Does the Animal Model Influence in Vertical Alveolar Distraction? A Systematic Review of the Literature

animals Review Does the Animal Model Influence in Vertical Alveolar Distraction? A Systematic Review of the Literature Mario García-González 1,* , Fernando Muñoz 1, Antonio González-Cantalapiedra 1, Mónica López-Peña 1and Nikola Saulacic 2 1Department of Veterinary Clinical Sciences, Faculty of Veterinary, University of Santiago de Compostela, 27002 Lugo, Spain; [email protected] (F.M.); [email protected] (A.G.-C.); [email protected] (M.L.-P.) 2Department of Cranio-Maxillofacial Surgery, Faculty of Medicine, University of Bern, 3008 Bern, Switzerland; [email protected] *Correspondence: [email protected] Received: 4 November 2020; Accepted: 7 December 2020; Published: 9 December 2020   Simple Summary: Vertical alveolar osteogenesis distraction (VAOD) technique appears to provide the best results in terms of vertical bone gain. Before its use in humans, most devices are tested on experimental animals. Currently, there is no consensus on which is the ideal biological animal model for VAOD studies. In this review, it has been found that the animal model influences the results. In addition, the most used, easier to handle, and with less complications was the Mongrel dog. The use of pigs and minipigs, given their difficult handling and poor hygiene, is not recommended. Abstract: This study is aimed at synthesizing all available evidence on vertical alveolar osteogenesis distraction (VAOD) in animal trials to determine whether the animal model used and its handling influence or not, and find which is the most appropriate animal model for this specific technique. This systematic review has been carried out following the PRISMA statements. Bibliographic sources have been consulted manually by two reviewers. Risk of bias was assessed using a version of the Newcastle-Ottawa-Scale (NOS). The selection criteria established by expert researchers were applied in order to decide which studies should be included in the review. Twenty-six studies met the inclusion criteria and were included in the review. Twenty-four of them had a high quality (score between 7 and 9), two medium quality (score between 4 and 6), and none low quality (score between 1 and 3). The highest possible score was 9 (using the NOS). Six studies complied with all NOS criteria. The animal model has been seen to influence the results, leading to failure in some cases. The most used animal model on VAOD, with fewer complications, was the Mongrel dog. The use of the pig and minipig is not recommended, due to the difficulties in handling and complications encountered. Keywords: animal model; animal experimentation; distraction osteogenesis; biomaterials; alveolar ridge augmentation; VAOD; systematic review 1. Introduction In oral implantology, one of the most common challenges is the deficiency of mandibular or maxillary alveolar bone height or width. The causes of bone loss include pathological processes such as trauma, periodontal disease, tumor resections, and congenital malformations [1]. Currently, the available techniques that allow the use of long implants without reducing the vertical size of the crown are: augmentation of the floor of the maxillary sinus, the placement of pterygoid implants, and dental nerve transposition [ 2 ]. To modify the crown-implant length ratio, other techniques such as guided bone regeneration (GBR), autologous bone grafting, and vertical Animals 2020,10, 2347; doi:10.3390/ani10122347 www.mdpi.com/journal/animals Animals 2020,10, 2347 2 of 13 alveolar distraction can be used [ 3 ]. All these techniques increase alveolar ridge height and, thereby, allow the utilization of shorter crowns and large implants. The biological basis of osteogenic distraction (OD) is called callotasis (etymology: tasis = elongation), which is the progressive elongation of the callus formed around bony portions created by the osteotomy. This elongation process is progressive, allowing for the preservation of the bloodstream. The bone regeneration mechanism is made up of two procedures: histogenesis (elongation of the soft tissues, like blood vessels, nerves, and mucoperiosteum) and osteogenesis (creation of the callus