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How to build a lung: latest advances and emerging themes in lung bioengineering

Martina M. De Santis, Deniz A. Bölükbas, Sandra Lindstedt, Darcy E. Wagner
European Respiratory Journal 2018 52: 1601355; DOI: 10.1183/13993003.01355-2016
Martina M. De Santis
1Lung Bioengineering and Regeneration, Dept of Experimental Medical Sciences, Lund University, Lund, Sweden
2Lung Repair and Regeneration (LRR), Comprehensive Pneumology Center (CPC), Helmholtz Zentrum Munich, Member of the German Center for Lung Research (DZL), Munich, Germany
3Stem Cell Centre, Lund University, Lund, Sweden
4Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
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  • ORCID record for Martina M. De Santis
Deniz A. Bölükbas
1Lung Bioengineering and Regeneration, Dept of Experimental Medical Sciences, Lund University, Lund, Sweden
3Stem Cell Centre, Lund University, Lund, Sweden
4Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
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Sandra Lindstedt
4Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
5Dept of Cardiothoracic Surgery, Heart and Lung Transplantation, Lund University Hospital, Lund, Sweden
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Darcy E. Wagner
1Lung Bioengineering and Regeneration, Dept of Experimental Medical Sciences, Lund University, Lund, Sweden
2Lung Repair and Regeneration (LRR), Comprehensive Pneumology Center (CPC), Helmholtz Zentrum Munich, Member of the German Center for Lung Research (DZL), Munich, Germany
3Stem Cell Centre, Lund University, Lund, Sweden
4Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
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  • ORCID record for Darcy E. Wagner
  • For correspondence: darcy.wagner@med.lu.se
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  • FIGURE 1
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    FIGURE 1

    Lung bioengineering approaches. In most approaches, a lung scaffold is seeded with autologous or allogeneic cells for bioengineering a lung. The cells can be expanded to appropriate numbers in bioreactors for cell expansion. Different lung scaffolds have been explored, including decellularised scaffolds and synthetic scaffolds. An emerging idea is the use of hybrid scaffolds that combine biological materials such as extracellular matrix (ECM) components with synthetic scaffolds in order to create a hybrid lung scaffold. Bioreactors for organ culture can then be used to mature and evaluate the repopulated lung scaffold before lung transplantation.

  • FIGURE 2
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    FIGURE 2

    Recapitulating the complexity of the lung architecture from proximal (trachea) to distal (bronchi and alveoli): haematoxylin/eosin (HE; left column) staining histology, transmission electron microscopy (TEM; centre column) and scanning electron microscopy (SEM; right column) images from proximal and distal native lung tissue. The lung architecture varies dramatically within the lung: moving from proximal to distal, the resolution required to mimic the native structures is higher (centimetres (cm)→micrometres (μm)→nanometres (nm)). To date, biological scaffolds are the only scaffolds that have a resolution that mimics that of the native lung across all length scales. The bronchi TEM micrograph of a thin section of the mucous membrane of a small human bronchus shows a ciliated cell (CC) with cilia (C) and microvilli, a goblet cell (GC) with an apical mucous plug (MU), basal cell (BC), fibres and fibroblasts (FB) in connective tissue and macrophages (MP). The bronchi SEM micrograph of the epithelial surface shows ciliary tufts (C) and a mucous plug (MU) of a goblet cell in the process of extrusion. The distal lung TEM and SEM micrographs of the structure of the alveolar septum in human lungs show a septal fibroblast (FB), capillary endothelium (EN), alveolar epithelium (EP) and fibre strands (F). HE histology scale bars: 100 µm; bronchi TEM scale bar: 5 µm; bronchi SEM scale bar: 10 µm; distal lung TEM scale bar: 2 µm; distal lung SEM scale bar: 10 µm. Electron microscopy images reproduced and modified from [129, 130] with permission.

