Grafting materials for alveolar cleft reconstruction -a systematic review

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Grafting materials for alveolar

cleft reconstruction

- a systematic review

Pegah Mirdamadian

Raha Salahshour Nargi

Supervisors: Manjula Herath, Aron Naimi-Akbar, Jonas Becktor

Department of Oral and Maxillofacial Surgery and Oral Medicine

Master Thesis in Odontology (30 ECTS)

Malmo University

Dentistry Program

Faculty of Odontology

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Abstract

Aim: The aim of this literature study was to systematically review the scientific evidence on

the most effective donor sites and/or bone substitute material for secondary alveolar cleft grafting in alveolar cleft patients.

Material and method: In order to acquire a systematic and transparent reporting this literature review was conducted according to the PRISMA statement. The literature search was

performed in the following four databases; PubMed, CENTRAL, Web of Science and Scopus. The quality of the included studies was assessed using the revised Cochrane Risk of Bias 2 tool (RoB 2 tool).

Result: The search identified 4754 studies. Five RCT studies was included in this systematic review and assessed different donor site or bone substitute materials. Two studies showed low risk of bias and three moderate risk of bias. Only one study showed a statistically significant difference when comparing iliac bone to substitute material however all studies presented substitute materials with satisfactory results.

Conclusion: According to the data from this systematic review no clear conclusion can be drawn regarding what the most effective bone donor site and/or tissue engineered bone substitute material to use in secondary bone grafts. Based on the available evidence iliac bone could still be regarded as a benchmark, but more research and RCT’s of high quality are required, especially for artificial bone substitute materials.

Sammanfattning

Syfte: Syftet med denna litteraturstudie var att systematiskt granska den vetenskapliga

evidensen gällande det mest effektiva bentagningsstället och/eller bensubstitutmaterialet vid sekundär bentransplantation hos patienter med käkspalt.

Material och metod: För att uppnå en systematisk och transparent rapportering av denna litteraturstudie följdes PRISMA statement. Litteratursökningen gjordes i följande fyra databaser; PubMed, CENTRAL, Web of Science och Scopus. Kvaliteten av inkluderade studier granskades med hjälp av Cochrane Risk of Bias 2 tool (Rob 2 tool).

Resultat: Sökningen identifierade 4754 studier. Fem RCT studier inkluderades i denna systematiska översikt vilka värderade olika bentagningsställen eller bensubstitut. Två studier bedömdes ha låg risk för bias och tre artiklar måttlig risk för bias. Endast en studie visade på en statistiskt signifikant skillnad vid jämförelse av höftben med bensubstitut däremot

presenterade samtliga studier substitutmaterial med tillfredsställande resultat.

Konklusion: Denna systematiska översikt visade att ingen klar slutsats kan dras gällande vilken det mest effektiva bentagningsstället eller bensubstitutsmaterialet är för sekundär bentransplantation hos patienter med käkspalt. Baserat på tillgänglig evidens kan transplantat från höftbenet fortfarande anses vara bäst lämpat men mer forskning samt RCT studier av hög kvalité erfordras, särskilt för artificiella bensubstitutmaterial.

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1. Introduction

1.1 Cleft lip and/or palate

Cleft lip and/or palate (CL/P) is a collective term used to describe an opening or division that is not anatomically normal, which arises early in pregnancy as a result of the improper fusion of soft tissue and/or bone which are required for normal facial development (1). The cleft can occur in novo (non-syndromic), be hereditary or part of a syndrome (syndromic). Available data worldwide indicates that the incidence approximately is 1 in 700 however with ethnic and geographical discrepancy (2).The incidence in Sweden is approximately 2.0/1000 live births corresponding to 200 children born per year with this congenital deformity (3). Cleft lip isolated or in combination with cleft palate is predominant in boys, while isolated cleft palate is more common in girls (4).

The condition has a multifactorial etiology, no individual causal factor is known to trigger the development of the clefts although genetic and environmental factors (alcohol, smoking, folic acid deficiency…) can be causative. The etiology of non-syndromic forms on CL/P is still not well understood (5)

Alveolar cleft is a bony discontinuation of the alveolar bone that occur in approximately 75% of cleft lip and palate patients (6). This type of cleft is usually located between the lateral incisor and canine (Fig. 1, 2). Since the alveolar bone functions as a supportive structure for the facial development and the teeth a number of consequences have been reported. Because of the abnormal development of the alveolar process dental anomalies like agenesis,

supernumerary teeth, peg-shaped lateral incisor as well as rotated teeth adjacent to the cleft occur. There is also evidence of delayed eruption in cleft patients (7). Oronasal fistulae, the communication between the oral and nasal cavity is also reported and can cause speech disturbances (8). Due to the fact that CL/P affects the appearance children may be stigmatized and several studies has reported a psychosocial association with the condition (9).

An additional type is the submucosal palatal cleft type which is a cleft in muscle tissue with an overlying intact mucosa. The mucosal coverage often results in this cleft being unnoticed during the neonatal period and discovered when the child starts talking as a nasal emission occurs due to velopharyngeal insufficiency becomes evident and the speech becomes nasal (10).

Figure 1. 3D-model of alveolar cleft between the lateral incisor and canine.

By: Manjula Herath

Figure 2. Axial CBCT x-ray of alveolar cleft between lateral incisor and canine.

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1.2 Embryology and classification

During the development of the face there are two important structures involved – the pharyngeal arches and the neural crest cells. The pharyngeal arches arise during the fourth week of embryonic development and are precursors for many structures. The neural crest cells derive from the neuroectoderm and are specialized cells that contribute to the mesenchyme of the head (ectomesenchyme) (11).

By the end of embryonic week 4, five facial prominences will develop around the primitive mouth, the stomatodeum, which occurs as a result of the proliferation of mesenchymal cells of neural crest origin. The unpaired frontnasal prominence forms the forehead, nose and

midsection of the upper lip. The bilateral maxillary prominences will form the maxilla, lateral aspects of the upper lip and the palate and the bilateral mandibular prominences give rise to the mandible and the lower lip. Normal facial development occurs as the result of the fusion between the five prominences between week 5 and 12 of pregnancy, clefts are the result of the absence of fusion (12).

