title: Directed oxygen gradients initiate a robust early remodeling response in engineered vascular grafts.
abstract: Whereas functionally different, both organogenesis and wound-healing processes create zones or regions of hypoxia that persist until capillary networks are formed to facilitate oxygen and nutrient delivery. Similarly, regenerative processes within in vitro engineered tissues experience the same hypoxic regions, but without the capacity to form functional capillaries resulting in a major limitation in developing full-thickness organs and tissues. Due to the importance of oxygen in wound healing and tissue regeneration, we hypothesize that directed oxygen gradients can be used to modulate cell function and promote more effective tissue regeneration. The effect of controlled oxygen gradients on human smooth muscle cells (SMCs) was assessed using dual chambered perfusion bioreactors to regulate transport conditions occurring in a model vascular construct. SMCs were seeded onto the ablumenal surface of the scaffold and cultured for 21 days under 3 independent gas environments: (1) 21% oxygen, (2) 11% oxygen, or (3) an ablumen to lumen oxygen gradient from 11% to 21%. When compared to 21% oxygen and 11% oxygen conditions, the directed 11%-21% oxygen gradient resulted in a raised metabolic activity and significantly improved cell migration. After 21 days from seeding, cells were shown to migrate entirely across the scaffold to the vessel lumen (>450 μm). Concomitant with a more uniform cell dispersion, scaffold mechanics were significantly enhanced with increased stiffness and tensile strength. Native oxygen gradients are known to play a pivotal role during organ development; these results show that directed oxygen gradients within in vitro systems can be used to facilitate early remodeling leading to significantly enhanced cell migration and scaffold biomechanics.
authors.affiliation: J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida 32611-6131, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Moore
authors.forename: Ruben
authors.initials: R
authors.lastname: Moore
authors.forename: Peter S
authors.initials: PS
authors.lastname: McFetridge
mesh_terms: D019149:Bioreactors; D001807:Blood Vessel Prosthesis; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D010100:Oxygen / Q000737:chemistry*; D013718:Tensile Strength; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry
chemical_list: D010100:Oxygen
references.citation: Nat Med. 2003 Jun;9(6):677-84
references.pmid: 12778166
references.citation: J Physiol. 1919 May 20;52(6):409-15
references.pmid: 16993405
references.citation: Biotechnol Bioeng. 2009 Aug 1;103(5):1003-15
references.pmid: 19422037
references.citation: Annu Rev Immunol. 1998;16:137-61
references.pmid: 9597127
references.citation: Can J Biochem Physiol. 1957 Aug;35(8):681-90
references.pmid: 13460788
references.citation: ASAIO J. 2005 May-Jun;51(3):252-61
references.pmid: 15968956
references.citation: Cell Metab. 2005 Jun;1(6):401-8
references.pmid: 16054089
references.citation: Stem Cells. 2003;21(3):337-47
references.pmid: 12743328
references.citation: Physiol Rev. 2003 Jul;83(3):933-63
references.pmid: 12843412
references.citation: J Vasc Surg. 2011 Nov;54(5):1451-60
references.pmid: 21872418
references.citation: Tissue Eng Part C Methods. 2012 Nov;18(11):903-12
references.pmid: 22616610
references.citation: Eur J Vasc Endovasc Surg. 2010 Jun;39(6):700-7
references.pmid: 20346708
references.citation: Tissue Eng Part A. 2009 Sep;15(9):2423-34
references.pmid: 19292659
references.citation: Biotechnol Bioeng. 2003 May 5;82(3):253-62
references.pmid: 12599251
references.citation: Circ Res. 1970 Nov;27(5):669-78
references.pmid: 5486243
references.citation: Circulation. 1999 Apr 20;99(15):2019-26
references.pmid: 10209007
references.citation: J Biomed Mater Res. 1999 Oct;47(1):65-70
references.pmid: 10400882
references.citation: J Cell Physiol. 2002 Apr;191(1):42-50
references.pmid: 11920680
references.citation: Acta Physiol (Oxf). 2011 Jul;202(3):311-22
references.pmid: 21281453
references.citation: Tissue Eng Part A. 2011 Jun;17(11-12):1583-93
references.pmid: 21303226
references.citation: N Engl J Med. 1994 Nov 10;331(19):1286-92
references.pmid: 7935686
references.citation: Development. 2003 Oct;130(20):4769-84
references.pmid: 12952899
references.citation: Life Sci. 2002 Nov 15;71(26):3031-45
references.pmid: 12408871
references.citation: Artif Organs. 2008 Sep;32(9):735-42
references.pmid: 18684203
references.citation: Am J Physiol Cell Physiol. 2011 Mar;300(3):C385-93
references.pmid: 21123733
references.citation: J Biomed Mater Res A. 2012 Aug;100(8):2194-203
references.pmid: 22623220
references.citation: Biotechnol Bioeng. 2006 Feb 5;93(2):332-43
references.pmid: 16270298
references.citation: Biomaterials. 2005 Dec;26(35):7481-503
references.pmid: 16023202
references.citation: Circulation. 2009 Jan 20;119(2):290-7
references.pmid: 19118259
references.citation: Biomaterials. 2002 Sep;23(17):3717-31
references.pmid: 12109697