Harnessing Oxidized Alginate Microgels for Rapid and Self‐Assembling Dental Tissue Organogenesis In Vitro and In Vivo

Regenerating dental tissues for craniofacial reconstruction remains challenging due to inadequate tissue organization and poor intercellular connectivity, often caused by residual biomaterials. Recapitulating key developmental processes, such as spontaneous cellular condensation and epithelial–mesenchymal interactions (EMI), is essential for engineering functional tissue architecture. This study introduces an innovative system that utilizes oxidized alginate (OA) microgels laden with high‐density human dental stem cells to promote self‐condensation and EMI. The OA microgels were prepared through sodium periodate oxidation and further optimized. In vitro studies demonstrated rapid self‐degradation of OA, which promoted efficient cell condensation and robust 3D tissue formation. Following subcutaneous transplantation into mice, the cell‐dense microgels exhibited functional integration with host tissues, along with robust vascularization and osteogenic differentiation. To demonstrate its potential for craniofacial regeneration, a tooth germ model (OA/Epithelium + OA/Mesenchyme) that mimics EMI was developed using embryonic dental epithelial and mesenchymal cells from Embryonic Day 14.5 mice. Immediate transplantation under the mouse kidney capsule resulted in bone organogenesis within two weeks. In summary, the OA microgel system provides initial mechanical support and then quickly degrades to enable critical cell‐cell interactions that mirror organ development. Thus, this scalable and cost‐effective approach holds significant promise for advancing dental tissue engineering.