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.

Background-Leaflet curvature is known to reduce mechanical stress. There are 2 major components that contribute to this curvature. Leaflet billowing introduces the most obvious form of leaflet curvature. The saddle shape of the mitral annulus imparts a more subtle form of leaflet curvature. This study explores the relative contributions of leaflet billowing and annular shape on leaflet curvature and stress distribution. Methods and Results-Both numerical simulation and experimental data were used. The simulation consisted of an array of numerically generated mitral annular phantoms encompassing flat to markedly saddle-shaped annular heights. Highest peak leaflet stresses occurred for the flat annulus. As saddle height increased, peak stresses decreased. The minimum peak leaflet stress occurred at an annular height to commissural width ratio of 15% to 25%. The second phase involved data acquisition for the annulus from 3 humans by 3D echocardiography, 3 sheep by sonomicrometry array localization, 2 sheep by 3D echocardiography, and 2 baboons by 3D echocardiography. All 3 species imaged had annuli of a similar shape, with an annular height to commissural width ratio of 10% to 15%. Conclusion-The saddle shape of the mitral annulus confers a mechanical advantage to the leaflets by adding curvature.This may be valuable when leaflet curvature becomes reduced due to diminished leaflet billowing caused by annular dilatation. The fact that the saddle shape is conserved across mammalian species provides indirect evidence of the advantages it confers. This analysis of mitral annular contour may prove applicable in developing the next generation of mitral annular prostheses.

A recent trend has emerged that involves myocardial injection of biomaterials, containing cells or acellular, following myocardial infarction (MI) to influence the remodeling response through both biological and mechanical effects. Despite the number of different materials injected in these approaches, there has been little investigation into the importance of material properties on therapeutic outcomes. This work focuses on the investigation of injectable hyaluronic acid (MeHA) hydrogels that have tunable mechanics and gelation behavior. Specifically, two MeHA formulations that exhibit similar degradation and tissue distribution upon injection but have differential moduli (∼8 versus ∼43 kPa) were injected into a clinically relevant ovine MI model to evaluate the associated salutary effect of intramyocardial hydrogel injection on the remodeling response based on hydrogel mechanics. Treatment with both hydrogels significantly increased the wall thickness in the apex and basilar infarct regions compared with the control infarct. However, only the higher-modulus (MeHA High) treatment group had a statistically smaller infarct area compared with the control infarct group. Moreover, reductions in normalized end-diastolic and end-systolic volumes were observed for the MeHA High group. This group also tended to have better functional outcomes (cardiac output and ejection fraction) than the low-modulus (MeHA Low) and control infarct groups. This study provides fundamental information that can be used in the rational design of therapeutic materials for treatment of MI.L eft ventricular (LV) remodeling caused by a myocardial infarction (MI) is responsible for almost 70% of the 5 million cases of heart failure that have occurred in the United States in recent years (1). Early infarct expansion or stretching has been associated with poor long-term prognosis (2-4) and has been identified as the mechanical phenomenon that initiates and sustains the process of adverse post-MI LV remodeling that leads to heart failure (5-10). Infarct expansion causes abnormal stress distribution in myocardial regions outside the infarction, especially in the adjacent borderzone region, putting this region at a mechanical disadvantage. With time, increased regional stress is the impetus for several maladaptive biologic processes, such as myocyte apoptosis and matrix metalloproteinase activation, that inherently alter the contractile properties of normally perfused myocardium (11,12). Once initiated, these maladaptive processes lead to a heart failure phenotype that is difficult to reverse by medical or surgical means.We have demonstrated that ventricular restraint early after MI reduces infarct expansion and limits long-term global LV remodeling in large-animal infarction models (10, 13-16). To circumvent the surgical placement of restraining devices early post-MI, our group and others have begun to explore the use of injectable materials to limit infarct expansion and normalize the regional stress distribution (17-26). Such an approach offers th...

ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an essential chemical energy source that governs myocardial contraction. Here, we demonstrate that the exchange of amine protons from creatine with protons in bulk water can be exploited to image creatine through chemical exchange saturation transfer (CrEST) in myocardial tissue. We show that CrEST provides about two orders of magnitude higher sensitivity compared to 1H magnetic resonance spectroscopy. Results of CrEST studies from ex vivo myocardial tissue strongly correlate with results from 1H and 31P magnetic resonance spectroscopy and biochemical analysis. We demonstrate the feasibility of CrEST measurement in healthy and infarcted myocardium in animal models in vivo on a 3-T clinical scanner. As proof of principle, we show the conversion of phosphocreatine to creatine by spatiotemporal mapping of creatine changes in the exercised human calf muscle. We also discuss the potential utility of CrEST in studying myocardial disorders.