title: Living-engineered valves for transcatheter venous valve repair.
abstract: BACKGROUND
  Chronic venous insufficiency (CVI) represents a major global health problem with increasing prevalence and morbidity. CVI is due to an incompetence of the venous valves, which causes venous reflux and distal venous hypertension. Several studies have focused on the replacement of diseased venous valves using xeno- and allogenic transplants, so far with moderate success due to immunologic and thromboembolic complications. Autologous cell-derived tissue-engineered venous valves (TEVVs) based on fully biodegradable scaffolds could overcome these limitations by providing non-immunogenic, non-thrombogenic constructs with remodeling and growth potential.
  
  
  METHODS
  Tri- and bicuspid venous valves (n=27) based on polyglycolic acid-poly-4-hydroxybutyrate composite scaffolds, integrated into self-expandable nitinol stents, were engineered from autologous ovine bone-marrow-derived mesenchymal stem cells (BM-MSCs) and endothelialized. After in vitro conditioning in a (flow) pulse duplicator system, the TEVVs were crimped (n=18) and experimentally delivered (n=7). The effects of crimping on the tissue-engineered constructs were investigated using histology, immunohistochemistry, scanning electron microscopy, grating interferometry (GI), and planar fluorescence reflectance imaging.
  
  
  RESULTS
  The generated TEVVs showed layered tissue formation with increasing collagen and glycosaminoglycan levels dependent on the duration of in vitro conditioning. After crimping no effects were found on the MSC level in scanning electron microscopy analysis, GI, histology, and extracellular matrix analysis. However, substantial endothelial cell loss was detected after the crimping procedure, which could be reduced by increasing the static conditioning phase.
  
  
  CONCLUSIONS
  Autologous living small-diameter TEVVs can be successfully fabricated from ovine BM-MSCs using a (flow) pulse duplicator conditioning approach. These constructs hold the potential to overcome the limitations of currently used non-autologous replacement materials and may open new therapeutic concepts for the treatment of CVI in the future.
authors.affiliation: 1 Swiss Center for Regenerative Medicine, University Hospital of Zurich , Zurich, Switzerland .
authors.forename: Benedikt
authors.initials: B
authors.lastname: Weber
authors.forename: Jérôme
authors.initials: J
authors.lastname: Robert
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Ksiazek
authors.forename: Yves
authors.initials: Y
authors.lastname: Wyss
authors.forename: Laura
authors.initials: L
authors.lastname: Frese
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Slamecka
authors.forename: Debora
authors.initials: D
authors.lastname: Kehl
authors.forename: Peter
authors.initials: P
authors.lastname: Modregger
authors.forename: Silvia
authors.initials: S
authors.lastname: Peter
authors.forename: Marco
authors.initials: M
authors.lastname: Stampanoni
authors.forename: Steven
authors.initials: S
authors.lastname: Proulx
authors.forename: Volkmar
authors.initials: V
authors.lastname: Falk
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hoerstrup
mesh_terms: D000818:Animals; D001705:Bioprosthesis; D002406:Catheterization, Peripheral / Q000295:instrumentation* / Q000379:methods; D002478:Cells, Cultured; D042783:Endothelial Cells; D019544:Equipment Failure Analysis; D005240:Feasibility Studies; D045164:Mesenchymal Stem Cell Transplantation / Q000295:instrumentation* / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology; D011474:Prosthesis Design; D012756:Sheep; D023822:Tissue Engineering / Q000295:instrumentation; D054457:Tissue Scaffolds; D016896:Treatment Outcome; D062666:Vascular Access Devices; D055422:Venous Valves / Q000166:cytology / Q000254:growth & development* / Q000601:surgery