Grafting materials for alveolar cleft reconstruction: a systematic review and best-evidence synthesis

YIJOM-3774; No of Pages 12

Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx http://dx.doi.org/10.1016/j.ijom.2017.08.003, available online at http://www.sciencedirect.com

Systematic Review Cleft Lip and Palate

Grafting materials for alveolar cleft reconstruction: a systematic review and bestevidence synthesis C. Wu, W. Pan, C. Feng, Z. Su, Z. Duan, Q. Zheng, C. Hua, C. Li: Grafting materials for alveolar cleft reconstruction: a systematic review and best-evidence synthesis. Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx. ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Abstract. The purpose of this study was to compare the efficacy of alveolar bone reconstruction for alveolar cleft patients performed with the traditional iliac graft or alternative/supplementary bone grafting materials. Electronic databases, relevant journals, and reference lists of the included studies were searched to the end of June 2016. A best-evidence synthesis was performed to draw conclusions. A total of 38 studies were included, which provided 25 pieces of evidence: seven of moderate evidence and 18 of insufficient evidence. The seven pieces of moderate evidence indicated that (1) bone morphogenetic protein 2 bound to absorbable collagen sponge shares similar cleft repair efficacy to the iliac graft; (2) covering the iliac graft with an acellular dermis matrix membrane may increase bone retention for unilateral cleft patients; (3) mixing iliac graft with platelet-rich plasma may increase bone retention for skeletally mature patients, but (4) does not achieve the same result for younger patients; and compared with the iliac graft, (5) the mandible graft is more effective, whereas (6) the cranium graft and (7) rib graft are less effective for alveolar cleft reconstruction. The efficacy of the remaining grafting materials was supported by insufficient evidence. More well-designed controlled studies are needed to ascertain the long-term clinical results of alveolar cleft reconstruction.

An alveolar cleft is a common congenital deformity with an incidence of 0.18–2.50 per 1000 births1, and presents in approximately 75% of cleft lip and palate patients2. Genetic and environmental factors may cause incomplete fusion of the maxillary prominence and intermaxillary 0901-5027/000001+012

prominence, which results in an alveolar cleft3,4. The existence of an alveolar cleft may impact facial symmetry, development of the dentition, speech, and oral hygiene. Reconstruction of the alveolar process can stabilize the maxillary segments, close the oronasal fistulae, elimi-

C. Wu1,2,a, W. Pan1,3,a, C. Feng1, Z. Su1, Z. Duan1, Q. Zheng1,4, C. Hua1,5,6, C. Li1,2,6 1 State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; 2Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China; 3Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China; 4Department of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, China; 5Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China; 6Department of Evidencebased Dentistry, West China School of Stomatology, Sichuan University, Chengdu, China**Address: Chunjie Li, Department of Head and Neck Oncology, West China School of Stomatology, Number 14, Unit 3, Renmin Nan Road, Chengdu City, Sichuan 610041, China. Tel.: +86 183 82439003.

Key words: alveolar bone grafting; autograft; bone substitutes; cleft palate; tissue engineering. Accepted for publication

nate the nose asymmetry, and provide bony support for tooth eruption, orthodontic treatment, and the placement of dental implants1,2,5. a Chenzhou Wu and Weiyi Pan are co-first authors of this article.

ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Wu C, et al. Grafting materials for alveolar cleft reconstruction: a systematic review and bestevidence synthesis, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.08.003

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Since the first description of secondary alveolar bone grafting (SABG) by Boyne and Sands in the 1970s6, it has become the most acknowledged method for the repair of alveolar clefts. SABG is usually performed at the mixed dentition stage, as it is believed that this will have minimal influence on maxillary growth. The iliac cancellous bone graft (ICBG) harvested from the anterior iliac crest has been the most common grafting material for the SABG procedure because of its abundance of bone, ease of harvest, and the ability to harvest simultaneously with alveolar cleft preparation5. Although the ICBG is considered the gold standard graft for the SABG procedure, it has some noted disadvantages. Donor site morbidity at the iliac crest is significant, such as postoperative pain, sensory disturbance, and claudication, and this results in a prolonged hospital stay7. There is also unavoidable bone absorption of the ICBG. It has been reported that the bone absorption rate could be more than 40% at 1 year after SABG8, which may increase the need for reoperation. Considering these shortcomings of the ICBG, alternative and supplementary grafting materials for SABG have been explored in a large number of studies. Transplantation of autogenous bone from other donor sites, for instance the cranium, mandibular symphysis, or tibia, may provide alternative choices with less donor site morbidity and a lower bone absorption rate than for the iliac crest7. Bone tissue engineering strategies, such as implanting bone scaffolds, growth factors, or autogenous cells, have also shown promising outcomes in repairing alveolar clefts and have the advantage of eliminating a second surgical site for bone harvesting8. Furthermore, because of the abundant growth factors and osteoinductive potential, tissue engineering strategies may increase bone retention and achieve a better alveolar reconstruction result than the ICBG9. This systematic review was conducted to compare the efficacy of alveolar bone reconstruction for alveolar cleft patients between the traditional iliac graft and alternative or supplementary bone grafting materials. The goal was to provide the clinician with options for use when selecting graft materials for alveolar cleft repair. Materials and methods

