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3D-printed bioactive ceramic (3DPBC) scaffolds composed of beta-tricalcium phosphate (β-TCP) and coated in the osteogenic agent dipyridamole (DIPY) have been previously shown to heal critically sized calvarial defects in several adult animal models.1-3 This bone tissue engineering construct has yet to be applied in a pediatric craniofacial model where the pathologic effects of osteogenic agents on the growing sutures may be of concern. The purpose of this study is to apply the described bone tissue engineering construct in a pediatric growing animal model and 1) quantify osteogenic potential in a growing calvarium; 2) maximize the scaffold design and dipyridamole concentration for the growing calvarium; and 3) characterize the effects of this bone tissue engineering construct on the growing suture.
Method/Description:
Bilateral calvarial defects (10 mm) were created in 5-week-old New Zealand White rabbits (n = 14) 2mm posterior and lateral to the coronal suture and sagittal sutures, respectively. 3DPBC scaffolds were constructed in quadrant form composed varying pore dimensions (220μm, 330μm, 500μm). Each scaffold was collagen coated and soaked in varying concentrations of DIPY (100μM, 1000μM, 10,000μM). Controls comprised empty defects and collagen coated scaffolds. Scaffolds were then placed into the calvarial defects to fill the bone space. Animals were euthanized 8-weeks post-operatively. Calvaria were analyzed using micro-computed tomography and 3D reconstruction. Mixed model analyses were conducted considering pore size and dosage effects on bone growth (a=0.05).
Results:
3DPBC scaffolds generated bone throughout the construct (defect marginal and central regions) while bone healing in empty sites was restricted to the defect margins confirming its critical size dimension at 8 weeks in vivo. When evaluating volume occupied by bone solely as factor of pore size (small, medium, and large), the small pores yielded the highest mean value (26.8% ± 3.4) when compared to medium and large. However, analysis indicted no statistical differences between the sizes (p>0.10). In assessing the effectiveness of coating the scaffold in either collagen or dipyridamole (DIPY), higher mean bone occupancy values were observed in the scaffolds coated in 1,000μM DIPY (27.9% ± 4.05), which was significantly greater in comparison to the collagen-coated scaffolds (20.9% ± 4.43, p=0.021). Growing cranial sutures remained patent across all concentrations of DIPY, including 10,000μM.
Conclusion:
3DPBC scaffolds effectively generates bone in a growing calvarial animal model. Pore size and dipyridamole dose has been optimized for the growing cranium. Cranial suture patency is preserved even at a 2 log increase over the effective ostetogenic dose.
References:
- Ishack S, Mediero A, Wilder T, Ricci JL, Cronstein BN. Bone regeneration in critical bone defects using three-dimensionally printed beta-tricalcium phosphate/hydroxyapatite scaffolds is enhanced by coating scaffolds with either dipyridamole or BMP-2. J Biomed Mater Res B Appl Biomater 2017;105:366-75.
- Simon JL, Michna S, Lewis JA, et al. In vivo bone response to 3D periodic hydroxyapatite scaffolds assembled by direct ink writing. J Biomed Mater Res A 2007;83:747-58.
- Bekisz JM, Flores RL, Witek L, et al. Dipyridamole enhances osteogenesis of three-dimensionally printed bioactive ceramic scaffolds in calvarial defects. J Craniomaxillofac Surg 2017.