A Peptide Modified Hydrogel Therapy for Acute Myocardial Infarction

Myocardial infarction (MI) results in the death of cardiomyocytes (CM) followed by scar formation and pathological remodeling of the heart. We postulate that immobilization of the pro-survival angiopoietin-1-derived peptide, QHREDGS, to a chitosan-collagen hydrogel could produce a clinically translatable thermo-responsive hydrogel to attenuate post-MI cardiac remodeling. Conjugation of QHREDGS peptide to chitosan does not interfere with gelation, structure, or mechanical properties of chitosan-collagen hydrogel blends. The storage modulus of 2.5mg/mL 1:1 mass:mass chitosan:collagen was measured to be 54.9±9.1 Pa and loss modulus of 6.1±0.9 Pa. Dose response of the QHREDGS peptide was assessed and it was found that CMs encapsulated in High peptide gel (651±8 nmol peptide/mL-gel) showed improved morphology, viability, and metabolic activity in comparison to the Low peptide (100±30 nmol peptide/mL-gel) and Control (No Peptide) groups. Construct (CMs in hydrogel) functional properties were not significantly different between the groups, however success rate of obtaining a beating construct was improved in the hydrogel with the High amount of QHREDGS peptide immobilized compared to the Low and Control groups. An adult Lewis rat left anterior descending coronary artery ligation procedure to mimic acute MI model was used to assess in vivo hydrogel performance. QHREDGS-conjugated hydrogel (QHG213H), Control gel, or PBS was injected into 3 locations in the MI zone. By in vivo tracking and chitosan staining, the hydrogel was demonstrated to remain in situ for 2 weeks and cleared in about 3 weeks. By echocardiography and pressure-volume analysis, the QHG213H hydrogel significantly improved cardiac function compared to the controls. Scar thickness and scar area fraction were also significantly improved with QHG213H gel injection compared to the controls. Mechanistically, there were significantly more cardiomyocytes, determined by cardiac troponin-T staining, in the MI zone of the QHG213H hydrogel group. No significant difference in inflammatory response between groups was observed as determined by gene regulation and cytokine analysis of excised heart sections 24 hours after treatment. The interaction of CMs with QHREDGS was found to be mediated by β1-integrins and to increase expression of the pro-survival effector MAPK.Ph.D