Implantation of recombinant human bone morphogenetic proteins with biomaterial carriers: A correlation between protein pharmacokinetics and osteoinduction in the rat ectopic model.
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.
Uludag
H
H
Department of Biomedical Engineering, 10-102 Clinical Sciences Building, University of Alberta, Edmonton, AB T6G 2G3. hasan.uludag@ualberta.ca
D'Augusta
D
D
Golden
J
J
Li
J
J
Timony
G
G
Riedel
R
R
Wozney
J M
JM
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
D001672:Biocompatible Materials; D019485:Bone Morphogenetic Proteins; D004337:Drug Carriers; D011994:Recombinant Proteins