Microcryogels as injectable 3-D cellular microniches for site-directed and augmented cell delivery

The success of cell therapy for tissue repair and regeneration demands efficient and reliable cell delivery methods. Here we established a novel microengineered cryogel (microcryogel) array chip containing microcryogels with predefined size and shape as injectable cell delivery vehicles. The microscale macroporous cryogels enabled automatic and homogeneous loading of tailored cellular niches (e.g. cells, matrices, bioactive factors) and could be easily harvested from the ready-to-use array chip. In contrast to microscale hydrogels, microcryogels exhibited excellent elasticity and could retain their shape and integrity after injection through the microsyringe routinely used for cell therapy. Human mesenchymal stromal cells loaded within microcryogels could be shielded from the mechanical insult and necrosis caused by during direct cell injection. After subcutaneous injection to the mice, cell-loaded microcryogels exhibited concentrated localization and enhanced retention at the injection site compared to dissociated cells. To demonstrate the potential therapeutic application for ischemic diseases, site-directed induction of angiogenesis was achieved subcutaneously in mice 2 weeks after injection of NIH/3T3 fibroblast-loaded microcryogels, indicating long-term engraftment, accumulative paracrine stimulation and augmented host tissue integration. Our results convincingly showed the great promise of microcryogels as 3-D cellular microniches and injectable cell delivery vehicles to tackle major challenges faced by cell therapy-based regenerative medicine including shear-induced damages, uncontrolled localization, poor retention, limited cellular survival and functionalities in vivo.