Department of Cranio-Maxillofacial Surgery, Maastricht University Medical Center, P. Debyelaan, Postbus 5800, 6202 AZ, Maastricht, The Netherlands. mkamal@ukaachen.de.
Department of Oral and Maxillofacial Surgery, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany. mkamal@ukaachen.de.
Department of Surgical Sciences, Faculty of Dentistry, Health Sciences Center, Kuwait University, 13110, Safat, Kuwait.
Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
Department of Oral and Maxillofacial Surgery, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
Department of Experimental Molecular Imaging, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
Department of Cranio-Maxillofacial Surgery, Maastricht University Medical Center, P. Debyelaan, Postbus 5800, 6202 AZ, Maastricht, The Netherlands.
Objectives: The purpose of the present study was to develop an animal model for creating alveolar cleft defects with properly simulated clinical defect environment for tissue-engineered bone-substitute materials testing without compromising the health of the animal. Cleft creation surgery was aimed at creating a complete alveolar cleft with a wide bone defect with an epithelial lining (oral mucosa) overlying the cleft defect.
Methods: A postmortem skull of a New Zealand White (NZW) rabbit skull (Oryctolagus cuniculus) underwent an osteological and imaging survey. A pilot postmortem surgery was conducted to confirm the feasability of a surgical procedure and the defect was also radiologically confirmed and illustrated with micro-computed tomography. Then, a surgical in vivo model was tested and evaluated in 16 (n = 16) 8-week-old NZW rabbits to create in vivo alveolar cleft creation surgery.
Results: Clinical examination and imaging analysis 8 weeks after cleft creation surgery revealed the establishment of a wide skeletal defect extending to the nasal mucosa simulating alveolar clefts in all of the rabbits.
Conclusions: Our surgical technique was successful in creating a sizable and predictable model for bone grafting material testing. The model allows for simulating the cleft site environment and can be used to evaluate various bone grafting materials in regard to efficacy of osteogenesis and healing potential without compromising the health of the animal.
Keywords: Animal testing; Cleft lip and palate; Grafting; Rabbit; Tissue-engineering.
el-Bokle D, Smith SJ, Germane N, Sharawy M.Cleft Palate Craniofac J. 1993 Nov;30(6):542-7. doi: 10.1597/1545-1569_1993_030_0542_ntfcpe_2.3.co_2.PMID: 8280731
Rychlik D, Wójcicki P, Koźlik M. Osteoplasty of the alveolar cleft defect. Adv Clin Exp Med. 2012;21:255–262. - PubMed
Santiago PE, Schuster LA, Levy-Bercowski D. Management of the alveolar cleft. Clin Plast Surg. 2014;41:219–232. doi: 10.1016/j.cps.2014.01.001. - DOI - PubMed
Seifeldin SA. Is alveolar cleft reconstruction still controversial? (review of literature) Saudi Dent J. 2016;28:3–11. doi: 10.1016/j.sdentj.2015.01.006. - DOI - PMC - PubMed
Chung VH, Chen AY, Jeng LB, Kwan CC, Cheng SH, Chang SC. Engineered autologous bone marrow mesenchymal stem cells: alternative to cleft alveolar bone graft surgery. J Craniofac Surg. 2012;23:1558–1563. doi: 10.1097/SCS.0b013e31825e4e30. - DOI - PubMed
Gładysz D, Hozyasz KK. Stem cell regenerative therapy in alveolar cleft reconstruction. Arch Oral Biol. 2015;60:1517–1532. doi: 10.1016/j.archoralbio.2015.07.003. - DOI - PubMed
Janssen NG, Weijs WLJ, Koole R, Rosenberg AJWP, Meijer GJ. Tissue engineering strategies for alveolar cleft reconstruction: a systematic review of the literature. Clin Oral Investig. 2014;18:219–226. doi: 10.1007/s00784-013-0947-x. - DOI - PubMed
Kawata T, Kohno S, Fujita T, Sugiyama H, Tokimasa C, Kaku M, Tanne K. New biomaterials and methods for craniofacial bone defect: chondroid bone grafts in maxillary alveolar clefts. J Craniofac Genet Dev Biol. 2000;20:49–52. - PubMed
