Abstract
Contributions from multidisciplinary investigations have focused attention on the potential of tissue engineering to yield novel therapeutics. Congenital malformations, including cleft palate, craniosynostosis, and craniofacial skeletal hypoplasias represent excellent targets for the implementation of tissue engineering applications secondary to the technically challenging nature and inherent inadequacies of current reconstructive interventions. Apropos to the search for answers to these clinical conundrums, studies have focused on elucidating the molecular signals driving the biologic activity of the aforementioned maladies. These investigations have highlighted multiple signaling pathways, including Wnt, fibroblast growth factor, transforming growth factor-β, and bone morphogenetic proteins, that have been found to play critical roles in guided tissue development. Furthermore, a comprehensive knowledge of these pathways will be of utmost importance to the optimization of future cell-based tissue engineering strategies. The scope of this review encompasses a discussion of the molecular biology involved in the development of cleft palate and craniosynostosis. In addition, we include a discussion of craniofacial distraction osteogenesis and how its applied forces influence cell signaling to guide endogenous bone regeneration. Finally, this review discusses the future role of cell-based tissue engineering in the treatment of congenital malformations.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- ASC:
-
adipose-derived stromal cells
- BMP:
-
bone morphogenetic proteins
- DO:
-
distraction osteogenesis
- ERK:
-
extracellular signal- related kinase
- FGF:
-
fibroblast growth factor
- FGFR:
-
fibroblast growth factor receptor
- GSK3β:
-
glycogen synthase kinase-3 beta
- TGFβ:
-
transforming growth factor beta
References
Robin NH, Baty H, Franklin J, Guyton FC, Mann J, Woolley AL, Waite PD, Grant J 2006 The multidisciplinary evaluation and management of cleft lip and palate. South Med J 99: 1111–1120
HCUP 2007 Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. Available at: http://www.ahrq.gov/data/hcup/
Chai Y, Maxson RE Jr 2006 Recent advances in craniofacial morphogenesis. Dev Dyn 235: 2353–2375
Kerrigan JJ, Mansell JP, Sengupta A, Brown N, Sandy JR 2000 Palatogenesis and potential mechanisms for clefting. J R Coll Surg Edinb 45: 351–358
Jin JZ, Ding J 2006 Analysis of cell migration, transdifferentiation and apoptosis during mouse secondary palate fusion. Development 133: 3341–3347
Liu KJ, Arron JR, Stankunas K, Crabtree GR, Longaker MT 2007 Chemical rescue of cleft palate and midline defects in conditional GSK-3beta mice. Nature 446: 79–82
Doble BW, Woodgett JR 2003 GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116: 1175–1186
Cohen P, Frame S 2001 The renaissance of GSK3. Nat Rev Mol Cell Biol 2: 769–776
Meijer L, Flajolet M, Greengard P 2004 Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol Sci 25: 471–480
Koo SH, Cunningham MC, Arabshahi B, Gruss JS, Grant JH 2001 The transforming growth factor-beta 3 knock-out mouse: an animal model for cleft palate. Plast Reconstr Surg 108: 938–948; discussion 949
Cui XM, Shiomi N, Chen J, Saito T, Yamamoto T, Ito Y, Bringas P, Chai Y, Shuler CF 2005 Overexpression of Smad2 in Tgf-beta3-null mutant mice rescues cleft palate. Dev Biol 278: 193–202
Yang LT, Kaartinen V 2007 Tgfb1 expressed in the Tgfb3 locus partially rescues the cleft palate phenotype of Tgfb3 null mutants. Dev Biol 312: 384–395
Spivak RM, Endo ME, Zajac A, Zoltick P, Ang B, Horn R, Flake A, Kirschner R, Nah H-D 2007 In utero gene delivery of adenovirus encoded TGF-beta3 restores physiologic palatal fusion and rescues cleft palate in a TGF-beta3 knockout mouse. J Am Coll Surg 205: S92
Juriloff DM, Harris MJ, McMahon AP, Carroll TJ, Lidral AC 2006 Wnt9b is the mutated gene involved in multifactorial nonsyndromic cleft lip with or without cleft palate in A/WySn mice, as confirmed by a genetic complementation test. Birth Defects Res A Clin Mol Teratol 76: 574–579
Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac D, Renier D 1995 Genetic study of nonsyndromic coronal craniosynostosis. Am J Med Genet 55: 500–504
Posnick JC 2000 Craniofacial syndromes and anomalies. In: Posnick JC (ed) Craniofacial and Maxillofacial Surgery in Children and Young Adults. W.B. Saunders, Philadelphia, pp 391–527
Shin J, Persing JA 2007 Non-syndromic craniosynostosis and deformational plagiocephaly. In: Thorne CH (ed) Grabb and Smith's Plastic Surgery. Lippincott, Williams, and Wilkins, Philadelphia, PA
Whitaker LA, Bartlett SP, Schut L, Bruce D 1987 Craniosynostosis: an analysis of the timing, treatment, and complications in 164 consecutive patients. Plast Reconstr Surg 80: 195–212
Warren SM, Brunet LJ, Harland RM, Economides AN, Longaker MT 2003 The BMP antagonist noggin regulates cranial suture fusion. Nature 422: 625–629
Cooper GM, Curry C, Barbano TE, Burrows AM, Vecchione L, Caccamese JF, Norbutt CS, Costello BJ, Losee JE, Moursi AM, Huard J, Mooney MP 2007 Noggin inhibits postoperative resynostosis in craniosynostotic rabbits. J Bone Miner Res 22: 1046–1054
Passos-Bueno MR, Wilcox WR, Jabs EW, Sertie AL, Alonso LG, Kitoh H 1999 Clinical spectrum of fibroblast growth factor receptor mutations. Hum Mutat 14: 115–125
Perlyn CA, Morriss-Kay G, Darvann T, Tenenbaum M, Ornitz DM 2006 A model for the pharmacological treatment of crouzon syndrome. Neurosurgery 59: 210–215; discussion 210–215.
