Abstract
Trachea-tissue engineering is a thriving new field in regenerative medicine that is reaching maturity and yielding numerous promising results. In view of the crucial role that the epithelium plays in the trachea, re-epithelialization of tracheal substitutes has gradually emerged as the focus of studies in tissue-engineered trachea. Recent progress in our understanding of stem cell biology, growth factor interactions and transplantation immunobiology offer the prospect of optimization of a tissue-engineered tracheal epithelium. In addition, advances in cell culture technology and successful applications of clinical transplantation are opening up new avenues for the construction of a tissue-engineered tracheal epithelium. Therefore, this review summarizes current advances, unresolved obstacles and future directions in the reconstruction of a tissue-engineered tracheal epithelium.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Tracheal replacement: a critical review. Ann. Thorac. Surg. 73(6), 1995–2004 (2002).
- 2 . Alternative approach to the surgical management of congenital tracheal stenosis. Ann. Thorac. Surg. 82(6), 2305–2307 (2006).
- 3 . Pediatric tracheal reconstruction with pericardial patch and strips of autotogous cartilage. Eur. J. Cardiothorac. Surg. 36(2), 344–351 (2009).
- 4 Long-term evaluation of the replacement of the trachea with an autologous aortic graft. Ann. Thorac. Surg. 75(5), 1572–1578 (2003).
- 5 Tracheal replacement with aortic allografts. N. Engl. J. Med. 355(18), 1938–1940 (2006).
- 6 Surgical technique and results of tracheal and carinal replacement with aortic allografts for salivary gland-type carcinoma. J. Thorac. Cardiovasc. Surg. 140(2), 387–393.e382 (2010).
- 7 . Aortic homograft reconstruction of partial laryngectomy defects: a new technique. Ann. Otol. Rhinol. Laryngol. 121(5), 301–306 (2012).
- 8 . Resection and reconstruction of the intrathoracic trachea. Br. J. Surg. 38(150), 200–205 (1950).
- 9 . Clinical-experience with the silicone tracheal prosthesis. J. Thorac. Cardiovasc. Surg. 99(4), 604–613 (1990).
- 10 . The history of tracheal surgery. Chest Surg. Clin. N. Am. 13(2), 175–189 (2003).
- 11 . Successful in vitro growth of human respiratory epithelium on a tracheal prosthesis. Laryngoscope 102(5), 528–531 (1992).
- 12 . Effects of media on differentiation of cultured human tracheal epithelium. In vitro cellular & developmental biology. Animal 39(1–2), 56–62 (2003).
- 13 . Expansion of cultures of human tracheal epithelium with maintenance of differentiated structure and function. BioTechniques 39(2), 249–255 (2005).
- 14 . Differentiated structure and function of cultures from human tracheal epithelium. Am. J. Physiol. 262(6 Pt 1), L713–L724 (1992).
- 15 . Tissue-engineered trachea: history, problems and the future. Eur. J. Cardiothorac. Surg. 30(5), 782–786 (2006).• Previous review of tissue-engineered trachea.
- 16 . Tracheobronchial bio-engineering: biotechnology fulfilling unmet medical needs. Adv. Drug Deliv. Rev. 63(4–5), 367–374 (2011).
- 17 . Engineering airway epithelium. J. Biomed. Biotechnol. 2012, 982971 (2012).• Precious and recent systematic review of tissue-engineered tracheal epithelium.
- 18 . Overview of tracheal tissue engineering: clinical need drives the laboratory approach. Ann. Biomed. Eng. 39(8), 2091–2113 (2011).• Precious and recent systematic review of tracheal tissue engineering.
- 19 . Tissue Eng. airway mucosa: a systematic review. Laryngoscope 124(4), 961–968 (2014).•• Precious and latest expert opinion review of tissue-engineered tracheal epithelium.
- 20 . Current concepts in tracheal reconstruction. Curr. Opin. Otolaryngol. Head Neck Surg. 20(4), 246–253 (2012).
