International Journal of Nanomedicine (Aug 2019)
Titania nanotube-based protein delivery system to inhibit cranial bone regeneration in Crouzon model of craniosynostosis
Abstract
Manpreet Bariana,1 John A Kaidonis,1 Dusan Losic,2 Sarbin Ranjitkar,1,* Peter J Anderson1,3,*1Adelaide Dental School, The University of Adelaide, Adelaide, SA 5005, Australia; 2School of Chemical Engineering, The University of Adelaide, Adelaide, SA 5005, Australia; 3Australian Craniofacial Unit, Adelaide, SA 5006, Australia*These authors contributed equally to this workBackground: Craniosynostosis is a developmental disorder characterized by the premature fusion of skull sutures, necessitating repetitive, high-risk neurosurgical interventions throughout infancy. This study used protein-releasing Titania nanotubular implant (TNT/Ti) loaded with glypican 3 (GPC3) in the cranial critical-sized defects (CSDs) in Crouzon murine model (Fgfr2c342y/+ knock-in mutation) to address a key challenge of delaying post-operative bone regeneration in craniosynostosis.Materials and methods: A 3 mm wide circular CSD was created in two murine models of Crouzon syndrome: (i) surgical control (CSDs without TNT/Ti or any protein, n=6) and (ii) experimental groups with TNT/Ti loaded with GPC3, further subdivided into the presence or absence of chitosan coating (on nanotubes) (n=12 in each group). The bone volume percentage in CSDs was assessed 90 days post-implantation using micro-computed tomography (micro-CT) and histological analysis.Results: Nano-implants retrieved after 90 days post-operatively depicted well-adhered, hexagonally arranged, and densely packed nanotubes with average diameter of 120±10 nm. The nanotubular architecture was generally well-preserved. Compared with the control bone volume percentage data (without GPC3), GPC3-loaded TNT/Ti without chitosan coating displayed a significantly lower volume percent in cranial CSDs (P<0.001). Histological assessment showed relatively less bone regeneration (healing) in GPC3-loaded CSDs than control CSDs.Conclusion: The finding of inhibition of cranial bone regeneration by GPC3-loaded TNT/Ti in vivo is an important advance in the novel field of minimally-invasive craniosynostosis therapy and holds the prospect of altering the whole paradigm of treatment for affected children. Future animal studies on a larger sample are indicated to refine the dosage and duration of drug delivery across different ages and both sexes with the view to undertake human clinical trials.Keywords: craniosynostosis, protein delivery, glypican, titania nanotube, murine
