Metabolic Response Modulations by Zwitterionic Hydrogels for Achieving Promoted Bone Regeneration

Abstract Zwitterionic materials containing both cationic and anionic ligands have been reported to promote hydroxyapaptite (HA)‐mineralization. However, how zwitterionic microenvironment regulates osteogenesis of bone marrow mesenchymal stem cells (BMSCs) and bone regeneration remains elusive. Here, a strategy using zwitterionic (2‐(N‐3‐sulfopropyl‐N, N‐dimethyl ammonium) ethyl methacrylate/ Methacrylated gelatin (DMAPS/GelMA) hydrogel to promote osteogenic differentiation of BMSCs in vitro and enhance bone defect repair in vivo is developed. This zwitterionic hydrogel exhibits high stereo‐affinity of fibronectin III7‐10 (FnIII7‐10) and accelerates endogenous stem cell recruitment during bone regeneration. Then, the metabolic architecture of zwitterion‐guided osteogenesis is explored by using precise untargeted metabolomics, and the metabolic profile is mapped in the zwitterionic microenvironment. The zwitterion‐dependent energetic metabolic profile reveals that amino acids capable of promoting osteogenesis, such as proline and hydroxyproline, are enriched in zwitterionic extracellular matrix (ECM); whereas, fatty acids suggestting the inflammatory response, such as dinoprostone and prostaglandin h2, are enriched in either positive‐charged ECM or negative‐charged ECM. This zwitterionic ECM‐dependent metabolic landscape is the underlying mechanism of zwitterionic hydrogel‐promoted osteogenic differentiation of BMSCs. Therefore, the study provides a deeper contextual understanding of zwitterionic‐directed bone regeneration, leading to stereochemical principles of valuable functionalized biomaterial design.