Sulfobetaine as a zwitterionic mediator for 3D hydroxyapatite mineralization

Both positively and negatively charged residues play pivotal roles in recruiting precursor ions or ion clusters, and lowering interfacial energy in natural biomineralization process. Synergistic utilization of opposite charges, however, has rarely been implemented in the design of cytocompatible synthetic scaffolds promoting hydroxyapatite (HA)-mineralization and osteointegration. We report the use of cytocompatible zwitterionic sulfobetaine ligands to enable 3-dimensional in vitro mineralization of HA across covalently crosslinked hydrogels. The overall charge-neutral zwitterionic hydrogel effectively recruited oppositely charged precursor ions while overcame excessive swelling exhibited by anionic and cationic hydrogels under physiological conditions, resulting in denser and structurally well-integrated mineralized composites. Further controls over the size, content, and spatial distribution of the mineral domains within the zwitterionic hydrogel are accomplished by facile adjustments of hydrogel crosslinking densities and the supersaturation rate governing heterogeneous mineral nucleation and growth. These findings should inspire many creative uses of zwitterionic polymers and polymer coatings for skeletal tissue repair and regeneration.