title: The modulation of endothelial cell morphology, function, and survival using anisotropic nanofibrillar collagen scaffolds.
abstract: Endothelial cells (ECs) are aligned longitudinally under laminar flow, whereas they are polygonal and poorly aligned in regions of disturbed flow. The unaligned ECs in disturbed flow fields manifest altered function and reduced survival that promote lesion formation. We demonstrate that the alignment of the ECs may directly influence their biology, independent of fluid flow. We developed aligned nanofibrillar collagen scaffolds that mimic the structure of collagen bundles in blood vessels, and examined the effects of these materials on EC alignment, function, and in vivo survival. ECs cultured on 30-nm diameter aligned fibrils re-organized their F-actin along the nanofibril direction, and were 50% less adhesive for monocytes than the ECs grown on randomly oriented fibrils. After EC transplantation into both subcutaneous tissue and the ischemic hindlimb, EC viability was enhanced when ECs were cultured and implanted on aligned nanofibrillar scaffolds, in contrast to non-patterned scaffolds. ECs derived from human induced pluripotent stem cells and cultured on aligned scaffolds also persisted for over 28 days, as assessed by bioluminescence imaging, when implanted in ischemic tissue. By contrast, ECs implanted on scaffolds without nanopatterning generated no detectable bioluminescent signal by day 4 in either normal or ischemic tissues. We demonstrate that 30-nm aligned nanofibrillar collagen scaffolds guide cellular organization, modulate endothelial inflammatory response, and enhance cell survival after implantation in normal and ischemic tissues.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA; Center for Tissue Regeneration, Repair and Restoration, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA; The Cardiovascular Institute, Stanford, CA, USA.
authors.forename: Ngan F
authors.initials: NF
authors.lastname: Huang
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Okogbaa
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Jerry C
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Arshi
authors.initials: A
authors.lastname: Jha
authors.affiliation: Fibralign Corp, Sunnyvale, CA, USA.
authors.forename: Tatiana S
authors.initials: TS
authors.lastname: Zaitseva
authors.affiliation: Fibralign Corp, Sunnyvale, CA, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Paukshto
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Sun
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Niraj
authors.initials: N
authors.lastname: Punjya
authors.affiliation: Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Fuller
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA; The Cardiovascular Institute, Stanford, CA, USA. Electronic address: john.cooke@stanford.edu.
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
mesh_terms: D000818:Animals; D016880:Anisotropy; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D003094:Collagen / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000628:therapy; D008297:Male; D008567:Membranes, Artificial; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D057139:Nanofibers / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D010641:Phenotype; D019919:Prosthesis Implantation; D040521:Subcutaneous Tissue / Q000187:drug effects; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D008567:Membranes, Artificial; D003094:Collagen