Mangasarian K, Li Y, Mansukhani A, Basilico C 1997 Mutation associated with Crouzon syndrome causes ligand-independent dimerization and activation of FGF receptor-2. J Cell Physiol 172: 117–125
Eswarakumar VP, Ozcan F, Lew ED, Bae JH, Tome F, Booth CJ, Adams DJ, Lax I, Schlessinger J 2006 Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis. Proc Natl Acad Sci USA 103: 18603–18608
Shukla V, Coumoul X, Wang RH, Kim HS, Deng CX 2007 RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nat Genet 39: 1145–1150
Shimoaka T, Ogasawara T, Yonamine A, Chikazu D, Kawano H, Nakamura K, Itoh N, Kawaguchi H 2002 Regulation of osteoblast, chondrocyte, and osteoclast functions by fibroblast growth factor (FGF)-18 in comparison with FGF-2 and FGF-10. J Biol Chem 277: 7493–7500
Spector JA, Mathy JA, Warren SM, Nacamuli RP, Song HM, Lenton K, Fong KD, Fang DT, Longaker MT 2005 FGF-2 acts through an ERK1/2 intracellular pathway to affect osteoblast differentiation. Plast Reconstr Surg 115: 838–852
Kim HJ, Lee MH, Park HS, Park MH, Lee SW, Kim SY, Choi JY, Shin HI, Kim HJ, Ryoo HM 2003 Erk pathway and activator protein 1 play crucial roles in FGF2-stimulated premature cranial suture closure. Dev Dyn 227: 335–346
Ilizarov GA, Deviatov AA 1971 Surgical elongation of the leg. Ortop Travmatol Protez 32: 20–25
Codivilla A 1994 On the means of lengthening, in the lower limbs, the muscles and tissues which are shortened through deformity. Clin Orthop Relat Res 301: 4–9
Ilizarov GA, Lediaev VI, Shitin VP 1969 [The course of compact bone reparative regeneration in distraction osteosynthesis under different conditions of bone fragment fixation (experimental study)]. Eksp Khir Anesteziol 14: 3–12
McCarthy JG, Schreiber J, Karp N, Thorne CH, Grayson BH 1992 Lengthening the human mandible by gradual distraction. Plast Reconstr Surg 89: 1–8
Bennett EC, Sidman JD 2002 Osteogenic distraction in the face. Facial Plast Surg Clin North Am 10: 181–190
Matsumoto K, Nakanishi H, Kubo Y, Yokozeki M, Moriyama K 2003 Advances in distraction techniques for craniofacial surgery. J Med Invest 50: 117–125
Singh DJ, Bartlett SP 2005 Congenital mandibular hypoplasia: analysis and classification. J Craniofac Surg 16: 291–300
Carter DR, Beaupre GS, Giori NJ, Helms JA 1998 Mechanobiology of skeletal regeneration. Clin Orthop Relat Res S41–S55
Loboa EG, Fang TD, Warren SM, Lindsey DP, Fong KD, Longaker MT, Carter DR 2004 Mechanobiology of mandibular distraction osteogenesis: experimental analyses with a rat model. Bone 34: 336–343
Loboa EG, Fang TD, Parker DW, Warren SM, Fong KD, Longaker MT, Carter DR 2005 Mechanobiology of mandibular distraction osteogenesis: finite element analyses with a rat model. J Orthop Res 23: 663–670
Gabbay JS, Zuk PA, Tahernia A, Askari M, O'Hara CM, Karthikeyan T, Azari K, Hollinger JO, Bradley JP 2006 In vitro microdistraction of preosteoblasts: distraction promotes proliferation and oscillation promotes differentiation. Tissue Eng 12: 3055–3065
Rhee ST, Buchman SR 2005 Colocalization of c-Src (pp60src) and bone morphogenetic protein 2/4 expression during mandibular distraction osteogenesis: in vivo evidence of their role within an integrin-mediated mechanotransduction pathway. Ann Plast Surg 55: 207–215
Rhee ST, El-Bassiony L, Buchman SR 2006 Extracellular signal-related kinase and bone morphogenetic protein expression during distraction osteogenesis of the mandible: in vivo evidence of a mechanotransduction mechanism for differentiation and osteogenesis by mesenchymal precursor cells. Plast Reconstr Surg 117: 2243–2249
Sojo K, Sawaki Y, Hattori H, Mizutani H, Ueda M 2005 Immunohistochemical study of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2, -4 (BMP-2, -4) on lengthened rat femurs. J Craniomaxillofac Surg 33: 238–245
