Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Bioengineering the gut: future prospects of regenerative medicine

Nature Reviews Gastroenterology & Hepatology volume 13, pages 543–556 (2016)Cite this article

Subjects

Key Points

  • The most common complications of surgical treatments for gastrointestinal disorders include stenosis or leakage; tissue engineering and regenerative medicine could reduce these complications

  • The gastrointestinal tract is complex in structure and function, which makes its regeneration challenging; however, a wide selection of cell sources and scaffolding materials are available

  • Alignment and innervation of the smooth muscle have important roles in mediating coordinated peristalsis and propulsion of luminal content; regeneration of the neuromuscular apparatus is of critical importance

  • The epithelial lining of the gastrointestinal tract has multiple roles in providing nutrition, innate immunity and protection; regeneration of a functional epithelium is essential for translational purposes

  • New stem cell strategies for in vitro modelling and in vivo therapies are emerging

  • Less is known about regeneration of the lymphatic system in the gastrointestinal tract and future studies must incorporate the lymphatics as part of the bioengineering process

Abstract

Functions of the gastrointestinal tract include motility, digestion and absorption of nutrients. These functions are mediated by several specialized cell types including smooth muscle cells, neurons, interstitial cells and epithelial cells. In gastrointestinal diseases, some of the cells become degenerated or fail to accomplish their normal functions. Surgical resection of the diseased segments of the gastrointestinal tract is considered the gold-standard treatment in many cases, but patients might have surgical complications and quality of life can remain low. Tissue engineering and regenerative medicine aim to restore, repair, or regenerate the function of the tissues. Gastrointestinal tissue engineering is a challenging process given the specific phenotype and alignment of each cell type that colonizes the tract — these properties are critical for proper functionality. In this Review, we summarize advances in the field of gastrointestinal tissue engineering and regenerative medicine. Although the findings are promising, additional studies and optimizations are needed for translational purposes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cross-sectional microscopy image of a human small intestine stained with haematoxylin and eosin.
Figure 2: An overview of gastrointestinal tract tissue engineering and regenerative medicine approaches.
Figure 3: A bioengineered, intrinsically innervated smooth muscle construct.

Similar content being viewed by others

References

  1. Said, H. M. Physiology of the Gastrointestinal Tract, Two Volume Set (Academic Press, 2012).

    Google Scholar 

  2. Sanders, K. M., Koh, S. D., Ro, S. & Ward, S. M. Regulation of gastrointestinal motility — insights from smooth muscle biology. Nat. Rev. Gastroenterol. Hepatol. 9, 633–645 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kiela, P. R. & Ghishan, F. K. Physiology of intestinal absorption and secretion. Best Pract. Res. Clin. Gastroenterol. 30, 145–159 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Alexander, J., Ganta, V. C., Jordan, P. & Witte, M. H. Gastrointestinal lymphatics in health and disease. Pathophysiology 17, 315–335 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Kulig, K. M. & Vacanti, J. P. Hepatic tissue engineering. Transpl. Immunol. 12, 303–310 (2004).

    CAS  PubMed  Google Scholar 

  6. Takahashi, Y., Takebe, T. & Taniguchi, H. Engineering pancreatic tissues from stem cells towards therapy. Regenerative Ther. 3, 15–23 (2016).

    Google Scholar 

  7. Moharamzadeh, K., Brook, I., Van Noort, R., Scutt, A. & Thornhill, M. Tissue-engineered oral mucosa: a review of the scientific literature. J. Dental Res. 86, 115–124 (2007).

    CAS  Google Scholar 

  8. Szymanski, P. T., Chacko, T. K., Rovner, A. S. & Goyal, R. K. Differences in contractile protein content and isoforms in phasic and tonic smooth muscles. Am. J. Physiol. 275, C684–C692 (1998).

    CAS  PubMed  Google Scholar 

  9. Patel, C. A. & Rattan, S. Spontaneously tonic smooth muscle has characteristically higher levels of RhoA/ROK compared with the phasic smooth muscle. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G830–G837 (2006).

    CAS  PubMed  Google Scholar 

  10. Gerthoffer, W., Murphey, K., Mangini, J., Boman, S. & Lattanzio, F. Myosin phosphorylation and calcium in tonic and phasic contractions of colonic smooth muscle. Am. J. Physiol. 260, G958–G964 (1991).

    CAS  PubMed  Google Scholar 

  11. Smith, G. T. et al. Anatomic localization of cholecystokinin receptors to the pyloric sphincter. Am. J. Physiol. 246, R127–R130 (1984).

    CAS  PubMed  Google Scholar 

  12. Hori, Y. et al. Experimental study on tissue engineering of the small intestine by mesenchymal stem cell seeding. J. Surg. Res. 102, 156–160 (2002).

    CAS  PubMed  Google Scholar 

  13. Somara, S., Gilmont, R. R., Dennis, R. G. & Bitar, K. N. Bioengineered internal anal sphincter derived from isolated human internal anal sphincter smooth muscle cells. Gastroenterology 137, 53–61 (2009).

    CAS  PubMed  Google Scholar 

  14. Raghavan, S. et al. Bioengineered three-dimensional physiological model of colonic longitudinal smooth muscle in vitro. Tissue Eng. Part C Methods 16, 999–1009 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Nakase, Y. et al. Tissue engineering of small intestinal tissue using collagen sponge scaffolds seeded with smooth muscle cells. Tissue Eng. 12, 403–412 (2006).

