B. Purcell, David C. Lobb, M. Charati
Mar 30, 2014
Citations
1
Influential Citations
379
Citations
Quality indicators
Journal
Nature materials
Abstract
Inhibitors of matrix metalloproteinases (MMPs) have been extensively explored to treat pathologies where excessive MMP activity contributes to adverse tissue remodeling. While MMP inhibition remains a relevant therapeutic target, MMP inhibitors have not translated to clinical application due 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 over-expression following a myocardial infarction (MI) significantly reduced MMP activity and attenuated adverse left ventricular remodeling in a porcine model of MI. Our findings demonstrate that local, on-demand MMP inhibition is achievable through the use of an injectable and bioresponsive hydrogel.