The study selection, quality assessment, and data extraction processes were performed by two authors in duplicate,

according to a protocol developed prior to the systematic review. The protocol has been registered in the PROSPERO database (CRD42014009942). Any disagreements were resolved by discussion. Inclusion criteria

The inclusion criteria for this systematic review were as follows: (1) the study design was required to be a randomized controlled trial (RCT) or non-randomized controlled trial (N-RCT). Systematic reviews, review articles, case series, case reports, historically controlled studies, and case–control studies were excluded. (2) All participants had to be alveolar cleft patients undergoing SABG, including patients with a unilateral cleft or bilateral cleft. SABG was defined as receiving alveolar bone grafting at stages later than the primary dentition, including those undergoing surgery in the mixed dentition and mature dentition stages. Studies only assessing the results of alveolar bone grafting in the primary dentition were excluded. (3) The control group patients had to undergo SABG with ICBG transplantation. Studies whose control group received other types of autogenous bone graft were excluded. The intervention group had to undergo the transplantation of any other different grafting material for comparison with ICBG transplantation. (4) In terms of outcomes, the study was required to assess the efficacy of alveolar bone reconstruction. The required primary outcomes were (i) bone volume, measured using three-dimensional imaging modalities, and (ii) bone height, including the clinical success rate, the exact bone height, and the percentage of bone height formation/resorption. The required secondary outcomes were alveolar bone width/thickness and bone density. Studies that did not report the above outcomes were excluded. Search strategy

The following electronic databases were searched without language limitation: MEDLINE (via OVID; 1948 to June 2016), Embase (via OVID; 1984 to June 2016), Cochrane Central Register of Controlled Trials (CENTRAL; issue 6, 2016), Chinese BioMedical Literature Database (CBM; 1978 to June 2016), and China Knowledge Infrastructure National (CNKI; 1994 to June 2016). Relevant journals and the reference lists of included studies were manually searched. The search strategy combined medical subject heading (MeSH) terms with free

text words. The MeSH terms used were ‘‘Cleft Palate’’, ‘‘Cleft Lip’’, ‘‘Bone Transplantation’’, and ‘‘Ilium’’. The titles and abstracts of all studies resulting from the search were initially screened to identify any eligible studies. The full texts of the possibly eligible studies were then obtained and a final judgement made. Methodological quality assessment

All studies that met the inclusion criteria were evaluated against the ‘treatment benefits’ section of the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence10. The evidence of ‘treatment benefit’ section is divided into five levels as follows: level 1 represents a systematic review of randomized trials or n-of-1 trials; level 2 represents a randomized trial or observational study with a dramatic effect; level 3 represents a non-randomized controlled cohort/follow-up study; level 4 represents case series, case–control studies, or historically controlled studies; level 5 represents mechanism-based reasoning. In this review, levels 1 and 2 were considered ‘high methodological quality’, whereas levels 3–5 were considered ‘low methodological quality’. Data extraction

The following data were extracted: investigators, study design and methodological quality, patient characteristics, interventions and controls, and outcomes. The patient characteristics extracted included the number of patients, types of cleft (if the study recruited only bilateral cleft patients, this was noted and a separate analysis was performed), and age at operation (if the mean age of the patients at operation was >16 years, this was noted specifically as ‘skeletally mature’ and a separate analysis was performed). If a single study reported both primary outcomes and secondary outcomes, only the primary outcomes were extracted and analyzed; if a single study reported only secondary outcomes, the secondary outcomes were extracted and analyzed. Meta-analysis

The meta-analysis was performed using RevMan version 5.3 (Cochrane Collaboration). For continuous data (e.g., bone filling rate), mean differences (MD) with the 95% confidence intervals (CI) were calculated. For dichotomous data (e.g., clinical success rate), risk ratios (RR) with the 95% CI were calculated. The significance of the pooled MD and RR were

Please cite this article in press as: Wu C, et al. Grafting materials for alveolar cleft reconstruction: a systematic review and bestevidence synthesis, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.08.003

YIJOM-3774; No of Pages 12

Grafting materials for alveolar cleft reconstruction determined by two-tailed Z-test, and P < 0.05 was considered statistically significant. Statistical heterogeneity between studies was checked by Cochran x2-based Q-test and the I2 static. When PH > 0.10 and I2 < 50%, a fixed-effects model was applied; when PH  0.10 or I2  50%, a random-effects model was applied. Furthermore, a fixed-effects model was applied when only two studies met the inclusion criteria and were sufficient to perform a meta-analysis. Best-evidence synthesis

