title: Human Vascular Microphysiological System for in vitro Drug Screening.
abstract: In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs with 400-800 μM diameters were made by embedding human neonatal dermal fibroblasts or human bone marrow-derived mesenchymal stem cells in dense collagen gel. TEBVs were mechanically strong enough to allow endothelialization and perfusion at physiological shear stresses within 3 hours after fabrication. After 1 week of perfusion, TEBVs exhibited endothelial release of nitric oxide, phenylephrine-induced vasoconstriction, and acetylcholine-induced vasodilation, all of which were maintained up to 5 weeks in culture. Vasodilation was blocked with the addition of the nitric oxide synthase inhibitor L-N(G)-Nitroarginine methyl ester (L-NAME). TEBVs elicited reversible activation to acute inflammatory stimulation by TNF-α which had a transient effect upon acetylcholine-induced relaxation, and exhibited dose-dependent vasodilation in response to caffeine and theophylline. Treatment of TEBVs with 1 μM lovastatin for three days prior to addition of Tumor necrosis factor - α (TNF-α) blocked the injury response and maintained vasodilation. These results indicate the potential to develop a rapidly-producible, endothelialized TEBV for microphysiological systems capable of producing physiological responses to both pharmaceutical and immunological stimuli.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27708.
authors.forename: C E
authors.initials: CE
authors.lastname: Fernandez
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27708.
authors.forename: R W
authors.initials: RW
authors.lastname: Yen
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27708.
authors.forename: S M
authors.initials: SM
authors.lastname: Perez
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27708.
authors.forename: H W
authors.initials: HW
authors.lastname: Bedell
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27708.
authors.forename: T J
authors.initials: TJ
authors.lastname: Povsic
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27708.
authors.forename: W M
authors.initials: WM
authors.lastname: Reichert
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27708.
authors.forename: G A
authors.initials: GA
authors.lastname: Truskey
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005347:Fibroblasts / Q000166:cytology*; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D023822:Tissue Engineering; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D010656:Phenylephrine; D009569:Nitric Oxide; D008148:Lovastatin; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester