Controlled bone formation using ultrasound-triggered release of BMP-2 from liposomes.
Recombinant human bone morphogenetic protein 2 (rhBMP-2) is used clinically to enhance implant-mediated bone regeneration. However, there are risks associated with the high rhBMP-2 dose that is required in the implant to mitigate diffusional loss over the therapeutic timespan. On-demand, localized control over delivery of rhBMP-2, days after implantation, would therefore be an attractive solution in the area of bone repair and reconstruction, yet this has posed a significant challenge, with little data to support in vivo efficacy to date. To address this, we have developed novel liposome-rhBMP-2 nanocomplexes that release rhBMP-2 in response to non-thermogenic, clinical diagnostic ultrasound exposure. In vitro validation shows that rhBMP-2 release is in proportion to applied ultrasound pressure and duration of exposure. Moreover, here we show in vivo validation of this ultrasound-triggered rhBMP-2 delivery system in a standard mouse bone regeneration model. Implanted into hindleg muscles, the liposome-rhBMP-2 nanocomplexes induced local bone formation only after ultrasound exposure. Such post-implantation control of delivery has potential to improve the safety, efficacy and cost of rhBMP-2 use in bone reconstruction. Furthermore, this first proof-of-concept demonstration of in vivo efficacy for ultrasound-triggered liposomal delivery of rhBMP-2 has broader implications for tunable delivery of a variety of drugs and biologics in medicine and tissue engineering.
Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada. Electronic address: gazellejean.crasto@utoronto.ca.
Gazelle J
GJ
Crasto
Dental Research Institute, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.
Norbert
N
Kartner
Imaging Research, Sunnybrook Research Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M4N 3M5, Canada.
Nikita
N
Reznik
Dental Research Institute, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.
Michael V
MV
Spatafora
Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.
Hanje
H
Chen
Imaging Research, Sunnybrook Research Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M4N 3M5, Canada.
Ross
R
Williams
Imaging Research, Sunnybrook Research Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M4N 3M5, Canada.
Peter N
PN
Burns
Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.
Cameron
C
Clokie
Dental Research Institute, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada; Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Morris F
MF
Manolson
Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.
Sean A F
SA
Peel
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage*; D001861:Bone Regeneration / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations; D065546:Drug Liberation; D008081:Liposomes; D008297:Male; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects*; D011994:Recombinant Proteins / Q000008:administration & dosage; D023822:Tissue Engineering / Q000379:methods; D016212:Transforming Growth Factor beta / Q000008:administration & dosage*; D014463:Ultrasonography / Q000379:methods
D055396:Bone Morphogenetic Protein 2; D003692:Delayed-Action Preparations; D008081:Liposomes; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2
Drug delivey; Nanoparticle; Protein therapy; Tissue implant; Tissue regeneration