Oesophagus Tissue Engineering: Future Options in Oesophageal Replacement Through Regenerative Medicine

  • Amulya K. SaxenaEmail author


Tissue engineering is a multidisciplinary science in which the principles of engineering are applied to biological sciences with the aim of providing solutions for current clinical problems. Tissue engineering of the oesophagus is a promising alternative to transposition procedures in oesophageal replacement; however, the proposition is challenging due to the anatomical complexity of this tubular organ. In this chapter, the principles and concepts of tissue engineering are discussed with an overview of issues relating to the sourcing of cells, design and selection of scaffolds and polymers, hybrid construct and coculture approaches of tissue engineering and the use of bioreactors. Finally, current research in the field of oesophageal tissue engineering, from in vitro studies of cell biology to in vivo large animal studies, are reviewed.


Oesophageal atresia Tracheoesophageal fistula Tissue engineering Stem cells Matrix Composite Oesophageal replacement Artificial organ 


  1. 1.
    Saxena AK. Congenital anomalies of soft tissues: birth defects depending on tissue engineering solutions and present advances in regenerative medicine. Tissue Eng B Rev. 2010;16:455–66.CrossRefGoogle Scholar
  2. 2.
    Cauchi JA, Buick RG, Gornall P, Simms MH, Parikh DH. Oesophageal substitution with free and pedicled jejunum: short- and long-term outcomes. Pediatr Surg Int. 2007;23:11–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Arul GS, Parikh D. Oesophageal replacement in children. Ann R Coll Surg Engl. 2008;90(1):7–12.Google Scholar
  4. 4.
    Yamamoto Y, Nakamura T, Shimizu Y, et al. Intrathoracic esophageal replacement in the dog with the use of an artificial esophagus composed of a collagen sponge with a double-layered silicone tube. J Thorac Cardiovasc Surg. 1999;118:276–86.CrossRefPubMedGoogle Scholar
  5. 5.
    Senker J, Enzing C, Joly PB, et al. European exploitation of biotechnology-do government policies help? A recent survey of public spending on biotechnology in Europe suggests that money alone cannot stimulate growth of the sector. Nat Biotechnol. 2000;18:605–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Tabata Y. Biomaterial technology for tissue engineering applications. J R Soc Interface. 2009;6 Suppl 3:S311–24.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Williams DF. On the nature of biomaterials. Biomaterials. 2009;30:5897–909.CrossRefPubMedGoogle Scholar
  8. 8.
    Carrel A, Lindbergh C. The culture of organs. New York: Paul B. Hoeber Inc., Harper Brothers; 1938.Google Scholar
  9. 9.
    Saxena AK, Marler J, Benvenuto M, Willital GH, Vacanti JP. Skeletal muscle tissue engineering using isolated myoblasts on synthetic biodegradable polymers: preliminary studies. Tissue Eng. 1999;5:525–31.CrossRefPubMedGoogle Scholar
  10. 10.
    Saxena AK, Ainoedhofer H, Höllwarth ME. Culture of ovine esophageal epithelial cells and in vitro esophagus tissue engineering. Tissue Eng C Methods. 2010;16:109–14.CrossRefGoogle Scholar
  11. 11.
    Priddle H, Jones DR, Burridge PW, et al. Hematopoiesis from human embryonic stem cells: overcoming the immune barrier in stem cell therapies. Stem Cells. 2006;24:815–24.CrossRefPubMedGoogle Scholar
  12. 12.
    Raikwar SP, Mueller T, Zavazava N. Strategies for developing therapeutic application of human embryonic stem cells. Physiology (Bethesda). 2006;21:19–28.CrossRefGoogle Scholar
  13. 13.
    Tian X, Kaufman DS. Hematopoietic development of human embryonic stem cells in culture. Methods Mol Med. 2005;105:425–36.PubMedGoogle Scholar
  14. 14.
    Trounson A. The production and directed differentiation of human embryonic stem cells. Endocr Rev. 2006;27:208–19.CrossRefPubMedGoogle Scholar
  15. 15.
