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Nat Mater. 2014 Jun;13(6):653-61. doi: 10.1038/nmat3922. Epub 2014 Mar 30.

Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition.

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Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina 29208, USA.
Gorman Cardiovascular Research Laboratory, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.


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.

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