title: Healing and remodeling of bioengineered pulmonary artery patches implanted in sheep.
abstract: OBJECTIVE
  We hypothesized that cell-seeded patches implanted into sheep pulmonary artery would undergo progressive and complete healing into a viable structure well integrated with the arterial wall.
  
  
  METHODS
  Autologous ovine blood-derived endothelial progenitor cells (EPCs) and bone marrow-derived mesenchymal stem cells (MSCs) were isolated and cultured in vitro. MSCs and EPCs were seeded onto poly-4-hydroxybutyrate (P4HB)-coated polyglycolic acid (PGA) nonwoven biodegradable mesh scaffolds (10x20 mm) and cultured for 5 days in a laminar fluid flow system. Seeded patches were implanted into the wall of sheep pulmonary artery for 1-2 weeks (n=4) or 4-6 weeks (n=3). Preimplant and postexplant specimens were analyzed by histology and immunohistochemistry.
  
  
  RESULTS
  Unimplanted constructs contained alpha-smooth muscle actin (SMA)-positive cells and early extracellular matrix formation (primarily glycosaminoglycans). One week after implantation, seeded patches had surface thrombus formation and macrophage infiltration. Seeded patches implanted for 2 weeks showed granulation tissue, early pannus formation, macrophages, foreign body giant cells around disintegrating polymer, and early angiogenesis (microvessel formation). After 4 weeks in vivo, seeded patches contained glycosaminoglycans, collagen, and coverage of the luminal surface by host artery-derived pannus containing alpha-SMA-positive cells and laminated elastin; polymer scaffold degradation was almost complete with replacement by fibrous tissue containing viable cells.
  
  
  CONCLUSIONS
  This study shows that cell-seeded patches implanted in sheep pulmonary artery remodel to layered and viable tissue well integrated into the native arterial wall. The key remodeling processes included (1) intimal overgrowth at the luminal surface (pannus formation; neointima) and (2) granulation tissue formation and fibrosis with foreign body reaction.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Mendelson
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
authors.forename: Bret A
authors.initials: BA
authors.lastname: Mettler
authors.forename: Virna
authors.initials: V
authors.lastname: Sales
authors.forename: David
authors.initials: D
authors.lastname: Martin
authors.forename: John E
authors.initials: JE
authors.lastname: Mayer
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Schoen
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D001807:Blood Vessel Prosthesis; D019917:Blood Vessel Prosthesis Implantation / Q000295:instrumentation*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000637:transplantation*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D005549:Foreign-Body Reaction / Q000378:metabolism / Q000473:pathology; D006097:Granulation Tissue / Q000378:metabolism / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D011091:Polyesters / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D011474:Prosthesis Design; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D012756:Sheep; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors; D023822:Tissue Engineering; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing
chemical_list: D001672:Biocompatible Materials; D016326:Extracellular Matrix Proteins; D011091:Polyesters; C107955:poly(4-hydroxybutanoate); D011100:Polyglycolic Acid