Background: Recombinant human bone morphogenetic proteins (rhBMPs) are bein
g tested in clinical studies for their capacity to elicit bone formation. B
iomaterials used in delivery systems also play a critical role in supportin
g the osteoinductive activity of BMPs, attributable to the controlled prese
ntation of the BMPs to target cells. Despite extensive preclinical studies,
the factors contributing to local rhBMP pharmacokinetics remain to be eluc
idated.
Methods: The rhBMP pharmacokinetics were studied in a rat subcutaneous impl
ant and in an intramuscular injection model. In situ levels of rhBMPs were
quantitated with use of I-125-labeled tracers. The effects of protein struc
tural features and the nature of the biomaterial implant were explored. Ost
eoinduction by biomaterial+rhBMP combinations was assessed by a semiquantit
ative, histology-based bone score.
Results: With the use of rhBMP-2, rhBMP-4, and an N truncated rhBMP-2, the
protein isoelectric point was found critical for the initial retention of r
hBMPs in an implant. Osteoinduction studies carried out in parallel indicat
ed that rhBMPs with a higher implant retention elicited more bone formation
. In the clinically used collagen+rhBMP-2 device, collagen crosslinking and
sterilization were most influential in rhBMP-2 retention. To increase rete
ntion at an application site, thermoreversible polymers were engineered and
shown to enhance local rhBMP-2 retention, especially by injectable deliver
y.
Conclusions: Two critical components of an osteoinductive device-namely, th
e biomaterial and the rhBMP-were shown to influence local protein pharmacok
inetics and osteoinductive activity of the device. Designer biomaterials ca
n provide an additional mechanism to modulate local protein pharmacokinetic
s.
Clinical Relevance: These studies form the foundation of next-generation os
teoinductive devices with improved potency at sites of desired bone regener
ation and reduced side effects at other sites.