Development of clefts

The palate begins to develop during week 5 and is not completed until week 12, the most critical time is between weeks 6 and 9 (12). From the frontnasal prominence originates the median palatine process which gives rise to the primary palate from where the lip, alveolar bone and anterior hard palate will develop. Disruptions during this period can result in clefting of the primary palate and causes lip and/or alveolar clefts.

From the maxillary prominences the lateral palatal processes will grow and form the

secondary palate, which consists of the hard palate posterior to the nasopalatine foramen and the soft palate. Disruptions in fusion during this time of merging results in palatal clefts (13).

Classification

Cleft types are classified depending on where the cleft is located. Through time there has been numerous classification systems for recording cleft lip and palate malformations (14). In table 1 we present a classification according to ICD-10 (International Statistical Classification of Disease and Related Health Problems – Tenth Revision) published by the World Health Organization (WHO), following cleft-diagnoses are registered in the Swedish cleft lip and palate registry (15,16).

Table 1. Classification of the subclasses of CL/P with explanation of location according to ICD-10.

ICD-10 diagnosis Explanation

Q35.3 Cleft soft palate Isolated cleft solely involving the soft palate Q35.5 Cleft hard palate with cleft soft palate Cleft involving both the hard and soft palate Q36.0 Cleft lip, bilateral Cleft isolated to the lip bilaterally

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1.3 Treatment

Management of cleft lip and palate patients require a multispecialty approach with qualified personnel (17). In Sweden the team typically involves a plastic surgeon, an orthodontist, a speech therapist, a maxillofacial surgeon and ENT-specialists. Other professions as psychologists may also be included (18).

Cleft lip and palate can be diagnosed prenatally with ultrasound. In these cases, parents can meet the treatment team before the delivery of the child and receive information. After birth, feeding the infant can be difficult due to poor intraoral suction. Special bottles are used in these cases. Early interventions include treatment with retrusion tape, stent and palatal molding to optimize the tissue positions presurgical (17,18).

There are multiple approaches for surgical treatment of cleft lip and palate patients, and it differs between practices (18). The euro cleft project which compared surgical approaches of different practices between 1996-2000, registered 201 centers and 194 different approaches (19) Alveolar cleft surgery can be separated into early intervention called boneless bone grafting (3 months) (20), early secondary (2-5 years, primary dentition), and secondary repair which is the widely accepted treatment (approximately 8-12 years, after the eruption of centrals but before canine eruption) (13).

Secondary surgical procedure is performed on patients with mixed dentition (17,21). The ideal time is when the canine root is approximately 1/3 developed, at the age of 9-12

according to El Deeb et al (22). Surgery at earlier stages might affect the development of the maxilla and is therefore not recommended. During secondary alveolar bone grafting, the cleft is surgically exposed and bone grafting is performed (21). The goal is to provide a bony support for the development of a normal occlusion, a stable palate, bony base for the nose, and improved esthetics (17,21). Fig. 3-8 demonstrates the steps of secondary alveolar bone grafting with iliac bone.

The most common and preferred donor site for bone grafting is iliac cancellous bone, because it is easy to harvest and has a high osteoinductive potential. In more recent studies iliac cancellous bone is incorporated with platelet rich plasma, with the goal to enhance

osteogenesis during the grafting procedure. PRP is a good source for growth factors and can be extracted from the autologous whole blood during surgery (23). Other possible donor sites are the cranium, tibia, mandibular ramus and symphysis (20). However, it is important to know that harvesting autogenous bone blocks is followed by risks such as post-operative donor site morbidity, post-operative pain and increased blood loss as well as infections (24,25)

Q37.2 Cleft soft palate with bilateral cleft lip

Bilateral cleft lip with incomplete palate Q37.3 Cleft soft palate with unilateral cleft

lip Unilateral cleft lip with incomplete palate

Q37.4 Cleft hard and soft palate with bilateral cleft lip

A bilateral cleft engaging lip, alveolar bone and palate

Q37.5 Cleft hard and soft palate with

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Other sources of bone graft material are allogeneic bone-graft substitutes such as deproteinized bovine bone matrix (DBBM) as well as alloplastic materials such as

hydroxyapatite (HA) and tricalcium phosphate (TCP), which are used as autologous grafts for reconstruction of alveolar clefts (20). Recombinant human bone morphogenetic protein-2 (rhBMP-2), an osteogenic agent, in combination with demineralized bone matrix has been used as an alternative for cleft repair (26).

Figure 3. Alveolar cleft located in quadrant one with displaced teeth

Photo: Manjula Herath

Figure 4. Marking of alveolar cleft area for surgery

Figure 5. Harvesting bone from the iliac bone for grafting of alveolar cleft

Figure 6. Blocks of harvested iliac bone

Figure 7. Bone grafting with harvested iliac bone in the alveolar cleft quadrant 1

Figure 8. Periostal flap repositioned and sutured after grafting

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1.4 Aim and issue

The aim of this literature study was to systematically review the scientific evidence on donor sites and bone substitute for secondary alveolar cleft grafting in alveolar cleft patients.

Research question

What is the most effective bone donor site and/or tissue engineered bone substitute material to use in secondary bone grafts in alveolar cleft patient?

1.5 Clinical, societal and ethical importance

Secondary alveolar bone is a widely accepted treatment by professionals but there is no universal consensus regarding type of bone, donor site and need for bone substitute. The latest Cochrane report on the topic was published in 2011 and included two trials, the authors concluded that due to high risk of bias the evidence is insufficient to conclude that one intervention is superior another (27).

Systematic reviews are important to identify, evaluate the current evidence and summarize available scientific studies in order to e.g. assess the best treatment of choice and make it accessible for health care workers. A systematic review of high quality follows a strict design based on a pre-specified and reproducible method and if done well provide reliable data on effects of different interventions. Besides this, systematic reviews can also highlight potential knowledge gaps which can be used to plan further research (28). This particular systematic review also captures the societal perspectives of alveolar bone grafts as it could help to lower costs in the health sector.

2. Material and method

2.1 Protocol and registration

A priori protocol for this systematic review was registered in PROSPERO (registration number CRD42020197451).