    CAS  PubMed  Google Scholar 

  16. Huber, A. & Badylak, S. F. Phenotypic changes in cultured smooth muscle cells: limitation or opportunity for tissue engineering of hollow organs? J. Tissue Eng. Regen. Med. 6, 505–511 (2012).

    CAS  PubMed  Google Scholar 

  17. Arey, L. & Tremaine, M. The muscle content of the lower oesophagus of man. Anat. Rec. 56, 315–320 (1933).

    Google Scholar 

  18. Tan, J. et al. Esophageal tissue engineering: an in-depth review on scaffold design. Biotechnol. Bioeng. 109, 1–15 (2012).

    CAS  PubMed  Google Scholar 

  19. Furness, J. & Costa, M. Types of nerves in the enteric nervous system. Neuroscience 5, 1–20 (1980).

    CAS  PubMed  Google Scholar 

  20. Hao, M. M. & Young, H. M. Development of enteric neuron diversity. J. Cell. Mol. Med. 13, 1193–1210 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Furness, J. Types of neurons in the enteric nervous system. J. Autonom. Nerv. Syst. 81, 87–96 (2000).

    CAS  Google Scholar 

  22. Sanders, K. M., Koh, S. D. & Ward, S. M. Interstitial cells of Cajal as pacemakers in the gastrointestinal tract. Annu. Rev. Physiol. 68, 307–343 (2006).

    CAS  PubMed  Google Scholar 

  23. Dickens, E. J., Edwards, F. & Hirst, G. Selective knockout of intramuscular interstitial cells reveals their role in the generation of slow waves in mouse stomach. J. Physiol. 531, 827–833 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Zheng, H., Park, K. S., Koh, S. D. & Sanders, K. M. Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine. Am. J. Physiol. Cell Physiol. 306, C705–C713 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Komuro, T. Structure and organization of interstitial cells of Cajal in the gastrointestinal tract. J. Physiol. 576, 653–658 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ward, S. & Sanders, K. Role of interstitial cells of Cajal in neural control of gastrointestinal smooth muscles. Neurogastroenterol. Motil. 16, 112–117 (2004).

    PubMed  Google Scholar 

  27. Kraehenbuh, J. P., Pringault, E., & Neutra, M. R. Review article: intestinal epithelia and barrier functions. Aliment. Pharmacol. Ther. 11, 3–9 (1997).

    Google Scholar 

  28. Peterson, L. W. & Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141–153 (2014).

    CAS  PubMed  Google Scholar 

  29. Martin-Belmonte, F. & Perez-Moreno, M. Epithelial cell polarity, stem cells and cancer. Nat. Rev. Cancer 12, 23–38 (2012).

    CAS  Google Scholar 

  30. Karlsson, J. et al. Regional variations in Paneth cell antimicrobial peptide expression along the mouse intestinal tract. BMC Immunol. 9, 37 (2008).

    PubMed  PubMed Central  Google Scholar 

  31. van der Flier, L. G. & Clevers, H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu. Rev. Physiol. 71, 241–260 (2009).

    CAS  PubMed  Google Scholar 

  32. Goto, Y. & Kiyono, H. Epithelial barrier: an interface for the cross-communication between gut flora and immune system. Immunol. Rev. 245, 147–163 (2012).

    CAS  PubMed  Google Scholar 

  33. Camilleri, M., Madsen, K., Spiller, R., Van Meerveld, B. & Verne, G. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol. Motil. 24, 503–512 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Marchiando, A. M. et al. The epithelial barrier is maintained by in vivo tight junction expansion during pathologic intestinal epithelial shedding. Gastroenterology 140, 1208–1218.e2 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ulluwishewa, D. et al. Regulation of tight junction permeability by intestinal bacteria and dietary components. J. Nutr. 141, 769–776 (2011).

    CAS  PubMed  Google Scholar 

  36. Swartz, M. A. The physiology of the lymphatic system. Adv. Drug Deliv. Rev. 50, 3–20 (2001).

    CAS  PubMed  Google Scholar 

  37. Sommer, F. & Bäckhed, F. The gut microbiota — masters of host development and physiology. Nat. Rev. Microbiol. 11, 227–238 (2013).

    CAS  PubMed  Google Scholar 

  38. Turner, J. R. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9, 799–809 (2009).

    CAS  PubMed  Google Scholar 

  39. Dommett, R., Zilbauer, M., George, J. T. & Bajaj-Elliott, M. Innate immune defence in the human gastrointestinal tract. Mol. Immunol. 42, 903–912 (2005).

    CAS  PubMed  Google Scholar 

  40. Atala, A., Bauer, S. B., Soker, S., Yoo, J. J. & Retik, A. B. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 367, 1241–1246 (2006).

    PubMed  Google Scholar 

  41. Macchiarini, P. et al. Clinical transplantation of a tissue-engineered airway. Lancet 372, 2023–2030 (2008).

    PubMed  Google Scholar 

  42. Fisher, M. B. & Mauck, R. L. Tissue engineering and regenerative medicine: recent innovations and the transition to translation. Tissue Eng. Part B Rev. 19, 1–13 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang, Y. Epidemiology of esophageal cancer. World J. Gastroenterol. 19, 5598–5606 (2013).