    Odorico JS, Kaufman DS, Thomson JA. Multilineage differentiation from human embryonic stem cell lines. Stem Cells. 2001;19:193–204.CrossRefPubMedGoogle Scholar
  16. 16.
    Cowan CA, Klimanskaya I, McMahon J, et al. Derivation of embryonic stem-cell lines from human blastocysts. N Engl J Med. 2004;350:1353–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Raghunath J, Salacinski HJ, Sales KM, et al. Advancing cartilage tissue engineering: the application of stem cell technology. Curr Opin Biotechnol. 2005;16:503–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Riha GM, Lin PH, Lumsden AB, Yao Q. Review: application of stem cells for vascular tissue engineering. Tissue Eng. 2005;11:1535–52.CrossRefPubMedGoogle Scholar
  19. 19.
    Risbud MV, Shapiro IM. Stem cells in craniofacial and dental tissue engineering. Orthod Craniofac Res. 2005;8:54–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Bruder SP, Fink DJ, Caplan AI. Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy. J Cell Biochem. 1994;56:283–94.CrossRefPubMedGoogle Scholar
  21. 21.
    Braccini A, Wendt D, Jaquiery C, et al. Three-dimensional perfusion culture of human bone marrow cells and generation of osteoinductive grafts. Stem Cells. 2005;23:1066–72.CrossRefPubMedGoogle Scholar
  22. 22.
    Gimble J, Guilak F. Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Cytotherapy. 2003;5:362–9.CrossRefPubMedGoogle Scholar
  23. 23.
    De Coppi P, Bartsch G, Siddiqui MM, et al. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol. 2007;25:100–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Miki T, Lehmann T, Cai H, et al. Stem cell characteristics of amniotic epithelial cells. Stem Cells. 2005;23:1549–59.CrossRefPubMedGoogle Scholar
  25. 25.
    Tasso R, Augello A, Cardia M, et al. Development of sarcomas in mice implanted with mesenchymal stem cells seeded onto bioscaffolds. Carcinogenesis. 2009;30:150–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Saxena AK. Tissue engineering: present concepts and strategies. J Indian Assoc Pediatr Surg. 2005;10:14–9.CrossRefGoogle Scholar
  27. 27.
    Langer R, Tirrell DA. Designing materials for biology and medicine. Nature. 2004;428:487–92.CrossRefPubMedGoogle Scholar
  28. 28.
    Ackbar R, Ainoedhofer H, Gugatschka, Saxena AK. Decellularized ovine esophageal mucosa for esophageal tissue engineering. Tech Health Care. 2012;20:215–23.Google Scholar
  29. 29.
    Wang H, Heilshorn SC. Adaptable hydrogel networks with reversible linkages for tissue engineering. Adv Mater. 2015;27:3717–36.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wang HY, Zhang YQ. Processing silk hydrogel and its applications in biomedical materials. Biotechnol Prog. 2015;31:630–40.CrossRefPubMedGoogle Scholar
  31. 31.
    Toh WS, Loh XJ. Advances in hydrogel delivery systems for tissue regeneration. Mater Sci Eng C Mater Biol Appl. 2014;45:690–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Saxena AK, Kofler K, Ainödhofer H, Höllwarth ME. Esophagus tissue engineering: hybrid approach with esophageal epithelium and unidirectional smooth muscle tissue component generation in vitro. J Gastrointest Surg. 2009;13:1037–43.CrossRefPubMedGoogle Scholar
  33. 33.
    Moharamzadeh K, Brook IM, Van Noort R, Scutt AM, Smith KG, Thornhill MH. Development, optimization and characterization of a full-thickness tissue engineered human oral mucosal model for biological assessment of dental biomaterials. J Mater Sci Mater Med. 2008;19:1793–801.CrossRefPubMedGoogle Scholar
  34. 34.
    Saxena AK. Tissue engineering and regenerative medicine research perspectives for pediatric surgery. Pediatr Surg Int. 2010;26:557–73.CrossRefPubMedGoogle Scholar
  35. 35.
