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 bon e morphogenetic protein (rhBMP) pharmacokinetics (PK) on rhBMP-induced oste oinductive activity. It was our working hypothesis that the PK of a rhBMP s ignificantly 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(R), hDBM, Osteograf/N(R), and Dexon(R)) was determined using I-125-labeled proteins in the rat ectopic assay. A se lect combination of rhBMP and carriers then was evaluated in the rat ectopi c assay for osteoinductive activity using a semi-quantitative histologic sc oring system. The results indicate that initial protein retention is depend ent on protein isoelectric point (pI); proteins with a higher pi yielded a higher implant retention. Subsequent PK was not strongly dependent on the p I or on the carrier. Because of the difference in early retention, the rhBM P-carrier combinations exhibited a >100-fold difference in implant-retained protein dose. When rhBMP-2 and rhBMP-4 were implanted with the carriers, m ore rhBMP-2 was retained in an implant, and the osteoinductive potency of r hBMP-2 typically was higher than rhBMP-4 at low implantation doses. We conc lude that protein pi plays a significant role in the local retention of imp lanted rhBMP and that higher retention yields a higher osteoinductive activ ity. (C) 2000 John Wiley & Sons, Inc.