    PubMed  PubMed Central  Google Scholar 

  44. Crew, K. D. & Neugut, A. I. Epidemiology of gastric cancer. World J. Gastroenterol. 12, 354–362 (2006).

    PubMed  PubMed Central  Google Scholar 

  45. Siegel, R., DeSantis, C. & Jemal, A. Colorectal cancer statistics, 2014. CA Cancer J. Clin. 64, 104–117 (2014).

    Google Scholar 

  46. Fujita, H. et al. Optimum treatment strategy for superficial esophageal cancer: endoscopic mucosal resection versus radical esophagectomy. World J. Surg. 25, 424–431 (2001).

    CAS  PubMed  Google Scholar 

  47. Gordon, A. C., Kojima, K., Inokuchi, M., Kato, K. & Sugihara, K. Long-term comparison of laparoscopy-assisted distal gastrectomy and open distal gastrectomy in advanced gastric cancer. Surg. Endosc. 27, 462–470 (2013).

    PubMed  Google Scholar 

  48. Lujan, J. et al. Laparoscopic versus open surgery for rectal cancer: results of a prospective multicentre analysis of 4,970 patients. Surg. Endosc. 27, 295–302 (2013).

    CAS  PubMed  Google Scholar 

  49. Isomoto, H., Yamaguchi, N., Minami, H. & Nakao, K. Management of complications associated with endoscopic submucosal dissection/endoscopic mucosal resection for esophageal cancer. Dig. Endosc. 25, 29–38 (2013).

    PubMed  Google Scholar 

  50. Fukuda, Y. et al. Prevalence of malnutrition among gastric cancer patients undergoing gastrectomy and optimal preoperative nutritional support for preventing surgical site infections. Ann. Surg. Oncol. 22, 778–785 (2015).

    Google Scholar 

  51. Nour, S., Beck, J. & Stringer, M. Colostomy complications in infants and children. Ann. R. Coll. Surg. Engl. 78, 526 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Dabirian, A., Yaghmaei, F., Rassouli, M. & Tafreshi, M. Z. Quality of life in ostomy patients: a qualitative study. Patient Prefer. Adherence 5, 1–5 (2010).

    PubMed  PubMed Central  Google Scholar 

  53. Schalamon, J., Mayr, J. & Höllwarth, M. Mortality and economics in short bowel syndrome. Best Pract. Res. Clin. Gastroenterol. 17, 931–942 (2003).

    CAS  PubMed  Google Scholar 

  54. Winkler, M. F. & Smith, C. E. Clinical, social, and economic impacts of home parenteral nutrition dependence in short bowel syndrome. JPEN J. Parenter. Enteral Nutr. 38 (1 Suppl.), 32S–37S (2014).

    PubMed  Google Scholar 

  55. Buchman, A. L., Scolapio, J. & Fryer, J. AGA technical review on short bowel syndrome and intestinal transplantation. Gastroenterology 124, 1111–1134 (2003).

    PubMed  Google Scholar 

  56. Fishbein, T. M. Intestinal transplantation. N. Engl. J. Med. 361, 998–1008 (2009).

    CAS  PubMed  Google Scholar 

  57. Sudan, D. Cost and quality of life after intestinal transplantation. Gastroenterology 130, S158–S162 (2006).

    PubMed  Google Scholar 

  58. Grant, D. et al. Intestinal transplant registry report: global activity and trends. Am. J. Transplant. 15, 210–219 (2015).

    CAS  PubMed  Google Scholar 

  59. Freeman, R. et al. Liver and intestine transplantation in the United States, 1997–2006. Am. J. Transplant. 8, 958–976 (2008).

    PubMed  Google Scholar 

  60. Brown, B. N. & Badylak, S. F. Extracellular matrix as an inductive scaffold for functional tissue reconstruction. Transl. Res. 163, 268–285 (2014).

    CAS  PubMed  Google Scholar 

  61. Crapo, P. M., Gilbert, T. W. & Badylak, S. F. An overview of tissue and whole organ decellularization processes. Biomaterials 32, 3233–3243 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Badylak, S. F., Taylor, D. & Uygun, K. Whole-organ tissue engineering: decellularization and recellularization of three-dimensional matrix scaffolds. Annu. Rev. Biomed. Eng. 13, 27–53 (2011).

    CAS  PubMed  Google Scholar 

  63. Gilbert, T. W., Sellaro, T. L. & Badylak, S. F. Decellularization of tissues and organs. Biomaterials 27, 3675–3683 (2006).

    CAS  PubMed  Google Scholar 

  64. Syed, O., Walters, N. J., Day, R. M., Kim, H.-W. & Knowles, J. C. Evaluation of decellularization protocols for production of tubular small intestine submucosa scaffolds for use in oesophageal tissue engineering. Acta Biomaterialia 10, 5043–5054 (2014).

    CAS  PubMed  Google Scholar 

  65. Badylak, S., Meurling, S., Chen, M., Spievack, A. & Simmons-Byrd, A. Resorbable bioscaffold for esophageal repair in a dog model. J. Pediatr. Surg. 35, 1097–1103 (2000).

    CAS  PubMed  Google Scholar 

  66. Doede, T., Bondartschuk, M., Joerck, C., Schulze, E. & Goernig, M. Unsuccessful alloplastic esophageal replacement with porcine small intestinal submucosa. Artif. Organs 33, 328–333 (2009).

