title: The enhancement of bone allograft incorporation by the local delivery of the sphingosine 1-phosphate receptor targeted drug FTY720.
abstract: Poor vascularization coupled with mechanical instability is the leading cause of post-operative complications and poor functional prognosis of massive bone allografts. To address this limitation, we designed a novel continuous polymer coating system to provide sustained localized delivery of pharmacological agent, FTY720, a selective agonist for sphingosine 1-phosphate receptors, within massive tibial defects. In vitro drug release studies validated 64% loading efficiency with complete release of compound following 14 days. Mechanical evaluation following six weeks of healing suggested significant enhancement of mechanical stability in FTY720 treatment groups compared with unloaded controls. Furthermore, superior osseous integration across the host-graft interface, significant enhancement in smooth muscle cell investment, and reduction in leukocyte recruitment was evident in FTY720 treated groups compared with untreated groups. Using this approach, we can capitalize on the existing mechanical and biomaterial properties of devitalized bone, add a controllable delivery system while maintaining overall porous structure, and deliver a small molecule compound to constitutively target vascular remodeling, osseous remodeling, and minimize fibrous encapsulation within the allograft-host bone interface. Such results support continued evaluation of drug-eluting allografts as a viable strategy to improve functional outcome and long-term success of massive cortical allograft implants.
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
authors.forename: Caren E
authors.initials: CE
authors.lastname: Petrie Aronin
authors.forename: Soo J
authors.initials: SJ
authors.lastname: Shin
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Naden
authors.forename: Peter D
authors.initials: PD
authors.lastname: Rios
authors.forename: Lauren S
authors.initials: LS
authors.lastname: Sefcik
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Zawodny
authors.forename: Namory D
authors.initials: ND
authors.lastname: Bagayoko
authors.forename: Quanjun
authors.initials: Q
authors.lastname: Cui
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Khan
authors.forename: Edward A
authors.initials: EA
authors.lastname: Botchwey
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D016025:Bone Transplantation / Q000502:physiology*; D001842:Bone and Bones / Q000187:drug effects / Q000648:ultrastructure; D020099:Coated Materials, Biocompatible / Q000737:chemistry; D019245:Compressive Strength; D055119:Elastic Modulus; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D018919:Neovascularization, Physiologic; D016348:Osseointegration; D011409:Propylene Glycols / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D023822:Tissue Engineering; D014184:Transplantation, Homologous
chemical_list: D020099:Coated Materials, Biocompatible; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine