Chinese herb-crosslinked hydrogel bearing rBMSCs-laden polyzwitterion microgels: Self-adaptive manipulation of micromilieu and stemness maintenance for restoring infarcted myocardium

Injectable hydrogels and stem cells have been increasingly applied to treat myocardial infarction (MI). However, the harsh microenvironment adversely affects the survival of implanted stem cells and ultimate therapeutic outcomes. Herein, we design and prepare rat bone marrow mesenchymal stem cells (rBMSCs)-embedded polyzwitterionic microgels ([email protected]) via in situ Michael addition reaction between multivinyl carboxybetaine macromonomer and thiol-ended polyethylene glycol mixed with rBMSCs in a microfluidic system. The [email protected] are then loaded into a tyramine-modified hyaluronic acid (HA-Tyr), into which Chinese herb puerarin (PUE) and horseradish peroxidase (HRP)/H2O2 are added to catalyze inter-phenol crosslinks to form an injectable HA-Tyr-PUE hydrogel encapsulating [email protected] ([email protected]@microgels). This [email protected]@microgels is injected into the infarct region of rats, where HA-Tyr-PUE hydrogel serves to favorably modulate the microenvironment by scavenging active oxygen and releasing oxygen, and rBMSCs remain stemness in highly hydrophilic microgels and exert a paracrine effect to facilitate anti-inflammation and angiogenesis. These concerted actions boost the highly efficient restoration of ventricular function and structure. The ROS-scavenging medicine-crosslinked biodegradable biomacromolecule hydrogel bearing stemness-maintained microgels can be expanded to diverse tissue engineering and regenerative medicine fields.