title: Fluid Flow Regulation of Revascularization and Cellular Organization in a Bioengineered Liver Platform.
abstract: OBJECTIVE
  Modeling of human liver development, especially cellular organization and the mechanisms underlying it, is fundamental for studying liver organogenesis and congenital diseases, yet there are no reliable models that mimic these processes ex vivo.
  
  
  METHODS
  Using an organ engineering approach and relevant cell lines, we designed a perfusion system that delivers discrete mechanical forces inside an acellular liver extracellular matrix scaffold to study the effects of mechanical stimulation in hepatic tissue organization.
  
  
  RESULTS
  We observed a fluid flow rate-dependent response in cell distribution within the liver scaffold. Next, we determined the role of nitric oxide (NO) as a mediator of fluid flow effects on endothelial cells. We observed impairment of both neovascularization and liver tissue organization in the presence of selective inhibition of endothelial NO synthase. Similar results were observed in bioengineered livers grown under static conditions.
  
  
  CONCLUSIONS
  Overall, we were able to unveil the potential central role of discrete mechanical stimulation through the NO pathway in the revascularization and cellular organization of a bioengineered liver. Last, we propose that this organ bioengineering platform can contribute significantly to the identification of physiological mechanisms of liver organogenesis and regeneration and improve our ability to bioengineer livers for transplantation.
authors.affiliation: 1 Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences , Winston-Salem, North Carolina.|2 University of Zaragoza , Zaragoza, Spain .|3 IIS Aragón , CIBERehd, Zaragoza, Spain .|4 Aragon Health Sciences Institute (IACS) , Zaragoza, Spain .
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Baptista
authors.affiliation: 1 Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences , Winston-Salem, North Carolina.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Moran
authors.affiliation: 1 Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences , Winston-Salem, North Carolina.
authors.forename: Dipen
authors.initials: D
authors.lastname: Vyas
authors.affiliation: 5 Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), University of Lisbon , Lisbon, Portugal .
authors.forename: Maria H
authors.initials: MH
authors.lastname: Ribeiro
authors.affiliation: 1 Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences , Winston-Salem, North Carolina.
authors.forename: Anthony
authors.initials: A
authors.lastname: Atala
authors.affiliation: 6 Department of Chemical, Paper and Biomedical Engineering, Miami University , Oxford, Ohio.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Sparks
authors.affiliation: 1 Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences , Winston-Salem, North Carolina.
authors.forename: Shay
authors.initials: S
authors.lastname: Soker
mesh_terms: D000818:Animals; D057005:Bioengineering / Q000379:methods*; D019149:Bioreactors; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D005109:Extracellular Matrix / Q000378:metabolism; D005289:Ferrets; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism; D010477:Perfusion; D010641:Phenotype; D051381:Rats; D012212:Rheology; D013314:Stress, Mechanical
chemical_list: D009569:Nitric Oxide