Khojasteh A, Kheiri L, Motamedian SR, Nadjmi N. Regenerative medicine in the treatment of alveolar cleft defect: a systematic review of the literature. J Craniomaxillofac Surg. 2015;43:1608–1613. doi: 10.1016/j.jcms.2015.06.041. - DOI - PubMed
Caballero M, Morse JC, Halevi AE, Emodi O, Pharaon MR, Wood JS, van Aalst JA. Juvenile swine surgical alveolar cleft model to test novel autologous stem cell therapies. Tissue Eng Part C Methods. 2015;21:898–908. doi: 10.1089/ten.tec.2014.0646. - DOI - PMC - PubMed
de Ruiter A, Meijer G, Dormaar T, Janssen N, van der Bilt A, Slootweg P, de Bruijn J, van Rijn L, Koole R. β-TCP versus autologous bone for repair of alveolar clefts in a goat model. Cleft Palate Craniofac J. 2011;48:654–662. doi: 10.1597/09-219. - DOI - PubMed
el-Bokle D, Smith SJ, Germane N, Sharawy M. New technique for creating permanent experimental alveolar clefts in a rabbit model. Cleft Palate Craniofac J. 1993;30:542–547. doi: 10.1597/1545-1569(1993)030<0542:NTFCPE>2.3.CO;2. - DOI - PubMed
El-Deeb M, Horswell B, Waite DE. A primate model for producing experimental alveolar cleft defects. J Oral Maxillofac Surg. 1985;43:523–527. doi: 10.1016/S0278-2391(85)80031-8. - DOI - PubMed
Gritli-Linde A. The mouse as a developmental model for cleft lip and palate research. Front Oral Biol. 2012;16:32–51. doi: 10.1159/000337523. - DOI - PubMed
Ishii Y. Experimental study of secondary bone graft of alveolar clefts using bone morphogenetic protein (BMP) Kokubyo Gakkai Zasshi. 2001;68:111–124. doi: 10.5357/koubyou.68.111. - DOI - PubMed
Liang L, Liu C. Trans-sutural distraction osteogenesis for alveolar cleft repair: an experimental canine study. Cleft Palate Craniofac J. 2012;49:701–707. doi: 10.1597/10-250. - DOI - PubMed
Liao LS, Tan Z, Zheng Q, Wu J, Shi B, He X, Meng T, Lu DW, Wang Y, Li S. Animal experimental study on repairing alveolar clefts by using rectilinear distraction osteogenesis. J Plast Reconstr Aesthet Surg. 2009;62:1573–1579. doi: 10.1016/j.bjps.2008.06.068. - DOI - PubMed
Mostafa NZ, Doschak MR, Major PW, Talwar R. Reliable critical sized defect rodent model for cleft palate research. J Craniomaxillofac Surg. 2014;42:1840–1846. doi: 10.1016/j.jcms.2014.07.001. - DOI - PubMed
Nguyen PD, Lin CD, Allori AC, Ricci JL, Saadeh PB, Warren SM. Establishment of a critical-sized alveolar defect in the rat: a model for human gingivoperiosteoplasty. Plast Reconstr Surg. 2009;123:817–825. doi: 10.1097/PRS.0b013e31819ba2f4. - DOI - PubMed
Papadopoulos MA, Papadopulos NA, Jannowitz C, Boettcher P, Henke J, Stolla R, Zeilhofer HF, Kovacs L, Biemer E. Three-dimensional cephalometric evaluation of maxillary growth following in utero repair of cleft lip and alveolar-like defects in the mid-gestational sheep model. Fetal Diagn Ther. 2006;21:105–114. doi: 10.1159/000089059. - DOI - PubMed
Pilanci O, Cinar C, Kuvat SV, Altintas M, Guzel Z, Kilic A. Effects of hydroxyapatite on bone graft resorption in an experimental model of maxillary alveolar arch defects. Arch Clin Exp Surg. 2013;2:170–175. doi: 10.5455/aces.20121018123137. - DOI
Raposo-Amaral CE, Kobayashi GS, Almeida AB, Bueno DF, Freitas FR, Vulcano LC, Passos-Bueno MR, Alonso N. Alveolar osseous defect in rat for cell therapy: preliminary report. Acta Cir Bras. 2010;25:313–317. - PubMed
Sawada Y, Hokugo A, Nishiura A, Hokugo R, Matsumoto N, Morita S, Tabata Y. A trial of alveolar cleft bone regeneration by controlled release of bone morphogenetic protein: an experimental study in rabbits. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108:812–820. doi: 10.1016/j.tripleo.2009.06.040. - DOI - PubMed
Wu L-L, Zhao Y, Chen C. Establishment of the animal model with unilateral alveolar cleft and its effect on the nose growth. Zhonghua Zheng Xing Wai Ke Za Zhi. 2010;26:39–42. - PubMed
Xu Y, Sun J, Chen Z. Establishment of a rat model for alveolar cleft with bone wax. J Oral Maxillofac Surg. 2015;73:733.e1–733.e10. doi: 10.1016/j.joms.2014.12.010. - DOI - PubMed
Harling TR, Stelnicki EJ, Hedrick MH, Longaker MT. In utero models of craniofacial surgery. World J Surg. 2003;27:108–116. doi: 10.1007/s00268-002-6745-2. - DOI - PubMed
