title: Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition.
abstract: Inhibitors of matrix metalloproteinases (MMPs) have been extensively explored to treat pathologies where excessive MMP activity contributes to adverse tissue remodelling. Although MMP inhibition remains a relevant therapeutic target, MMP inhibitors have not translated to clinical application owing to the dose-limiting side effects following systemic administration of the drugs. Here, we describe the synthesis of a polysaccharide-based hydrogel that can be locally injected into tissues and releases a recombinant tissue inhibitor of MMPs (rTIMP-3) in response to MMP activity. Specifically, rTIMP-3 is sequestered in the hydrogels through electrostatic interactions and is released as crosslinks are degraded by active MMPs. Targeted delivery of the hydrogel/rTIMP-3 construct to regions of MMP overexpression following a myocardial infarction significantly reduced MMP activity and attenuated adverse left ventricular remodelling in a porcine model of myocardial infarction. Our findings demonstrate that local, on-demand MMP inhibition is achievable through the use of an injectable and bioresponsive hydrogel.
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Brendan P
authors.initials: BP
authors.lastname: Purcell
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina 29208, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lobb
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Manoj B
authors.initials: MB
authors.lastname: Charati
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shauna M
authors.initials: SM
authors.lastname: Dorsey
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Wade
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina 29208, USA.
authors.forename: Kia N
authors.initials: KN
authors.lastname: Zellars
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina 29208, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Doviak
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina 29208, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Pettaway
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina 29208, USA.
authors.forename: Christina B
authors.initials: CB
authors.lastname: Logdon
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina 29208, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Shuman
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina 29208, USA.
authors.forename: Parker D
authors.initials: PD
authors.lastname: Freels
authors.affiliation: Gorman Cardiovascular Research Laboratory, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Gorman
authors.affiliation: Gorman Cardiovascular Research Laboratory, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gorman
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina 29208, USA.
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Burdick
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D013552:Swine; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000737:chemistry / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D020100:Hydrogels; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D020782:Matrix Metalloproteinases