and consequently the generation of new bone) [4]. The OD technique involves the following phases: (A) surgery, (B) latency, (C) distraction, and (D) consolidation. The distraction period includes two different phenomena: the distraction frequency (which is the amount of distraction activations that are performed per day) and the distraction rate (which is the daily amount of bone gained between the basal bone and the transport fragment, measured usually in millimeters) [1]. The vertical alveolar osteogenesis distraction (VAOD) procedure is an effective remedy for soft tissue and bone formation in boneless areas which hinder the rehabilitation with dental implant [ 1 , 3 ]. On the transport segment and the basal bone, a distraction device is placed after executing an osteotomy in the alveolar bone. Periosteum blood flow must be maintained so that the transport segment remains vascularized. Then, the transport segment is submitted to gradual pulling forces to move away from the basal bone. This procedure activates the mechanism which will promote the bone regeneration and the maturity of the distraction callus created [3]. Berhard von Langenbeck carried out, in 1869, the first experimental research on long bone distraction. The fist studies on oral distraction were conducted in 1927 by Rosenthal [ 4 ]. In view of the numerous complications that arose, several authors criticized the procedure. In human membranous mandibular bone, the first osteogenic distraction was performed by Snyder et al. in 1973 [ 5 ]. Nevertheless, Gabriel Abramowitch Ilizarov developed the full technique in the 1950s, performing numerous experiments in dogs. Thanks to this author, a great advance in the clinical use of the procedure was achieved. Ilizarov also defined the biological basis of the distraction osteogenesis: (1) tension-stress principle influence, (2) bone shape and mass influence, and (3) influence of interaction between mechanical load and blood supply [4]. We can differentiate between two types of distraction gadgets: extraosseous and intraosseous. Depending on their role, there is also a distinction between distractor-implants and distractors [ 1 ]. Finally, distractor devices can be classified into horizontal or vertical according to the direction of the regenerated new bone segment. In a systematic review, Esposito et al. [ 1 ] did not have sufficient proof about which was the best procedure. Nevertheless, they informed that VAOD had the best capacity for vertical regeneration among the existing procedures. Compared to other tissue augmentation treatments, the distraction technique has several advantages [6]: - No donor site morbidity. - Simplest procedure. - Graft resorption less chance. - The quantity gained is more predictable. - The rate of infection and bone resorption is lower - Most of complications are minor. - Possibility of implant placement in the transported fragment. - The consolidation period is shorter, so the treatment has a shorter duration. - When the results are not satisfactory, complementary techniques can be used. However, it also presents a series of possible disadvantages (Supplementary Table S1) [6,7]. Animals 2020,10, 2347 3 of 13 Nonetheless, OD has achieved a certain level of application in maxillofacial and implant surgery as a technique for alveolar bone augmentation. However, there is still no consensus on which is the ideal animal biological model for vertical bone distraction assessment. For the experimental evaluation of alveolar distraction, we need a suitable biological model. This model should offer an adequate amount of bone for the device to be placed on, and subsequently design distraction devices for clinical use in humans. Tests for mandibular alveolar distraction have been developed in small animals, such as rats or rabbits, and in medium and large animals, such as dogs, sheep, minipigs, goats, and primates. Nonhuman primates could represent the ideal biological model for the VAOD research. However, its high cost, the ethical concerns, and difficult handling make it almost not feasible. Currently, the selection of an animal biological model for VAOD is still undefined [8]. This study is aimed at collecting all available evidence on VAOD studies in animals to determine whether the animal model used and its handling influence or not, and find which is the most appropriate animal model for VAOD studies. 