Delivery systems for BMPs: factors contributing to protein retention at an application site.
BACKGROUND
Recombinant human bone morphogenetic proteins (rhBMPs) are being tested in clinical studies for their capacity to elicit bone formation. Biomaterials used in delivery systems also play a critical role in supporting the osteoinductive activity of BMPs, attributable to the controlled presentation of the BMPs to target cells. Despite extensive preclinical studies, the factors contributing to local rhBMP pharmacokinetics remain to be elucidated.


METHODS
The rhBMP pharmacokinetics were studied in a rat subcutaneous implant and in an intramuscular injection model. In situ levels of rhBMPs were quantitated with use of 125I-labeled tracers. The effects of protein structural features and the nature of the biomaterial implant were explored. Osteoinduction by biomaterial+rhBMP combinations was assessed by a semiquantitative, 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 rhBMPs in an implant. Osteoinduction studies carried out in parallel indicated 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 retention at an application site, thermoreversible polymers were engineered and shown to enhance local rhBMP-2 retention, especially by injectable delivery.


CONCLUSIONS
Two critical components of an osteoinductive device--namely, the biomaterial and the rhBMP--were shown to influence local protein pharmacokinetics and osteoinductive activity of the device. Designer biomaterials can provide an additional mechanism to modulate local protein pharmacokinetics.


CONCLUSIONS
These studies form the foundation of next-generation osteoinductive devices with improved potency at sites of desired bone regeneration and reduced side effects at other sites.
Uludag
H
H
Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. hasan.uludag@ualberta.ca
Gao
T
T
Porter
T J
TJ
Friess
W
W
Wozney
J M
JM
D000818:Animals; D001672:Biocompatible Materials; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003094:Collagen; D004337:Drug Carriers; D016503:Drug Delivery Systems; D020007:Implants, Experimental; D007273:Injections, Intramuscular; D007457:Iodine Radioisotopes; D008297:Male; D010012:Osteogenesis / Q000187:drug effects*; D011108:Polymers; D051381:Rats; D020318:Rats, Long-Evans; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D016212:Transforming Growth Factor beta
C525718:BMP2 protein, human; C525809:BMP4 protein, human; D001672:Biocompatible Materials; C525720:Bmp2 protein, rat; C525811:Bmp4 protein, rat; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004337:Drug Carriers; D007457:Iodine Radioisotopes; D011108:Polymers; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen