Xiao Zhang1, Jiabing Fan1, Chung-Sung Lee1, Soyon Kim1, Chen Chen1, Tara Aghaloo2, Min Lee3. 1. Division of Advanced Prosthodontics, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, California 90095, United States. 2. Division of Diagnostic and Surgical Sciences, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, California 90095, United States. 3. Division of Advanced Prosthodontics, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, California 90095, United States; Department of Bioengineering, University of California at Los Angeles, 420 Westwood Plaza, Los Angeles, California 90095, United States.
Abstract
The hedgehog signaling pathway plays a critical role in bone development and regeneration. Applications of hedgehog morphogens or small molecular agonists are of interest in bone repair but constrained by low stability, high dose requirement, and nonspecific targeting in vivo. Herein, a nanoparticulate agonist as a new type of hedgehog signaling activator is developed for efficacious bone healing. The shell of nanoparticulate agonist consists of palmitic acid and oxysterol, which could modify hedgehog function and bind with the smoothened receptor to positively modulate hedgehog signaling. Meanwhile, the core is assembled with sonic hedgehog gene/polyethyleneimine complex, which could synergistically enhance hedgehog signaling with oxysterol constituents. Moreover, alendronate is introduced into nanoparticulate agonist to bind with hydroxyapatite for potential bone tissue targeting. Lastly, the nanoparticulate agonist surface is decorated with the guanidine group to overcome cell membrane barriers. The created multifunctional nanoparticulate agonist is successfully integrated onto apatite-coated three-dimensional scaffolds and demonstrates greatly improved osteogenesis in vitro and calvarial bone healing. This work suggests a novel biomaterial design to specifically promote hedgehog signaling for the treatment of bone defects.
The hedgehog signaling pathway plays a critical role in bone development and regeneration. Applications of hedgehog morphogens or small molecular agonists are of interest in bone repair but constrained by low stability, high dose requirement, and nonspecific targeting in vivo. Herein, a nanoparticulate agonist as a new type of hedgehog signaling activator is developed for efficacious bone healing. The shell of nanoparticulate agonist consipan class="Chemical">sts of palmitic acid and oxysterol, which could modify hedgehog function and bind with the smoothened receptor to positively modulate hedgehog signaling. Meanwhile, the core is assembled with sonic hedgehog gene/polyethyleneimine complex, which could synergistically enhance hedgehog signaling with oxysterol constituents. Moreover, alendronate is introduced into nanoparticulate agonist to bind with hydroxyapatite for potential bone tissue targeting. Lastly, the nanoparticulate agonist surface is decorated with the guanidine group to overcome cell membrane barriers. The created multifunctional nanoparticulate agonist is successfully integrated onto apatite-coated three-dimensional scaffolds and demonstrates greatly improved osteogenesis in vitro and calvarial bone healing. This work suggests a novel biomaterial design to specifically promote hedgehog signaling for the treatment of bone defects.
Entities:
Keywords:
bone repair; bone targeting; hedgehog signaling; nanoparticle; sterosome
Authors: Gazelle J Crasto; Norbert Kartner; Nikita Reznik; Michael V Spatafora; Hanje Chen; Ross Williams; Peter N Burns; Cameron Clokie; Morris F Manolson; Sean A F Peel Journal: J Control Release Date: 2016-09-28 Impact factor: 9.776