Chung-Sung Lee¹, Soyon Kim¹, Jiabing Fan¹, Hee Sook Hwang¹, Tara Aghaloo² and Min Lee^1,3,*

¹Division of Advanced Prosthodontics, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
²Division of Diagnostic and Surgical Sciences, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
³Department of Bioengineering, University of California at Los Angeles, 420 Westwood Plaza, Los Angeles, CA 90095, USA.

^*Corresponding author.

Biomaterial delivery of bioactive agents and manipulation of stem cell fate are an attractive approach to promote tissue regeneration. Here, smoothened agonist sterosome is developed using small-molecule activators [20S-hydroxycholesterol (OHC) and purmorphamine (PUR)] of the smoothened protein in the hedgehog pathway as carrier and cargo. Sterosome presents inherent osteoinductive property even without drug loading. Sterosome is covalently immobilized onto three-dimensional scaffolds via a bioinspired polydopamine intermediate to fabricate a hybrid scaffold for bone regeneration. Sterosome-immobilized hybrid scaffold not only provides a favorable substrate for cell adhesion and proliferation but also delivers bioactive agents in a sustained and spatially targeted manner. Furthermore, this scaffold significantly improves osteogenic differentiation of bone marrow stem cells through OHC/PUR-mediated synergistic activation of the hedgehog pathway and also enhances bone repair in a mouse calvarial defect model. This system serves as a versatile biomaterial platform for many applications, including therapeutic delivery and endogenous regenerative medicine.