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@PHDTHESIS{Lngen:855981,
      author       = {Lüngen, Anja Elisabeth},
      othercontributors = {Jockenhövel, Stefan and Cornelissen, Christian Gabriel},
      title        = {{R}espiratorisches {T}issue {E}ngineering : {E}ntwicklung
                      eines respiratorischen {M}ukosa-Äquivalents},
      school       = {Rheinisch-Westfälische Technische Hochschule Aachen},
      type         = {Dissertation},
      address      = {Aachen},
      reportid     = {RWTH-2022-10579},
      pages        = {54 Seiten : Illustrationen, Diagramme},
      year         = {2022},
      note         = {Dissertation, Rheinisch-Westfälische Technische Hochschule
                      Aachen, 2022, Kumulative Dissertation},
      abstract     = {Patients diagnosed with irresectable airway stenosis caused
                      by long-term intubation, tracheostomy or lung cancer often
                      face limited therapeutic options and low quality of life. So
                      far, an optimal airway replacement strategy does not exist,
                      leaving an unmet clinical need in the treatment of patients
                      with advanced airway obstruction. In the future, a
                      tissue-engineered substitute could compensate this shortfall
                      by overcoming limitations with regard to mechanical
                      stability, functional mucociliary clearance and proper
                      implant vascularization. However, to prevent complications
                      like inflammation, necrosis and infection, a mature vascular
                      network and a protective mucociliated respiratory epithelium
                      are crucial for any tissue-engineered airwaygraft. In this
                      thesis, the optimal in vitro differentiation conditions in
                      terms of nutrition medium demand for respiratory epithelial
                      cells were initially investigated. This was followed by the
                      evaluation of a fibrin-based in vitro tri-culture model of
                      the respiratory mucosa, consisting of different mesenchymal
                      stromal cells, respiratory epithelial cells and human
                      umbilical veinendothelial cells. The first study compared
                      differentiation behavior of primary human respiratory
                      epithelial cells in four separate differentiation media.
                      Mucociliary differentiation was analyzed after cultivating
                      the cells at the air-liquid interface for four weeks.
                      Electron microscopy, histology and immunohistochemical
                      staining revealed that a retinoic-acid-supplemented mixture
                      most likelyled to a mucociliary phenotype in vitro.
                      Furthermore, enzyme-linked immunosorbent assay results
                      highlighted the importance of a balance in concentrations of
                      retinoic acid, vascularendothelial growth factor, epidermal
                      growth factor and fibroblast growth factor β for the
                      differentiation outcome. On the other hand, low levels of
                      these growth factors in mediasupernatants correlated with
                      absent ciliation in epithelial cells. In the second study,
                      different supporting cell types were compared with regard to
                      their ability to promote mucociliary differentiation of
                      respiratory epithelial cells and vascularization mediated by
                      human umbilical vein endothelial cells in a fibrin-based
                      tri-culture. In addition to the tri-cultures cultivated for
                      four weeks at the air-liquid interface, co-cultures of the
                      threes upporting cell types with either epithelial cells or
                      endothelial cells were used as controls. Tricultures with
                      bone-marrow derived mesenchymal stromal cells as supporting
                      cell type most closely resembled the native respiratory
                      mucosa with regard to ciliation, mucus production and
                      expression of epithelial cell markers. This was followed by
                      human nasal fibroblasts as supporting cell type, while
                      adipose-derived mesenchymal stromal cells did not
                      promoteciliation. Vascularization was comparable between
                      tri-cultures, although more branched andextended
                      vascular-like structures were found in tri-cultures with
                      bone-marrow derived cells. Concentrations of pro-angiogenic
                      and inflammatory cytokines revealed to be reduced in
                      tricultures compared to co-cultures. The results described
                      in this work contribute to an enhanced standardization of
                      the in vitroculture of respiratory epithelial cells and give
                      valuable insight in cell-cell interactions of the
                      respiratory mucosa. Moreover, these studies represent an
                      important step towards a ciliated and vascularized
                      tissue-engineered airway replacement.},
      cin          = {923510 / 923810},
      ddc          = {610},
      cid          = {$I:(DE-82)811001-1_20140620$ / $I:(DE-82)923820_20191118$},
      typ          = {PUB:(DE-HGF)11},
      url          = {https://publications.rwth-aachen.de/record/855981},
}