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The Journal of Bone and Joint Surgery (American) 85:75-81 (2003)
© 2003 The Journal of Bone and Joint Surgery, Inc.

Basic Science

rhBMP-2 Release from Injectable Poly(DL-Lactic-co-glycolic Acid)/Calcium-Phosphate Cement Composites

P. Quinten Ruhe, MD, Elizabeth L. Hedberg, BS, Nestor Torio Padron, MD, Paul H.M. Spauwen, MDPhD, John A. Jansen, DDSPhD and Antonios G. Mikos, PhD

Corresponding author: Antonios G. Mikos, PhD
Department of Bioengineering, Rice University, MS-142, P.O. Box 1892, Houston, TX 77251. E-mail address: mikos{at}rice.edu

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from the National Institutes of Health (R01-AR42639), Nanoscale Science and Engineering Initiative of the National Science Foundation (EEC-0118001) (A.G.M.), Netherlands Technology Foundation, and Van Walree Fund, Royal Netherlands Academy of Arts and Science. Yamanouchi Europe BV supplied the rhBMP-2, and Chrysalis Biotechnology Inc. labeled the rhBMP-2. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. 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.

Abstract

Background: In bone tissue engineering, poly(DL-lactic-co-glycolic acid) (PLGA) microparticles are frequently used as a delivery vehicle for bioactive molecules. Calcium phosphate cement is an injectable, osteoconductive, and degradable bone cement that sets in situ. The objective of this study was to create an injectable composite based on calcium phosphate cement embedded with PLGA microparticles for sustained delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2).

Methods: 125 I-labeled rhBMP-2 was incorporated in PLGA microparticles. PLGA microparticle/calcium-phosphate cement composites were prepared in a ratio of 30:70 by weight. Material properties were evaluated by scanning electron microscopy, microcomputed tomography, and mechanical testing. Release kinetics of rhBMP-2 from PLGA/calcium-phosphate cement disks and PLGA microparticles alone were determined in vitro in two buffer solutions (pH 7.4 and pH 4.0) for up to twenty-eight days.

Results: The entrapment yield of rhBMP-2 in PLGA microparticles was a mean (and standard deviation) of 79% ± 8%. Analysis showed spherical PLGA microparticles (average size, 17.2 ±1.3 µm) distributed homogeneously throughout the nanoporous disks. The average compressive strength was significantly lower (p < 0.001) for PLGA and calcium-phosphate cement composite scaffolds than for calcium-phosphate cement scaffolds alone (6.4 ± 0.6 MPa compared with 38.6 ± 2.6 MPa, respectively). Average rhBMP-2 loading was 5.0 ± 0.4 µg per 75-mm 3 disk. Release of rhBMP-2 was limited for all formulations. At pH 7.4, 3.1% ± 0.1% of the rhBMP-2 was released from the PLGA/calcium-phosphate cement disks and 18.0% ± 1.9% was released from the PLGA microparticles alone after twenty-eight days. At pH 4.0, PLGA/calcium-phosphate cement disks revealed more release of rhBMP-2 than did PLGA microparticles alone (14.5% ± 6.3% compared with 5.4% ± 0.7%) by day 28.

Conclusions: These results indicate that preparation of a PLGA/calcium-phosphate cement composite for the delivery of rhBMP-2 is feasible and that the release of rhBMP-2 is dependent on the composite composition and nanostructure as well as the pH of the release medium.

Clinical Relevance: An osteoconductive and osteoinductive rhBMP-2-loaded PLGA/calcium-phosphate cement composite may potentially result in an injectable bone-graft substitute for the regeneration of bone in ectopic or orthotopic sites.


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