Tables

  • Figures
  • TABLE 1

    Challenges within the field of ex vivo lung tissue engineering

    AreaFocus for future research/future perspectives
    Scaffold sourceCan a suitable acellular xenograft source be identified?
    Can allogeneic human scaffolds be used?
    Does the age (neonatal or aged) of the scaffold impact the biomaterial?
    Evaluate immunogenicity of scaffold with and without cells.
    Cell sourcesAre all of the more than 40 cell types found within the lung required to make a functional lung?
    Can allogeneic cells be used or do we need to use autologous cells?
    Where will we source cells for patients with chronic or genetic lung diseases?
    What types of cell sources can be used (e.g. endogenous progenitor cells, induced pluripotent stem cells)?
    ManufacturingWhich Good Manufacturing Practice manufacturing method will be suitable for scaffold generation, storage and maturation?
    Which standardised approaches for the characterisation and validation of the scaffold will be required?
    How can we obtain enough cells to recellularise and how will they be re-introduced into the scaffold?
    Will bioengineered lungs need to be tailored for patients with specific lung diseases (e.g. the main lung transplant recipients (chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, cystic fibrosis and α1-antitrypsin deficiency)).
    MaturationWill different bioreactors be needed for the different cell types in the lung?
    What time span and/or maturation level will be required?
    What degree of vascularisation of the scaffold will be required?
    Surgical and clinical approachHow will we assess the functionality prior to transplantation?
    Will ex vivo lung perfusion parameters be enough to predict success?
    What surgical techniques could be used for pieces of bioengineered lung tissue?
    Will special post-operative care be required?
    Will the patients need to be immunosuppressed?
  • TABLE 2