- 21 . The airway epithelium: more than just a structural barrier. Ther. Adv. Respir. Dis. 5(4), 255–273 (2011).
- 22 Immunocompetent 3D model of human upper airway for disease modeling and in vitro drug evaluation. Mol. Pharm. 11(7), 2082–2091 (2014).
- 23 . The airway epithelium: structural and functional properties in health and disease. Respirology 8(4), 432–446 (2003).
- 24 . Structure and function of the polymeric mucins in airways mucus. Annu. Rev. Physiol. 70, 459–486 (2008).
- 25 . Mucins, mucus, and sputum. Chest 135(2), 505–512 (2009).
- 26 . Optical method for quantifying rates of mucus secretion from single submucosal glands. Am. J. Physiol. Lung Cell. Mol. Physiol. 281(2), L458–L468 (2001).
- 27 . Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling. Dis. Models Mech. 3(9–10), 545–556 (2010).
- 28 . In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations. Am. J. Physiol. Lung Cell. Mol. Physiol. 286(4), L643–L649 (2004).
- 29 Cholinergic chemosensory cells in the trachea regulate breathing. Proc. Natl Acad. Sci. USA 108(23), 9478–9483 (2011).
- 30 . Chemosensory brush cells of the trachea. A stable population in a dynamic epithelium. Am. J. Respir. Cell Mol. Biol. 49(2), 190–196 (2013).
- 31 . Epithelial stem cells of the lung: privileged few or opportunities for many? Development 133(13), 2455–2465 (2006).
- 32 . Ciliated epithelial cell lifespan in the mouse trachea and lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 295(1), L231–L234 (2008).
- 33 . Endogenous lung stem cells and contribution to disease. J. Pathol. 217(2), 254–264 (2009).
- 34 . Responses of the human airway epithelium transcriptome to in vivo injury. Physiol. Genomics 29(2), 139–148 (2007).
- 35 . Expression of phenotypic markers during regeneration of rat tracheal epithelium following mechanical injury. Am. J. Respir. Cell Mol. Biol. 11(1), 85–94 (1994).
- 36 . Maintenance and repair of the bronchiolar epithelium. Proc. Am. Thorac. Soc. 5(3), 328–333 (2008).
- 37 . Processes involved in the repair of injured airway epithelia. Arch. Immunol. Ther. Exp. 51(5), 283–288 (2003).
- 38 . Epithelial cell-extracellular matrix interactions and stem cells in airway epithelial regeneration. Proc. Am. Thorac. Soc. 5(6), 689–694 (2008).
- 39 . Epithelial cells and fibroblasts: structural repair and remodelling in the airways. Paediatr. Respir. Rev. 5(Suppl. A), S35–S40 (2004).
- 40 Transdifferentiation of ciliated cells during repair of the respiratory epithelium. Am. J. Respir. Cell Mol. Biol. 34(2), 151–157 (2006).
- 41 . New insights into airway remodelling in asthma and its possible modulation. Curr. Opin. Allergy Clin. Immunol. 8(5), 367–375 (2008).
- 42 . Wound healing and regenerative strategies. Oral Dis. 17(6), 541–549 (2011).
- 43 . Tissue engineering: the design and fabrication of living replacement devices for surgical reconstruction and transplantation. Lancet 354(Suppl. 1), Si32–Si34 (1999).
- 44 . Tissue engineering toward organ replacement: a promising approach in airway transplant. Int. J. Artific. Organs 32(11), 763–768 (2009).
- 45 . Engineered whole organs and complex tissues. Lancet 379(9819), 943–952 (2012).
- 46 . Engineering complex tissues. Sci. Transl. Med. 4(160), 160rv112 (2012).
- 47 Airway tissue engineering: an update. Expert Opin. Biol. Ther. 14(10), 1477–1491 (2014).