    PubMed  Google Scholar 

  67. Wang, Z. Q., Watanabe, Y. & Toki, A. Experimental assessment of small intestinal submucosa as a small bowel graft in a rat model. J. Pediatr. Surg. 38, 1596–1601 (2003).

    PubMed  Google Scholar 

  68. Nakao, M. et al. Proposal of intestinal tissue engineering combined with Bianchi's procedure. J. Pediatr. Surg. 50, 573–580 (2014).

    PubMed  Google Scholar 

  69. Briel, J. W. et al. Prevalence and risk factors for ischemia, leak, and stricture of esophageal anastomosis: gastric pull-up versus colon interposition. J. Am. Coll. Surg. 198, 536–541 (2004).

    PubMed  Google Scholar 

  70. Badylak, S. F. et al. Esophageal preservation in five male patients after endoscopic inner-layer circumferential resection in the setting of superficial cancer: a regenerative medicine approach with a biologic scaffold. Tissue Eng. Part A 17, 1643–1650 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Nieponice, A. et al. Patch esophagoplasty: esophageal reconstruction using biologic scaffolds. Ann. Thorac. Surg. 97, 283–288 (2014).

    PubMed  Google Scholar 

  72. Badylak, S. F., Valentin, J. E., Ravindra, A. K., McCabe, G. P. & Stewart-Akers, A. M. Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng. Part A 14, 1835–1842 (2008).

    CAS  PubMed  Google Scholar 

  73. Sjöqvist, S. et al. Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats. Nat. Commun. 5, 3562 (2014).

    PubMed  PubMed Central  Google Scholar 

  74. Nieponice, A., Gilbert, T. W., Johnson, S. A., Turner, N. J. & Badylak, S. F. Bone marrow-derived cells participate in the long-term remodeling in a mouse model of esophageal reconstruction. J. Surg. Res. 182, e1–e7 (2013).

    CAS  PubMed  Google Scholar 

  75. Diemer, P., Markoew, S., Le, D. & Qvist, N. Poly-ε-caprolactone mesh as a scaffold for in vivo tissue engineering in rabbit esophagus. Dis. Esophagus 28, 240–245 (2014).

    PubMed  Google Scholar 

  76. Freud, E., Efrati, I., Kidron, D. & Mares, A. Comparative experimental study of esophageal wall regeneration after prosthetic replacement. J. Biomed. Mater. Res. 45, 84–91 (1999).

    CAS  PubMed  Google Scholar 

  77. Miyazawa, M. et al. Extensive regeneration of the stomach using bioabsorbable polymer sheets. Surgery 158, 1283–1290 (2015).

    PubMed  Google Scholar 

  78. Hori, Y. et al. Functional analysis of the tissue-engineered stomach wall. Artif. Organs 26, 868–872 (2002).

    PubMed  Google Scholar 

  79. Araki, M. et al. Development of a new tissue-engineered sheet for reconstruction of the stomach. Artif. Organs 33, 818–826 (2009).

    CAS  PubMed  Google Scholar 

  80. Denost, Q. et al. Colorectal tissue engineering: a comparative study between porcine small intestinal submucosa (SIS) and chitosan hydrogel patches. Surgery 158, 1714–1723 (2015).

    PubMed  Google Scholar 

  81. Nakatsu, H. et al. Influence of mesenchymal stem cells on stomach tissue engineering using small intestinal submucosa. J. Tissue Eng. Regen. Med. 9, 296–604 (2013).

    PubMed  PubMed Central  Google Scholar 

  82. Qin, H. H. & Dunn, J. C. Small intestinal submucosa seeded with intestinal smooth muscle cells in a rodent jejunal interposition model. J. Surg. Res. 171, e21–e26 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Walthers, C. M., Nazemi, A. K., Patel, S. L., Wu, B. M. & Dunn, J. C. The effect of scaffold macroporosity on angiogenesis and cell survival in tissue-engineered smooth muscle. Biomaterials 35, 5129–5137 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Walthers, C. M., Lee, M., Wu, B. M. & Dunn, J. C. Smooth muscle strips for intestinal tissue engineering. PLoS ONE 9, e114850 (2014).

    PubMed  PubMed Central  Google Scholar 

  85. Raghavan, S. & Bitar, K. N. The influence of extracellular matrix composition on the differentiation of neuronal subtypes in tissue engineered innervated intestinal smooth muscle sheets. Biomaterials 35, 7429–7440 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Zakhem, E., Elbahrawy, M., Orlando, G. & Bitar, K. N. Successful implantation of an engineered tubular neuromuscular tissue composed of human cells and chitosan scaffold. Surgery 158, 1598–1608 (2015).

    PubMed  PubMed Central  Google Scholar 

  87. Franck, D. et al. In vitro evaluation of bi-layer silk fibroin scaffolds for gastrointestinal tissue engineering. J. Tissue Eng. 5, 2041731414556849 (2014).

    PubMed  PubMed Central  Google Scholar 

  88. Metzger, M. et al. Expansion and differentiation of neural progenitors derived from the human adult enteric nervous system. Gastroenterology 137, 2063–2073.e4 (2009).