In order to draw explicit conclusions on the efficacy of different grafting materials for alveolar reconstruction, a best-evidence synthesis system was applied11,12. Briefly, this rating system took into account the consistency of findings with regard to the numbers, methodological quality, and outcomes that were generated from the studies included. Methodological quality was that of the original study. Findings for the same patients, interventions and controls, and outcomes (PICO) were synthesized to produce new evidence, which was defined as synthesized evidence (SE). If the findings with the same PICO were sufficient to be pooled, these were preferentially included in a meta-analysis rather than in the evidence synthesis process. If one finding had a unique PICO, for example only one study compared the efficacy of alveolar cleft reconstruction between ICBG and tibia graft, it would not be synthesized and would produce a piece of insufficient SE. SE was divided into three levels as outlined below. Strong SE was provided by (1) a metaanalysis of findings in multiple (2) highquality studies (HQS), when the findings were sufficient to be pooled; (2) generally consistent findings in multiple (2) HQS, when a meta-analysis was not available. Moderate SE was provided by (1) a metaanalysis of findings in HQS and low-quality studies (LQS), or of findings in multiple (2) LQS, when the findings were sufficient to be pooled; (2) generally consistent findings in one HQS and one or more LQS, or in multiple (2) LQS, when a meta-analysis was not available. Insufficient SE was provided by (1) only one available study; (2) inconsistent findings in multiple (2) studies, when a metaanalysis was not available. If at least 75% of the studies with the same PICO reported similar results, it was defined as ‘consistent’. For the studies that were not sufficient to be pooled, if two or more studies were of high methodological

quality, the studies of low methodological quality were disregarded in the synthesis. In contrast, if HQS and LQS existed at the same time and were sufficient to be pooled, all of them were included in a meta-analysis and none were disregarded. Results Results of the search

A total of 1321 studies were identified in the electronic and manual search, after removing duplicates. Of these, 1272 were excluded after screening the titles and abstracts. After reading the full texts, 38 studies were included and 11 were excluded with reasons (Fig. 1).

3

the 38 studies reported the results of unilateral patients and bilateral patients separately38, and another study reported two types of bone graft46. Thus 40 findings were generated from the 38 studies included and were used for the synthesis of further evidence (Table 1). As stated previously, in the case of findings sufficient to be pooled, these would preferentially be included in a meta-analysis rather than the evidence synthesis process. Of the 40 findings generated from the 38 studies, 14 were sufficient to apply four independent metaanalyses; the remaining 26 findings were included in the evidence synthesis. These are described in detail below. Results of the meta-analysis

Characteristics and quality assessment of the studies included

Among the 38 included studies, 14 were of high methodological quality (all were RCTs) and 24 studies were of low methodological quality (all were N-RCTs)13– 50 . Twenty studies included unilateral patients, 16 studies included both unilateral and bilateral patients, and the remaining two studies did not report the specific types of cleft included. With regard to age at operation, three studies recruited only skeletally mature patients (over 16 years old), while the other 35 studies included younger patients. Thirteen studies reported bone substitute materials, 15 reported ICBG plus supplementary materials, and 10 studies reported autogenous bone grafts from other donor sites. One of

Four findings (from two HQS and two LQS with moderate SE) evaluated the bone volume change after transplantation of an absorbable collagen sponge (ACS) with bound bone morphogenetic protein 2 (BMP-2) or transplantation of an ICBG into the cleft area16–19. A total of 100 patients were included, with 54 in the BMP-2/ACS group and 46 in the control group. As there was significant statistical heterogeneity between studies (PH = 0.05, I2 = 62%), a random-effects model was applied. As shown in Fig. 2, the pooled result suggests that BMP-2/ACS and ICBG have a similar bone filling rate (MD = 2.16, 95% CI 10.10 to 5.78, P = 0.62). Four findings (from two HQS and two LQS with moderate SE) investigated

Fig. 1. Flow diagram of study inclusion.

Please cite this article in press as: Wu C, et al. Grafting materials for alveolar cleft reconstruction: a systematic review and bestevidence synthesis, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.08.003

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whether covering ICBG with acellular dermal matrix (ADM) could improve the clinical success rate of SABG for patients with a unilateral alveolar cleft36–39. A total of 292 patients were included, among whom 121 received ADM while the remaining 171 did not. Statistical heterogeneity did not exist between studies (PH = 0.22, I2 = 33%), thus a fixed-effects model was applied. The results of the meta-analysis indicate that the use of ADM could increase the success rate by 34% (RR 1.34, 95% CI 1.15–1.55, P = 0.0001) (Fig. 3). Four findings (from one HQS and three LQS with moderate SE) compared the efficacy of alveolar cleft reconstruction between cranium graft and ICBG41–44. Among the 310 recruited patients, 117 were allocated to the cranium graft group. As no statistical heterogeneity was observed (PH = 0.24, I2 = 28%), a fixedeffects model was applied. The results of the meta-analysis show that the cranium graft was 14% less effective than the ICBG in terms of the clinical success rate (RR 0.86, 95% CI 0.76–0.97, P = 0.01) (Fig. 4). Only two findings (from two LQS with moderate SE) compared the rib graft and ICBG in terms of the cleft repair success rate, thus a fixed-effects model was applied46,47. Among the 173 recruited patients, only 38 patients received the rib graft. As shown in Fig. 5, the rib graft was significantly less effective than the ICBG in terms of the clinical success rate (RR 0.55, 95% CI 0.37–0.83, P = 0.004). Results of the best-evidence synthesis