2. Materials and Methods This systematic review has been carried out following the PRISMA statements (Supplementary Table S2). Ethics approval was not required for this review. It was performed in the following health science data bases: PubMed, Scopus, and Web of Science (WOS) (limiting the search until December 2019). This search was carried out manually during the month of December 2019 by two reviewers. The selection criteria incorporated permutations of the following terms: “Alveolar vertical distraction”, “dental implant”, “animal model”, “biological model”, “alveolar ridge”, “vertical alveolar ridge distraction”, “distraction osteogenesis”, “alveolar ridge augmentation”, “alveolar bone loss”, “atrophic jaws”. PICO methodology. Animal models (P =patients), experimental studies (I =intervention), of different species (C =comparison), used for VAOD (O =result). PICO question: What is the most appropriate animal model to use in VAOD experimental studies? Eligibility criteria. The studies have been selected according to the following pattern: 1. Experimental studies of alveolar bone distraction aimed at vertical augmentation. 2. Animals used as biological models. 3. Articles in English. Quality assessment. We used a version of the Newcastle-Ottawa Scale (NOS) to evaluate the quality of the studies with a maximum of 9 stars. Within the analysis, the studies were defined as low quality (1–3), medium quality (4–6), or high quality (7–9). The quality of the studies was assessed in duplicate and independently by two reviewers (M.G.-G and F.M.). Analysis and extraction of parameters of interest. The studies were evaluated by analyzing the following items: number of animals used (patient number), age, weight, distractor details, number of distractors used, number of distraction segments, location of the distractor (jaw/maxilla and segment site), distraction succession (phase of latency, phase of activation and phase of consolidation), rate and frequency of distraction, vertical bone gain obtained at the end of the study, specification of the quantification method analysis, and description of the complications observed. Regarding the studies in which complications were observed, they were classified as minor and major [9]. In addition, the phase in which they were observed was detailed [10]. 3. Results The initial search generated 921 articles. Figure 1shows the flow chart of the selected articles submitted to the review process. After the exclusion of duplicates and studies in humans, there was a remaining total of 63 articles. Based on abstracts and titles, 37 studies were removed after applying study criteria; 5 studies were written in a language other than English (3 in Chinese, 1 in Japanese, and 1 in German), 5 were eliminated because they did not practice oral distraction in the alveolar Animals 2020,10, 2347 4 of 13 bone, and 27 studies were removed because horizontal distraction was performed. After full text reading, 26 studies [ 8 , 11 – 34 ] complying with the inclusion rules were selected for the review. Twenty studies were in dogs (with a total of 145 animals and 223 placed devices), 2 in rabbits (72 animals and 72 devices), 2 in sheep (18 animals and 26 devices), 1 in minipigs (3 animals and 3 devices), and 1 in baboons (3 animals and 3 devices). Animals 2020, 10, x 4 of 13 animals and 72 devices), 2 in sheep (18 animals and 26 devices), 1 in minipigs (3 animals and 3 devices), and 1 in baboons (3 animals and 3 devices). Figure 1. Flow chart of the selected studies. Based on this review, 24 articles were rated as high quality, 2 as medium quality, and 0 as low quality. Six studies obtained a maximum score of 9 stars (Table 1). All animals used were adults and skeletally mature. The average age by species is 18 months in dogs and 13 months in sheep. The most commonly used breed was Mongrel in dogs, New Zealand in rabbits, Gottingen in minipigs, and Papio Anubis in non-human primates. The average weight was 17.3 kg in dogs (ranging from 9 to 40 kg), 4.1 kg in rabbits (ranging from 4.15 to 0.55 kg), and 45 in sheep. The 26 