    CAS  PubMed  Google Scholar 

  89. Anitha, M. et al. Characterization of fetal and postnatal enteric neuronal cell lines with improvement in intestinal neural function. Gastroenterology 134, 1424–1435 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Hotta, R. et al. Transplanted progenitors generate functional enteric neurons in the postnatal colon. J. Clin. Invest. 123, 1182–1191 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Pan, W. K., Zheng, B. J., Gao, Y., Qin, H. & Liu, Y. Transplantation of neonatal gut neural crest progenitors reconstructs ganglionic function in benzalkonium chloride-treated homogenic rat colon. J. Surg. Res. 167, e221–e230 (2011).

    CAS  PubMed  Google Scholar 

  92. Almond, S., Lindley, R. M., Kenny, S. E., Connell, M. G. & Edgar, D. H. Characterisation and transplantation of enteric nervous system progenitor cells. Gut 56, 489–496 (2007).

    PubMed  Google Scholar 

  93. Raghavan, S., Gilmont, R. R. & Bitar, K. N. Neuroglial differentiation of adult enteric neuronal progenitor cells as a function of extracellular matrix composition. Biomaterials 34, 6649–6658 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Macheiner, T., Ackbar, R. & Saxena, A. K. Isolation, identification and culture of myenteric plexus cells from ovine esophagus. Esophagus 10, 144–148 (2013).

    Google Scholar 

  95. Hanani, M. Multiple myenteric networks in the human appendix. Auton. Neurosci. 110, 49–54 (2004).

    PubMed  Google Scholar 

  96. Hagl, C. I., Heumüller-Klug, S., Wink, E., Wessel, L. & Schäfer, K.-H. The human gastrointestinal tract, a potential autologous neural stem cell source. PLoS ONE 8, e72948 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Bitar, K. N. & Zakhem, E. Is bioengineering a possibility in gastrointestinal disorders? Expert Rev. Gastroenterol. Hepatol. 9, 1463–1465 (2015).

    CAS  PubMed  Google Scholar 

  98. Guilak, F. et al. Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell 5, 17–26 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Rego, S. L., Raghavan, S., Zakhem, E. & Bitar, K. N. Enteric neural differentiation in innervated, physiologically functional, smooth muscle constructs is modulated by bone morphogenic protein 2 secreted by sphincteric smooth muscle cells. J. Tissue Eng. Regen. Med. http://dx.doi.org/10.1002/term.2027 (2015).

  100. Anitha, M. et al. BMP2 promotes differentiation of nitrergic and catecholaminergic enteric neurons through a Smad1-dependent pathway. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G375–G383 (2010).

    CAS  PubMed  Google Scholar 

  101. Zakhem, E. & Bitar, K. N. Development of chitosan scaffolds with enhanced mechanical properties for intestinal tissue engineering applications. J. Funct. Biomater. 6, 999–1011 (2015).

    PubMed  PubMed Central  Google Scholar 

  102. Zakhem, E., Raghavan, S., Gilmont, R. R. & Bitar, K. N. Chitosan-based scaffolds for the support of smooth muscle constructs in intestinal tissue engineering. Biomaterials 33, 4810–4817 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Zakhem, E., Raghavan, S. & Bitar, K. N. Neo-innervation of a bioengineered intestinal smooth muscle construct around chitosan scaffold. Biomaterials 35, 1882–1889 (2014).

    CAS  PubMed  Google Scholar 

  104. Vrana, N. E. et al. Engineering functional epithelium for regenerative medicine and in vitro organ models: a review. Tissue Eng. Part B Rev. 19, 529–543 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Paz, A. C. et al. Challenges and opportunities for tissue-engineering polarized epithelium. Tissue Eng. Part B Rev. 20, 56–72 (2013).

    PubMed  Google Scholar 

  106. Macheiner, T., Kuess, A., Dye, J. & Saxena, A. K. A novel method for isolation of epithelial cells from ovine esophagus for tissue engineering. Biomed. Mater. Eng. 24, 1457–1468 (2014).

    CAS  PubMed  Google Scholar 

  107. Ohki, T. et al. Treatment of oesophageal ulcerations using endoscopic transplantation of tissue-engineered autologous oral mucosal epithelial cell sheets in a canine model. Gut 55, 1704–1710 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Ohki, T. et al. Prevention of esophageal stricture after endoscopic submucosal dissection using tissue-engineered cell sheets. Gastroenterology 143, 582–588.e2 (2012).

    PubMed  Google Scholar 

  109. Poghosyan, T. et al. In vitro development and characterization of a tissue-engineered conduit resembling esophageal wall using human and pig skeletal myoblast, oral epithelial cells, and biologic scaffolds. Tissue Eng. Part A 19, 2242–2252 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Shabafrooz, V. et al. The effect of hyaluronic acid on biofunctionality of gelatin–collagen intestine tissue engineering scaffolds. J. Biomed. Mater. Res. Part A 102, 3130–3139 (2014).

    Google Scholar 

  111. Costello, C. M. et al. Synthetic small intestinal scaffolds for improved studies of intestinal differentiation. Biotechnol. Bioeng. 111, 1222–1232 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Yu, J., Peng, S., Luo, D. & March, J. C. In vitro 3D human small intestinal villous model for drug permeability determination. Biotechnol. Bioeng. 109, 2173–2178 (2012).

    CAS  PubMed  Google Scholar 

  113. Nelson, R. L. Epidemiology of fecal incontinence. Gastroenterology 126, S3–S7 (2004).

    PubMed  Google Scholar 

  114. Bharucha, A. E. Fecal incontinence 1, 2. Gastroenterology 124, 1672–1685 (2003).

    PubMed  Google Scholar 

  115. Hecker, L., Baar, K., Dennis, R. G. & Bitar, K. N. Development of a three-dimensional physiological model of the internal anal sphincter bioengineered in vitro from isolated smooth muscle cells. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G188–G196 (2005).