2.2 Research specification

In order to formulate a structured and focused research question in terms of patient, intervention, control group and clinical outcome PICO was used (29).

What is the most effective bone donor site and/or tissue engineered bone substitute material to use in secondary alveolar bone grafts in alveolar cleft patients?

2.3 Eligibility criteria

Studies included in this systematic review were randomized controlled trials (RCT), non-randomized controlled trials (N-RCT), cohort studies, systematic reviews and meta-analysis Eligible studies were selected according to PICO and inclusion/exclusion criteria as presented in Table 2.

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Table 2. PICO framework, inclusion and exclusion criteria for selecting studies

*SABG will be 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 assessing the results of alveolar bone grafting in the primary dentition will be excluded.

2.4 Information sources

An electronic search was performed in the following separate databases; PubMed, CENTRAL (Cochrane Central Register of Controlled Trials), Scopus and Web of Science until the 12th_of

August. No filters were used in the search. In order to acquire a systematic and transparent reporting this literature review was conducted according to the PRISMA statement (30) (Appendix 1).

2.5 Search strategies

A main search strategy was developed for PubMed in collaboration with a university librarian this strategy was then adapted to the remaining databases. (Table 3) For PubMed and

CENTRAL, a combination of MeSH-terms and free text was used and for Scopus and Web of Science exclusively the free text was adopted. Titles and abstracts retrieved were imported to EndNote (Reference Management software) for removal of duplicates. Reference

management was carried out with the aid of Rayyan, a web and mobile app for systematic reviews (31).

Population Patients with unilateral or bilateral alveolar clefts undergoing

SABG*.

Intervention Autologous bone graft

Bone substitute material

Control Autologous bone graft

Bone substitute material

Outcome Bone volume

Bone height/width

Patient reported outcome measures (PROM) Health economic outcomes

Complications

Eruption of permanent maxillary canine of the grafted site

Inclusion criteria Systematic reviews

Randomized control studies Non-randomized control studies Cohort studies

English and Swedish language

Alveolar cleft patients undergoing SABG Clinical and/or radiological diagnosis

Exclusion criteria Animal studies

Studies assessing the results of alveolar bone grafting in primary dentition

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2.6 Study selection

The list of publications after duplicate removal was divided between two independent groups, group 1 (ANA, PM, RS) and group 2 (MH, JB). Each reviewer in the groups excluded

irrelevant articles based on title and abstract, uncertainties regarding including a publication based on title and abstract were retained until the following step: full-text screening. Studies for full-text screening was divided between group 1 and 2, all potentially eligible studies were read in full-text by each review respectively, any disagreement was discussed in the separate groups until consensus decision was reached. Studies were included if fulfilled PICO and inclusion and exclusion criteria. Excluded articles read in full-text were recorded and will be referenced in this review. If enough applicable studies of sufficient quality a meta-analysis was planned be performed.

Table 3. Search strategy in PubMed, CENTRAL, Web of Science and Scopus

Due to time constraints, it was agreed at this stage to only proceed with RCT’s for this master thesis. This systematic review will be further developed for publication and will include RCT, non-RCTs, cohort studies and systematic reviews as planned.

2.7 Quality assessment and data extraction

The Cochrane risk of Bias 2 tool was developed 2008 for assessing the quality of RCT studies. The tool was revised 2019 and the revised Risk of Bias 2 tool (RoB2 tool) was developed (32). The tool consists of domains of bias where each focus on different aspects of the studies; randomization process, intended intervention, outcome data and reported result. Each domain present questions aiming at different features of the studies relevant for judging the risk of bias of that particular domain which is expressed low, high or some concern. (Appendix 2) Lastly the overall risk of bias for the study is decided by adding the risk of

Database Indexing terms Abstract (n)

PubMed (((”Cleft Palate” [Mesh]) OR (”Cleft Lip” [Mesh]))) OR ((“cleft lip”)) OR (“cleft palate”)) OR (cleft)))

AND

(((“Alveolar Ridge Augmentation”[Mesh]) OR

(“Alveoloplasty”[Mesh]) OR (“Surgery, Oral”[Mesh]) OR (“Alveolar Bone Grafting”[Mesh])) OR ((Alveoloplasty) OR (“oral surgery”) OR (“alveolar bone grafting”) OR (“bone graft”))) 1 664 CENTRAL 111 Web of Science 753 Scopus 2226 Total 4754

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biases of all domains (33). For this systematic review quality assessment was carried out in concordance by four reviewers (ANA, MH, PM, RS).

3. Results

3.1 Literature search

The literature identification yielded a total of 4754, the number of publications retrieved from each data base is presented in table 3. A flow chart of the screening process for systematic reviews according to PRISMA is presented in Fig. 9. After duplicate removal 3424 articles remained and after title-abstract screening a total of 109 publications were assessed for full-text screening. A total of 86 studies were excluded during the full-full-text assessment and are presented in Appendix 3. The most common reason for excluding a study was wrong study type.

In February 2021 an update on the PubMed (table 3) search was made, which resulted in 77 new title and abstracts, none of which met the inclusion criteria.

3.2 Quality assessment and study characteristics

Quality assessment using RoB-2 tool was performed on 23 RCT’s, which identified 2 studies of low risk of bias (B.M Attar et al. 2017; Shirani et al. 2017) (34,35) and 3 studies were considered having some concern (Desai et al. 2019; Torres Bezerra et al. 2019; Shawky et al. 2016) (36–38). In the remaining 18 studies a high risk of bias was found. The most common reason for high risk of bias was because poorly described or unclear randomization process. Data extraction with the key characteristics for each of the 5 included studies are presented in Table 5 (reference number here). Studies excluded based on high risk of bias is presented in Appendix 4. Quality assessment of some concern and low risk of bias studies are presented in Table 4.

As the results from the included studies were not comparable no meta-analysis was undertaken.

