title: The influence of collagen and hyaluronan matrices on the delivery and bioactivity of bone morphogenetic protein-2 and ectopic bone formation.
abstract: Bone morphogenetic protein-2 (BMP-2) is known to enhance fracture healing when delivered via a bovine collagen sponge. However, collagen rapidly releases BMP-2 with a high burst phase that is followed by a low sustained phase. As a result, supra-physiological doses of BMP-2 are often required to successfully treat bone defects. High BMP-2 dosing can introduce serious side effects that include edema, bone overgrowth, cyst-like bone formation and significant inflammation. As the release behavior of BMP-2 carriers significantly affects the efficacy of fracture healing, we sought to compare the influence of two BMP-2 delivery matrices with contrasting release profiles on BMP-2 bioactivity and ectopic bone formation. We compared a thiol-modified hyaluronan (Glycosil™) hydrogel that exhibits a low burst followed by a sustained release of BMP-2 to a collagen sponge for the delivery of three different doses of BMP-2, the bioactivities of released BMP-2 and ectopic bone formation. Analysis of bone formation by micro-computed tomography revealed that low burst followed by sustained release of BMP-2 from a hyaluronan hydrogel induced up to 456% more bone compared to a BMP-2 dose-matched collagen sponge that has a high burst and sustained release. This study demonstrates that BMP-2 released with a low burst followed by a sustained release of BMP-2 is more desirable for bone formation. This highlights the therapeutic potential of hydrogels, particularly hyaluronan-based, for the delivery of BMP-2 for the treatment of bone defects and may help abrogate the adverse clinical effects associated with high dose growth factor use.
authors.affiliation: Institute of Medical Biology, A(∗)STAR, 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore.
authors.forename: Gajadhar
authors.initials: G
authors.lastname: Bhakta
authors.forename: Zophia X H
authors.initials: ZX
authors.lastname: Lim
authors.forename: Bina
authors.initials: B
authors.lastname: Rai
authors.forename: Tingxuan
authors.initials: T
authors.lastname: Lin
authors.forename: James H
authors.initials: JH
authors.lastname: Hui
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Victor
authors.initials: V
authors.lastname: Nurcombe
authors.forename: Simon M
authors.initials: SM
authors.lastname: Cool
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects; D002417:Cattle; D002460:Cell Line; D003094:Collagen / Q000494:pharmacology*; D016503:Drug Delivery Systems; D005260:Female; D006820:Hyaluronic Acid / Q000494:pharmacology*; D020100:Hydrogels; D051379:Mice; D009999:Ossification, Heterotopic / Q000188:drug therapy*; D019919:Prosthesis Implantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D055114:X-Ray Microtomography
chemical_list: D001672:Biocompatible Materials; D055396:Bone Morphogenetic Protein 2; D020100:Hydrogels; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D006820:Hyaluronic Acid; D003094:Collagen
keywords: Collagen sponge; Glycosaminoglycan; Hydrogel; Osteogenesis; Release kinetics