Particle-based artificial three-dimensional stem cell spheroids for revascularization of ischemic diseases

Development of new approaches to biomimetically reconstruct vasculature networks remains challenging in regenerative medicine. We introduce a particle-based artificial stem cell spheroid (ASSP) technology that recapitulates paracrine functions of three-dimensional (3D) SSPs for vasculature regeneration. Specifically, we used a facile method to induce the aggregation of stem cells into 3D spheroids, which benefited from hypoxia microenvironment–driven and enhanced secretion of proangiogenic bioactive factors. Furthermore, we artificially reconstructed 3D spheroids (i.e., ASSP) by integration of SSP-secreted factors into micro-/nanoparticles with cell membrane–derived surface coatings. The easily controllable sizes of the ASSP particles provided superior revascularization effects on the ischemic tissues in hindlimb ischemia models through local administration of ASSP microparticles and in myocardial infarction models via the systemic delivery of ASSP nanoparticles. The strategy offers a promising therapeutic option for ischemic tissue regeneration and addresses issues faced by the bottlenecked development in the delivery of stem cell therapies.