Delivery systems for BMPs: Factors contributing to protein retention at anapplication site

Citation
H. Uludag et al., Delivery systems for BMPs: Factors contributing to protein retention at anapplication site, J BONE-AM V, 83A, 2001, pp. S128-S135
Citations number
23
Categorie Soggetti
Ortopedics, Rehabilitation & Sport Medicine","da verificare
Journal title
JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME
ISSN journal
00219355 → ACNP
Volume
83A
Year of publication
2001
Part
2
Supplement
1
Pages
S128 - S135
Database
ISI
SICI code
0021-9355(2001)83A:<S128:DSFBFC>2.0.ZU;2-O
Abstract
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.