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Sustained Delivery of rhBMP-2 by Means of Poly(Lactic-co-Glycolic Acid) Microspheres: Cranial Bone Regeneration without Heterotopic Ossification or Craniosynostosis

Wink, Jason D. M.D., M.T.R.; Gerety, Patrick A. M.D.; Sherif, Rami D. B.A.; Lim, Youngshin Ph.D.; Clarke, Nadya A. M.D.; Rajapakse, Chamith S. Ph.D.; Nah, Hyun-Duck D.M.D., Ph.D.; Taylor, Jesse A. M.D.

Plastic & Reconstructive Surgery: July 2014 - Volume 134 - Issue 1 - p 51–59
doi: 10.1097/PRS.0000000000000287
Experimental: Original Articles

Background: Commercially available recombinant human bone morphogenetic protein 2 (rhBMP2) has demonstrated efficacy in bone regeneration, but not without significant side effects. The authors used rhBMP2 encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres placed in a rabbit cranial defect model to test whether low-dose, sustained delivery can effectively induce bone regeneration.

Methods: The rhBMP2 was encapsulated in 15% PLGA using a double-emulsion, solvent extraction/evaporation technique, and its release kinetics and bioactivity were tested. Two critical-size defects (10 mm) were created in the calvaria of New Zealand white rabbits (5 to 7 months of age, male and female) and filled with a collagen scaffold containing either (1) no implant, (2) collagen scaffold only, (3) PLGA-rhBMP2 (0.1 μg per implant), or (4) free rhBMP2 (0.1 μg per implant). After 6 weeks, the rabbits were killed and defects were analyzed by micro–computed tomography, histology, and finite element analysis.

Results: The rhBMP2 delivered by means of bioactive PLGA microspheres resulted in higher volumes and surface area coverage of new bone than an equal dose of free rhBMP2 by micro–computed tomography (p = 0.025 and p = 0.025). Finite element analysis indicated that the mechanical competence using the regional elastic modulus did not differ with rhBMP2 exposure (p = 0.70). PLGA-rhBMP2 did not demonstrate heterotopic ossification, craniosynostosis, or seroma formation.

Conclusions: Sustained delivery by means of PLGA microspheres can significantly reduce the rhBMP2 dose required for de novo bone formation. Optimization of the delivery system may be a key to reducing the risk for recently reported rhBMP2-related adverse effects.

Philadelphia, Pa.

From the Division of Plastic Surgery and the Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, The Children’s Hospital of Philadelphia.

Received for publication June 28, 2013; accepted November 13, 2013.

Poster presentation at the 92nd Annual Meeting of the American Association of Plastic Surgeons, in New Orleans, Louisiana, April 20 through 23, 2013; and podium presentation at the 58th Annual Meeting of the Plastic Surgery Research Council, in Santa Monica, California, May 2 through 4, 2013; the 12th International Congress on Cleft Lip/Palate and Related Craniofacial Anomalies, in Orlando, Florida, May 5 through 10, 2013; and the 15th Congress of the International Society for Craniofacial Surgery, in Jackson Hole, Wyoming, September 10 through 14, 2013.

Disclosure: The authors have no financial interest in any of the products, devices, or drugs mentioned in this article.

Jesse A. Taylor, M.D., The Perelman School of Medicine at the University of Pennsylvania, The Children’s Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Ninth Floor, Philadelphia, Pa. 19104, taylorj5@email.chop.edu

©2014American Society of Plastic Surgeons