    CAS  PubMed  Google Scholar 

  116. Raghavan, S. et al. Successful implantation of bioengineered, intrinsically innervated, human internal anal sphincter. Gastroenterology 141, 310–319 (2011).

    PubMed  PubMed Central  Google Scholar 

  117. Gilmont, R. R., Raghavan, S., Somara, S. & Bitar, K. N. Bioengineering of physiologically functional intrinsically innervated human internal anal sphincter constructs. Tissue Eng. Part A 20, 1603–1611 (2014).

    PubMed  PubMed Central  Google Scholar 

  118. Raghavan, S. et al. Perianal implantation of bioengineered human internal anal sphincter constructs intrinsically innervated with human neural progenitor cells. Surgery 155, 668–674 (2014).

    PubMed  Google Scholar 

  119. Bitar, K. N. et al. 600 in situ implantation of autologous Biosphincter™ re-instates continence in a large animal model of passive fecal incontinence. Gastroenterology 148, S-117 (2015).

    Google Scholar 

  120. Rego, S. L., Zakhem, E., Orlando, G. & Bitar, K. N. Bioengineering functional human sphincteric and non-sphincteric gastrointestinal smooth muscle constructs. Methods 99, 128–134 (2015).

    PubMed  PubMed Central  Google Scholar 

  121. Rego, S. L., Zakhem, E., Orlando, G. & Khalil, B. Bioengineered human pyloric sphincters using autologous smooth muscle and neural progenitor cells. Tissue Eng. Part A 22, 151–160 (2016).

    CAS  PubMed  Google Scholar 

  122. Kellersman, R., Zhong, R., Kiyochi, H., Garcia, B. & Grant, D. R. Reconstruction of the intestinal lymphatic drainage after small bowel transplantation. Transplantation 69, 10–16 (2000).

    CAS  PubMed  Google Scholar 

  123. Duxbury, M. S. et al. Lymphangiogenesis in tissue-engineered small intestine. Transplantation 77, 1162–1166 (2004).

    PubMed  Google Scholar 

  124. Perez, A. et al. Tissue-engineered small intestine: ontogeny of the Immune System12. Transplantation 74, 619–623 (2002).

    CAS  PubMed  Google Scholar 

  125. Dixon, J. B., Raghunathan, S. & Swartz, M. A. A tissue-engineered model of the intestinal lacteal for evaluating lipid transport by lymphatics. Biotechnol. Bioeng. 103, 1224–1235 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Gardner-Thorpe, J. et al. Angiogenesis in tissue-engineered small intestine. Tissue Eng. 9, 1255–1261 (2003).

    CAS  PubMed  Google Scholar 

  127. Choi, R. & Vacanti, J. Preliminary studies of tissue-engineered intestine using isolated epithelial organoid units on tubular synthetic biodegradable scaffolds. Transplant. Proc. 29, 848–851 (1997).

    CAS  PubMed  Google Scholar 

  128. van Rijn, J. M., Schneeberger, K., Wiegerinck, C. L., Nieuwenhuis, E. E. & Middendorp, S. Novel approaches: tissue engineering and stem cells — in vitro modelling of the gut. Best Pract. Res. Clin. Gastroenterol. 30, 281–293 (2016).

    CAS  Google Scholar 

  129. Grikscheit, T. C. et al. Tissue-engineered colon exhibits function in vivo. Surgery 132, 200–204 (2002).

    PubMed  Google Scholar 

  130. Grikscheit, T. C. et al. Tissue-engineered large intestine resembles native colon with appropriate in vitro physiology and architecture. Ann. Surg. 238, 35 (2003).

    PubMed  PubMed Central  Google Scholar 

  131. Grikscheit, T., Ochoa, E. R., Srinivasan, A., Gaissert, H. & Vacanti, J. P. Tissue-engineered esophagus: experimental substitution by onlay patch or interposition. J. Thorac. Cardiovasc. Surg. 126, 537–544 (2003).

    PubMed  Google Scholar 

  132. Grikscheit, T., Srinivasan, A. & Vacanti, J. P. Tissue-engineered stomach: a preliminary report of a versatile in vivo model with therapeutic potential. J. Pediatr. Surg. 38, 1305–1309 (2003).

    PubMed  Google Scholar 

  133. Grikscheit, T. C. et al. Tissue-engineered small intestine improves recovery after massive small bowel resection. Ann. Surg. 240, 748–754 (2004).

    PubMed  PubMed Central  Google Scholar 

  134. Sala, F. G., Kunisaki, S. M., Ochoa, E. R., Vacanti, J. & Grikscheit, T. C. Tissue-engineered small intestine and stomach form from autologous tissue in a preclinical large animal model. J. Surg. Res. 156, 205–212 (2009).

    PubMed  Google Scholar 

  135. Speer, A. L., Sala, F. G., Matthews, J. A. & Grikscheit, T. C. Murine tissue-engineered stomach demonstrates epithelial differentiation. J. Surg. Res. 171, 6–14 (2011).

    CAS  PubMed  Google Scholar 

  136. Spurrier, R. G., Speer, A. L., Hou, X., El-Nachef, W. N. & Grikscheit, T. C. Murine and human tissue-engineered esophagus form from sufficient stem/progenitor cells and do not require microdesigned biomaterials. Tissue Eng. Part A 21, 906–915 (2015).

    CAS  PubMed  Google Scholar 

  137. Levin, D. E. et al. Human tissue-engineered small intestine forms from postnatal progenitor cells. J. Pediatr. Surg. 48, 129–137 (2013).

    PubMed  Google Scholar 

  138. Grant, C. N. et al. Human and mouse tissue-engineered small intestine both demonstrate digestive and absorptive function. Am. J. Physiol. Gastrointest. Liver Physiol. 308, G664–G677 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Yen, T.-H. & Wright, N. A. The gastrointestinal tract stem cell niche. Stem Cell Rev. 2, 203–212 (2006).

    CAS  PubMed  Google Scholar 

  140. DeWard, A. D., Cramer, J. & Lagasse, E. Cellular heterogeneity in the mouse esophagus implicates the presence of a nonquiescent epithelial stem cell population. Cell Rep. 9, 701–711 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    CAS  PubMed  Google Scholar 

  142. Sato, T. et al. Single Lgr5 stem cells build crypt villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    CAS  PubMed  Google Scholar 

  143. Yui, S. et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 18, 618–623 (2012).

    CAS  PubMed  Google Scholar 

  144. Watson, C. L. et al. An in vivo model of human small intestine using pluripotent stem cells. Nat. Med. 20, 1310–1314 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013).

    CAS  PubMed  Google Scholar 

  146. Takebe, T. et al. Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation. Cell Stem Cell 16, 556–565 (2015).

    CAS  PubMed  Google Scholar 

  147. Taka-aki, K. N. et al. Generation of stomach tissue from mouse embryonic stem cells. Nat. Cell Biol. 17, 984–993 (2015).

    Google Scholar 

  148. Lee, M., Wu, B. M., Stelzner, M., Reichardt, H. M. & Dunn, J. C. Intestinal smooth muscle cell maintenance by basic fibroblast growth factor. Tissue Eng. Part A 14, 1395–1402 (2008).

    CAS  PubMed  Google Scholar 

  149. Heise, R. L., Ivanova, J., Parekh, A. & Sacks, M. S. Generating elastin-rich small intestinal submucosa-based smooth muscle constructs utilizing exogenous growth factors and cyclic mechanical stimulation. Tissue Eng. Part A 15, 3951–3960 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Yazdani, S. K. et al. Smooth muscle cell seeding of decellularized scaffolds: the importance of bioreactor preconditioning to development of a more native architecture for tissue-engineered blood vessels. Tissue Eng. Part A 15, 827–840 (2009).

    CAS  PubMed  Google Scholar 

  151. Rühl, A. Glial cells in the gut. Neurogastroenterol. Motil. 17, 777–790 (2005).

    PubMed  Google Scholar 

  152. Bassotti, G., Villanacci, V., Antonelli, E., Morelli, A. & Salerni, B. Enteric glial cells: new players in gastrointestinal motility? Lab. Invest. 87, 628–632 (2007).

    CAS  PubMed  Google Scholar 

  153. Sanders, K. M. & Ward, S. M. Interstitial cells of Cajal: a new perspective on smooth muscle function. J. Physiol. 576, 721–726 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Watters, D., Smith, A., Eastwood, M., Anderson, K. & Elton, R. Mechanical properties of the rat colon: the effect of age, sex and different conditions of storage. Q. J. Exp. Physiol. 70, 151–162 (1985).

    CAS  PubMed  Google Scholar 

  155. Watters, D. et al. Mechanical properties of the colon: comparison of the features of the African and European colon in vitro. Gut 26, 384–392 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Sarkar, S., Salacinski, H., Hamilton, G. & Seifalian, A. The mechanical properties of infrainguinal vascular bypass grafts: their role in influencing patency. Eur. J. Vasc. Endovasc. Surg. 31, 627–636 (2006).

    CAS  PubMed  Google Scholar 

  157. Lee, S. J. et al. Development of a composite vascular scaffolding system that withstands physiological vascular conditions. Biomaterials 29, 2891–2898 (2008).

    CAS  PubMed  Google Scholar 

  158. Lovett, M., Lee, K., Edwards, A. & Kaplan, D. L. Vascularization strategies for tissue engineering. Tissue Eng. Part B Rev. 15, 353–370 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Rouwkema, J., Rivron, N. C. & van Blitterswijk, C. A. Vascularization in tissue engineering. Trends Biotechnol. 26, 434–441 (2008).

    CAS  PubMed  Google Scholar 

  160. Lee, K. Y., Peters, M. C., Anderson, K. W. & Mooney, D. J. Controlled growth factor release from synthetic extracellular matrices. Nature 408, 998–1000 (2000).

    CAS  PubMed  Google Scholar 

  161. Ovsianikov, A. et al. Laser fabrication of three-dimensional CAD scaffolds from photosensitive gelatin for applications in tissue engineering. Biomacromolecules 12, 851–858 (2011).

    CAS  PubMed  Google Scholar 

  162. Gauvin, R. et al. Microfabrication of complex porous tissue engineering scaffolds using 3D projection stereolithography. Biomaterials 33, 3824–3834 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Pennathur, A., Gibson, M. K., Jobe, B. A. & Luketich, J. D. Oesophageal carcinoma. Lancet 381, 400–412 (2013).

