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The Journal of Bone and Joint Surgery (American) 83:S128-S135 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.

Delivery Systems for the BMPs

Delivery Systems for BMPs: Factors Contributing to Protein Retention at an Application Site

Hasan Uludag, PhD, Tiejun Gao, PhD, Thomas J. Porter, PhD, Wolfgang Friess, PhD and John M. Wozney, PhD

From Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Biopharmaceutical Characterization and Analysis Group and Bone Biology and Applications Group, Genetics Institute, Inc., Andover, Massachusetts, U.S.A.; and Department of Pharmaceutical Technology, University of Erlangen, Erlangen, Germany
Hasan Uludag, PhD
Tiejun Gao, PhD
Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, 1098 EDC Building, Edmonton, Alberta T6G 2V2, Canada. E-mail address for Hasan Uludag: hasan.uludag{at}ualberta.ca

Thomas J. Porter, PhD
Biopharmaceutical Characterization and Analysis Group

John M. Wozney, PhD
Bone Biology and Applications Group
Genetics Institute, Inc., One Burtt Road, Andover, MA 01810, U.S.A.

Wolfgang Friess, PhD
Department of Pharmaceutical Technology, University of Erlangen, Cauerstrasse 4, Erlangen 91058, Germany

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from Genetics Institute, Inc. In addition, one or more of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (Genetics Institute, Inc.). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

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.

Clinical Relevance: 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.


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