A total of 26 findings were not sufficient for meta-analysis and were included in the evidence synthesis process. According to the principles of best-evidence synthesis described above, none were disregarded in this process. Among the 26 findings, 18 could not be synthesized and thus provided 18 pieces of insufficient evidence. The remaining eight studies were synthesized and subsequently provided three pieces of moderate SE, as follows: (1) two consistent findings in two LQS demonstrated that platelet-rich plasma (PRP) could not help younger patients to achieve better alveolar bone retention28,29; (2) two consistent findings in one HQS26 and one LQS27 suggested that adding PRP could increase bone retention for skeletally mature patients; (3) four consistent findings in four LQS indicated that the mandible graft was more effective than the ICBG in alveolar reconstruction46,48–50.

To sum up, 25 pieces of evidence were acquired after the best-evidence synthesis, among which none were graded as strong, seven were graded as moderate, and the remaining 18 were graded as insufficient. With regard to bone substitute materials, moderate SE indicated that BMP-2 bound to ACS shared similar cleft repair efficiency to the ICBG. For ICBG supplementary materials, moderate SE showed that covering the ICBG with an ADM membrane could increase bone retention for unilateral cleft patients; mixing ICBG with PRP could increase bone retention for skeletally mature patients, but could not achieve the same results for younger patients. With regard to autogenous bone grafts, moderate SE indicated that the mandible graft was more effective than the ICBG, whereas the cranium graft and rib graft were less effective in terms of alveolar cleft reconstruction. Vast heterogeneity was found among the studies investigating the remaining grafting materials, thus only insufficient evidence was obtained. Detailed results of the best-evidence synthesis are given in Table 2.

pair mainly include the following three types. Bioceramics

The efficacy of each type of bioceramic was supported by a single study, thus the SE for each was found to be insufficient. Bioceramics may be an ideal bone substitute because of their good biocompatibility and osteoinduction potential53. Based on the studies included, it was found that the clinical success rates of bioglass and beta-tricalcium phosphate (b-TCP) were similar to that of ICBG13,14, while hydroxyapatite showed a higher clinical success than ICBG15, although with insufficient SE in all cases. These results suggest that bioceramics might be ideal bone substitutes in alveolar cleft repair. This could be due to the bioceramics providing a scaffold that is slowly absorbed over a relatively long period time, allowing the new bone to reach stability. However, as each type of the bioceramic applied in alveolar cleft repair was only supported by one available study, further studies are needed to determine the definite outcomes.

Discussion

The untreated alveolar cleft may be associated with concomitant oronasal fistulae, crowded dentition, and a lack of bony support for the anterior teeth1,2. It has been shown in many studies that bone grafting can re-establish the continuity of the dental arch, stabilize the premaxilla, provide bony support for tooth eruption, and close the oronasal fistulae50–52. ICBG is the most acknowledged grafting material for alveolar cleft reconstruction, although it still has some disadvantages, such as inevitable bone absorption and severe donor site morbidity at the iliac crest. Following a systematic search of the literature, it was found that alternative and supplementary grafting materials to ICBG for alveolar cleft reconstruction mainly include three categories, namely bone substitute materials, ICBG supplementary materials, and autogenous bone grafts. After the best-evidence synthesis, some preliminary conclusions were reached as outlined below.

Bone substitute materials

The purpose of using bone substitute materials is to eliminate the need for a second surgical site for bone harvesting, thereby avoiding donor site morbidity. Substitute materials for alveolar cleft re-

BMP-2 composite bone substitutes

BMP-2 is the strongest known bone growth factor so far and can promote bone formation effectively53. The use of BMP-2 in oral and maxillofacial surgeries has been investigated widely, including its use in the repair of large jaw defects and premaxillary clefts19,20,54,55. After pooling the findings of relevant studies, moderate SE was found that the amount of new bone formation with BMP-2 bound to ACS is similar to that of ICBG when used for cleft repair16,17. There is disagreement regarding whether implanting BMP-2 can achieve a better or similar bone formation result compared with ICBG. Specifically, different carriers may lead to distinct clinical success rates16–24. According to the limited published evidence, demineralized bone matrix (DBM) might currently be the most appropriate carrier22. Concerning the timing of implantation, better results may be achieved in skeletally mature patients than in patients at the mixed dentition stage18. With regard to the concentration of BMP-2, the concentration most commonly applied was 1.5 mg/ml16–18,20. Little bone formation was observed when the concentration applied was 50 mg/ml21, while the bone size was acceptable when the concentration was increased to 250 mg/ml21. According to these findings, it is considered that more studies are

Please cite this article in press as: Wu C, et al. Grafting materials for alveolar cleft reconstruction: a systematic review and bestevidence synthesis, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.08.003

YIJOM-3774; No of Pages 12

Cleft typea (Age at surgery)

Investigators

Bone substitute materials vs. ICBG Yuan et al.13 U Chen et al.14

U+B 15

Benlidayi et al.

