Injectable 3D Porous Micro‐Scaffolds with a Bio‐Engine for Cell Transplantation and Tissue Regeneration

Abstract Bio‐scaffolds designed to mimic endogenous niches have been used extensively in stem cell therapy and tissue regeneration. However, limited entry of nutrients and cells inside the scaffold can lead to poor cell survival and proliferation, and scaffold implantation can require an invasive surgical approach. Here, a noninvasive method using injectable 3D porous micro‐scaffolds with a bio‐engine is developed for cell transplantation and tissue regeneration. A liquid nitrogen flash‐frozen and immediately smashed method is developed to prepare 3D porous nanocarriers‐alginate composite micro‐scaffolds (NAC/MS). Compared to common scaffolds, human mesenchymal stem cells (hMSCs) grown in NAC/MS show high survival and proliferation rates; this is due to the small size of the micro‐scaffolds, which allows access to nutrients. Bio‐factors are loaded into nanocarriers to produce a bio‐engine that can initiate and promote stem cells differentiation in a bionic manner, behaving like an engine. Transplanted hMSCs show significantly enhanced expansion and mineralization in vivo. Furthermore, NAC/MS can promote in situ regeneration of bone in cranial defects in dogs. The biomimetic NAC/MS provide an injectable niche to cell survival, proliferation, and fate control during tissue regeneration or cell therapy, which are critical for developing organoid culture devices and cells local delivery vehicles.