Hedrick MH, Rice HE, Vander Wall KJ, Adzick NS, Harrison MR, Siebert J, Hoffman WY, Longaker MT. Delayed in utero repair of surgically created fetal cleft lip and palate. Plast Reconstr Surg. 1996;97:900–905. doi: 10.1097/00006534-199604001-00003. - DOI - PubMed
Wenghoefer MHO, Deprest J, Goetz W, Kuijpers-Jagtman AM, Bergé S. Prenatal cleft lip and maxillary alveolar defect repair in a 2-step fetal lamb model. J Oral Maxillofac Surg. 2007;65:2479–2486. doi: 10.1016/j.joms.2007.06.642. - DOI - PubMed
Igawa HH, Ohura T, Iwao F, Yamamoto Y, Fujioka H. Intrauterine repair of cleft lip in mouse fetuses. Congenit Anom. 1991;31:95–100. doi: 10.1111/j.1741-4520.1991.tb00363.x. - DOI
Leitao JM, Pereira LA, Gonçalves FL, Schmidt AF, Sbragia L. The ideal timing for experimental cleft lip creation. Cleft Palate Craniofac J. 2011;48:38–43. doi: 10.1597/09-163. - DOI - PubMed
Schardein J, Petrere J, Hentz D, Camp R, Kurtz S. Cannibalistic traits observed in rats treated with a teratogen. Lab Anim. 1978;12:81–83. doi: 10.1258/002367778780953080. - DOI - PubMed
Li Y, Chen S-K, Li L, Qin L, Wang X-L, Lai Y-X. Bone defect animal models for testing efficacy of bone substitute biomaterials. J Orthop Transl. 2015;3:95–104. doi: 10.1016/j.jot.2015.05.002. - DOI - PMC - PubMed
Mapara M, Thomas BS, Bhat K. Rabbit as an animal model for experimental research. Dent Res J. 2012;9:111–118. doi: 10.4103/1735-3327.92960. - DOI - PMC - PubMed
Pearce A, Richards R, Milz S, Schneider E, Pearce S. Animal models for implant biomaterial research in bone: a review. Eur Cell Mater. 2007;13:1–10. doi: 10.22203/eCM.v013a01. - DOI - PubMed
Wang X, Mabrey JD, Agrawal CM. An interspecies comparison of bone fracture properties. Biomed Mater Eng. 1998;8:1–10. - PubMed
Al-Asfour A, Andersson L, Kamal M, Joseph B. New bone formation around xenogenic dentin grafts to rabbit tibia marrow. Dent Traumatol. 2013;29:455–460. doi: 10.1111/edt.12045. - DOI - PubMed
Andersson L, Ramzi A, Joseph B. Studies on dentin grafts to bone defects in rabbit tibia and mandible; development of an experimental model. Dent Traumatol. 2009;25:78–83. doi: 10.1111/j.1600-9657.2008.00703.x. - DOI - PubMed
Kolk A, Handschel J, Drescher W, Rothamel D, Kloss F, Blessmann M, Heiland M, Wolff KD, Smeets R. Current trends and future perspectives of bone substitute materials—from space holders to innovative biomaterials. J Craniomaxillofac Surg. 2012;40:706–718. doi: 10.1016/j.jcms.2012.01.002. - DOI - PubMed
Harvold E. Cleft palate, an experiment. Acta Odontol Scand. 1950;9:84–87. doi: 10.3109/00016355009087227. - DOI - PubMed
Kim J-H, Moon H-J, Kim T-H, Jo J-M, Yang SH, Naskar D, Kundu SC, Chrzanowski W, Kim H-W. A novel in vivo platform for studying alveolar bone regeneration in rat. J Tissue Eng. 2013;4:2041731413517705. doi: 10.1177/2041731413517705. - DOI - PMC - PubMed
Puumanen K, Kellomaki M, Ritsila V, Bohling T, Tormala P, Waris T, Ashammakhi N. A novel bioabsorbable composite membrane of polyactive 70/30 and bioactive glass number 13–93 in repair of experimental maxillary alveolar cleft defects. J Biomed Mater Res B Appl Biomater. 2005;75:25–33. doi: 10.1002/jbm.b.30218. - DOI - PubMed
Takano-Yamamoto T, Kawakami M, Sakuda M. Defects of the rat premaxilla as a model of alveolar clefts for testing bone-inductive agents. J Oral Maxillofac Surg. 1993;51:887–891. doi: 10.1016/S0278-2391(10)80110-7. - DOI - PubMed
Bykowski MR, Naran S, Winger DG, Losee JE. The rate of oronasal fistula following primary cleft palate surgery: a meta-analysis. Cleft Palate Craniofac J. 2015;52:e81–e87. doi: 10.1597/14-127. - DOI - PubMed
Maslamani M, Almusawi A, Joseph B, Gabato S, Andersson L. An experimental model for studies on delayed tooth replantation and ankylosis in rabbits. Dent Traumatol. 2016;32:443–449. doi: 10.1111/edt.12287. - DOI - PubMed
Directive C. 86/609/EEC of 24 November 1986 on the approximation of laws, regulations and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes. Off J Eur Commun. 1986;29:L358.