U

Alonso et al.16

U

Canan Jr et al.17

U

Herford et al.18

U+B

Balaji

19

U+B

Dickinson et al.20 Neovius et al.21

U (skeletally mature) U

Francis et al.22

U

She et al.23

U

Wang and Sun24

U

Pradel and Lauer25

U+B

ICBG plus supplementary materials vs. ICBG Marukawa et al.26 U (skeletally mature) U Oyama et al.27 (skeletally mature) Lee et al.28 U+B 29

Luaces-Rey et al.

U+B

Segura-Castillo et al.30

U+B

Huo et al.31

U+B

Thuaksuban et al.32 MacIsaac et al.

33

U+B U+B

Intervention

Control

Outcome

Bioglass (n = 14) b-TCP (n = 14) HA (n = 11) BMP-2/ACS (n = 8) BMP-2/ACS (n = 6) BMP-2/ACS (n = 10) BMP-2/ACS (n = 30) BMP-2/ACS (n = 9) BMP-2/hydrogel (n = 4) BMP-2/DBM (n = 26) BMP-2/DBB (n = 12) BMP-2/b-TCP (n = 12) Osteoblasts/ACS (n = 4)

ICBG (n = 25) ICBG (n = 10) ICBG (n = 12) ICBG (n = 8) ICBG (n = 6) ICBG (n = 2) ICBG (n = 30) ICBG (n = 12) ICBG (n = 3) ICBG (n = 19) ICBG (n = 15) ICBG (n = 12) ICBG (n = 4)

Clinical success rate

PRP + ICBG (n = 14) PRP + ICBG (n = 7) PRP + ICBG (n = 30) PRP + ICBG (n = 30) Fibrin glue + ICBG (n = 13) DDM + ICBG (n = 26) DBB + ICBG (n = 14) DBM + ICBG (n = 14)

ICBG (n = 14) ICBG (n = 5) ICBG (n = 30) ICBG (n = 30) ICBG (n = 14) ICBG (n = 62) ICBG (n = 13) ICBG (n = 22)

Bone absorption rate Bone density Bone filling rate

Clinical success rate Clinical success rate Bone filling rate Bone filling rate Bone filling rate Bone filling rate Bone filling rate Bone height Bone filling rate Clinical success rate Clinical success rate Clinical success rate Bone filling rate

Bone absorption rate Bone density Bone formation score Bone absorption rate Bone density Clinical success rate Bone height Bone density Bone level distribution

Study design and methodological quality

Included in meta-analysis

Included in evidence synthesis

Level of synthesized evidence

RCT High N-RCT Low N-RCT Low RCT High RCT High N-RCT Low N-RCT Low RCT High RCT High N-RCT Low N-RCT Low RCT High N-RCT Low

–

Yes

Insufficient

–

Yes

Insufficient

–

Yes

Insufficient

Yes

–

Moderate

–

Yes

Insufficient

–

Yes

Insufficient

–

Yes

Insufficient

–

Yes

Insufficient

–

Yes

Insufficient

–

Yes

Insufficient

RCT High N-RCT Low N-RCT Low N-RCT Low RCT High N-RCT Low RCT High N-RCT Low

–

Yes

Moderate

–

Yes

Moderate

–

Yes

Insufficient

–

Yes

Insufficient

–

Yes

Insufficient

–

Yes

Insufficient

Grafting materials for alveolar cleft reconstruction

Please cite this article in press as: Wu C, et al. Grafting materials for alveolar cleft reconstruction: a systematic review and bestevidence synthesis, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.08.003

Table 1. Characteristics of included studies.

5

Investigators Peled et al.34

U

Deng et al.35

U

Li et al.36

U

Shen et al.37

U

Clavijo-Alvarez et al.

39

U

Liu and Ma38

U

Liu and Ma38

B

Kubota and Shirasuna40

U+B

Autogenous bone grafts vs. ICBG LaRossa et al.41

U+B

Kortebein et al.42

U+B

Cohen et al.

43

N/A

Sadove et al.44

U

Sivarajasingam et al.45

N/A

Freihofer et al.46

U+B

47

Hogeman et al.

U+B

Freihofer et al.46

U+B

Enemark et al.48

U

Sindet-Pedersen and Enemark49

U

Koole et al.