Table 4 Risk of bias within each study according to the revised RoB-2 tool

Low Medium High Risk of bias Study Randomization process Deviation from the intended interventions (effect of assignment to intervention) Missing outcome data Measurement of the outcome Selection of the reported result Overall risk of bias BM Attar et al (34) Desai et al (36) Shawky et al (38) Shirani et al (35) Torres Bezerra et al (37)

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PRISMA 2009 Flow Diagram

Figure 9. PRISMA flow diagram presentering the search steps with reasons for exclusion

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal. pmed1000097

For more information, visitwww.prisma-statement.org

Records identified through database searching

(n = 4754)

Additional records identified through other sources

(n = 0)

Records screened after duplicates removed

(n = 3424)

Records excluded (n = 3320)

Full-text articles assessed for eligibility

(n = 109)

Full-text articles excluded, with reason

(n = 86)

See appendix 3

RCT studies included for quality

assessment (RoB2) (n = 23)

RCT studies included for quality assessment (RoB2)

(n = 5) In cl u d ed E li gi b il it y Sc re eni ng Id en ti fi cat ion

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13 First author, year, country, reference Population Study group material Control group material

Outcome Follow up Main findings Adverse effects Conclusion

BM Attar et al, 2016, Iran (34) n: 10 study group 10 control group Age: 8-14 years Mandibular symphysis (2/3 autologous, 1/3 allogeneic) and L-PRF

Iliac bone - Volume of residual alveolar defects (cm3) -Volume of regenerated bone (cm3) -Percentage bone reconstruction (%) 1 week, 1 mo., 3 mo., 6 mo., 12 mo. Study group Preop volume: 0.89 +0.29cm3 After 12mo: 0.28+0.15cm3 Volume of new bone

formed/%bone reconstruction: 0.61+0.19cm3 / 69.57%+10.13%

Control group

Preop volume: 0.95+0.27cm3 After 12mo: 0.26+0.13cm3 Volume of new bone

formed/%bone reconstruction: 0.69+0.19cm3 / 73.86%+6.93%

Temporary sensory

complications in chin and lower lip in study group with resolution within 3 mo. Study could walk normally the day after surgery. Control group mean time needed before walking normally 5.9 + 2.1 days Satisfactory results, fistula repaired. No statistically significant difference between the groups.

Desai et al, 2019, India (36) n: 20 study group /20 control group Age: 9-18 years Anterior iliac bone + PRF Anterior iliac bone Bone resorption (postop vertical bone height in relation to interdental bone height) 4-point scale: Immediate postoperative, 3 mo., 6 mo., 9 mo. Study group:

3 mo. 14 patients grade 1

After 6mo and 9mo – 19 patients grade 1 resorption, 1 patient grade 2.

Control group:

3 mo. – 16 patients grade1,

1 patient (5%) in study group and control group 6 patients (30%) showed serious discharge. No significant difference between groups at 3 and 6mo, but significant after 9 mo.

PRF favors reduced bone resorption and

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14 Grade 1: 0–25 % bone resorption Grade 2: 25–50% Grade 3: 50–75% Grade 4: 75– 100% 1 patient grade 2

6 mo. 14 patients grade 1. 6 patients grade 2

9 mo. 12 patients grade 1, 8 patients grade 2. Dehiscence 4 patients study group (20%), 8 patients (40%) in control group. improved wound healing. Shirani et al, 2016, Iran (35) n: 8 study group 8 control group Age: study group mean age 10.6 years, control group mean age 10.4 years Iliac + PRGF FDBA + PRGF Volume of regenerated bone (cm3)

6 mo. Study group:

- baseline volume cleft before surgery (v1) – 1.3 cm3

- mean regenerated bone volume 6 months (v2) – 1.0 cm3

-v2/v1 (ratio of bone formation) = 0.7 (70%)

Control group:

- baseline volume cleft before surgery (v1) – 1.2 cm2

- mean regenerated bone volume 6 months (v2) – 0.6 cm3

-v2/v1 (ratio of bone formation) = 0.5 (50%) 1 patient in study group excluded due to dehiscence and infection. Iliac + PRGF resulted in scar at surgical site Iliac bone in combination with PRGF was more successful.

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15 Shawky et al, 2000, Egypt (38) n: 12 study group 12 control group Age: 9-14 years Anterior iliac bone + PRF Anterior iliac bone - Volume of residual alveolar defects(cm3) -Volume of regenerated bone (cm3) -Percentage bone formation (%) -Density (Hus) of newly formed bone

6 mo. Study group:

- baseline volume of defect: mean 0.96 + 0.259 cm3

- final volume of defect: mean 0.18 + 0.08 cm3

-Mean amount of newly formed bone volume 0.78 cm3.

-82.6% new bone.

-Bone density – mean 360.82 HU

Control group:

- baseline volume of defect: mean 0.9 + 0.28 cm3

- final volume of defect: mean 0.275 + 0.05 cm3

-Mean amount of newly formed bone volume 0.62cm3.

-68.38 new bone %

-Bone density – mean 384.03 HU

No adverse effects

Percentage of newly formed bone in study group was statistically significant increase in comparison to the control group. Difference in bone density not statistically significant. Torres Bezerra et al, 2019, Brazil (37) n: 20 Control group: 10 Study group: 10 patients Autogenous bone graft from mandibular symphysis Bio-Oss associated with PRP - Mean volume of residual alveolar defects (mm) -Mean area of residual alveolar defect (mm)

1-year postop Study group:

Baseline area: 345.81mm2 Baseline volume: 374.88mm3 1year post op:

Area: 265.08mm2 Volume: 254.12mm3

No adverse effects

Significant reduction regarding mean area and mean volume within groups. No statistically significant difference between study and control group

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Abbreviations: n, number om patients; L-PRF, leukocyte-rich-plateletal-rich-fibrin; mo., months pre-op, preoperative; PRF, platelet rich fibrin; FDBA, freeze-dried bone allograft; PRGF, plasma rich in growth factors; HU, Hounsfield scale; Bio-Oss, Deproteinized Bovine bone graft; PRP, platelet rich plasm

Mean age: Study group: 15.6 years Control group: 14.5 years Control group: Baseline area: 274.39mm2 Baseline volume: 277.87 mm3 1year post op:

Area: 132.72mm2 Volume: 96.19mm3

regarding mean area and mean volume.

