Optimized use of a biodegradable polymer as a carrier material for the local delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2).
To improve the efficacy of a block copolymer of poly-d, l-lactic acid with randomly inserted p-dioxanone and polyethylene glycol (PLA-DX-PEG) as a drug delivery system for recombinant human bone morphogenetic proteins (rhBMPs), we examined the relationship between the volume of PLA-DX-PEG, the dose of rhBMP-2 and osteoinduction in a mouse model of ectopic bone formation. In a series of studies, we compared the size and bone mineral content (BMC) of ectopically induced bone by PLA-DX-PEG and collagen sponges carrying different quantities of rhBMP (0, 1, 2, 5, 10, 20 microg). An additional experiment was designed to investigate how a range of PLA-DX-PEG polymer volumes (15, 30, 60, 90 mg) with a fixed rhBMP concentration (0.01 wt%), altered the size and BMC of the induced ossicle. The influence of polymer volume was also examined in a further experiment wherein a fixed amount of rhBMP was placed in a range of PLA-DX-PEG copolymer volumes to give different concentrations of the protein per implant (0.02-0.0017 wt%). The results indicate that the bone yields were linearly dependent on the dose of rhBMP and also were proportional to the polymer volume above the minimal concentration of rhBMP-2 (0.0017 wt% in this series). The optimal concentration of rhBMP-2 in PLA-DX-PEG was 0.003 wt% in mice. The data provide important insights into the fabrication of implants that provide efficacious delivery of rhBMP-2 using the lowest possible dose of this expensive osteoinductive protein. This information will be of value for the clinical use of BMPs.
Kato
Minori
M
Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka City University 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. minori@msic.med.osaka-cu.ac.jp
Toyoda
Hiromitsu
H
Namikawa
Takashi
T
Hoshino
Masatoshi
M
Terai
Hidetomi
H
Miyamoto
Shimpei
S
Takaoka
Kunio
K
D000818:Animals; D001673:Biodegradation, Environmental; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004343:Drug Implants / Q000737:chemistry*; D006801:Humans; D007773:Lactates / Q000737:chemistry*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011092:Polyethylene Glycols / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000494:pharmacology*
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004337:Drug Carriers; D004343:Drug Implants; D007773:Lactates; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C432470:polylactic acid-dioxanone-polyethylene glycol block copolymer; D011092:Polyethylene Glycols