50

U

Intervention

Control

Outcome

Membrane + ICBG (n = 10) Bio-Gide + ICBG (n = 24) ADM + ICBG (n = 48) ADM + ICBG (n = 5) ADM + ICBG (n = 15) ADM + ICBG (n = 53) ADM + ICBG (n = 10) Periosteum + ICBG (n = 31)

ICBG (n = 5) ICBG (n = 41) ICBG (n = 60) ICBG (n = 17) ICBG (n = 20) ICBG (n = 74) ICBG (n = 20) ICBG (n = 37)

Bone height/width Bone volume Clinical success rate

Cranium graft (n = 60) Cranium graft (n = 27) Cranium graft (n = 15) Cranium graft (n = 15) Tibia graft (n = 10) Rib graft (n = 6) Rib graft (n = 32) Mandible graft (n = 6) Mandible graft (n = 44) Mandible graft (n = 20) Mandible graft (n = 25)

ICBG (n = 56) ICBG (n = 108) ICBG (n = 14) ICBG (n = 15) ICBG (n = 14) ICBG (n = 22) ICBG (n = 113) ICBG (n = 10) ICBG (n = 57) ICBG (n = 20) ICBG (n = 25)

Clinical success rate

Clinical success rate Clinical success rate Clinical success rate Clinical success rate Clinical success rate Clinical success rate

Clinical success rate Clinical success rate Clinical success rate Bone density Clinical success rate Clinical success rate Clinical success rate Bone level distribution Bone level distribution Bone absorption rate

Included in meta-analysis

Included in evidence synthesis

Level of synthesized evidence

RCT High RCT High RCT High RCT High N-RCT Low N-RCT Low N-RCT Low N-RCT Low

–

Yes

Insufficient

–

Yes

Insufficient

Yes

–

Moderate

–

Yes

Insufficient

–

Yes

Insufficient

N-RCT Low N-RCT Low N-RCT Low RCT High N-RCT Low N-RCT Low N-RCT Low N-RCT Low N-RCT Low N-RCT Low N-RCT Low

Yes

–

Moderate

–

Yes

Insufficient

Yes

–

Moderate

–

Yes

Moderate

ACS, absorbable collagen sponge; ADM, acellular dermal matrix; BMP-2, bone morphogenetic protein 2; b-TCP, beta-tricalcium phosphate; DBB, deproteinized bovine bone; DBM, demineralized bone matrix; DDM, demineralized dentinal matrix; HA, hydroxyapatite; ICBG, iliac cancellous bone graft; N/A, not available; N-RCT, non-randomized controlled trial; PRP, platelet rich plasma; RCT, randomized controlled trial. a U, unilateral; B, bilateral.

Wu et al.

Cleft typea (Age at surgery)

Study design and methodological quality

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Please cite this article in press as: Wu C, et al. Grafting materials for alveolar cleft reconstruction: a systematic review and bestevidence synthesis, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.08.003

Table 1 (Continued )

YIJOM-3774; No of Pages 12

Grafting materials for alveolar cleft reconstruction

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Fig. 2. Meta-analysis results for bone morphogenetic protein 2 (BMP-2) vs. iliac cancellous bone graft (ICBG)—bone filling rate.

needed to determine the most appropriate BMP-2 carrier, concentration, and patient population for treatment.

to reduce the bone absorption were identified. The three main types are described below.

Cell treatment

PRP and fibrin glue

The advantage of autogenous cell treatment is that the seed cells have no antigenicity and may completely reconstruct the alveolar process in function and structure. However, just one included study reporting the implantation of osteoblasts with ACS met the inclusion criteria25. Thus insufficient evidence was obtained showing that treatment with osteoblasts/ACS shared a similar bone filling rate to ICBG after 6 months of follow-up. Cell treatment has been one of the research hotspots for alveolar cleft treatment in recent years. Autogenous osteoblasts25,56 and bone marrow stem cells57,58 are the most commonly used seed cells. Loaded onto various scaffolds and with various growth factors, autogenous cells may provide promising cleft repair results59,60. However, as most publications on cell treatments have been case reports or case series, no conclusions can yet be drawn due to the lack of control groups.

PRP contains abundant growth factors, such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor beta (TGF-b)26, which can theoretically promote bone growth and reduce bone absorption. For skeletally mature patients, moderate SE was found that PRP could reduce bone absorption26,27. For younger patients, moderate SE was found that PRP does not reduce bone absorption28,29. These results could be explained by the low bone growth activity in skeletally mature patients, which may be promoted by growth factors in PRP. In contrast, the bone growth activity in young patients is relatively high, thus PRP has a limited effect. Fibrin glue is a type of degradable bio-adhesive (consisting of fibrinogen and prothrombin) that may enhance cell migration and nourish the scar tissues30,61. Only one study involving the application of fibrin glue was included, thus insufficient evidence was found that fibrin glue reduces bone absorption and increases bone density30.

ICBG supplementary material

The absorption rate of the ICBG may be as high as 50% to 80%49. In order to remedy this deficiency, a large number of studies have been conducted to investigate whether the use of supplementary materials with the ICBG could reduce this bone absorption. Numerous supplementary materials

Scaffolds

In this review, the use of each type of scaffold was supported by a single study, thus all evidence was insufficient. Deproteinized bovine bone (DBB) is the inor-

ganic bone scaffold left after the deproteinization of bovine bone. This material has no antigenicity and can guide the ingrowth of bone cells and blood vessels32. It was found that DBB mixed with ICBG shared similar cleft repair results to ICBG alone, although the SE was insufficient. In other words, DBB failed to improve bone retention32. This result may be due to the fact that DBB lacks bioactive growth factors and mainly consists of inorganic materials. Demineralized dentinal matrix (DDM) is a powder made from human teeth that contains BMP and collagen31. DBM is a type of bone matrix obtained after demineralizing human bone and contains abundant bone growth factors33,62. In contrast to DBB, DDM and DBM may improve the success rate of bone grafting when added to the ICBG31,32. In addition, the above scaffolds may not only promote bone retention, but may also play a role as bone substitutes in partially increasing the volume of the ICBG. Thus, it could be considered that partial replacement of the ICBG with these scaffolds showed no negative effect (similar or better than ICBG alone) on the efficiency of alveolar reconstruction.