- 48 . Growth and differentiation of mouse tracheal epithelial cells: selection of a proliferative population. Am. J. Physiol. Lung Cell. Mol. Physiol. 283(6), L1315–L1321 (2002).
- 49 . Well-differentiated human airway epithelial cell cultures. Methods Mol. Med. 107, 183–206 (2005).
- 50 . Do airway epithelium air–liquid cultures represent the in vivo airway epithelium transcriptome? Am. J. Respir. Cell Mol. Biol. 44(4), 465–473 (2011).
- 51 . A composite tissue-engineered trachea using sheep nasal chondrocyte and epithelial cells. FASEB J. 17(8), 823–828 (2003).
- 52 . Autologous implantation of bilayered tissue-engineered respiratory epithelium for tracheal mucosal regenesis in a sheep model. Cells Tissues Organs 192(5), 292–302 (2010).
- 53 . Possibility of skin epithelial cell transdifferentiation in tracheal reconstruction. Artific. Organs 35(2), 122–130 (2011).
- 54 . Replacement of a tracheal defect with a tissue-engineered prosthesis: early results from animal experiments. J. Thorac. Cardiovasc. Surg. 128(1), 124–129 (2004).
- 55 Tissue engineering for regeneration of the tracheal epithelium. Ann. Otol. Rhinol. Laryngol. 115(7), 501–506 (2006).
- 56 Bioengineered trachea with fibroblasts in a rabbit model. Ann. Otol. Rhinol. Laryngol. 118(11), 796–804 (2009).•• Important study demonstrating the effect of fibroblasts on tracheal epithelial regeneration.
- 57 . Effect of fibroblasts on epithelial regeneration on the surface of a bioengineered trachea. Ann. Otol. Rhinol. Laryngol. 117(1), 59–64 (2008).
- 58 In situ tissue engineering for tracheal reconstruction using a luminar remodeling type of artificial trachea. J. Thorac. Cardiovasc. Surg. 138(4), 811–819 (2009).
- 59 . Bone marrow-derived mesenchymal stem cells enhance cryopreserved trachea allograft epithelium regeneration and vascular endothelial growth factor expression. Transplantation 92(6), 620–626 (2011).
- 60 A tissue-engineered trachea derived from a framed collagen scaffold, gingival fibroblasts and adipose-derived stem cells. Biomaterials 31(18), 4855–4863 (2010).
- 61 Regeneration of the trachea using a bioengineered scaffold with adipose-derived stem cells. Ann. Otol. Rhinol. Laryngol. 117(6), 453–463 (2008).
- 62 Preclinical regulatory validation of an engineered diaphragmatic tendon made with amniotic mesenchymal stem cells. J. Pediatr. Surg. 46(1), 57–61 (2011).
- 63 . Bronchial brush biopsy. A valuable diagnostic technique in the presurgical evaluation of indeterminate lung densities. Ann. Thorac. Surg. 13(6), 519–528 (1972).
- 64 An in vitro model of differentiated human airway epithelia. Methods for establishing primary cultures. Methods Mol. Biol. 188, 115–137 (2002).•• Previous methods for establishing primary cultures of human airway epithelia in vitro.
- 65 Replacement of a tracheal stenosis with a tissue-engineered human trachea using autologous stem cells: a case report. Tissue Eng. A 20(1–2), 389–397 (2014).
- 66 The use of nasal epithelial stem/progenitor cells to produce functioning ciliated cells in vitro. Am. J. Rhinol. Allergy 26(5), 345–350 (2012).
- 67 . Human respiratory epithelial cells from nasal turbinate expressed stem cell genes even after serial passaging. Med. J. Malaysia 66(5), 440–442 (2011).
- 68 . Tracheal allotransplantation after withdrawal of immunosuppressive therapy. N. Engl. J. Med. 362(2), 138–145 (2010).
- 69 . Tracheal allograft after withdrawal of immunosuppressive therapy. N. Engl. J. Med. 370(16), 1568–1570 (2014).•• A series of tracheal allotransplantations using heterotopic vascularized tracheal allograft after withdrawal of immunosuppressive therapy.
