title: Implantation of recombinant human bone morphogenetic proteins with biomaterial carriers: A correlation between protein pharmacokinetics and osteoinduction in the rat ectopic model.
abstract: This study was carried out to determine the effect of recombinant human bone morphogenetic protein (rhBMP) pharmacokinetics (PK) on rhBMP-induced osteoinductive activity. It was our working hypothesis that the PK of a rhBMP significantly affects its osteoinductive activity. The PK of various rhBMPs (rhBMP-2, rhBMP-4, rhBMP-6, and chemically modified rhBMP-2) implanted with four biomaterial carries (Helistat, hDBM, Osteograf/N, and Dexon) was determined using (125)I-labeled proteins in the rat ectopic assay. A select combination of rhBMP and carriers then was evaluated in the rat ectopic assay for osteoinductive activity using a semi-quantitative histologic scoring system. The results indicate that initial protein retention is dependent on protein isoelectric point (pI); proteins with a higher pI yielded a higher implant retention. Subsequent PK was not strongly dependent on the pI or on the carrier. Because of the difference in early retention, the rhBMP-carrier combinations exhibited a >100-fold difference in implant-retained protein dose. When rhBMP-2 and rhBMP-4 were implanted with the carriers, more rhBMP-2 was retained in an implant, and the osteoinductive potency of rhBMP-2 typically was higher than rhBMP-4 at low implantation doses. We conclude that protein pI plays a significant role in the local retention of implanted rhBMP and that higher retention yields a higher osteoinductive activity.
authors.affiliation: Department of Biomedical Engineering, 10-102 Clinical Sciences Building, University of Alberta, Edmonton, AB T6G 2G3. hasan.uludag@ualberta.ca
authors.forename: H
authors.initials: H
authors.lastname: Uludag
authors.forename: D
authors.initials: D
authors.lastname: D'Augusta
authors.forename: J
authors.initials: J
authors.lastname: Golden
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: G
authors.initials: G
authors.lastname: Timony
authors.forename: R
authors.initials: R
authors.lastname: Riedel
authors.forename: J M
authors.initials: JM
authors.lastname: Wozney
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001672:Biocompatible Materials; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016723:Bone Remodeling / Q000187:drug effects*; D016466:CHO Cells; D006224:Cricetinae; D004337:Drug Carriers; D016503:Drug Delivery Systems; D006801:Humans; D008969:Molecular Sequence Data; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D001672:Biocompatible Materials; D019485:Bone Morphogenetic Proteins; D004337:Drug Carriers; D011994:Recombinant Proteins