Abstract 10587: On-demand Delivery of TIMP-3 From Matrix Metalloproteinase Degradable Hydrogels Attenuates Post Myocardial Infarction Remodeling
Background: Following a myocardial infarction (MI), an imbalance of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) contributes to extracellular matrix instability, left ventricular (LV) wall thinning, and subsequent LV dysfunction. While MMP inhibition remains a relevant therapeutic target post-MI, systemic administration of pharmacologic MMP inhibitors have been problematic due to dosing and off-target effects. Accordingly, we developed a unique approach of locally delivering recombinant TIMP-3 within the MI region of pigs by designing injectable hydrogels containing MMP-cleavable crosslinks, where the local presence of active MMPs controls the release of encapsulated rTIMP-3.
Methods/Results: An injectable gel for rTIMP-3 encapsulation was fabricated by chemically modifying hyaluronic acid (HA) and dextran sulfate (DS) polymers with complimentary aldehyde (ALD) and hydrazide (HYD) groups (Fig. 1A). Upon mixing the ALD and HYD components in a dual-barrel syringe, gels formed within 1 minute that were stable in saline, but degraded in the presence of MMP-2. MI was induced in adult pigs randomized to receive 9x 100μL MI region injections of gel/rTIMP-3 (20μg rTIMP-3/injection, n=5), or saline (MI only, n=5). Ejection fraction and in vivo MMP activity were measured after 14 days with echocardiography and a validated substrate microdialysis assay, respectively. MMP activity was elevated following MI and was significantly reduced by injection of the MMP-cleavable hydrogel loaded with rTIMP-3 (Fig. 1B). In addition, LV MI wall thickness and ejection fraction were significantly improved in the gel/rTIMP-3 group (Fig. 1B).
Conclusion: MI region injections of a hydrogel, which releases rTIMP-3 in proportion to local MMP activity, attenuated adverse LV remodeling process. These unique findings demonstrated that MMP activity within the MI region is a viable target for therapeutic intervention through local delivery of MMP inhibitors.
- © 2013 by American Heart Association, Inc.