TABLE 2

Compilation of studies of breakthrough advances within the field of ex vivo lung tissue engineering

Year	Material	Method	Scaffold	Significant advance	End-points	Reference
Synthetic
2006	Polyglycolic acid and pluronic F-127 hydrogel	Microfabrication techniques	Alveoli-like structures	Growth of lung progenitor cells on a synthetic scaffold and transplanted	In vitro, in vivo	[79]
2006	Poly-dl-lactic acid	Microfilm templates and 3D foam	Alveoli-like structures	Alveolar epithelial cells can be grown on porous synthetic materials	In vitro	[120]
2012	Decorin-containing matrices	Electrospinning	Trachea	Electrospinning decorin matrices for a tissue-engineered trachea	In vitro	[73]
2013	Hydroxyethyl methacrylate–alginate–gelatine cryogel	Cryogelation	Alveoli-like structures	Macroporous matrix with ability to recruit cells when implanted in vivo	In vitro, in vivo	[84]
2014	Gelatine/microbubble scaffold	Microfluidics	Alveoli-like structures	Differentiation of lung stem/progenitor cells into alveolar pneumocytes and induction of angiogenesis within a manufactured scaffold	In vitro, in vivo	[82]
2015	Polyethylene glycol-based hydrogel	Microsphere templates	Alveoli-like structures	Cytocompatible manufacturing method for co-culture of alveoli-like structures	In vitro	[86]
2016	POSS-PCU (polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane)	Dispersion of porogens	Trachea	Use of engineered pores to improve integration capacity of a synthetic scaffold	In vitro, in vivo	[72]
2017	Alginate beads	Alginate beads	Alveoli-like structures	Self-assembled alveoli-like structures with human cells	In vitro	[87]
2018	Matrix metalloproteinase-degradable polyethylene glycol-based hydrogel	Microsphere templates	Alveoli-like structures	Controlled degradation with specific matrix metalloproteinase-cleavable sites in alveolar-like structures	In vitro	[85]
Acellular
1981	Alveolar basement membrane (various origins)	Decellularisation	Alveolar basement membrane	First decellularisation attempt to obtain alveolar basement membrane	In vitro	[121]
1986	Human alveolar and amniotic matrix	Decellularisation	Acellular alveolar versus amniotic basement membranes	First repopulation experiment on acellular lung tissue; differentiation on various basement membranes	In vitro	[122]
2010	Rat lung	Decellularisation	Rat acellular lung	Orthotopic transplantation	In vitro, in vivo	[68]
2010	Rat lung	Decellularisation	Rat acellular lung	Orthotopic transplantation and first report of decellularisation of human lung	In vitro, in vivo	[48]
2011	Rat lung and liver	Decellularisation	Rat acellular lung and liver	Cellular differentiation on the scaffolds	In vitro	[123]
2012	Mouse lung	Decellularisation	Mouse acellular lung and slices	Comparison of different detergent-based protocols for mouse lung de- and recellularisation	In vitro	[52]
2012	Human lung	Decellularisation	Human acellular lung and slices	De- and recellularisation of human normal and fibrotic lungs	In vitro	[49]
2013	Human and porcine lung	Decellularisation	Human and porcine lung and slices	De- and recellularisation of human and porcine lungs	In vitro	[33]
2013	Mouse lung	Decellularisation	Mouse acellular lung and slices	Effects of age and emphysematous and fibrotic injury on murine recellularisation	In vitro	[124]
2013	Mouse lung	Decellularisation	Mouse acellular lung and slices	Effects of storage and sterilisation on de- and recellularised whole lung	In vitro	[42]
2014	Human and porcine lung	Decellularisation	3D lung segments	Small segments to retain 3D lung structure in acellular scaffolds from large animals and human origin for physiological recellularisation	In vitro	[24]
2014	Rat and human lung	Decellularisation	Rat and human acellular lung	Transplant of iPSC-derived re-epithelialised and re-endothelialised scaffold	In vitro, in vivo	[51]
2015	Rat and human lung	Decellularisation	Rat and human acellular lung	Regeneration of functional pulmonary vasculature	In vitro, in vivo	[65]
2016	Porcine lung	Decellularisation	Porcine lung extracellular matrix hydrogel	First extracellular matrix hydrogel derived from acellular lung	In vitro, in vivo	[125]
2016	Porcine lung: wild-type and α1,3-galactosyltransferase knockout	Decellularisation	Porcine lung	Comparison of de- and recellularisation of wild-type and α1,3-galactosyltransferase knockout pig lungs; identification of residual immunogens in wild-type lungs	In vitro	[25]
2017	Porcine lung	Decellularisation	Porcine lung	Orthotopic transplantation of porcine scaffold recellularised with human cells	In vitro, in vivo	[35]
Hybrid
2006	Polylactic-co-glycolic acid, poly-l-lactic acid and Matrigel porous foam and nanofibrous matrix	Microfabrication techniques	Alveoli-like structures	First hybrid material attempt for lung tissue engineering	In vitro	[80]
2008	Matrigel plug combined with fibroblast growth factor 2-loaded polyvinyl sponge	Microfabrication techniques	Vascularised pulmonary tissue constructs	Distal pulmonary epithelial differentiation can be maintained in vivo; donor-derived endothelial cells contribute to the formation of vessels	In vitro, in vivo	[126]
2011	Lung extract-coated poly-ε-caprolactone nanofibres	Electrospinning	Electrospun nanofibres coated with lung extracts from fibrotic or nonfibrotic mice	Ex vivo system to recapitulate the 3D fibrotic lung microenvironment	In vitro	[22]
2011	Collagen–Matrigel/alginate microcapsules	Microsphere encapsulation	Alveoli-like structures	Fibroblasts, epithelial cells and alveolar type II form alveolus-like structures in collagen–Matrigel/alginate-poly-l-lysine-alginate microcapsule engineered scaffolds	In vitro	[127]
2017	Poly-ε-caprolactone and decellularised aorta	Electrospinning, decellularisation	Electrospun poly-ε-caprolactone stents in acellular rabbit aorta	Hybrid trachea scaffold for tracheal replacement	In vitro, in vivo	[128]
Cells
2014	Human pluripotent stem cells	NA	NA	Functional human pluripotent stem cell-derived distal lung epithelial cells seeded onto human scaffold	In vitro, in vivo	[59]
2015	Human endothelial and perivascular cells	NA	NA	Regeneration of functional pulmonary vasculature	In vitro, in vivo	[65]
2016	Human respiratory epithelial cells	NA	NA	Scalable cell culture system	In vitro, in vivo	[107]
2016	KRT5⁺TP63⁺ basal epithelial stem cells	NA	NA	Recellularisation	In vitro	[64]
2018	Chondrocytes, endothelial cells and mesenchymal stem cells	3D bioprinting	None	Scaffold-free manufacturing of a rat trachea mimic	In vitro, in vivo	[101]

3D: three-dimensional; iPSC: induced pluripotent stem cell; NA: not applicable.