Extracellular Matrix/Glycopeptide Hybrid Hydrogel as an Immunomodulatory Niche for Endogenous Cardiac Repair after Myocardial Infarction

Abstract

The treatment of myocardial infarction (MI) remains a substantial challenge due to excessive inflammation, massive cell death, and restricted regenerative potential, leading to maladaptive healing process and eventually heart failure. Current strategies of regulating inflammation or improving cardiac tissue regeneration have limited success. Herein, a hybrid hydrogel coassembled by acellular cardiac extracellular matrix (ECM) and immunomodulatory glycopeptide is developed for endogenous tissue regeneration after MI. The hydrogel constructs a niche recapitulating the architecture of native ECM for attracting host cell homing, controlling macrophage differentiation via glycopeptide unit, and promoting endotheliocyte proliferation by enhancing the macrophage‐endotheliocyte crosstalk, which coordinate the innate healing mechanism for cardiac tissue regeneration. In a rodent MI model, the hybrid hydrogel successfully orchestrates a proreparative response indicated by enhanced M2 macrophage polarization, increased angiogenesis, and improved cardiomyocyte survival, which alleviates infarct size, improves wall thicknesses, and enhances cardiac contractility. Furthermore, the safety and effectiveness of the hydrogel are demonstrated in a porcine MI model, wherein proteomics verifies the regulation of immune response, proangiogenesis, and accelerated healing process. Collectively, the injectable composite hydrogel serving as an immunomodulatory niche for promoting cell homing and proliferation, inflammation modulation, tissue remodeling, and function restoration provides an effective strategy for endogenous cardiac repair.

Hydrogels for the Treatment of Myocardial Infarction: Design and Therapeutic Strategies

“…[ 139 ] Acellular hydrogel scaffolds can be implanted at the site of MI to provide necessary mechanical support for damaged myocardium, and can also be used as a dynamic bioactive substance to promote angiogenesis and other endogenous tissue repair mechanisms. [ 140,141 ] Acellular hydrogels of different tissue sources have unique properties in alleviating cardiac remodeling and ECM homeostasis after MI. [ 56,142 ] The advantages of acellular hydrogels in the treatment of MI are as follows: First, acellular hydrogels have good biocompatibility and can reduce immune rejection.…”

Pro‐Regenerative Glycopeptide Hydrogel Activates Type 2 Immune Response for Wound Healing via Macrophage‐T Cell Crosstalk

“…[6] In our previous studies, [7] with a bottom-up design concept, ECM-mimicking glycopeptide was constructed to prime M2-type macrophage polarization via mannose receptor activation, which notably promoted the regeneration of skin with chronic or non-healing wounds [8] and cardiac tissue. [9] After macrophage polarization, T-cell response elicited in the injured tissue environment may determine the level of inflammation, tissue remodeling, and angiogenesis. There is evidence supporting the crucial role of T cells, including regulatory T cells (Tregs), T H 2, 𝛾𝛿T, and T H 17 cells in wound repair and tissue regeneration.…”

Silk fibroin and hydroxypropyl cellulose composite injectable hydrogel-containing extracellular vesicles for myocardial infarction repair

“…Injectable hydrogel is an important material widely used in cardiac tissue engineering to provide mechanical support to the heart by intracardiac injection, which in turn improves the compliance of the ventricular wall. In addition, the injectable hydrogel is an excellent platform for sustained drug release for myocardial tissue repair, thus promoting myocardial regeneration and repair [14][15][16]. And they can protect EVs from rapid clearance and provide a microenvironment optimized for cell proliferation in damaged tissues when injected into myocardium.…”