articles selected involved 241 patients with 327 distractors; 158 patients had been treated with an extraosseous and 83 with an intraosseous device (Table 2). Indication and location for distraction. In 23 studies (217 patients), the jaw was used for distraction and in 3 the maxilla (24 patients). The most common location for distraction was the posterior region of the left jaw in all species (82 patients), followed by the posterior region of the right jaw (59 patients); 220 patients had unilateral and 21 bilateral oral distraction (Supplementary Table S3). Device details. Thirteen different types of commercial distraction devices and other prototypes were found: - 8 intraosseous devices: 3i (Standard threaded implant, 3i System, Implant Innovations, West Palm Beach, FL, USA), DL-system (Dep. of Oral & Maxillofacial Surgery, Fourth Military Medical University, Shaanxi, China), AW (Alveo-Wider; Okada Medical Supply, Tokyo, Japan), DK KXSLD (Dikang Biomedical Co., Ltd., Chengdu, China), STATA 4.0 (STATA Corp, College Station, TX, USA), OMS (Oral & Maxillofacial Surgery, School of Stomatology, The 4th Military Medical Univ, Xi’an, China), ABDUL (Dentium Co Ltd., Seoul, Korea & Osstem Co Ltd., Seoul, Korea), and DID (DID-Trade Inc., Klagenfurt, Austria). - 5 extraosseous devices: KLS Martin (Tuttlingen, Germany), OPD (U-shaped body, Synthes Maxillofacial, Paoli, PA, USA), KLS Martin (Jacksonville, FL, USA), TRACK 1.0 mm-System (Gebrüder Martin GmbH & Co. KG, Tuttlingen, Germany), and Impladent SL (Barcelona, Spain). Figure 1. Flow chart of the selected studies. Based on this review, 24 articles were rated as high quality, 2 as medium quality, and 0 as low quality. Six studies obtained a maximum score of 9 stars (Table 1). All animals used were adults and skeletally mature. The average age by species is 18 months in dogs and 13 months in sheep. The most commonly used breed was Mongrel in dogs, New Zealand in rabbits, Gottingen in minipigs, and Papio Anubis in non-human primates. The average weight was 17.3 kg in dogs (ranging from 9 to 40 kg), 4.1 kg in rabbits (ranging from 4.15 to 0.55 kg), and 45 in sheep. The 26 articles selected involved 241 patients with 327 distractors; 158 patients had been treated with an extraosseous and 83 with an intraosseous device (Table 2). Indication and location for distraction. In 23 studies (217 patients), the jaw was used for distraction and in 3 the maxilla (24 patients). The most common location for distraction was the posterior region of the left jaw in all species (82 patients), followed by the posterior region of the right jaw (59 patients); 220 patients had unilateral and 21 bilateral oral distraction (Supplementary Table S3). Animals 2020,10, 2347 5 of 13 Table 1. Score by studies using NOS Scale. Author Year Specie Stars Quality Cano [11] 2006 Dog 9 High Esposito [12] 2017 Dog 9 High Li [13] 2014 Dog 9 High Terbish [14] 2015 Dog 9 High Zhan [15] 2018 Dog 9 High Shao [21] 2013 Dog 9 High Altug [16] 2011 Rabbit 8 High Faber [17] 2005 Dog 8 High Oda [19] 2000 Dog 8 High Oda [18] 1999 Dog 8 High Rachmiel [20] 2004 Sheep 8 High Yi [22] 2009 Dog 8 High Zhao [23] 2009 Dog 8 High Block [24] 1998 Dog 8 High Block [25] 1996 Dog 8 High Block [26] 2000 Dog 8 High Demetoglu [27] 2017 Dog 8 High Martínez-González [8] 2005 Minipig 8 High Martínez-González [8] 2005 Dog 8 High Perry [28] 2006 Dog 8 High Takeuchi [29] 2010 Dog 8 High Xie [30] 2012 Dog 7 High Boyne [31] 2004 Baboon 7 High Gaggl [32] 2000 Sheep 7 High Bayar [33] 2012 Rabbit 6 Medium Hwang [34] 2004 Dog 5 Medium Device details. Thirteen different types of commercial distraction devices and other prototypes were found: - 8 intraosseous devices: 3i (Standard threaded implant, 3i System, Implant Innovations, West Palm Beach, FL, USA), DL-system (Dep. of Oral & Maxillofacial Surgery, Fourth Military Medical University, Shaanxi, China), AW (Alveo-Wider; Okada Medical Supply, Tokyo, Japan), DK KXSLD (Dikang Biomedical Co., Ltd., Chengdu, China), STATA 4.0 (STATA Corp, College Station, TX, USA), OMS (Oral & Maxillofacial Surgery, School of Stomatology, The 4th Military Medical Univ, Xi’an, China), ABDUL (Dentium Co Ltd., Seoul, Korea & Osstem Co Ltd., Seoul, Korea), and DID (DID-Trade Inc., Klagenfurt, Austria). - 