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This systematic review included results from five RCT’s, two articles of low and three articles of moderate risk of bias. Common to these articles was that they compared autogenous bone graft such as iliac bone or mandibular symphysis to a combination of autogenous bone with supplementary material or a bone substitute material.

Majority of the studies used iliac bone as bone grafting material for either the study or control group. Torres Bezerra et al (37)was the only exception, although they also used autogenous bone graft but from the mandibular symphysis. Shirani et al (35)used a combination of iliac bone with PRGF for their study.

Anterior iliac bone with or without PRF/PRP

Shawky et al (38) and Desai et al (36) investigated the effect of adding PRF to iliac bone and compared it to solely iliac bone as a grafting material. Shawky et al only included patients with unilateral cleft in both study and control group, but Desai et al also included some patients with bilateral cleft in both groups. The biggest difference between the two studies was that use of different outcome measures. Shawky et al investigated volume of residual alveolar defect, volume of regenerated bone, percentage bone formation and density, while Desai et al measured bone resorption and wound healing.

Shawky et al reported positive results when PRF was added to iliac bone, when investigating the quantity of new bone formed. There was a higher percentage of new bone formation but when measuring bone density, the density was a bit lower in the study group, even though the difference was not statistically significant.

Desai et al also reported satisfactory results when using iliac bone + PRF. There was a significant difference when measuring bone resorption at 9 months, indicating that bone resorption was reduced when PRF was used. Additionally, less adverse effects were documented for the study group suggesting that wound healing was also improved.

Iliac bone versus other alternatives

Two of the studies included in this review compared iliac bone to other alternatives for bone grafting on patients with unilateral cleft. Attar et al used a combination of mandibular symphysis, allograft and L-PRF as intervention in the study group, and iliac bone in the control group. When measuring bone volume and percentage bone reconstruction both groups showed successful results, although the difference between the groups was very small and not significant. Patients where bone graft was harvested from iliac bone required approximately 5.9 days before they could walk normally. When grafting from the chin, 3 patients

experienced temporary sensory complications in chin and lower lip that was resolved within 3 months.

Shirani et al (35,37) presented results for both secondary and tertiary grafting but presented them separately, therefore results could be assessed for this review. The study group consisted of autogenous iliac bone with PRGF and the control group consisted of an allograft (FDBA) with PRGF. In both groups mean regenerated bone volume was close to the baseline volume cleft before surgery, but a higher ratio of bone formation was evident in the study group, which made iliac bone in combination with PRGF the more successful choice.

Mandibular symphysis as grafting material

Torres Bezerra et al (37) and Attar et al (34) both included bone grafting from mandibular symphysis in their study. As mentioned, Attar et al used a combination of grafting materials

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in their study group, bone from mandibular symphysis included and compared to iliac bone. Torres et al study aim was to compare the outcome of autologous bone grafting from

mandibular symphysis to an artificial material called Bio-Oss in combination with PRP. At first, they included 28 patients in their study but then decided only 20 patients were eligible. No further explanation was given. They operated on patients with unilateral cleft, except for one patient in the study group that had a bilateral cleft which they recorded as 2 separate clefts and therefore registered the number of patients to study group as 11. Both alternatives demonstrated satisfactory results with significant reduction in mean area and volume within each group separately. When looking at the 1 year post operational volume and area

reduction, the change was bigger for the control group. Even though the difference was not statistically significant, Torres Bezerra et al indicated that Bio-Oss in combination with PRP was a good option for alveolar bone grafting material.

4. Discussion

4.1 Methodological discussion

In order to avoid missing important studies when doing a systematic review Cochrane is recommending using at least three different data bases for the search (39). The three databases considered most important are; CENTRAL Medline and Embase. The authors of this

systematic review did not have access to Embase therefore databases Web of Science and Scopus was also searched.

Of the total 23 RCT’s identified after full-text screening, 18 were excluded (Appendix 4), due to high risk of bias regarding the randomization process. Randomization means that the selection of patients for different interventions takes place in a random way and not based on patient characteristics, e.g. by coin tossing or sealed envelopes. The majority of the studies mentioned that the trial was randomized but no more than that. There was no detailed description of the sequence generation process.

Domain 2 of the RoB-2 tool assesses the risk of bias regarding effect of assignment to

intervention (Appendix 2). None of the included RCT’s achieved to fulfill the criteria to blind the patients and operators (Fig. 8). Since the five articles either included the iliac bone or mandibular symphysis both the study participants and the surgeons were aware of the intervention as bone is harvested, therefore for this systematic review this domain was regarded less relevant. There was also an overall high risk of bias on domain 5 assessing the risk of bias in selection of the reported result as none of the included studies mentioned any protocol or pre-specified analysis plan, but in relation to the aim of this systematic review and the general trend of absence of mentioned protocol it was regarded irrelevant. Based on this, articles with high risk of bias on one or both of these domains could still be evaluated as having some concern or low on the overall risk of bias. Domain 1 (randomization) was regarded the most important and in order for a study to be judged as low risk of bias this domain had to be estimated low.

The systematic review by Cochrane from 2011 on this topic included two RCT’s, “Dickinson et al, 2008 (40) and Segura-Castillo, 2005” (41) although considered as high risk of bias. None of these were included in this systematic review. The study by Dickinson et al was excluded due to high risk of bias because of unclear description of randomization. The publication by Seguro-Castillo was excluded during the title-abstract screening and it was decided to investigate why there was a discrepancy between the assessment done by Cochrane and this systematic review. The title that the authors based the exclusion on was “Technical

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Strategies – Reduction of Bone Resorption by the Application of Fibrin Glue in the

Reconstruction of the Alveolar Cleft” and exclusion was motivated because the article was considered focusing on different techniques rather than different grafting materials. The study was assessed in full-text and met the criteria for quality assessment but was in the later step excluded due to inadequate description of randomization sequence.

4.2 Result discussion

Only one included study, Shirani et al (35) examined the use of allograft. In this particular study the allograft FDBA in combination with PRGF did not perform better than iliac bone and PRGF, the ratio bone formation in the iliac bone group was 70% and in the allograft group 50%. But because the advantages of using allografts such as avoid second operation site for harvesting bone, decreased surgical time, decreased risk of post-operational pain and recovery more studies on allografts need to be carried and possibly with combination other supplementary material other than PRGF.