    Hoerstrup SP, Sodian R, Sperling JS, Vacanti JP, Mayer Jr JE. New pulsatile bioreactor for in vitro formation of tissue engineered heart valves. Tissue Eng. 2000;6:75–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Mironov V, Kasyanov V, McAllister K, Oliver S, Sistino J, Markwald R. Perfusion bioreactor for vascular tissue engineering with capacities for longitudinal stretch. J Craniofac Surg. 2003;14:340–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Scaglione S, Zerega B, Badano R, Benatti U, Fato M, Quarto R. A three-dimensional traction/torsion bioreactor system for tissue engineering. Int J Artif Organs. 2010;33:362–9.PubMedGoogle Scholar
  38. 38.
    Niklason LE, Gao J, Abbott WM, et al. Functional arteries grown in vitro. Science. 1999;84:489–93.CrossRefGoogle Scholar
  39. 39.
    Barron V, Lyons E, Stenson-Cox C, et al. Bioreactors for cardiovascular cell and tissue growth: a review. Ann Biomed Eng. 2003;31:1017–30.CrossRefPubMedGoogle Scholar
  40. 40.
    Takimoto Y, Okumura N, Nakamura T, et al. Long-term follow-up of the experimental replacement of the esophagus with a collagen–silicone composite tube. Asaio J. 1993;39:M736–9.PubMedGoogle Scholar
  41. 41.
    Yamamoto Y, Nakamura T, Shimizu Y, et al. Intrathoracic esophageal replacement with a collagen sponge–silicone double-layer tube: evaluation of omental-pedicle wrapping and prolonged placement of an inner stent. Asaio J. 2000;46:734–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Hori Y, Nakamura T, Kimura D, et al. Effect of basic fibroblast growth factor on vascularization in esophagus tissue engineering. Int J Artif Organs. 2003;26:241–4.PubMedGoogle Scholar
  43. 43.
    Badylak S, Meurling S, Chen M, et al. Resorbable bioscaffold for esophageal repair in a dog model. J Pediatr Surg. 2000;35:1097–103.CrossRefPubMedGoogle Scholar
  44. 44.
    Badylak SF, Vorp DA, Spievack AR, et al. Esophageal reconstruction with ECM and muscle tissue in a dog model. J Surg Res. 2005;128:87–97.CrossRefPubMedGoogle Scholar
  45. 45.
    Doede T, Bondartschuk M, Joerck C, et al. Unsuccessful alloplastic esophageal replacement with porcine small intestinal submucosa. Artif Organs. 2009;33:328–33.CrossRefPubMedGoogle Scholar
  46. 46.
    Kofler K, Ainoedhofer H, Höllwarth ME, Saxena AK. Fluorescence-activated cell sorting of PCK-26 antigen-positive cells enables selection of ovine esophageal epithelial cells with improved viability on scaffolds for esophagus tissue engineering. Pediatr Surg Int. 2010;26:97–104.CrossRefPubMedGoogle Scholar
  47. 47.
    Beckstead BL, Pan S, Bhrany AD, Bratt-Leal AM, Ratner BD, Giachelli CM. Esophageal epithelial cell interaction with synthetic and natural scaffolds for tissue engineering. Biomaterials. 2005;26:6217–28.CrossRefPubMedGoogle Scholar
  48. 48.
    Leong MF, Chian KS, Mhaisalkar PS, Ong WF, Ratner BD. Effect of electrospun poly(D, L-lactide) fibrous scaffold with nanoporous surface on attachment of porcine esophageal epithelial cells and protein adsorption. J Biomed Mater Res A. 2009;89:1040–8.CrossRefPubMedGoogle Scholar
  49. 49.
    Zhu Y, Leong MF, Ong WF, Chan-Park MB, Chian KS. Esophageal epithelium regeneration on fibronectin grafted poly(L-lactide-co-caprolactone) (PLLC) nanofiber scaffold. Biomaterials. 2007;28:861–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Sato M, Ando N, Ozawa S, et al. An artificial esophagus consisting of cultured human esophageal epithelial cells, polyglycolic acid mesh, and collagen. Asaio J. 1994;40:M389–92.CrossRefPubMedGoogle Scholar
  51. 51.