- 70 . Skin stem cells: rising to the surface. J. Cell Biol. 180(2), 273–284 (2008).
- 71 . Somatic epidermal stem cells can produce multiple cell lineages during development. Stem Cells 20(1), 21–31 (2002).
- 72 . Extensive tissue-regenerative capacity of neonatal human keratinocyte stem cells and their progeny. J. Clin. Invest. 113(3), 390–400 (2004).
- 73 . Stem cells are dispensable for lung homeostasis but restore airways after injury. Proc. Natl Acad. Sci. USA 106(23), 9286–9291 (2009).
- 74 . Tissue engineering and the use of stem/progenitor cells for airway epithelium repair. Eur. Cells Mater. 19, 284–299 (2010).•• Precious expert opinion review of stem/progenitor cells used for tissue-engineered tracheal epithelium.
- 75 . Cellular and molecular characteristics of basal cells in airway epithelium. Exp. Lung Res. 27(5), 401–415 (2001).
- 76 . Number and proliferation of basal and parabasal cells in normal human airway epithelium. Am. J. Respir. Crit. Care Med. 157(6 Pt 1), 2000–2006 (1998).
- 77 . Evidence for stem-cell niches in the tracheal epithelium. Am. J. Respir. Cell Mol. Biol. 24(6), 662–670 (2001).
- 78 . Airway epithelial stem cells and the pathophysiology of chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 3(8), 718–725 (2006).
- 79 . Growth and differentiation of tracheal epithelial progenitor cells. Am. J. Physiol. 266(3 Pt 1), L296–L307 (1994).
- 80 . Properties of rat tracheal epithelial cells separated based on expression of cell surface alpha-galactosyl end groups. Am. J. Respir. Cell Mol. Biol. 4(6), 544–554 (1991).
- 81 . Progenitor cells of the adult human airway involved in submucosal gland development. Development 121(7), 2031–2046 (1995).
- 82 Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc. Natl Acad. Sci. USA 106(31), 12771–12775 (2009).
- 83 . Aquaporin-3 expression in human fetal airway epithelial progenitor cells. Stem Cells 23(7), 992–1001 (2005).
- 84 Isolation and in vitro characterization of basal and submucosal gland duct stem/progenitor cells from human proximal airways. Stem Cells Transl. Med. 1(10), 719–724 (2012).
- 85 Novel stem/progenitor cell population from murine tracheal submucosal gland ducts with multipotent regenerative potential. Stem Cells 29(8), 1283–1293 (2011).
- 86 . Airway glandular development and stem cells. Curr. Top. Dev. Biol. 64, 33–56 (2004).
- 87 . Isolation of basal cells and submucosal gland duct cells from mouse trachea. J. Visual. Exp. (67), e3731 (2012).
- 88 . Repair and regeneration of tracheal surface epithelium and submucosal glands in a mouse model of hypoxic-ischemic injury. Respirology 17(7), 1101–1113 (2012).
- 89 . Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J. Cell. Physiol. 213(2), 341–347 (2007).
- 90 . Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp. Hematol. 37(12), 1445–1453 (2009).
- 91 Effectiveness of human mesenchymal stem cells derived from bone marrow cryopreserved for 23–25 years. Cryobiology 64(3), 167–175 (2012).
- 92 . Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair – current views. Stem Cells 25(11), 2896–2902 (2007).
- 93 . Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol. Ther. 17(6), 939–946 (2009).
- 94 In vitro differentiation of human mesenchymal stem cells to epithelial lineage. J. Cell. Mol. Med. 11(3), 502–508 (2007).
- 95 Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105(3), 369–377 (2001).
- 96 Bone marrow-derived SP cells can contribute to the respiratory tract of mice in vivo. J. Cell Sci. 118(Pt 11), 2441–2450 (2005).
