Injectable and Bioresponsive Hydrogels for On-demand Matrix Metalloproteinase Inhibition

Overview

Journal Nat Mater

Date 2014 Apr 1

PMID 24681647

Citations 136

Authors

Brendan P Purcell

David Lobb

Manoj B Charati

Shauna M Dorsey

Ryan J Wade

Kia N Zellars

Heather Doviak

Sara Pettaway

Christina B Logdon

James A Shuman

Parker D Freels

Joseph H Gorman 3rd

Robert C Gorman

Francis G Spinale

Jason A Burdick

Affiliations

Soon will be listed here.

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.

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