Shawky et al (38) reported a statistically significant increase when combining PRF with iliac bone and Desai et al described that PRF reduced bone resorption and reduced healing. Desai et al did not report a statistically significant difference as Shawky et al did but the results point towards that combining iliac bone with either PRF and PRP is satisfactory and could be an alternative to solely using iliac bone. There is a need for more RCT studies of high quality on this topic in order to draw a conclusion but there is a low certainty that there is an effect. Complications to the intervention was documented in three of the studies. Attar et al (34) reported sensory complications when grafting was made from the chin symphysis as well as patients having problems with walking after iliac bone surgery. Shirani et al and Desai et al both reported complications such as dehiscence when iliac bone was used as a bone grafting material. Torres Bezerra et al (37) compared Bio-Oss in combination with PRP to autogenous material and reported reduction of mean area and mean volume of the cleft in both groups although the difference between the groups was not significant. Bio-Oss in combination with PRP showed favorable results and could be utilized as an alternative to autologous bone but more studies are needed and with larger sample groups.

Of the excluded articles in the full-text stage (Appendix 3), six where found to be on going trials which are only registered in Clinical Trials database (42). The authors of these will prior to publication be contacted in order to acquire possible preliminary results.

The main limitation when it came to assemble the results and constructing a meta-analysis was that the studies showed a substantial heterogenicity in regarding the selection of patients, interventions and outcome. Therefore, meta-analysis was precluded.

Because of language restriction this systematic review might have missed RCT’s that might have affected the outcomes and conclusions of this review.

4.3 Conclusion

According to the data from this systematic review no clear conclusion can be drawn regarding which is the most effective bone donor site and/or tissue engineered bone substitute material to use in secondary bone grafts. Based on the available evidence, iliac bone could still be regarded as a benchmark.

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As mentioned previously the latest systematic review on the topic was published 2011 by Cochrane, although a decade has passed since no new evidence or considerable progress has been made in the field of secondary alveolar bone grafting. Of the 23 RCT studies that this systematic review yielded in, solely 5 studies passed the criteria of adequate quality for inclusion. With this said, RCT’s of high quality are required with respect to a clear

presentation of the randomization process as well as measurement of outcome data. Further, future studies should aim to limit age to 8-12 years old (mixed dentition) in order to avoid including patients with permanent dentition, as it could affect the results. Lastly, studies examining artificial bone substitute material is of interest to examine further with the prospect to replace autologous bone in the future.

Acknowledgements

We would like to thank Martina Vall at the library of Malmo University for excellent assistance with the search strategy.

Funding

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30. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. International Journal of Surgery. 2010;8(5).

31. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan—a web and mobile app for systematic reviews. Systematic Reviews. 2016 Dec 5;5(1).

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34. Movahedian Attar B, Naghdi N, Etemadi Sh M, Mehdizadeh M. Chin Symphysis Bone, Allograft, and Platelet-Rich Fibrin: Is the Combination Effective in Repair of Alveolar Cleft? Journal of Oral and Maxillofacial Surgery. 2017 May;75(5).

35. Shirani G, Abbasi AJ, Mohebbi SZ, Moharrami M. Comparison between autogenous iliac bone and freeze-dried bone allograft for repair of alveolar clefts in the presence of plasma rich in growth factors: A randomized clinical trial. Journal of

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37. Bezerra BT, Pinho JNA, Figueiredo FED, Brandão JRMCB, Ayres LCG, da Silva LCF. Autogenous Bone Graft Versus Bovine Bone Graft in Association with Platelet-Rich Plasma for the Reconstruction of Alveolar Clefts: A Pilot Study. The Cleft Palate-Craniofacial Journal. 2019 Jan 12;56(1).

38. Shawky H, Seifeldin SA. Does Platelet-Rich Fibrin Enhance Bone Quality and Quantity of Alveolar Cleft Reconstruction? The Cleft Palate-Craniofacial Journal. 2016 Sep 1;53(5).

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40. Dickinson BP, Ashley RK, Wasson KL, OHara C, Gabbay J, Heller JB, et al. Reduced Morbidity and Improved Healing with Bone Morphogenic Protein-2 in Older Patients with Alveolar Cleft Defects. Plastic and Reconstructive Surgery. 2008 Jan;121(1). 41. Segura-Castillo JL, Aguirre-Camacho H, González-Ojeda A, Michel-Perez J.

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Appendix 1

Section/topic # Checklist item Reported _{on page #}

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. _{Main page}

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and

implications of key findings; systematic review registration number.

2

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. _4-7

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons,

outcomes, and study design (PICOS). 8

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide

registration information including registration number. 8

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,

language, publication status) used as criteria for eligibility, giving rationale. _{table 2}9 and Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify

additional studies) in the search and date last searched. 9

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be

repeated. 10

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,

included in the meta-analysis). 10

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes

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Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and

simplifications made. Table 2

Risk of bias in individual

studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. 10 and 11 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). _{In results} Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency

(e.g., I2) for each meta-analysis. 17 and 18

Page 1 of 2

Section/topic # Checklist item Reported _{on page #}

Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective

reporting within studies). -

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating

which were pre-specified. -

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at

each stage, ideally with a flow diagram. Figure 10 _and

Appendix 3, 4 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and

provide the citations. Table 5

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Table 4 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each

intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Table 5 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. _- Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). _- Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). _-

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Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to

key groups (e.g., healthcare providers, users, and policy makers). 19 and 20

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of

identified research, reporting bias). 19

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. ₂₀

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the

systematic review. 20

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal. pmed1000097

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Appendix 2

Risk of bias assessment

Responses underlined in green are potential markers for low risk of bias, and responses in red are potential markers for a risk of bias. Where questions relate only to sign posts to other questions, no formatting is used.

Domain 1: Risk of bias arising from the randomization process

Signalling questions Comments Response options

1.1 Was the allocation sequence random? Y / PY / PN / N / NI

1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?

Y / PY / PN / N / NI

1.3 Did baseline differences between

intervention groups suggest a problem with the randomization process?