Fang TD, Salim A, Xia W, Nacamuli RP, Guccione S, Song HM, Carano RA, Filvaroff EH, Bednarski MD, Giaccia AJ, Longaker MT 2005 Angiogenesis is required for successful bone induction during distraction osteogenesis. J Bone Miner Res 20: 1114–1124
Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC 2004 Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10: 858–864
Cetrulo CL Jr, Knox KR, Brown DJ, Ashinoff RL, Dobryansky M, Ceradini DJ, Capla JM, Chang EI, Bhatt KA, McCarthy JG, Gurtner GC 2005 Stem cells and distraction osteogenesis: endothelial progenitor cells home to the ischemic generate in activation and consolidation. Plast Reconstr Surg 116: 1053–1064; discussion 1065–1057.
Mimeault M, Hauke R, Batra SK 2007 Stem cells: a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies. Clin Pharmacol Ther 82: 252–264
Weissman IL 2002 Stem cells–scientific, medical, and political issues. N Engl J Med 346: 1576–1579
Bahadur G 2003 The moral status of the embryo: the human embryo in the UK Human Fertilisation and Embryology (Research Purposes) Regulation 2001 debate. Reprod Biomed Online 7: 12–16
De Coppi P, Bartsch G Jr, Siddiqui MM, Xu T, Santos CC, Perin L, Mostoslavsky G, Serre AC, Snyder EY, Yoo JJ, Furth ME, Soker S, Atala A 2007 Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 25: 100–106
Lee OK, Kuo TK, Chen WM, Lee KD, Hsieh SL, Chen TH 2004 Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 103: 1669–1675
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR 1999 Multilineage potential of adult human mesenchymal stem cells. Science 284: 143–147
Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH 2002 Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13: 4279–4295
Gronthos S, Brahim J, Li W, Fisher LW, Cherman N, Boyde A, DenBesten P, Robey PG, Shi S 2002 Stem cell properties of human dental pulp stem cells. J Dent Res 81: 531–535
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S 2007 Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861–872
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA 2007 Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917–1920
Mulliken JB, Glowacki J 1980 Induced osteogenesis for repair and construction in the craniofacial region. Plast Reconstr Surg 65: 553–560
Bostrom R, Mikos A (eds) 1997 Tissue engineering of bone. Birkhauser, Boston, pp 215–234
Mofid MM, Manson PN, Robertson BC, Tufaro AP, Elias JJ, Vander Kolk CA 2001 Craniofacial distraction osteogenesis: a review of 3278 cases. Plast Reconstr Surg 108: 1103–1114; discussion 1115–1107.
Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH 2001 Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7: 211–228
Cowan CM, Shi YY, Aalami OO, Chou YF, Mari C, Thomas R, Quarto N, Contag CH, Wu B, Longaker MT 2004 Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol 22: 560–567
Yoon E, Dhar S, Chun DE, Gharibjanian NA, Evans GR 2007 In vivo osteogenic potential of human adipose-derived stem cells/poly lactide-co-glycolic acid constructs for bone regeneration in a rat critical-sized calvarial defect model. Tissue Eng 13: 619–627
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Panetta, N., Gupta, D., Slater, B. et al. Tissue Engineering in Cleft Palate and Other Congenital Malformations. Pediatr Res 63, 545–551 (2008). https://doi.org/10.1203/PDR.0b013e31816a743e
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/PDR.0b013e31816a743e
This article is cited by
-
Harnessing electromagnetic fields to assist bone tissue engineering
Stem Cell Research & Therapy (2023)
-
Development of a multilayered palate substitute in rabbits: a histochemical ex vivo and in vivo analysis
Histochemistry and Cell Biology (2017)
-
Is tissue engineering a new paradigm in medicine? Consequences for the ethical evaluation of tissue engineering research
Medicine, Health Care and Philosophy (2009)