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

    YearMaterialMethodScaffoldSignificant advanceEnd-pointsReference
    Synthetic 
     2006Polyglycolic acid and pluronic F-127 hydrogelMicrofabrication techniquesAlveoli-like structuresGrowth of lung progenitor cells on a synthetic scaffold and transplantedIn vitro,
    in vivo
    [79]
     2006Poly-dl-lactic acidMicrofilm templates and 3D foamAlveoli-like structuresAlveolar epithelial cells can be grown on porous synthetic materialsIn vitro[120]
     2012Decorin-containing matricesElectrospinningTracheaElectrospinning decorin matrices for a tissue-engineered tracheaIn vitro[73]
     2013Hydroxyethyl methacrylate–alginate–gelatine cryogelCryogelationAlveoli-like structuresMacroporous matrix with ability to recruit cells when implanted in vivoIn vitro,
    in vivo
    [84]
     2014Gelatine/microbubble scaffoldMicrofluidicsAlveoli-like structuresDifferentiation of lung stem/progenitor cells into alveolar pneumocytes and induction of angiogenesis within a manufactured scaffoldIn vitro,
    in vivo
    [82]
     2015Polyethylene glycol-based hydrogelMicrosphere templatesAlveoli-like structuresCytocompatible manufacturing method for co-culture of alveoli-like structuresIn vitro[86]
     2016POSS-PCU (polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane)Dispersion of porogensTracheaUse of engineered pores to improve integration capacity of a synthetic scaffoldIn vitro,
    in vivo
    [72]
     2017Alginate beadsAlginate beadsAlveoli-like structuresSelf-assembled alveoli-like structures with human cellsIn vitro[87]
     2018Matrix metalloproteinase-degradable polyethylene glycol-based hydrogelMicrosphere templatesAlveoli-like structuresControlled degradation with specific matrix metalloproteinase-cleavable sites in alveolar-like structuresIn vitro[85]
    Acellular
     1981Alveolar basement membrane (various origins)DecellularisationAlveolar basement membraneFirst decellularisation attempt to obtain alveolar basement membraneIn vitro[121]
     1986Human alveolar and amniotic matrixDecellularisationAcellular alveolar versus amniotic basement membranesFirst repopulation experiment on acellular lung tissue; differentiation on various basement membranesIn vitro[122]
     2010Rat lungDecellularisationRat acellular lungOrthotopic transplantationIn vitro,
    in vivo
    [68]
     2010Rat lungDecellularisationRat acellular lungOrthotopic transplantation and first report of decellularisation of human lungIn vitro,
    in vivo
    [48]
     2011Rat lung and liverDecellularisationRat acellular lung and liverCellular differentiation on the scaffoldsIn vitro[123]
     2012Mouse lungDecellularisationMouse acellular lung and slicesComparison of different detergent-based protocols for mouse lung de- and recellularisationIn vitro[52]
     2012Human lungDecellularisationHuman acellular lung and slicesDe- and recellularisation of human normal and fibrotic lungsIn vitro[49]
     2013Human and porcine lungDecellularisationHuman and porcine lung and slicesDe- and recellularisation of human and porcine lungsIn vitro[33]
     2013Mouse lungDecellularisationMouse acellular lung and slicesEffects of age and emphysematous and fibrotic injury on murine recellularisationIn vitro[124]
     2013Mouse lungDecellularisationMouse acellular lung and slicesEffects of storage and sterilisation on de- and recellularised whole lungIn vitro[42]
     2014Human and porcine lungDecellularisation3D lung segmentsSmall segments to retain 3D lung structure in acellular scaffolds from large animals and human origin for physiological recellularisationIn vitro[24]
     2014Rat and human lungDecellularisationRat and human acellular lungTransplant of iPSC-derived re-epithelialised and re-endothelialised scaffoldIn vitro,
    in vivo
    [51]
     2015Rat and human lungDecellularisationRat and human acellular lungRegeneration of functional pulmonary vasculatureIn vitro,
    in vivo
    [65]
     2016Porcine lungDecellularisationPorcine lung extracellular matrix hydrogelFirst extracellular matrix hydrogel derived from acellular lungIn vitro,
    in vivo
    [125]
     2016Porcine lung: wild-type and α1,3-galactosyltransferase knockoutDecellularisationPorcine lungComparison of de- and recellularisation of wild-type and α1,3-galactosyltransferase knockout pig lungs; identification of residual immunogens in wild-type lungsIn vitro[25]
     2017Porcine lungDecellularisationPorcine lungOrthotopic transplantation of porcine scaffold recellularised with human cellsIn vitro,
    in vivo
    [35]
    Hybrid
     2006Polylactic-co-glycolic acid, poly-l-lactic acid and Matrigel porous foam and nanofibrous matrixMicrofabrication techniquesAlveoli-like structuresFirst hybrid material attempt for lung tissue engineeringIn vitro[80]
     2008Matrigel plug combined with fibroblast growth factor 2-loaded polyvinyl spongeMicrofabrication techniquesVascularised pulmonary tissue constructsDistal pulmonary epithelial differentiation can be maintained in vivo; donor-derived endothelial cells contribute to the formation of vesselsIn vitro,
    in vivo
    [126]
     2011Lung extract-coated poly-ε-caprolactone nanofibresElectrospinningElectrospun nanofibres coated with lung extracts from fibrotic or nonfibrotic miceEx vivo system to recapitulate the 3D fibrotic lung microenvironmentIn vitro[22]
     2011Collagen–Matrigel/alginate microcapsulesMicrosphere encapsulationAlveoli-like structuresFibroblasts, epithelial cells and alveolar type II form alveolus-like structures in collagen–Matrigel/alginate-poly-l-lysine-alginate microcapsule engineered scaffoldsIn vitro[127]
     2017Poly-ε-caprolactone and decellularised aortaElectrospinning, decellularisationElectrospun poly-ε-caprolactone stents in acellular rabbit aortaHybrid trachea scaffold for tracheal replacementIn vitro,
    in vivo
    [128]
    Cells
     2014Human pluripotent stem cellsNANAFunctional human pluripotent stem cell-derived distal lung epithelial cells seeded onto human scaffoldIn vitro,
    in vivo
    [59]
     2015Human endothelial and perivascular cellsNANARegeneration of functional pulmonary vasculatureIn vitro,
    in vivo
    [65]
     2016Human respiratory epithelial cellsNANAScalable cell culture systemIn vitro,
    in vivo
    [107]
     2016KRT5+TP63+ basal epithelial stem cellsNANARecellularisationIn vitro[64]
     2018Chondrocytes, endothelial cells and mesenchymal stem cells3D bioprintingNoneScaffold-free manufacturing of a rat trachea mimicIn vitro,
    in vivo
    [101]

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

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    How to build a lung: latest advances and emerging themes in lung bioengineering
    Martina M. De Santis, Deniz A. Bölükbas, Sandra Lindstedt, Darcy E. Wagner
    European Respiratory Journal Jul 2018, 52 (1) 1601355; DOI: 10.1183/13993003.01355-2016

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    How to build a lung: latest advances and emerging themes in lung bioengineering
    Martina M. De Santis, Deniz A. Bölükbas, Sandra Lindstedt, Darcy E. Wagner
    European Respiratory Journal Jul 2018, 52 (1) 1601355; DOI: 10.1183/13993003.01355-2016
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    • Article
      • Abstract
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      • Introduction
      • Manufacturing lung scaffolds
      • Acellular lung scaffolds
      • Artificial lung scaffolds
      • Cell types and scaling-up cell culture methods
      • Bioreactor strategies for lung bioengineering
      • Regulatory and ethical implications for translating lung bioengineering approaches
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