title: Aligned-Braided Nanofibrillar Scaffold with Endothelial Cells Enhances Arteriogenesis.
abstract: The objective of this study was to enhance the angiogenic capacity of endothelial cells (ECs) using nanoscale signaling cues from aligned nanofibrillar scaffolds in the setting of tissue ischemia. Thread-like nanofibrillar scaffolds with porous structure were fabricated from aligned-braided membranes generated under shear from liquid crystal collagen solution. Human ECs showed greater outgrowth from aligned scaffolds than from nonpatterned scaffolds. Integrin α1 was in part responsible for the enhanced cellular outgrowth on aligned nanofibrillar scaffolds, as the effect was abrogated by integrin α1 inhibition. To test the efficacy of EC-seeded aligned nanofibrillar scaffolds in improving neovascularization in vivo, the ischemic limbs of mice were treated with EC-seeded aligned nanofibrillar scaffold; EC-seeded nonpatterned scaffold; ECs in saline; aligned nanofibrillar scaffold alone; or no treatment. After 14 days, laser Doppler blood spectroscopy demonstrated significant improvement in blood perfusion recovery when treated with EC-seeded aligned nanofibrillar scaffolds, in comparison to ECs in saline or no treatment. In ischemic hindlimbs treated with scaffolds seeded with human ECs derived from induced pluripotent stem cells (iPSC-ECs), single-walled carbon nanotube (SWNT) fluorophores were systemically delivered to quantify microvascular density after 28 days. Near infrared-II (NIR-II, 1000-1700 nm) imaging of SWNT fluorophores demonstrated that iPSC-EC-seeded aligned scaffolds group showed significantly higher microvascular density than the saline or cells groups. These data suggest that treatment with EC-seeded aligned nanofibrillar scaffolds improved blood perfusion and arteriogenesis, when compared to treatment with cells alone or scaffold alone, and have important implications in the design of therapeutic cell delivery strategies.
authors.affiliation: †Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, United States.|‡Stanford Cardiovascular Institute, Stanford University, Stanford, California 94305, United States.
authors.forename: Karina H
authors.initials: KH
authors.lastname: Nakayama
authors.affiliation: ‡Stanford Cardiovascular Institute, Stanford University, Stanford, California 94305, United States.|§Department of Chemistry, Stanford University, Stanford, California 94305, United States.
authors.forename: Guosong
authors.initials: G
authors.lastname: Hong
authors.affiliation: ‡Stanford Cardiovascular Institute, Stanford University, Stanford, California 94305, United States.
authors.forename: Jerry C
authors.initials: JC
authors.lastname: Lee
authors.affiliation: ⊥Department of Cardiothoracic Surgery, Stanford University, Stanford, California 94305, United States.
authors.forename: Jay
authors.initials: J
authors.lastname: Patel
authors.affiliation: ⊥Department of Cardiothoracic Surgery, Stanford University, Stanford, California 94305, United States.
authors.forename: Bryan
authors.initials: B
authors.lastname: Edwards
authors.affiliation: ∥Fibralign Corporation, Union City, California 94587, United States.
authors.forename: Tatiana S
authors.initials: TS
authors.lastname: Zaitseva
authors.affiliation: ∥Fibralign Corporation, Union City, California 94587, United States.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Paukshto
authors.affiliation: ‡Stanford Cardiovascular Institute, Stanford University, Stanford, California 94305, United States.|§Department of Chemistry, Stanford University, Stanford, California 94305, United States.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Dai
authors.affiliation: #Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, Texas 77030, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
authors.affiliation: ‡Stanford Cardiovascular Institute, Stanford University, Stanford, California 94305, United States.|⊥Department of Cardiothoracic Surgery, Stanford University, Stanford, California 94305, United States.
authors.forename: Y Joseph
authors.initials: YJ
authors.lastname: Woo
authors.affiliation: †Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, United States.|‡Stanford Cardiovascular Institute, Stanford University, Stanford, California 94305, United States.|⊥Department of Cardiothoracic Surgery, Stanford University, Stanford, California 94305, United States.
authors.forename: Ngan F
authors.initials: NF
authors.lastname: Huang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D066026:Endothelial Progenitor Cells / Q000166:cytology* / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply / Q000601:surgery; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D037742:Nanotubes, Carbon; D018919:Neovascularization, Physiologic; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D037742:Nanotubes, Carbon
keywords: angiogenesis; carbon nanotube; induced pluripotent stem cell; ischemia; nanofibrillar; peripheral arterial disease