- 97 Identification of a bone marrow-derived epithelial-like population capable of repopulating injured mouse airway epithelium. J. Clin. Invest. 119(2), 336–348 (2009).
- 98 . Current applications of mesenchymal stem cells for tissue replacement in otolaryngology-head and neck surgery. Am. J. Stem Cells 1(3), 225–238 (2012).
- 99 . Failure of bone marrow to reconstitute lung epithelium. Am. J. Respir. Cell Mol. Biol. 33(4), 328–334 (2005).
- 100 . Limited restoration of cystic fibrosis lung epithelium in vivo with adult bone marrow-derived cells. Am. J. Respir. Crit. Care Med. 173(2), 171–179 (2006).
- 101 Osteoinduction in human fat-derived stem cells by recombinant human bone morphogenetic protein-2 produced in Escherichia coli. Biotechnol. Lett. 30(1), 15–21 (2008).
- 102 The repair of critical-sized bone defects using expedited, autologous BMP-2 gene-activated fat implants. Tissue Eng. A 16(3), 1093–1101 (2010).
- 103 . Effects of multiple agents on epithelial differentiation of rabbit adipose-derived stem cells in 3D culture. Tissue Eng. A 18(17–18), 1760–1770 (2012).
- 104 . Tracheal reconstruction in a canine model. Otolaryngol. Head Neck Surg. 150(3), 428–433 (2014).
- 105 Embryonic stem cells generate airway epithelial tissue. Am. J. Respir. Cell Mol. Biol. 32(2), 87–92 (2005).
- 106 . Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132(4), 661–680 (2008).
- 107 . Coculture of embryonic stem cells with pulmonary mesenchyme: a microenvironment that promotes differentiation of pulmonary epithelium. Tissue Eng. 11(7–8), 1177–1187 (2005).
- 108 . Ciliated cells differentiated from mouse embryonic stem cells. Stem Cells 24(5), 1381–1388 (2006).
- 109 Inhibitory Smad proteins promote the differentiation of mouse embryonic stem cells into ependymal-like ciliated cells. Biochem. Biophys. Res. Commun. 401(1), 1–6 (2010).
- 110 . Induction of ciliated cells from avian embryonic stem cells using three-dimensional matrix. Tissue Eng. C Methods 16(5), 929–936 (2010).
- 111 Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470(7332), 105–109 (2011).
- 112 Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell 10(4), 398–411 (2012).
- 113 Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs. Cell Stem Cell 10(4), 385–397 (2012).
- 114 . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4), 663–676 (2006).
- 115 Disease-specific induced pluripotent stem cells. Cell 134(5), 877–886 (2008).
- 116 . Advances in understanding the cell types and approaches used for generating induced pluripotent stem cells. J. Hematol. Oncol. 7(1), 50 (2014).
- 117 . Alveolar epithelial differentiation of human induced pluripotent stem cells in a rotating bioreactor. Biomaterials 35(2), 699–710 (2014).
- 118 Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. Nat. Biotechnol. 30(9), 876–882 (2012).
- 119 Epigenetic memory in induced pluripotent stem cells. Nature 467(7313), 285–290 (2010).
- 120 . Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat. Rev. Genet. 15(2), 82–92 (2014).
- 121 . Generating pluripotent stem cells: differential epigenetic changes during cellular reprogramming. FEBS Lett. 586(18), 2874–2881 (2012).
- 122 Human amniotic fluid stem cells can integrate and differentiate into epithelial lung lineages. Stem Cells 26(11), 2902–2911 (2008).
- 123 . Amniotic fluid-derived stem cells in regenerative medicine research. Arch. Pharmacol. Res. 35(2), 271–280 (2012).
- 124 Human amniotic-fluid-derived stem cells: a unique source for regenerative medicine. Expert Opin. Biol. Ther. 14(6), 831–839 (2014).
- 125 . Stem cells derived from amniotic fluid: new potentials in regenerative medicine. Reprod. Biomed. Online 18(Suppl. 1), 17–27 (2009).