Membrane barriers

Membrane barriers can block the ingrowth of soft tissue, induce bone growth, and thus improve bone retention. Included studies reported several different membrane barriers, including polylactic–polyglycolic acid membrane34, Bio-Gide

Fig. 3. Meta-analysis results for iliac cancellous bone graft covered by an acellular dermis matrix membrane (ADM + ICB) vs. iliac cancellous bone graft alone (ICBG)—clinical success rate.

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Fig. 4. Meta-analysis results for cranium graft vs. iliac cancellous bone graft alone (ICBG)—clinical success rate.

Fig. 5. Meta-analysis results for rib graft vs. iliac cancellous bone graft alone (ICBG)—clinical success rate.

membrane35, ADM membrane36–39, and free iliac periosteum40. Moderate SE was found that covering the ICBG with an ADM membrane could improve the success rate of bone grafting for unilateral cleft patients36,37. The other membranes achieved the same results as ADM34,35,40. However, as the use of all of these membranes was supported by a single study in each case, the level of evidence was graded as insufficient for all. It is noteworthy that for bilateral cleft patients, the success rate of cleft repair was not significantly improved by covering ICBG with an ADM membrane39. This may be a result of insufficient soft tissue closure, a poor blood supply, and the relatively greater mobility of bone segments in bilateral clefts38,63. As the treatment results for bilateral clefts are not always ideal, further investigations aimed at improving the treatment of bilateral alveolar clefts are needed.

ing autogenous bone grafts from other donor sites to replace the ICBG.

Cranium graft

The cranium is regarded as an advantageous donor site because of the resemblance of its intramembranous ossification process to that of the maxilla and the lesser postoperative pain compared to the ilium43. Moderate SE was found that the success rate of the cranium graft was lower than that of the ICBG41–44. Moreover, there is limited available cancellous bone in the cranium and the harvesting procedure is relatively difficult. Potential complications, such as epidural haematoma and leakage of cerebrospinal fluid, are severe43. Thus this site is not recommended as a common donor site.

Autogenous bone grafts harvested from different donor sites may differ in cellular viability and absorption rate due to their different osteogenesis modalities and embryonic origins. In addition, the complications and difficulties of bone harvesting at the different donor sites are also distinct. The anterior iliac crest is now the most commonly chosen donor site for SABG procedures. However, the clinical application of the ilium is criticized for its obvious complications and morbidities. Therefore, clinicians have been investigat-

Rib graft

The rib is the most common donor site for primary alveolar bone grafting operations performed during infancy. However, the application of rib grafts for SABG was found to be significantly less effective than ICBG in alveolar cleft reconstruction, with moderate SE46,47. Moreover, since the rib has a comparatively higher proportion of cortical bone, the application of rib grafts in SABG may affect the following orthodontic treatment66. In conclusion, the authors have reservations about the use of the rib as an alternative donor site for SABG. Mandible graft

Tibia graft Autogenous bone grafts

olar bone anatomy reconstruction was found.

Because of its simple anatomical structure, the tibia has some advantages as a donor site, such as less intraoperative blood loss, milder postoperative pain, and markedly shorter length of hospital stay than for the ilium graft64,65. However, the developing epiphysis, which is close to the harvest site in the tibia, may easily be injured resulting in a growth disorder65. In the present review, only one study comparing the tibia graft and ICBG was included and this showed no significant differences in the bone density between these two grafts45. In other words, no study reporting the efficacy of the tibia graft in comparison to the ICBG for alve-

The advantages of the mandible as a donor site are that the scar is in the oral cavity and that its embryonic origin is the same as that of the maxilla. Moderate SE was found that the efficacy of alveolar cleft repair with a mandible graft is better than that with the ICBG46,48–50. This indicates that the mandible graft may be the best alternative choice for SABG. The reason for this excellent bone incorporation may be that the mandible and maxilla have the same ectomesenchymal origin and intramembranous ossification process50. However, when a relatively large cleft needs to be repaired, the mandible may not be able to meet the bone volume requirements. A previous study has shown that the maximum bone volume offered by the mandi-

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Table 2. Results of the best-evidence synthesis. Intervention

