Elastin-like recombinamers-based hydrogel modulates post-ischemic remodeling in a non-transmural myocardial infarction in sheep

Abstract

Ischemic heart disease is a leading cause of mortality due to irreversible damage to cardiac muscle. Inspired by the post-ischemic microenvironment, we devised an extracellular matrix (ECM)–mimicking hydrogel using catalyst-free click chemistry covalent bonding between two elastin-like recombinamers (ELRs). The resulting customized hydrogel included functional domains for cell adhesion and protease cleavage sites, sensitive to cleavage by matrix metalloproteases overexpressed after myocardial infarction (MI). The scaffold permitted stromal cell invasion and endothelial cell sprouting in vitro. The incidence of non-transmural infarcts has increased clinically over the past decade, and there is currently no treatment preventing further functional deterioration in the infarcted areas. Here, we have developed a clinically relevant ovine model of non-transmural infarcts induced by multiple suture ligations. Intramyocardial injections of the degradable ELRs-hydrogel led to complete functional recovery of ejection fraction 21 days after the intervention. We observed less fibrosis and more angiogenesis in the ELRs-hydrogel–treated ischemic core region compared to the untreated animals, as validated by the expression, proteomic, glycomic, and histological analyses. These findings were accompanied by enhanced preservation of GATA4+ cardiomyocytes in the border zone of the infarct. We propose that our customized ECM favors cardiomyocyte preservation in the border zone by modulating the ischemic core and a marked functional recovery. The functional benefits obtained by the timely injection of the ELRs-hydrogel in a clinically relevant MI model support the potential utility of this treatment for further clinical translation.

Targeted Myocardial Restoration with Injectable Hydrogels—In Search of The Holy Grail in Regenerating Damaged Heart Tissue

“…This would suggest that injectable hydrogels have the ability to retain the highly complex and intricate architecture of the heart post-MI, resulting in increased EF [ 2 ]. This would be in line with the findings of studies [ 13 , 14 , 15 , 16 , 17 , 18 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 30 ], which reported both attenuated LV remodeling and an increase in EF.…”

“…The hydrogel characterization and its mode of delivery are tabulated in Table 2 . Few studies reported the delivery of injectable hydrogel without a cellular component [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ], while the rest chose a different composition of cells and type of matrix.…”

“…These parameters were measured via immunohistochemistry, Masson’s trichrome stain, MRI, and computed tomography (CT). Out of the 21 studies, only 5 studies [ 10 , 13 , 14 , 23 , 28 ] measured the effect of treatment on fibrosis, with Zhou et al [ 10 ] reporting equivocal scar size and the rest reporting reduced fibrosis with treatment.…”

A Brief History in Cardiac Regeneration, and How the Extra Cellular Matrix May Turn the Tide

“…Although still in their infancy, the move toward a synthetic ECM hydrogel will facilitate the clinical usability of such a therapeutic strategy. A recent study has demonstrated the potential of this by developing a degradable elastin-like polypeptide hydrogel, which mimics the ECM ( 61 ). Intramyocardial injection of this hydrogel in a sheep model for myocardial infarction lead to a reduction in fibrosis, increased angiogenesis, improved cardiac function and cardiomyocyte integrity in the border zone of the infarcts ( 61 ).…”

“…A recent study has demonstrated the potential of this by developing a degradable elastin-like polypeptide hydrogel, which mimics the ECM ( 61 ). Intramyocardial injection of this hydrogel in a sheep model for myocardial infarction lead to a reduction in fibrosis, increased angiogenesis, improved cardiac function and cardiomyocyte integrity in the border zone of the infarcts ( 61 ). Taken together, these steps will not only help our understanding of cardiac regeneration as a whole, but will also lead to an improved outcome for patients suffering from HF.…”