- 126 . Amniotic liquid derived stem cells as reservoir of secreted angiogenic factors capable of stimulating neo-arteriogenesis in an ischemic model. Biomaterials 32(15), 3689–3699 (2011).
- 127 Recruitment of host's progenitor cells to sites of human amniotic fluid stem cells implantation. Biomaterials 32(18), 4218–4227 (2011).
- 128 . Epithelial and mesenchymal stem cells from the umbilical cord lining membrane. Cell Transplant. 23(4–5), 497–503 (2014).
- 129 . Umbilical cord blood banking: implications for perinatal care providers. J. Obstetr. Gynaecol. Can. 27(3), 263–290 (2005).
- 130 . New strategies in cord blood cells transplantation. Cell Biol. Int. 37(9), 865–874 (2013).
- 131 . Stem cell comparison: what can we learn clinically from unrelated cord blood transplantation as an alternative stem cell source? Cytotherapy 17(6), 695–701 (2015).
- 132 . [Umbilical cord blood as a source of stem cells]. Acta Medica Croatica: Casopis Hravatske Akademije Medicinskih Znanosti 60(3), 215–225 (2006).
- 133 . Improving the outcome of umbilical cord blood transplantation through ex vivo expansion or graft manipulation. Cytotherapy 17(6), 730–738 (2015).
- 134 . Umbilical cord blood graft enhancement strategies: has the time come to move these into the clinic? Bone Marrow Transplant. 48(7), 884–889 (2013).
- 135 Derivation of lung epithelium from human cord blood-derived mesenchymal stem cells. Am. J. Respir. Crit. Care Med. 177(7), 701–711 (2008).
- 136 Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood 122(17), 3074–3081 (2013).
- 137 . Umbilical cord blood cell transplantation from an unrelated donor: dual transplantation. Methods Find. Exp. Clin. Pharmacol. 32(Suppl. A), 47–51 (2010).
- 138 . Engineering functional epithelium for regenerative medicine and in vitro organ models: a review. Tissue Eng. B Rev. 19(6), 529–543 (2013).•• Precious and recent review of epithelial tissue engineering.
- 139 Tracheal remodeling: comparison of different composite cultures consisting of human respiratory epithelial cells and human chondrocytes. In vitro cellular & developmental biology. Animal 43(1), 28–36 (2007).
- 140 Modification of macroporous titanium tracheal implants with biodegradable structures: tracking in vivo integration for determination of optimal in situ epithelialization conditions. Biotechnol. Bioeng. 109(8), 2134–2146 (2012).
- 141 In vitro reconstitution of the tracheal epithelium. Am. J. Respir. Cell Mol. Biol. 20(2), 312–318 (1999).
- 142 Effect of fibroblasts on tracheal epithelial regeneration in vitro. Tissue Eng. 12(9), 2619–2628 (2006).
- 143 Potential of heterotopic fibroblasts as autologous transplanted cells for tracheal epithelial regeneration. Tissue Eng. 13(9), 2175–2184 (2007).
- 144 . Airway branching morphogenesis in three dimensional culture. Respir. Res. 11, 162 (2010).
- 145 The air–liquid interface and use of primary cell cultures are important to recapitulate the transcriptional profile of in vivo airway epithelia.American journal of physiology. Lung Cell. Mol. Physiol. 300(1), L25–L31 (2011).
- 146 Tissue engineered epithelial cell sheets for the creation of a bioartificial trachea. Tissue Eng. 12(5), 1275–1283 (2006).
- 147 . Epithelial integrins with special reference to oral epithelia. J. Dental Res. 90(12), 1367–1376 (2011).
- 148 . The influence of elastin-like recombinant polymer on the self-renewing potential of a 3D tissue equivalent derived from human lamina propria fibroblasts and oral epithelial cells. Biomaterials 32(25), 5756–5764 (2011).
