Thermodynamically Controlled Self‐Assembly of Hierarchically Staggered Architecture as an Osteoinductive Alternative to Bone Autografts

Abstract Osteoinductive synthetic biomaterials for replacing autografts can be developed by mimicking bone hierarchy and surface topography for host cell recruitment and differentiation. Until now, it has been challenging to reproduce a bone‐like staggered hierarchical structure since the energy change underlying synthetic pathways in vitro is essentially different from that of the natural process in vivo. Herein, a bone‐like hierarchically staggered architecture is reproduced under thermodynamic control involving two steps: fabrication of a high‐energy polyacrylic acid‐calcium intermediate and selective mineralization in collagenous gap regions driven by an energetically downhill process. The intermediate energy interval could easily be adjusted to determine different mineralization modes, with distinct morphologies and biofunctions. Similar to bone autografts, the staggered architecture offers a bone‐specific microenvironment for stem cell recruitment and multidifferentiation in vitro, and induces neo‐bone formation with bone marrow blood vessels by host stem cell homing in vivo. This work provides a novel perspective for an in vitro simulating biological mineralization process and proof of concept for the clinical application of smart biomaterials.