination with calcium phos- phate ceramics. Stem Cells Transl Med 2016;5:1362–74. 31. Viña JA, El-Alami M, Gambini J, Borras C, Viña J, Peñarrocha MA. Application of mes- enchymal stem cells in bone regenerative procedures in oral implantology. A literature review. J Clin Exp Dent 2014;6:e60–5. Please cite this article in press as: Niño-San review and meta-analysis, Int J Oral Maxil 32. Starch-Jensen T, Aludden H, Hallman M, Dahlin C, Christensen AE, Mordenfeld A. A systematic review and meta-analysis of long-term studies (five or more years) assessing maxillary sinus floor augmenta- tion. Int J Oral Maxillofac Surg 2018;47:103–16. 33. Jensen T, Schou S, Stavropoulos A, Terhey- den H, Holmstrup P. Maxillary sinus floor augmentation with Bio-Oss or Bio-Oss mixed with autogenous bone as graft: a systematic review. Clin Oral Implants Res 2012;23:263–73. doval TC, et al. Efficacy of stem cells in maxil lofac Surg (2018), https://doi.org/10.1016/j.ijo Address: Belmiro Cavalcanti do Egito Vasconcelos Department of Oral and Maxillofacial Surgery University of Pernambuco – School of Dentistry (UPE/FOP) Av. General Newton Cavalcanti 1650 – Tabatinga Camaragibe CEP 54.756-220 Pernambuco Brazil E-mail: belmiro.vasconcelos@upe.br lary sinus floor augmentation: systematic m.2018.04.022 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0145 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0145 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0145 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0150 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0150 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0150 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0150 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0150 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0150 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0150 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0155 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0155 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0155 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0155 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0155 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0160 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0160 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0160 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0160 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0160 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0160 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0160 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0165 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0165 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0165 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0165 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0165 http://refhub.elsevier.com/S0901-5027(18)30153-X/sbref0165 mailto:belmiro.vasconcelos@upe.br https://doi.org/10.1016/j.ijom.2018.04.022 Efficacy of stem cells in maxillary sinus floor augmentation: systematic review and meta-analysis Materials and methods Study design and registry Eligibility criteria Search strategy Data collection process Evaluation of risk of bias Summary measures Results Selection of studies Implant survival rate Imaging characteristics Histomorphometric characteristics Assessment of risk of bias Discussion Funding Competing interests Ethical approval Patient consent Acknowledgements References