Injectable Extracellular Matrix Microparticles Promote Heart Regeneration in Mice with Post‐ischemic Heart Injury

Abstract

Ischemic heart injury causes permanent cardiomyocyte loss and fibrosis impairing cardiac function. Tissue derived biomaterials have shown promise as an injectable treatment for the post-ischemic heart. Specifically, decellularized extracellular matrix (dECM) is a protein rich suspension that forms a therapeutic hydrogel once injected and improves the heart post-injury response in rodents and pig models. Current dECM-derived biomaterials are delivered to the heart as a liquid dECM hydrogel precursor or colloidal suspension, which gels over several minutes. To increase the functionality of the dECM therapy, an injectable solid dECM microparticle formulation derived from heart tissue to control sizing and extend stability in aqueous conditions is developed. When delivered into the infarcted mouse heart, these dECM microparticles protect cardiac function promote vessel density and reduce left ventricular remodeling by sustained delivery of biomolecules. Longer retention, higher stiffness, and slower protein release of dECM microparticles are noted compared to liquid dECM hydrogel precursor. In addition, the dECM microparticle can be developed as a platform for macromolecule delivery. Together, the results suggest that dECM microparticles can be developed as a modular therapy for heart injury.

Multifunctional biomaterial platforms for blocking the fibrosis process and promoting cellular restoring effects in myocardial fibrosis therapy

“…Injectable hydrogels can be derived from a variety of materials, including natural gel materials such as Homogeneous or heterogeneous ECM (X. Wang et al, 2022;Wang X et al, 2021), alginate (J. Yu et al, 2009), HA (Dorsey et al, 2015;, collagens (C. Fan et al, 2019), fibrous protein (Losi et al, 2010;Awada et al, 2017), heparin (Prokoph et al, 2012), and chitosan, etc.…”

“…Injectable hydrogels can be derived from a variety of materials, including natural gel materials such as Homogeneous or heterogeneous ECM (X. Wang et al, 2022 ; Wang X et al, 2021 ), alginate (J. Yu et al, 2009 ), HA ( Dorsey et al, 2015 ; Y.…”

“…Decellularized extracellular matrix gels are a mature process in which decellularized extracellular matrix is obtained and digested by digestive enzymes to prepare an injectable extracellular matrix pre-gel, which is injected into the body and re-geled into the extracellular matrix state under physiological conditions (X. Wang et al, 2022 ; Wang X et al, 2021 ). Unlike the in vitro environment, the achievement of normal physiological functions of tissues involves the participation of a very large number of enzymes that are not present in the in vitro environment.…”

“…On the contrary, the restoration of normal physiological function and structure of ECM has now been shown to be beneficial to myocardial fibrosis (X. Wang et al, 2022 ). At present, biomaterials are currently applied to restore the ECM with functions including re-establishing microenvironmental blood flow, providing mechanical support, softening the fibrotic ECM, and protecting cardiomyocyte (Y.…”

“…The decellularized extracellular matrix (dECM), obtained by decellularization is rich in biologic factors, which can provide a cellular growth environment, softenten the microenvironment, maintain the normal function of normal cardiomyocytes, reduce the conversion of cardiac fibroblasts to myofibroblasts, decrease the expression of transforming growth factor-β (TGF-β), and reduce matrix collagen deposition (X. Wang et al, 2022 ; Wang X et al, 2021 ). Using natural gel to treat cardiomyocyte injury is theoretically very promising, but there are still some problems.…”