Faculty Bibliography

BACKGROUND:Vascularized bone tissue transfer, commonly used to reconstruct large mandibular defects, is challenged by long operative times, extended hospital stay, donor-site morbidity, and resulting health care. 3D-printed osseoconductive tissue-engineered scaffolds may provide an alternative solution for reconstruction of significant mandibular defects. This pilot study presents a novel 3D-printed bioactive ceramic scaffold with osseoconductive properties to treat segmental mandibular defects in a rabbit model. METHODS:Full-thickness mandibulectomy defects (12 mm) were created at the mandibular body of eight adult rabbits and replaced by 3D-printed ceramic scaffold made of 100% β-tricalcium phosphate, fit to defect based on computed tomography imaging. After 8 weeks, animals were euthanized, the mandibles were retrieved, and bone regeneration was assessed. Bone growth was qualitatively assessed with histology and backscatter scanning electron microscopy, quantified both histologically and with micro computed tomography and advanced 3D image reconstruction software, and compared to unoperated mandible sections (UMSs). RESULTS:Histology quantified scaffold with newly formed bone area occupancy at 54.3 ± 11.7%, compared to UMS baseline bone area occupancy at 55.8 ± 4.4%, and bone area occupancy as a function of scaffold free space at 52.8 ± 13.9%. 3D volume occupancy quantified newly formed bone volume occupancy was 36.3 ± 5.9%, compared to UMS baseline bone volume occupancy at 33.4 ± 3.8%, and bone volume occupancy as a function of scaffold free space at 38.0 ± 15.4%. CONCLUSIONS:3D-printed bioactive ceramic scaffolds can restore critical mandibular segmental defects to levels similar to native bone after 8 weeks in an adult rabbit, critical sized, mandibular defect model.

PURPOSE/OBJECTIVE:The objective of this study was to test the osteogenic capacity of dipyridamole-loaded, three-dimensionally printed, bioactive ceramic (3DPBC) scaffolds using a translational, skeletally mature, large-animal calvarial defect model. MATERIALS AND METHODS/METHODS:Custom 3DPBC scaffolds designed to present lattice-based porosity only towards the dural surface were either coated with collagen (control) or coated with collagen and immersed in a 100 μM concentration dipyridamole (DIPY) solution. Sheep (n = 5) were subjected to 2 ipsilateral trephine-induced (11-mm diameter) calvarial defects. Either a control or a DIPY scaffold was placed in each defect, and the surgery was repeated on the contralateral side 3 weeks later. Following sacrifice, defects were evaluated through microcomputed tomography and histologic analysis for bone, scaffold, and soft tissue quantification throughout the defect. Parametric and non-parametric methods were used to determine statistical significance based on data distribution. RESULTS:No exuberant or ectopic bone formation was observed, and no histologic evidence of inflammation was noted within the defects. Osteogenesis was higher in DIPY-coated scaffolds compared to controls at 3 weeks (p = 0.013) and 6 weeks (p = 0.046) in vivo. When bone formation was evaluated as a function of defect radius, average bone formation was higher for DIPY relative to control scaffolds at both time points (significant at defect central regions at 3 weeks and at margins at 6 weeks, p = 0.046 and p = 0.031, respectively). CONCLUSION/CONCLUSIONS:Dipyridamole significantly improves the calvarial bone regeneration capacity of 3DPBC scaffolds. The most significant difference in bone regeneration was observed centrally within the interface between the 3DPBC scaffold and the dura mater.

Background: Mutations in plakophilin-2 (PKP2) are the most common cause of familial Arrhythmogenic Right Ventricular Cardiomyopathy, a disease characterized by ventricular arrhythmias, sudden death, and progressive fibrofatty cardiomyopathy. The relation between loss of PKP2 expression and structural cardiomyopathy remains under study, though paracrine activation of pro-fibrotic intracellular signaling cascades is a likely event. Previous studies have indicated that ATP release into the intracellular space, and activation of adenosine receptors, can regulate fibrosis in various tissues. However, the role of this mechanism in the heart, and in the specific case of a PKP2-initiated cardiomyopathy, remains unexplored. Objectives: To investigate the role of ATP/adenosine in the progression of a PKP2-associated cardiomyopathy. Methods: HL1 cells were used to study PKP2- and Connexin43 (Cx43)-dependent ATP release. A cardiac-specific, tamoxifen-activated PKP2 knock-out murine model (PKP2cKO) was used to define the effect of adenosine receptor blockade on the progression of a PKP2-dependent cardiomyopathy. Results: HL1 cells silenced for PKP2 showed increased ATP release compared to control. Knockout of Cx43 in the same cells blunted the effect. PKP2cKO transcriptomic data revealed overexpression of genes involved in adenosine-receptor cascades. Istradefylline (an adenosine 2A receptor blocker) tempered the progression of fibrosis and mechanical failure observed in PKP2cKO mice. In contrast, PSB115, a blocker of the 2B adenosine receptor, showed opposite effects. Conclusion: Paracrine adenosine 2A receptor activation contributes to the progression of fibrosis and impaired cardiac function in animals deficient in PKP2. Given the limitations of the animal model, translation to the case of patients with PKP2 deficiency needs to be done with caution.