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Dipyridamole Augments Three-Dimensionally Printed Bioactive Ceramic Scaffolds to Regenerate Craniofacial Bone

Lopez, Christopher D., B.A.; Diaz-Siso, J. Rodrigo, M.D.; Witek, Lukasz, M.Sci., Ph.D.; Bekisz, Jonathan M., B.A.; Gil, Luiz F., D.D.S., Ph.D.; Cronstein, Bruce N., M.D.; Flores, Roberto L., M.D.; Torroni, Andrea, M.D., Ph.D.; Rodriguez, Eduardo D., M.D., D.D.S.; Coelho, Paulo G., D.D.S., Ph.D.

Plastic and Reconstructive Surgery: May 2019 - Volume 143 - Issue 5 - p 1408–1419
doi: 10.1097/PRS.0000000000005531

Background: Autologous bone grafts remain a standard of care for the reconstruction of large bony defects, but limitations persist. The authors explored the bone regenerative capacity of customized, three-dimensionally printed bioactive ceramic scaffolds with dipyridamole, an adenosine A2A receptor indirect agonist known to enhance bone formation.

Methods: Critical-size bony defects (10-mm height, 10-mm length, full-thickness) were created at the mandibular rami of rabbits (n = 15). Defects were replaced by a custom-to-defect, three-dimensionally printed bioactive ceramic scaffold composed of β-tricalcium phosphate. Scaffolds were uncoated (control), collagen-coated, or immersed in 100 μM dipyridamole. At 8 weeks, animals were euthanized and the rami retrieved. Bone growth was assessed exclusively within scaffold pores, and evaluated by micro–computed tomography/advanced reconstruction software. Micro–computed tomographic quantification was calculated. Nondecalcified histology was performed. A general linear mixed model was performed to compare group means and 95 percent confidence intervals.

Results: Qualitative analysis did not show an inflammatory response. The control and collagen groups (12.3 ± 8.3 percent and 6.9 ± 8.3 percent bone occupancy of free space, respectively) had less bone growth, whereas the most bone growth was in the dipyridamole group (26.9 ± 10.7 percent); the difference was statistically significant (dipyridamole versus control, p < 0.03; dipyridamole versus collagen, p < 0.01 ). There was significantly more residual scaffold material for the collagen group relative to the dipyridamole group (p < 0.015), whereas the control group presented intermediate values (nonsignificant relative to both collagen and dipyridamole). Highly cellular and vascularized intramembranous-like bone healing was observed in all groups.

Conclusion: Dipyridamole significantly increased the three-dimensionally printed bioactive ceramic scaffold’s ability to regenerate bone in a thin bone defect environment.

New York, N.Y.; and Florianópolis, Santa Catarina, Brazil

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 at New York University College of Dentistry; the Icahn School of Medicine at Mount Sinai; the New York University School of Medicine; and the Department of Dentistry, Universidade Federal de Santa Catarina.

Received for publication November 17, 2017; accepted October 10, 2018.

The first two authors contributed equally to this work.

Presented in abstract form at Plastic Surgery The Meeting 2017, Annual Meeting of the American Society of Plastic Surgeons, in Orlando, Florida, October 6 through 10, 2017; and the International Society of Craniofacial Surgery Biennial Meeting, in Cancun, Mexico, October 24 through 28, 2017.

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.

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Paulo G. Coelho, D.D.S., Ph.D., New York University College of Dentistry, Hansjörg Wyss Department of Plastic Surgery, New York University Langone Health School of Medicine, Mechanical and Aerospace Engineering, New York University Tandon School of Engineering, 433 1st Avenue, Room 844, New York, N.Y. 10010,

©2019American Society of Plastic Surgeons