    Hayashi K, Ando N, Ozawa S, et al. A neo-esophagus reconstructed by cultured human esophageal epithelial cells, smooth muscle cells, fibroblasts, and collagen. Asaio J. 2004;50:261–6.CrossRefPubMedGoogle Scholar
  52. 52.
    Grikscheit T, Ochoa ER, Srinivasan A, et al. Tissue-engineered esophagus: experimental substitution by onlay patch or interposition. J Thorac Cardiovasc Surg. 2003;126:537–44.CrossRefPubMedGoogle Scholar
  53. 53.
    Soltysiak P, Saxena AK. Micro-computed tomography for implantation site imaging during in situ oesophagus tissue engineering in a live small animal model. J Tissue Eng Regen Med. 2009;3:573–6.CrossRefPubMedGoogle Scholar
  54. 54.
    Ohki T, Yamato M, Murakami D, Takagi R, Yang J, Namiki H, Okano T, Takasaki K. Treatment of oesophageal ulcerations using endoscopic transplantation of tissue-engineered autologous oral mucosal epithelial cell sheets in a canine model. Gut. 2006;55:1704–10.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Wei RQ, Tan B, Tan MY, Luo JC, Deng L, Chen XH, Li XQ, Zuo X, Zhi W, Yang P, Xie HQ, Yang ZM. Grafts of porcine small intestinal submucosa with cultured autologous oral mucosal epithelial cells for esophageal repair in a canine model. Exp Biol Med (Maywood). 2009;234:453–61.CrossRefGoogle Scholar
  56. 56.
    Nakase Y, Nakamura T, Kin S, Nakashima S, Yoshikawa T, Kuriu Y, Sakakura C, Yamagishi H, Hamuro J, Ikada Y, Otsuji E, Hagiwara A. Intrathoracic esophageal replacement by in situ tissue-engineered esophagus. J Thorac Cardiovasc Surg. 2008;136:850–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Wei HJ, Liang HC, Lee MH, Huang YC, Chang Y, Sung HW. Construction of varying porous structures in acellular bovine pericardia as a tissue-engineering extracellular matrix. Biomaterials. 2005;26:1905–13.CrossRefPubMedGoogle Scholar
  58. 58.
    Saxena AK, Baumgart H, Komann C, Ainoedhofer H, Soltysiak P, Kofler K, Höllwarth ME. Esophagus tissue engineering: in situ generation of rudimentary tubular vascularized esophageal conduit using the ovine model. J Pediatr Surg. 2010;45:859–64.CrossRefPubMedGoogle Scholar
  59. 59.
    Vineberg A, Pifarre R, Mercier C. An operation designed to promote the growth of new coronary arteris, using a detached omental graft: a preliminary report. Can Med Assoc J. 1962;16:1116–8.Google Scholar
  60. 60.
    Straw RC, Tomlinson JL, Constantinescu G, Turk MA, Hogan PM. Use of a vascular skeletal muscle graft for canine esophageal reconstruction. Vet Surg. 1987;16:155–63.CrossRefPubMedGoogle Scholar
  61. 61.
    Harley BA, Hastings AZ, Yannas IV, Sannino A. Fabricating tubular scaffolds with a radial pore size gradient by a spinning technique. Biomaterials. 2006;27:866–74.CrossRefPubMedGoogle Scholar
  62. 62.
    Soltysiak P, Höllwarth ME, Saxena AK. Comparison of suturing techniques in the formation of collagen scaffold tubes for composite tubular organ tissue engineering. Biomed Mater Eng. 2010;20:1–11.PubMedGoogle Scholar
  63. 63.
    Andrade MG, Weissman R, Reis SR. Tissue reaction and surface morphology of absorbable sutures after in vivo Exposure. J Mater Sci Mater Med. 2006;17:949–61.CrossRefPubMedGoogle Scholar
  64. 64.
    Saxena AK, Kofler K, Ainoedhofer H, Kuess A, Höllwarth ME. Complexity of approach and demand for esophagus tissue engineering. Tissue Eng A. 2008;14:829.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of Pediatric SurgeryChelsea Children’s Hospital, Chelsea and Westminster NHS Fdn Trust, Imperial College LondonLondonUK

Personalised recommendations