title: MMP-sensitive PEG diacrylate hydrogels with spatial variations in matrix properties stimulate directional vascular sprout formation.
abstract: The spatial presentation of immobilized extracellular matrix (ECM) cues and matrix mechanical properties play an important role in directed and guided cell behavior and neovascularization. The goal of this work was to explore whether gradients of elastic modulus, immobilized matrix metalloproteinase (MMP)-sensitivity, and YRGDS cell adhesion ligands are capable of directing 3D vascular sprout formation in tissue engineered scaffolds. PEGDA hydrogels were engineered with mechanical and biofunctional gradients using perfusion-based frontal photopolymerization (PBFP). Bulk photopolymerized hydrogels with uniform mechanical properties, degradation, and immobilized biofunctionality served as controls. Gradient hydrogels exhibited an 80.4% decrease in elastic modulus and a 56.2% decrease in immobilized YRGDS. PBFP hydrogels also demonstrated gradients in hydrogel degradation with degradation times ranging from 10-12 hours in the more crosslinked regions to 4-6 hours in less crosslinked regions. An in vitro model of neovascularization, composed of co-culture aggregates of endothelial and smooth muscle cells, was used to evaluate the effect of these gradients on vascular sprout formation. Aggregate invasion in gradient hydrogels occurred bi-directionally with sprout alignment observed in the direction parallel to the gradient while control hydrogels with homogeneous properties resulted in uniform invasion. In PBFP gradient hydrogels, aggregate sprout length was found to be twice as long in the direction parallel to the gradient as compared to the perpendicular direction after three weeks in culture. This directionality was found to be more prominent in gradient regions of increased stiffness, crosslinked MMP-sensitive peptide presentation, and immobilized YRGDS concentration.
authors.affiliation: Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Turturro
authors.forename: Megan C
authors.initials: MC
authors.lastname: Christenson
authors.forename: Jeffery C
authors.initials: JC
authors.lastname: Larson
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Young
authors.forename: Eric M
authors.initials: EM
authors.lastname: Brey
authors.forename: Georgia
authors.initials: G
authors.lastname: Papavasiliou
mesh_terms: D001696:Biomechanical Phenomena; D018929:Cell Culture Techniques; D055119:Elastic Modulus; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D023822:Tissue Engineering; D054457:Tissue Scaffolds
chemical_list: D020100:Hydrogels; D010455:Peptides; C437167:poly(ethylene glycol)diacrylate; D011092:Polyethylene Glycols; D020782:Matrix Metalloproteinases
references.citation: FASEB J. 2007 Dec;21(14):3896-903
references.pmid: 17644610
references.citation: Nat Med. 2000 Apr;6(4):389-95
references.pmid: 10742145
references.citation: Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1978-86
references.pmid: 17644568
references.citation: Acta Biomater. 2011 Aug;7(8):3027-35
references.pmid: 21601017
references.citation: Langmuir. 2004 Jun 22;20(13):5153-6
references.pmid: 15986641
references.citation: Biomaterials. 2010 Oct;31(30):7836-45
references.pmid: 20667588
references.citation: Biomaterials. 2010 May;31(14):3840-7
references.pmid: 20185173
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19771-6
references.pmid: 17179050
references.citation: Exp Cell Res. 2006 Aug 1;312(13):2424-32
references.pmid: 16730349
references.citation: J Biomed Mater Res A. 2004 Mar 15;68(4):704-16
references.pmid: 14986325
references.citation: J Biomed Mater Res A. 2007 Feb;80(2):297-305
references.pmid: 16960833
references.citation: J Cell Biol. 2003 Jun 23;161(6):1163-77
references.pmid: 12810700
references.citation: J Biol Chem. 2008 May 16;283(20):13905-12
references.pmid: 18347025
references.citation: Eur J Cell Biol. 2006 Apr;85(3-4):219-24
references.pmid: 16546564
references.citation: J Biomed Mater Res A. 2010 Jan;92(1):94-102
references.pmid: 19165799
references.citation: Biomacromolecules. 2011 Jan 10;12(1):242-6
references.pmid: 21128597
references.citation: FASEB J. 2003 Dec;17(15):2260-2
references.pmid: 14563693
references.citation: J Appl Physiol (1985). 2007 Feb;102(2):722-34
references.pmid: 17038488
references.citation: J Mater Sci Mater Med. 2012 Apr;23(4):1109-17
references.pmid: 22331376
references.citation: Langmuir. 2007 Oct 23;23(22):11168-73
references.pmid: 17892312
references.citation: Ann Biomed Eng. 2004 Aug;32(8):1100-7
references.pmid: 15446506
references.citation: Nat Rev Mol Cell Biol. 2009 Jan;10(1):21-33
references.pmid: 19197329
references.citation: Cell. 1997 Jan 10;88(1):39-48
references.pmid: 9019403
references.citation: Biomaterials. 2009 Sep;30(26):4318-24
references.pmid: 19500842
references.citation: Tissue Eng Part B Rev. 2008 Dec;14(4):341-66
references.pmid: 18803499
references.citation: Biomaterials. 2005 Jun;26(16):3227-34
references.pmid: 15603817
references.citation: Ann Biomed Eng. 2004 Mar;32(3):407-17
references.pmid: 15095815
references.citation: Biomaterials. 2010 Nov;31(32):8454-64
references.pmid: 20684983
references.citation: J Investig Med. 2010 Oct;58(7):838-44
references.pmid: 20683343
references.citation: J Biomater Sci Polym Ed. 2012;23(7):917-39
references.pmid: 21477459
references.citation: Acta Biomater. 2010 Jul;6(7):2532-9
references.pmid: 20051270
references.citation: Colloids Surf B Biointerfaces. 2009 Sep 1;72(2):230-5
references.pmid: 19419847
references.citation: Biomaterials. 2011 Feb;32(5):1301-10
references.pmid: 21040970
references.citation: FASEB J. 2008 Jun;22(6):1649-59
references.pmid: 18180334
references.citation: J Biomed Mater Res. 1998 Feb;39(2):266-76
references.pmid: 9457557
references.citation: J Biomater Sci Polym Ed. 2009;20(12):1763-79
references.pmid: 19723440
references.citation: Biomaterials. 2001 Nov;22(22):3045-51
references.pmid: 11575479
references.citation: FASEB J. 2001 Feb;15(2):447-57
references.pmid: 11156960
references.citation: Nat Biotechnol. 2001 Jul;19(7):661-7
references.pmid: 11433279
references.citation: Microvasc Res. 2010 Jul;80(1):3-9
references.pmid: 20053366
references.citation: Comb Chem High Throughput Screen. 2009 Jul;12(6):598-603
references.pmid: 19601757
references.citation: J Control Release. 2005 Dec 5;109(1-3):139-48
references.pmid: 16290119
references.citation: Biotechnol Bioeng. 2010 Feb 15;105(3):636-44
references.pmid: 19816965
references.citation: Tissue Eng Part C Methods. 2010 Dec;16(6):1533-42
references.pmid: 20626274