- 149 . High-throughput reconstitution of epithelial–mesenchymal interaction in folliculoid microtissues by biomaterial-facilitated self-assembly of dissociated heterotypic adult cells. Biomaterials 31(15), 4341–4352 (2010).
- 150 . Structure and function of basement membranes. Exp. Biol. Med. 232(9), 1121–1129 (2007).
- 151 . Laminin nanofiber meshes that mimic morphological properties and bioactivity of basement membranes. Tissue Eng. C Methods 15(1), 11–21 (2009).
- 152 . Hybrid titanium/biodegradable polymer implants with an hierarchical pore structure as a means to control selective cell movement. PLoS ONE 6(5), e20480 (2011).
- 153 . Approaches to study differentiation and repair of human airway epithelial cells. Methods Mol. Biol. 742, 173–185 (2011).
- 154 Culture of primary ciliary dyskinesia epithelial cells at air–liquid interface can alter ciliary phenotype but remains a robust and informative diagnostic aid. PLoS ONE 9(2), e89675 (2014).
- 155 . Transcriptional profiling of mucociliary differentiation in human airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 37(2), 169–185 (2007).
- 156 . Phenotypic modification of human airway epithelial cells in air–liquid interface culture induced by exposure to the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Ultrastruct. Pathol. 39(2), 104–109 (2015).
- 157 Cell sheet engineering: recreating tissues without biodegradable scaffolds. Biomaterials 26(33), 6415–6422 (2005).
- 158 . Nanostructured designs of biomedical materials: applications of cell sheet engineering to functional regenerative tissues and organs. J. Control. Release 101(1–3), 69–84 (2005).
- 159 Cell delivery in regenerative medicine: the cell sheet engineering approach. J. Control. Release 116(2), 193–203 (2006).•• Important study describing epithelial cell sheets for engineering bioartificial trachea.
- 160 . Cell sheets engineering for esophageal regenerative medicine. Ann. Transl. Med. 2(3), 28 (2014).
- 161 Carrier-free cultured autologous oral mucosa epithelial cell sheet (CAOMECS) for corneal epithelium reconstruction: a histological study. Ocul. Surf. 13(2), 150–163 (2015).
- 162 Autologous human nasal epithelial cell sheet using temperature-responsive culture insert for transplantation after middle ear surgery. J. Tissue Eng. Regen. Med.
doi:10.1002/term.2012 (2015) (Epub ahead of print). - 163 Clinical transplantation of a tissue-engineered airway. Lancet 372(9655), 2023–2030 (2008).•• The first report for clinical application of a successful, stem cell-based tissue-engineered tracheal transplantation in humans.
- 164 The first tissue-engineered airway transplantation: 5-year follow-up results. Lancet 383(9913), 238–244 (2014).•• Five years follow-up of the first tissue-engineered airway transplantation.
- 165 Regenerative medicine of the trachea: the first human case. Ann. Otol. Rhinol. Laryngol. 114(6), 429–433 (2005).
- 166 Clinical application of in situ tissue engineering using a scaffolding technique for reconstruction of the larynx and trachea. Ann. Otol. Rhinol. Laryngol. 117(9), 673–678 (2008).
- 167 Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet 380(9846), 994–1000 (2012).•• An important clinical report of the first tissue-engineered tracheal replacement in the pediatric patient.
- 168 Tissue-engineered tracheal replacement in a child: a 4-year follow-up study. Am. J. Transplant.
doi: 10.1111/ajt.13318 (2015) (Epub ahead of print).•• Four-year follow up of the first pediatric patient who received tissue-engineered tracheal replacement. - 169 First human transplantation of a bioengineered airway tissue. J. Thorac. Cardiovasc. Surg. 128(4), 638–641 (2004).
- 170 . Pumpless extracorporeal gas exchange aiding central airway surgery. J. Thorac. Cardiovasc. Surg. 136(5), 1372–1374 (2008).