Level of SE

Bone substitute materials vs. ICBG Bioglass Insufficient

b-TCP

Insufficient

HA BMP-2/ACS

Insufficient Moderate Insufficient

BMP-2/hydrogel

Insufficient

BMP-2/DBM

Insufficient

BMP-2/DBB

Insufficient

BMP-2/b-TCP

Insufficient

Osteoblasts/ACS

Insufficient

Results of SE

Origin of evidence

No significant differences in the effectiveness of alveolar reconstruction were found13 No significant differences in the effectiveness of alveolar reconstruction were found14 HA was more effective than ICBG in alveolar reconstruction15 For younger patients, BMP-2 bound to ACS shared a similar alveolar cleft filling rate to ICBG16–19 For skeletally mature patients, BMP-2/ACS was more effective than ICBG in alveolar reconstruction20 No significant differences were found in the effectiveness of alveolar reconstruction21 BMP-2 bound to DBM was more effective than ICBG in alveolar reconstruction22 No significant differences were found in the effectiveness of alveolar reconstruction23 No significant differences were found in the effectiveness of alveolar reconstruction24 No significant differences were found in the effectiveness of alveolar reconstruction25

One available study

ICBG plus supplementary materials vs. ICBG PRP + ICBG Moderate For younger patients, adding PRP to ICBG did not increase bone retention28,29 For skeletally mature patients, adding PRP could increase bone Moderate retention26,27 Insufficient Adding fibrin glue to ICBG could increase bone retention and bone Fibrin glue + ICBG density30 Insufficient Adding DDM to ICBG could increase bone retention31 DDM + ICBG DBB + ICBG Insufficient Adding DBB to ICBG did not increase bone retention or bone density32 DBM + ICBG Insufficient Adding DBM to ICBG could increase bone retention33 Membrane + ICBG Insufficient Covering ICBG with a resorbable membrane could increase bone retention34 Insufficient Covering ICBG with a Bio-Gide membrane could increase bone Bio-Gide + ICBG retention35 Moderate For unilateral cleft patients, covering ICBG with ADM could increase ADM + ICBG bone retention36,37,39 For bilateral cleft patients, the application of ADM did not increase bone Insufficient retention38 Insufficient Covering the ICBG with free iliac periosteum could increase bone Periosteum + ICBG retention40 Autogenous bone graft vs. ICBG Cranium graft Moderate Tibia graft Insufficient Rib graft Moderate Mandible graft

Moderate

Cranium graft was less effective than ICBG in alveolar reconstruction41–44 No significant differences were found in alveolar bone density45 Rib graft was less effective than ICBG in alveolar reconstruction46,47 Mandible graft was more effective than ICBG in alveolar reconstruction46,48–50

One available study One available study A meta-analysis One available study One available study One available study One available study One available study One available study

Two LQS One HQS and one LQS One available study One One One One

available available available available

study study study study

One available study A meta-analysis One available study One available study

A meta-analysis One available study A meta-analysis Four LQS

ACS, absorbable collagen sponge; ADM, acellular dermal matrix; BMP-2, bone morphogenetic protein-2; b-TCP, beta-tricalcium phosphate; DBB, deproteinized bovine bone; DBM, demineralized bone matrix; DDM, demineralized dentinal matrix; HA, hydroxyapatite; ICBG, iliac cancellous bone graft; HQS, high quality studies; LQS, low quality studies; PRP, platelet rich plasma; SE, synthesized evidence.

ble is only up to 1.5 ml67. Expanding the mandible graft with b-TCP might be useful in situations where insufficient mandible bone can be harvested68.

Summary

To summarize, the studies included in this review showed enormous heterogeneity in the selection of patients, interventions, and outcomes assessed. Therefore, only a few explicit conclusions could be drawn.

Some suggestions and recommendations are proposed here for future studies. First, it is strongly recommended that the results obtained for unilateral and bilateral cleft patients are reported separately when both are included in a study, particularly for bilateral cleft patients who still present unsatisfactory treatment outcomes. Second, only a few studies investigating bone substitute materials22,23,28 and ICBG supplementary materials37,38,45 reported that there was no impact on tooth eruption.

However, to comprehensively assess the quality of newly regenerated alveolar bone, tooth eruption as well as the periodontal status of the teeth adjacent to the cleft, the subsequent orthodontic movement, and dental implant treatment are of great importance and should be further confirmed in clinical studies69. Third, when evaluating the effectiveness of alveolar bone reconstruction, the bone thickness and bone width should be reported, as well as the bone height. As conventional two-dimensional intraoral

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films have the disadvantages of image overlapping and deformation, which could result in overestimation of the bone graft status70,71, three-dimensional imaging techniques are required. Multislice computed tomography and cone beam computed tomography are recommended, as these have been shown to improve the accuracy of imaging assessment72,73. Finally, the studies included varied greatly in postoperative observation points and maximum follow-up period. Since de novo osteogenesis is a long-term process, it is recommended that the follow-up period be at least 12 months to reliably ascertain the long-term clinical results of the alveolar reconstruction. Funding

This systematic review was supported by Outstanding Youth Foundation of Sichuan University (2082604194311). Competing interests

None. Ethical approval

Not required. Patient consent

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Address: Chengge Hua Department of Oral and Maxillofacial Surgery West China School of Stomatology Number 14 Unit 3

Renmin Nan Road Chengdu City Sichuan 610041 China Tel.: +86 28 85501428 E-mails: [email protected],

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