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Regeneration of a Pediatric Alveolar Cleft Model Using Three-Dimensionally Printed Bioceramic Scaffolds and Osteogenic Agents: Comparison of Dipyridamole and rhBMP-2

Lopez, Christopher D. M.D.; Coelho, Paulo G. D.D.S., Ph.D.; Witek, Lukasz M.Sci., Ph.D.; Torroni, Andrea M.D., Ph.D.; Greenberg, Michael I. B.A.; Cuadrado, Dean L. B.A.; Guarino, Audrey M. B.A.; Bekisz, Jonathan M. M.D.; Cronstein, Bruce N. M.D.; Flores, Roberto L. M.D.

Plastic and Reconstructive Surgery: August 2019 - Volume 144 - Issue 2 - p 358-370
doi: 10.1097/PRS.0000000000005840

Background: Alveolar clefts are traditionally treated with secondary bone grafting, but this is associated with morbidity and graft resorption. Although recombinant human bone morphogenetic protein-2 (rhBMP-2) is under investigation for alveolar cleft repair, safety concerns remain. Dipyridamole is an adenosine receptor indirect agonist with known osteogenic potential. This study compared dipyridamole to rhBMP-2 at alveolar cleft defects delivered using bioceramic scaffolds.

Methods: Skeletally immature New Zealand White rabbits underwent unilateral, 3.5 × 3.5-mm alveolar resection adjacent to the growing suture. Five served as negative controls. The remaining defects were reconstructed with three-dimensionally printed bioceramic scaffolds coated with 1000 μm of dipyridamole (n = 6), 10,000 μm of dipyridamole (n = 7), or 0.2 mg/ml of rhBMP-2 (n = 5). At 8 weeks, new bone was quantified. Nondecalcified histologic evaluation was performed, and new bone was evaluated mechanically. Statistical analysis was performed using a generalized linear mixed model and the Wilcoxon rank sum test.

Results: Negative controls did not heal, whereas new bone formation bridged all three-dimensionally printed bioceramic treatment groups. The 1000-μm dipyridamole scaffolds regenerated 28.03 ± 7.38 percent, 10,000-μm dipyridamole scaffolds regenerated 36.18 ± 6.83 percent (1000 μm versus 10,000 μm dipyridamole; p = 0.104), and rhBMP-2–coated scaffolds regenerated 37.17 ± 16.69 percent bone (p = 0.124 versus 1000 μm dipyridamole, and p = 0.938 versus 10,000 μm dipyridamole). On histology/electron microscopy, no changes in suture biology were evident for dipyridamole, whereas rhBMP-2 demonstrated early signs of suture fusion. Healing was highly cellular and vascularized across all groups. No statistical differences in mechanical properties were observed between either dipyridamole or rhBMP-2 compared with native bone.

Conclusion: Dipyridamole generates new bone without osteolysis and early suture fusion associated with rhBMP-2 in skeletally immature bone defects.

New York, N.Y.

From the Hansjörg Wyss Department of Plastic Surgery and the Division of Translational Medicine, Department of Medicine, New York University Langone Health; the Department of Biomaterials and Biomimetics, New York University College of Dentistry; and the Icahn School of Medicine at Mount Sinai.

Received for publication June 10, 2018; accepted February 6, 2019.

Presented in part at Plastic Surgery The Meeting 2018, Annual Meeting of the American Society of Plastic Surgeons, in Chicago, Illinois, September 28 through October 1, 2018.

Disclosure:Dr. Cronstein is a co-inventor of the dipyridamole-related technology. Dr. Coelho is a co-inventor of the 3D printed scaffold technology. The other authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

Christopher D. Lopez, M.D., Hansjörg Wyss Department of Plastic Surgery, New York University Langone Health, 307 East 33rd Street, New York, N.Y. 10016,, Twitter: @cd_lopez_, Instagram: @c_low24_

Copyright © 2019 by the American Society of Plastic Surgeons