ABSTRACT
Hepatocyte growth factor (HGF) has been shown to have anti-fibrotic, pro-angiogenic, and cardioprotective effects; however, it is highly unstable and expensive to manufacture, hindering its clinical translation. Recently, a HGF fragment (HGF-f), an alternative c-MET agonist, was engineered to possess increased stability and recombinant expression yields. In this study, we assessed the potential of HGF-f, delivered in an extracellular matrix (ECM)-derived hydrogel, as a potential treatment for myocardial infarction (MI). HGF-f protected cardiomyocytes from serum-starvation and induced down-regulation of fibrotic markers in whole cardiac cell isolate compared to the untreated control. The ECM hydrogel prolonged release of HGF-f compared to collagen gels, and in vivo delivery of HGF-f from ECM hydrogels mitigated negative left ventricular (LV) remodeling, improved fractional area change (FAC), and increased arteriole density in a rat myocardial infarction model. These results indicate that HGF-f may be a viable alternative to using recombinant HGF, and that an ECM hydrogel can be employed to increase growth factor retention and efficacy.
Subject(s)
Drug Delivery Systems , Hepatocyte Growth Factor/therapeutic use , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Myocardial Infarction/drug therapy , Myocardial Infarction/physiopathology , Protein Engineering , Ventricular Remodeling , Animals , Blood Vessels/drug effects , Blood Vessels/pathology , Cell Size/drug effects , Disease Models, Animal , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Female , Fibrosis/pathology , Heart Function Tests , Humans , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/pathology , Myocytes, Cardiac/pathology , Myocytes, Smooth Muscle/metabolism , Neovascularization, Physiologic/drug effects , Peptide Fragments/pharmacology , Peptide Fragments/therapeutic use , Proto-Oncogene Proteins c-met/metabolism , Rats, Sprague-Dawley , Sus scrofa , Ultrasonography , Ventricular Remodeling/drug effectsABSTRACT
Skeletal muscle tissue has an inherent capacity for regeneration following injury. However, severe trauma, such as volumetric muscle loss, overwhelms these natural muscle repair mechanisms prompting the search for a tissue engineering/regenerative medicine approach to promote functional skeletal muscle restoration. A desirable approach involves a bioscaffold that simultaneously acts as an inductive microenvironment and as a cell/drug delivery vehicle to encourage muscle ingrowth. Both biologically active, naturally derived materials (such as extracellular matrix) and carefully engineered synthetic polymers have been developed to provide such a muscle regenerative environment. Next generation naturally derived/synthetic "hybrid materials" would combine the advantageous properties of these materials to create an optimal platform for cell/drug delivery and possess inherent bioactive properties. Advances in scaffolds using muscle tissue engineering are reviewed herein.
