title: The In Vitro and In Vivo Response to MMP-Sensitive Poly(Ethylene Glycol) Hydrogels.
abstract: Enzyme-sensitive hydrogels are a promising class of materials for cell encapsulation and tissue engineering because their ability to be degraded by cell-secreted factors. However, it is well known that nearly all synthetic biomaterials elicit a foreign body response (FBR) upon implantation. Therefore, this study aimed to evaluate the in vitro and in vivo response to an enzyme-sensitive hydrogel. Hydrogels were formed from poly(ethylene glycol) with the peptide crosslinker, C-VPLS↓LYSG-C, which is susceptible to matrix metalloproteinases 2 and 9. We evaluated the hydrogel by exogenously delivered enzymes, encapsulated mesenchymal stem cells as a tissue engineering relevant cell type, and by macrophage-secreted factors in vitro and for the FBR through macrophage attachment in vitro and in a subcutaneous mouse model. These hydrogels rapidly degraded upon exposure to exogenous MMP-2 and to lesser degree with MMP-9. Encapsulated mesenchymal stem cells were capable of degrading the hydrogels via matrix metalloproteinases. Inflammatory macrophages were confirmed to attach to the hydrogels, but were not capable of rapidly degrading the hydrogels. In vivo, these hydrogels remained intact after 4 weeks and exhibited a classic FBR with inflammatory cells at the hydrogel surface and a fibrous capsule. In summary, these findings suggest that while this MMP-2/9 sensitive hydrogel is readily degraded in vitro, it does not undergo rapid degradation by the FBR. Thus, the long term stability of these hydrogels in vivo coupled with the ability for encapsulated cells to degrade the hydrogel makes them promising materials for tissue engineering.
authors.affiliation: Department of Chemical and Biological Engineering, University of Colorado, 3415 Colorado Ave, UCB 596, Boulder, CO, 80303, USA.|BioFrontiers Institute, University of Colorado, 3415 Colorado Avenue, Boulder, CO, 80303, USA.
authors.forename: Luke D
authors.initials: LD
authors.lastname: Amer
authors.affiliation: Department of Chemical and Biological Engineering, University of Colorado, 3415 Colorado Ave, UCB 596, Boulder, CO, 80303, USA. Stephanie.Bryant@Colorado.EDU.|BioFrontiers Institute, University of Colorado, 3415 Colorado Avenue, Boulder, CO, 80303, USA. Stephanie.Bryant@Colorado.EDU.|Material Science and Engineering Program, University of Colorado, 3415 Colorado Avenue, Boulder, CO, 80303, USA. Stephanie.Bryant@Colorado.EDU.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Bryant
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018914:Cells, Immobilized; D020100:Hydrogels / Q000737:chemistry*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry*; D023822:Tissue Engineering / Q000379:methods*
chemical_list: D020100:Hydrogels; D011092:Polyethylene Glycols; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C000595209:polyethylene glycol 1000
keywords: Cell encapsulation; Enzyme-sensitive hydrogel; Foreign body response; Macrophage; Mesenchymal stem cell