Development of a Biomaterial Scaffold Integrated with Osteoinductive Oxysterol Liposomes to Enhance Hedgehog Signaling and Bone Repair

Mol Pharm. 2021 Apr 5;18(4):1677-1689. doi: 10.1021/acs.molpharmaceut.0c01136. Epub 2021 Mar 24.


Bone repair requires the tightly regulated control of multiple intrinsic and extrinsic cell types and signaling pathways. One of the positive regulatory signaling pathways in membranous and endochondral bone healing is the Hedgehog (Hh) signaling family. Here, a novel therapeutic liposomal delivery vector was developed by self-assembly of an Hh-activating cholesterol analog with an emulsifier, along with the addition of Smoothened agonist (SAG) as a drug cargo, for the enhancement of Hh signaling in bone regeneration. The drug-loaded nanoparticulate agonists of Hh signaling were immobilized onto trabecular bone-mimetic apatite-coated 3D scaffolds using bioinspired polydopamine adhesives to ensure favorable microenvironments for cell growth and local therapeutic delivery. Results showed that SAG-loaded liposomes induced a significant and dose-dependent increase in Hh-mediated osteogenic differentiation, as evidenced by in vitro analysis of bone marrow stromal cells, and in vivo calvarial bone healing, as evidenced using all radiographic parameters and histomorphometric analyses. Moreover, favorable outcomes were achieved in comparison to standards of care, including collagen sponge-delivered rBMP2 or allograft bone. In summary, this study demonstrates using a nanoparticle packaged Hh small molecule as a widely applicable bone graft substitute for robust bone repair.

Keywords: bone repair; bone tissue engineering; hedgehog signaling; liposome; scaffold.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apatites / chemistry
  • Bone Regeneration / drug effects*
  • Bone Transplantation
  • Cell Differentiation / drug effects
  • Cyclohexylamines / chemistry
  • Cyclohexylamines / pharmacology*
  • Disease Models, Animal
  • Female
  • Hedgehog Proteins / metabolism*
  • Humans
  • Liposomes
  • Male
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / physiology
  • Mice
  • Osteogenesis / drug effects
  • Oxysterols / administration & dosage*
  • Signal Transduction / drug effects
  • Skull / diagnostic imaging
  • Skull / injuries
  • Skull / surgery
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Tissue Scaffolds / chemistry*
  • X-Ray Microtomography


  • Apatites
  • Cyclohexylamines
  • Hedgehog Proteins
  • Liposomes
  • Oxysterols
  • SAG compound
  • Thiophenes