    PubMed  Google Scholar 

  164. Rustgi, A. K. & El-Serag, H. B. Esophageal carcinoma. N. Engl. J. Med. 371, 2499–2509 (2014).

    PubMed  Google Scholar 

  165. Bickenbach, K. & Strong, V. E. Comparisons of gastric cancer treatments: East versus West. J. Gastric Cancer 12, 55–62 (2012).

    PubMed  PubMed Central  Google Scholar 

  166. Huscher, C. G. et al. Laparoscopic versus open subtotal gastrectomy for distal gastric cancer: five-year results of a randomized prospective trial. Ann. Surg. 241, 232 (2005).

    PubMed  PubMed Central  Google Scholar 

  167. Jones, K. L. Gastroparesis: prevalence, clinical significance and treatment. Can. J. Gastroenterol. 14, 805 (2001).

    Google Scholar 

  168. Peyret, B. et al. Prevalence of liver complications in children receiving long-term parenteral nutrition. Eur. J. Clin. Nutr. 65, 743–749 (2011).

    CAS  PubMed  Google Scholar 

  169. Yamamoto, T. & Keighley, M. R. Proctocolectomy is associated with a higher complication rate but carries a lower recurrence rate than total colectomy and ileorectal anastomosis in Crohn colitis. Scand. J. Gastroenterol. 34, 1212–1215 (1999).

    CAS  PubMed  Google Scholar 

  170. Sohn, G. et al. Surgical outcomes after total colectomy with ileorectal anastomosis in patients with medically intractable slow transit constipation. J. Kor. Soc. Coloproctol. 27, 180–187 (2011).

    Google Scholar 

  171. Baumgart, D. C. & Carding, S. R. Inflammatory bowel disease: cause and immunobiology. Lancet 369, 1627–1640 (2007).

    CAS  PubMed  Google Scholar 

  172. O'Dwyer, R. H. et al. Clinical features and colonic motor disturbances in chronic megacolon in adults. Dig. Dis. Sci. 60, 2398–2407 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Topor, L., Ulici, A., Malureanu, D., Stoica, I. & Moga, A. Difficulties in the diagnostics and treatment of near-total congenital megacolon. Chirurgia (Bucur.) 109, 701–704 (2014).

    CAS  Google Scholar 

  174. Kouranloo, J., Sadeghian, N. & Monfared, M. K. Treatment and postoperative complication of 420 patients with congenital megacolon. Saudi Med. J. 24, S25–S28 (2003).

    PubMed  Google Scholar 

  175. Bharucha, A. E. & Rao, S. S. An update on anorectal disorders for gastroenterologists. Gastroenterology 146, 37–45.e2 (2014).

    PubMed  Google Scholar 

  176. Whitehead, W. E. et al. Fecal incontinence in US adults: epidemiology and risk factors. Gastroenterology 137, 512–517.e2 (2009).

    PubMed  PubMed Central  Google Scholar 

  177. Van Koughnett, J. A. & Wexner, S. D. Current management of fecal incontinence: choosing amongst treatment options to optimize outcomes. World J. Gastroenterol. 19, 9216–9230 (2013).

    PubMed  PubMed Central  Google Scholar 

  178. Micci, M. A. et al. Neural stem cell transplantation in the stomach rescues gastric function in neuronal nitric oxide synthase-deficient mice. Gastroenterology 129, 1817–1824 (2005).

    CAS  PubMed  Google Scholar 

  179. Hotta, R. et al. Transplanted progenitors generate functional enteric neurons in the postnatal colon. J. Clin. Invest. 0, 0–0 (2013).

    Google Scholar 

  180. Liu, W., Wu, R. D., Dong, Y. L. & Gao, Y. M. Neuroepithelial stem cells differentiate into neuronal phenotypes and improve intestinal motility recovery after transplantation in the aganglionic colon of the rat. Neurogastroenterol. Motil. 19, 1001–1009 (2007).

    CAS  PubMed  Google Scholar 

  181. Metzger, M., Caldwell, C., Barlow, A. J., Burns, A. J. & Thapar, N. Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders. Gastroenterology 136, 2214–2225.e3 (2009).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work of the authors is supported by Army, Navy, NIH, Air Force, VA and Health Affairs to support the AFIRM II effort, under Award No. W81XWH-13-2-0052; GU 7 and NIH/NIDDK R01DK071614 and R42DK105593.

Author information

Authors and Affiliations

  1. Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way NE, Winston Salem, 27101, North Carolina, USA

    Khalil N. Bitar & Elie Zakhem

  2. Department of Molecular Medicine and Translational Sciences, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston Salem, 27157, North Carolina, USA

    Khalil N. Bitar & Elie Zakhem

  3. Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, 391 Technology Way NE, Winston Salem, 27101, North Carolina, USA

    Khalil N. Bitar

Authors
  1. Khalil N. Bitar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elie Zakhem
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.N.B. and E.Z. researched data for article, contributed to discussion of content, wrote, reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Khalil N. Bitar.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bitar, K., Zakhem, E. Bioengineering the gut: future prospects of regenerative medicine. Nat Rev Gastroenterol Hepatol 13, 543–556 (2016). https://doi.org/10.1038/nrgastro.2016.124

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2016.124

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research