Risk-of-bias judgement Low / High / Some concerns

Optional: What is the predicted direction of bias

arising from the randomization process? NA / Favours experimental / Favours comparator / Towards null /Away from null / Unpredictable

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Domain 2: Risk of bias due to deviations from the intended interventions (effect of assignment to intervention)

2.1. Were participants aware of their assigned

intervention during the trial? Y / PY / PN / N / NI

2.2. Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?

Y / PY/ PN / N / NI

2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the trial context?

NA / Y / PY / PN / N / NI

2.4 If Y/PY to 2.3: Were these deviations likely

to have affected the outcome? NA / Y / PY / PN / N / NI

2.5. If Y/PY/NIto 2.4: Were these deviations from intended intervention balanced between groups?

2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?

2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?

due to deviations from intended interventions? Favours comparator / Towards NA / Favours experimental /

null /Away from null / Unpredictable

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Domain 3: Missing outcome data

3.1 Were data for this outcome available for all, or nearly all, participants randomized?

3.2 If N/PN/NI to 3.1: Is there evidence that the result was not biased by missing outcome data?

NA / Y / PY / PN / N

3.3 If N/PN to 3.2: Could missingness in the

outcome depend on its true value? NA / Y / PY/ PN / N / NI

3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?

due to missing outcome data? Favours comparator / Towards NA / Favours experimental /

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Domain 4: Risk of bias in measurement of the outcome

4.1 Was the method of measuring the outcome

inappropriate? Y / PY / PN / N / NI

4.2 Could measurement or ascertainment of the outcome have differed between

intervention groups?

4.3 If N/PN/NI to 4.1 and 4.2: Were outcome assessors aware of the intervention received by study participants?

4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?

4.5 If Y/PY/NI to 4.4: Is it likely that

assessment of the outcome was influenced by knowledge of intervention received?

in measurement of the outcome? Favours comparator / Towards NA / Favours experimental /

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Domain 5: Risk of bias in selection of the reported result

5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?

Is the numerical result being assessed likely to have been selected, on the basis of the results, from...

5.2. ... multiple eligible outcome

measurements (e.g. scales, definitions, time points) within the outcome domain?

5.3 ... multiple eligible analyses of the data? Y / PY / PN / N / NI

due to selection of the reported result? Favours comparator / Towards NA / Favours experimental /

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Overall risk of bias

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Optional: What is the overall predicted direction

of bias for this outcome? NA / Favours experimental / Favours comparator /

Towards null /Away from null / Unpredictable

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Appendix 3

Table presenting publications excluded on relevance.

Reference Reason for exclusion

Abramowicz S, Katsnelson A, Forbes PW, Padwa BL. Anterior versus posterior

approach to iliac crest for alveolar cleft bone grafting.

Retrospective

Aiyesha Wahaj, Kashif Hafeez, Muhammad Sohail Zafar,

Role of bone graft materials for cleft lip and palate patients: A systematic review,

Systematic Review

Allard RH, Lekkas C, Swart JG. Autologous versus homologous bone grafting in

osteotomies, secondary cleft repairs and ridge augmentations: a clinical study.

Retrospective

Alonso N, Risso GH, Denadai R, Raposo-Amaral CE. Effect of maxillary alveolar reconstruction on nasal symmetry of cleft lip and palate patients: a study comparing iliac crest bone graft and recombinant human bone morphogenetic protein-2

Wrong outcome

Alonso, N. Tanikawa, D. Y. S.; Rocha, D. L; Callan, Rdflw; Ozawa, t.O,; DoAmaral, C. E, R; DeAlmeiuda, A. B. A.; Preliminary Results of Maxillary Alveoalr Cleft Repair using Recombinant Human Bone

Morphogenic Protein-2.

Conference abstract

Amini, P. & Milani, A. & Rahmani, N.. (2016). Radiological assessment of using allograft in combination with platelet-rich fibrin in alveolar cleft grafting. 26. 175-185.

Foreign language

Bajestan MN, Rajan A, Edwards SP, Aronovich S, Cevidanes LHS, Polymeri A, Travan S, Kaigler D. Stem cell therapy for reconstruction of alveolar cleft and trauma defects in adults: A randomized controlled, clinical trial.

Wrong population

Balaji SM. Alveolar cleft defect closure with iliac bone graft, rhBMP-2 and rhBMP-2 with zygoma shavings: Comparative study.

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35 Bekisz JM, Fryml E, Flores RL. A Review of Randomized Controlled Trials in Cleft and Craniofacial Surgery.

Wrong outcome

Benlidayi ME, Tatli U, Kurkcu M, Uzel A, Oztunc H. Comparison of bovine-derived hydroxyapatite and autogenous bone for secondary alveolar bone grafting in patients with alveolar clefts.

Retrospective

Borba AM, Borges AH, da Silva CS, Brozoski MA, Naclério-Homem Mda G, Miloro M. Predictors of complication for alveolar cleft bone graft.

Retrospective

Borstlap WA, Heidbuchel KL, Freihofer HP, Kuijpers-Jagtman AM. Early secondary bone grafting of alveolar cleft defects. A comparison between chin and rib grafts.

nRCT

Carlini JL, Biron C, Gomes KU, Da Silva RM. Surgical repositioning of the

premaxilla with bone graft in 50 bilateral cleft lip and palate patients.

Retrospective cohort study, wrong study design

Cohen M, Figueroa AA, Haviv Y, Schafer ME, Aduss H. Iliac versus cranial bone for secondary grafting of residual alveolar clefts.

Retrospective

da Rosa WLO, da Silva TM, Galarça AD, Piva E, da Silva AF. Efficacy of rhBMP-2 in Cleft Lip and Palate Defects: Systematic Review and Meta-analysis.

Systematic Review

De Santis, P,; Savoia, A. Allopastic material in cleft palate and lip sequelae

Foreign language Du F, Wu H, Li H, Cai L, Wang Q, Liu X,

Xiao R, Yin N, Cao Y. Bone Marrow Mononuclear Cells Combined with Beta-Tricalcium Phosphate Granules for Alveolar Cleft Repair: A 12-Month Clinical Study.

