Plastic Surgery Research Council

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Integrating Tissue Engineering Principles for Skeletal Regeneration of the Radius and Mandible in Translational Models
Christopher D. Lopez, BA1,2, Lukasz Witek, MSci, PhD2, Nick Tovar, PhD2, J. Rodrigo Diaz-Siso, MD1, Jonathan M. Bekisz, BA1, Bruce N. Cronstein, MD3, Roberto L. Flores, MD1, Paulo G. Coelho, DDS, PhD2,1.
1Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health, New York, NY, USA, 2Department of Biomaterials & Biomimetics, NYU College of Dentistry, New York, NY, USA, 3Department of Medicine, NYU Langone Health, New York, NY, USA.

Purpose: Vascularized bone flaps can successfully reconstruct large bony defects of the upper extremity and mandible, but these interventions have several limitations. Tissue engineering may offer alternative solutions but there is a paucity of translational work investigating large bony defect healing. Furthermore, several osteogenic biomolecules exist, but well-investigated molecules such as rhBMP-2 have concerning effects, including: exuberant bone formation, osteolysis and malignant degeneration. We recently reported that 3D-printed bioceramic scaffolds designed with osseoconductive geometries(1) can regenerate vascularized bone at critical-sized mandibulectomies(2). We have also recently reported that adenosine A2A receptor ligation can facilitate robust osteogenesis as well as to BMP-2 by upregulating osteoblast proliferation and attenuating osteoclast activity(3). This study investigates the combined regenerative capacity of 3D-printed bioceramic scaffolds locally delivering Dipyridamole (DIPY), an adenosine A2A receptor indirect agonist, at critical-sized bony defects of the rabbit radius and mandible.

Injury Model SiteNegative Control (no scaffold placement)Uncoated Scaffold100uM DIPY Coated Scaffold1,000uM DIPY Coated ScaffoldCOLL-coated scaffold

Methods: Experimental group design is described in Table 1. Critical-sized (~11mm) full-thickness bony defects were created in rabbit radii (n=20) and rabbit mandibular rami (n=15). Defects were replaced with 3D-printed bioceramic scaffolds designed through microCT imaging to fit and fill defects. Within the ramus defect, devices differed only in DIPY concentration. No activity restriction occurred post-
operatively. At t=8 weeks, animals were euthanized. Bone regeneration was assessed within scaffold interstices with microCT/AMIRA 3D reconstruction software and non-decalcified histology. Mechanical properties assessed included reduced elastic modulus through nanoidentation. One-way ANOVA analysis was performed, significance at α=0.05.
Results: Highly cellular and vascularized intramembranous-like bone healing was observed irrespective of anatomic site or scaffold treatment. Bone generation was seen only within scaffold porosity and no exuberant or ectopic bone formation was observed.
Radii critical-sized defect negative controls failed to regenerate to any significant degree & was quantified at 12.12±4.73% (significantly less than all groups, p<0.05). Bone regeneration were quantified at 23.87±7.31% (uncoated), 30.21±6.75% (100μM DIPY), and 41.81±4.6% (1,000μM DIPY) of scaffold interstices. 1,000μM DIPY bone formation was significantly greater than uncoated group (p=0.001) and 100μM-coated group (p=0.02). Reduced elastic modulus values were not statistically different from native bone for all groups.
Mandibular rami bone regeneration were quantified at 12.3±8.3% (uncoated), 6.9±8.3% (COLL) and 26.9±10.7% (100μM-DIPY) (p<0.03 DIPY vs. control and p<0.01 DIPY vs. COLL).
Conclusions: Rapid, controlled, and defect-specific bone regeneration using 3D-printed bioceramic scaffolds is feasible and enhanced with local A2AR activation. Dipyridamole and β-tricalcium phosphate have well-established safety profiles, making this regenerative approach highly translatable. Further studies are warranted.
Acknowledgements: This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases 5R01AR068593-02 & 3R01AR068593-02S1
References: [1]Coelho+Arch Biochem Biophys, 2014;561[2]Lopez+J Surg Res(accepted 2017)[3]Mediero+ FASEB,2015;29(4)

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