5 extraosseous devices: KLS Martin (Tuttlingen, Germany), OPD (U-shaped body, Synthes Maxillofacial, Paoli, PA, USA), KLS Martin (Jacksonville, FL, USA), TRACK 1.0 mm-System (Gebrüder Martin GmbH & Co. KG, Tuttlingen, Germany), and Impladent SL (Barcelona, Spain). The most commonly used distractor device was OPD, which was employed in 2 studies and treated 72 patients [ 33 , 34 ]. The same prototype of Impladent SL (Barcelona) was used in 2 studies to treat a total of 11 patients [8,11]. The rest of devices were used in just 1 study. The total number of movable segments were 278. One or more devices may have been placed per segment. VAOD protocol. A latency period of 7 days was by most of the studies, with a mean of 6.13, ranging from 0 [ 15 ] to 8 days [ 12 ]. In the distraction period, there were multiple sequences in terms of frequency and rate. This was the period with most discrepancies. However, in none of the studies was performed the daily augmentation of over 1 mm. Ten days was the distraction period in most of the studies, with an average of 9.15 (ranging from 5 to 28) days. The mean distraction rate was 0.8 (0.25 to 1 mm) per day. The distraction frequency varied between 1 and 2 times per day. In one study, the frequency was 1 time every two days [ 13 ]. The consolidation period average was 9.93 weeks (ranging from 0 Animals 2020,10, 2347 6 of 13 to 50 weeks). Zhan et al. [ 15 ] did not have a consolidation period (0 weeks). Oda et al. [18] applied the longest consolidation period (50 weeks). Table 3shows in detail the characteristics of the latency, distraction, and consolidation phases of the studies included in the review. Vertical bone gain. The main gain achieved in these studies was 6.13 mm (ranging from 2.72 to 8.96 mm). The average gain for extraosseous distractors was 6.26 mm and 6.02 in the case of intraosseous distractors. The study with the highest gain was that of Xie et al. [ 30 ], who recorded a gain of 8.96 mm, using an intraosseous distractor (STATA 4.0) (STATA Corp, College Station, TX, USA), whereas the lowest gain (2.72 mm) was obtained by Esposito et al. [ 12 ], using an intraosseous prototype. For extraosseous devices, Block et al. [ 24 ] obtained the highest bone gain (8.85 mm) using a prototype, while the lowest (3.25 mm) was obtained by Terbish et al. [14], using a prototype device. Quantification methods. The quantification methods used whereas follows: histomorphometry (21 studies), X-rays (17 studies), microtomography (5 studies), immunohistochemistry (1 study), and fluorescence microscopy (1 study). Complications and treatment. Complications were found in 12 studies, whereas 11 studies claimed to have had no complications; 3 of them did not supply information. Out of 241 patients, 24 (9.95%) exhibited complications; 11 of them (4.56% of the total) were major and 13 (5.1% of the total) minor complications. By order of frequency, the minor complications were infection (5 patients, 20.83% out of complications), edema (5, 20.83%), dehiscence (2, 8.32%), and alveolar arterial hemorrhage (1, 4.16%). Using the same criteria, the major complications were: device removal due to a moderate infection (6, 25%), support plate deviation (2, 8.32%), intra-surgical death (1, 4.16%), mandibular fracture (1, 4.16%), and severe diarrhea and death (1, 4.16%). In 3.31% of the total patients, the distractor was affected due to moderate infection and death of animals, which had to be removed from the study. Table 4shows the complications and treatment classified according to the protocol phase. Animals 2020,10, 2347 7 of 13 Table 2. Individual parameters of each study (P =prototype). Author Year Distractor Design Animal Breed Patient Number Age (Months) Weight (Kg) N◦ Distractors N◦ Segments Extraosseous Intraosseous Terbish [14] 2015 P Dog Beagle 16 16 to 18 15 to 16 16 16 16 / Oda [18] 1999 3i Dog Mongrel 5 Adult 15 to 17 10 5 /10 Takeuchi [29] 2010 TRACK Dog Beagle 11 12 to 24 10 11 11 11 / Zhao [23] 2009 DL Dog Mongrel 6 18 /12 6 /12 Block [24] 1998 P Dog Mongrel 4 Adult /4 4 4 / Cano [11] 2006 Impladent SL Dog Beagle 5 24 10 to 15 4 5 4 / Faber [17] 2005 P Dog Mongrel 5 Adult 11 to 16.4 10 5 10 / Perry [28] 2005 P Dog American foxhound 5 Adult 25 to 