Wrong publication type

Elfaramawi, T.I. & Faramawey, M.I. & Dahaba, M.M. & Hakam, M.M. (2015). Deproteinized Bovine Bone Graft in Maxillary Alveolar Cleft Reconstruction.

Enemark H, Jensen J, Bosch C. Mandibular bone graft material for reconstruction of alveolar cleft defects: long-term results.

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36 Franco Bueno, D. Bone Tissue Engineering with Dental Pulp Stem Cells for Alveolar Cleft Repair

NCT, trial not completed/results not published

Freihofer HP, Borstlap WA, Kuijpers-Jagtman AM, Voorsmit RA, van Damme PA, Heidbüchel KL, Borstlap-Engels VM. Timing and transplant materials for closure of alveolar clefts. A clinical comparison of 296 cases.

Retrospective

Freihofer HP, Kuijpers-Jagtman AM. Early secondary osteoplastic closure of the residual alveolar cleft in combination with orthodontic treatment.

Gimbel M, Ashley RK, Sisodia M, Gabbay JS, Wasson KL, Heller J, Wilson L,

Kawamoto HK, Bradley JP. Repair of alveolar cleft defects: reduced morbidity with bone marrow stem cells in a resorbable matrix.

nRCT

Giudice G, Cutrignelli DA, Leuzzi S, Robusto F, Sportelli P, Nacchiero E. Autologous bone grafting with platelet-rich plasma for alveolar cleft repair in patient with cleft and palate.

Retrospective

Greived, M. Cost Effectiveness in Alveolar Bone Grafting in Patients with Cleft Lip and Palate.

Guo J, Li C, Zhang Q, Wu G, Deacon SA, Chen J, Hu H, Zou S, Ye Q. Secondary bone grafting for alveolar cleft in children with cleft lip or cleft lip and palate.

Systematic Review

Hammoudeh JA, Fahradyan A, Gould DJ, Liang F, Imahiyerobo T, Urbinelli L, Nguyen JT, Magee W 3rd, Yen S, Urata MM. A Comparative Analysis of

Recombinant Human Bone Morphogenetic Protein-2 with a Demineralized Bone Matrix versus Iliac Crest Bone Graft for Secondary Alveolar Bone Grafts in Patients with Cleft Lip and Palate: Review of 501 Cases.

Retrospective

Hebatallah G Samra El-Shamy. Evaluation of Platelet Rich Fibrin/Biphasic Calcium Phosphate Effect Versus Autogenous Bone Graft on Reconstruction of Alveolar Cleft.

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37 Herford AS, Boyne PJ, Rawson R, Williams RP. Bone morphogenetic protein-induced repair of the premaxillary cleft.

Retrospective

Jahanbin A, Zarch HH, Irani S, Eslami N, Kermani H. Recombinant Human Bone Morphogenic Protein-2 Combined with Autogenous Bone Graft for Reconstruction of Alveolar Cleft.

nRCT

Janssen NG, Weijs WL, Koole R, Rosenberg AJ, Meijer GJ. Tissue engineering strategies for alveolar cleft reconstruction: a systematic review of the literature.

Systematic Review

Kadry, W. Tissue Engineered Constructs for Alveolar Cleft Repair.

Kamal M, Ziyab AH, Bartella A, Mitchell D, Al-Asfour A, Hölzle F, Kessler P, Lethaus B. Volumetric comparison of autogenous bone and tissue-engineered bone replacement materials in alveolar cleft repair: a systematic review and meta-analysis.

Systematic Review

Kessler P, Thorwarth M, Bloch-Birkholz A, Nkenke E, Neukam FW. Harvesting of bone from the iliac crest--comparison of the anterior and posterior sites.

Unclear outcome

Khojasteh A, Kheiri L, Motamedian SR, Nadjmi N. Regenerative medicine in the treatment of alveolar cleft defect: A systematic review of the literature.

Systematic Review

Koole R, Bosker H, van der Dussen FN. Late secondary autogenous bone grafting in cleft patients comparing mandibular

(ectomesenchymal) and iliac crest (mesenchymal) grafts.

Retrospective

Kortebein MJ, Nelson CL, Sadove AM. Retrospective analysis of 135 secondary alveolar cleft grafts using iliac or calvarial bone.

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38 Kupfer P, Abbott MM, Abramowicz S,

Meara JG, Padwa BL. Cost differences between the anterior and posterior approaches to the iliac crest for alveolar bone grafting in patients with cleft lip/palate.

Retrospective

Lee C, Nishihara K, Okawachi T, Iwashita Y, Majima HJ, Nakamura N. A quantitative radiological assessment of outcomes of autogenous bone graft combined with platelet-rich plasma in the alveolar cleft.

nRCT

Li S, Zhang C, Yuan T. [Osteogenic potential of platelet-rich plasma combined with cells and artificial bone].

Wrong publication type, not primary study

Liang F, Yen SL, Imahiyerobo T, Sanborn L, Yen L, Yen D, Nazarian S, Jedrzejewski B, Urata M, Hammoudeh J.

Three-Dimensional Cone Beam Computed Tomography Volumetric Outcomes of rhBMP-2/Demineralized Bone Matrix versus Iliac Crest Bone Graft for Alveolar Cleft Reconstruction.

nRCT

Luaces-Rey R, Arenaz-Búa J, Lopez-Cedrún-Cembranos JL, Herrero-Patiño S, Sironvalle-Soliva S, Iglesias-Candal E, Pombo-Castro M. Is PRP useful in alveolar cleft reconstruction? Platelet-rich plasma in secondary alveoloplasty.

nRCT

M.E Deeb. Reconstruction of alveolar clefts with mandibular or iliac crest bone grafts: A comparative study.

Discussion paper, not primary study

Ma L, Yali H, Guijun L, Dong F. Effectiveness of corticocancellous bone graft in cleft lip and palate patients: A systematic review.

Systematic Review

MacIsaac ZM, Rottgers SA, Davit AJ 3rd, Ford M, Losee JE, Kumar AR. Alveolar reconstruction in cleft patients: decreased morbidity and improved outcomes with supplemental demineralized bone matrix and cancellous allograft.

Grafting materials for alveolar cleft reconstruction -a systematic review