30 5 5 /5 Demetoglu [27] 2017 P Dog Beagle 10 Adult 35 to 40 20 20 /20 Oda [19] 2000 P Dog Mongrel 6 Adult 17 to 20 12 6 6 / Block [25] 1996 P Dog Mongrel 4 Adult /4 4 4 / Li [13] 2014 DK KXSLD Dog Mongrel 9 24 20 18 18 /18 Block [26] 2000 P Dog Mongrel 8 Adult /8 8 /8 Xie [30] 2012 STATA 4.0 Dog Mongrel 18 Adult 21 to 26 36 18 /36 Shao [21] 2013 OMS Dog Mongrel 6 24 /18 12 /12 Hwang [34] 2004 ABDUL Dog Beagle 4 Adult /4 4 /4 Yi [22] 2009 P Dog Mongrel 4 Adult 9 to 10 8 8 8 / Esposito [12] 2017 P Dog Beagle 4 19 to 27 12.8 16 12 /16 Zhan [15] 2018 P Dog Beagle 12 12 to 15 7 to 10 4 12 4 / Rachmiel [20] 2004 KLS Martin Sheep /10 12 45 10 10 10 / Gaggl [32] 2000 DID Sheep /8 36 /16 8 /16 Martínez-González [8] 2005 Impladent SL Dog Beagle 3 Adult /3 3 3 / Martínez-González [8] 2005 Impladent SL Minipig Göttingen 3 Adult /3 3 3 / Boyne [31] 2004 KLS Martin Monkey Papio anubis baboons 3 Adult /3 3 3 / Altug [16] 2011 OPD Rabbit New Zealand 36 Adult 4.15 ±0.55 36 36 36 / Bayar [33] 2012 OPD Rabbit New Zealand 36 Adult /36 36 36 / Animals 2020,10, 2347 8 of 13 Table 3. Distraction protocol details of each study. Author Year Distractor Detail Animal Latency Days Distraction Days Consolidation Weeks Rate/Frequency Gain (mm) Terbish [14] 2015 P Dog 7 10 2 to 6 0.4 mm/twice daily 3.25 ±0.95 Oda [18] 1999 3i Dog 7 6 50 0.9 mm/day 3.98 ±0.39 Takeuchi [29] 2010 TRACK Dog 7 6 8 0.9 mm/day - Zhao [23] 2009 DL Dog 7 8 12 1 mm/day 7.25 ±0.40 Block [24] 1998 P Dog 7 10 10 0.5 mm/twice daily 8.85 Cano [11] 2006 Impladent SL Dog 7 5 4 and 8 1 mm/day 5.49 ±0.9 Faber [17] 2005 P Dog 7 9 0 to 14 0.65 mm/day 5.45 ±2.01 Perry [28] 2005 P Dog 7 10 12 0.5 mm/twice daily - Demetoglu [27] 2017 P Dog 7 10 12 1 mm/day - Oda [19] 2000 P Dog 7 7 8 or 12 1 mm/day 6.51 Block [25] 1996 P Dog 7 10 10 0.5 mm/twice daily - Li [13] 2014 DK KXSLD Dog 5 12 4, 8 and 12 1 mm/2 days 5.71 Block [26] 2000 P Dog 7 10 10 0.5 mm/twice daily 8.8 ±1 Xie [30] 2012 STATA 4.0 Dog 7 - 12 and 24 - 8.96 ±1.89 Shao [21] 2013 OMS Dog 5 12 4, 8 and 12 1 mm/2 days 5.8 ±0.2 Hwang [34] 2004 ABDUL Dog - - - - - Yi [22] 2009 P Dog 7 5 6 0.5 mm/twice daily - Esposito [12] 2017 P Dog 8 8 10 0.75 mm/day 2.72 Zhan [15] 2018 P Dog 0 28 0 0.5 mm/2 days - Rachmiel [20] 2004 KLS Martin Sheep 5 24 12 0.5 mm/day - Gaggl [32] 2000 DID Sheep 7 8 4, 8, 12 and 24 0.5 mm/day - Martínez-González [8] 2005 Impladent SL Dog 7 5 2 1 mm/day - Martínez-González [8] 2005 Impladent SL Minipig 7 5 2 1 mm/day - Boyne [31] 2004 KLS Martin Baboon 7 10 20 1 mm/day - Altug [16] 2011 OPD Rabbit 1 and 7 10 2, 4 and 8 0.25 mm/twice daily - Bayar [33] 2012 OPD Rabbit 7 10 2, 4, and 8 0.25 mm/twice daily - Animals 2020,10, 2347 9 of 13 Table 4. Complications and treatments of the selected studies. Author Year No. Patients Complications Affected Patients Period Major/Minor Treatment Terbish [14] 2015 16 Infection 2 (12.5%) Phase 3. Distraction Minor Conservative Oda [18]1999 5 Dehiscence 2 (40%) Phase 3. Distraction Minor Conservative Infection 2 (40%) Phase 4. Consolidation Minor Conservative Takeuchi [29] 2010 11 No Zhao [23] 2009 6 Several diarrhea 1 (16.67%) Phase 2. Latency Major Death Block [24] 1998 4 Alveolar artery cut 1 (25%) Phase 1. Surgery Minor Suture Cano [11] 2006 5 Moderate Infection 2 (40%) Phase 2. Latency Major Device removal Faber [17] 2005 5 Moderate edema 5 (100%) Phase 2. Latency Minor Conservative Perry [28] 2005 5 No Demetoglu [27]2017 10 Intra-surgery death 1 (10%) Phase 1. Surgery Major Death Infection 1 (10%) Phase 4. Consolidation Minor Conservative Oda [19] 2000 6 Support plate deviation 2 (33.34%) Phase 3. Distraction Major Screw recolocation Block [25] 1996 4 No Li [13] 2014 9 No Block [26] 2000 8 No Xie [30] 2012 18 No Shao [21] 2013 6 No Hwang [34] 2004 4 * * * * * Yi [22] 2009 4 No Esposito [12] 2017 4 Mandibular fracture 1 (25%) Phase 4. Consolidation Major Euthanasia Zhan [15] 2018 12 No Rachmiel [20] 2004 10 No Gaggl [32] 2000 8 * * * * * Martínez-González [8] 2005 3 Moderate Infection 1 (33.34%) Phase 3. Distraction Major Device removal Martínez-González [8] 2005 3 Moderate Infection 3 (100%) Phase 2. Latency Major Device removal Boyne [31] 2004 3 * * * * * Altug [16] 2011 36 No Bayar [33] 2012 36 * * * * * * No mention any about complications.