Assessment of Hedgehog Signaling Pathway Activation for Craniofacial Bone Regeneration in a Critical-Sized Rat Mandibular Defect.

IMPORTANCE: Osseous craniofacial defects are currently reconstructed with bone grafting, rigid fixation, free tissue transfer, and/or recombinant human bone morphogenetic protein 2. Although these treatment options often have good outcomes, they are associated with substantial morbidity, and many patients are not candidates for free tissue transfer. OBJECTIVE: To assess whether polysaccharide-based scaffold (PS) constructs that are cross-linked with smoothened agonist (SAG), vascular endothelial growth factor (VEGF), and bone morphogenetic protein 6 (BMP-6) would substantially increase bone regeneration. DESIGN, SETTING, AND PARTICIPANTS: This animal model study was conducted at the University of Virginia School of Medicine Cui Laboratory from March 1, 2017, to June 30, 2017. Thirty-three 10-week-old female Lewis rats were acquired for the study. Bilateral nonsegmental critical-sized defects were created in the angle of rat mandibles. The defects were either left untreated or filled with 1 of the 9 PSs. The rats were killed after 8 weeks, and bone regeneration was evaluated using microcomputed tomographic imaging and mechanical testing. Analysis of variance testing was used to compare the treatment groups. MAIN OUTCOMES AND MEASURES: Blinded analysis and computer analysis of the microcomputed tomographic images were used to assess bone regeneration. RESULTS: In the 33 female Lewis rats, minimal healing was observed in the untreated mandibles. Addition of SAG was associated with increases in bone regeneration and bone density in all treatment groups, and maximum bone healing was seen in the group with BMP-6, VEGF, and SAG cross-linked to PS. For each of the 5 no scaffold group vs BMP-6, VEGF, and SAG cross-linked to PS group comparisons, mean defect bone regeneration was 4.14% (95% CI, 0.94%-7.33%) vs 66.19% (95% CI, 54.47%-77.90%); mean bone volume, 14.52 mm3 (95% CI, 13.07-15.97 mm3) vs 20.87 mm3 (95% CI, 14.73- 27.01 mm3); mean bone surface, 68.97 mm2 (95% CI, 60.08-77.85 mm2) vs 96.77 mm2 (95% CI, 76.11-117.43 mm2); mean ratio of bone volume to total volume, 0.11 (95% CI, 0.10-0.11) vs 0.15 (95% CI, 0.10-0.19); and mean connectivity density 0.03 (95% CI, 0.02-0.05) vs 0.32 (95% CI, 0.25-0.38). On mechanical testing, mandibles with untreated defects broke with less force than control mandibles in which no defect was made, although this force did not reach statistical significance. No significant difference in force to fracture was observed among the treatment groups. CONCLUSIONS AND RELEVANCE: In this rat model study, activation of the hedgehog signaling pathway using smoothened agonist was associated with increased craniofacial bone regeneration compared with growth factors alone, including US Food and Drug Administration-approved recombinant human bone morphogenetic protein 2. Pharmaceuticals that target this pathway may offer a new reconstructive option for bony craniofacial defects as well as nonunion and delayed healing fractures. LEVEL OF EVIDENCE: NA.

Overview of a combined computational-experimental evaluation for the assessment of panoramic sunroof impact characteristics for ejection mitigation.

OBJECTIVE: To meet increasing customer demand, many vehicle manufacturers are now offering a panoramic sunroof option in their vehicle lineup. Currently, there is no regulatory or consumer test aimed at assessing the potential for ejection mitigation of roof glazing, which leaves manufacturers to develop internal performance standards to guide designs. The goal of this study was to characterize the variety of occupant-to-roof impacts involving unbelted occupants in rollover crashes to determine the ranges of possible effective masses and impact velocities. This information can be used to define occupant retention requirements and performance criteria for roof glazing in occupant ejection protection. METHODS: This study combined computational (MADYMO and LS-Dyna) simulations of occupant kinematics in rollover crashes with laboratory rollover crash tests using the dynamic rollover test system (DRoTS) and linked them through controlled anthropomorphic test device (ATD)-to-roof ("drop") impact tests. The DRoTS and the ATD drop tests were performed to explore impact scenarios and estimate dummy-to-roof impact impulses. Next, 13 sets of vehicle kinematics and deformation data were extracted from a combination of vehicle dynamics and finite element model simulations that reconstructed variations of rollover crash cases from the field data. Then occupant kinematics data were extracted from a full-factorial sensitivity study that used MADYMO simulations to investigate how changes in anthropometry and seating position would affect occupant-roof impacts across all 13 cases. Finite element (FE) simulations of ATD and Global Human Body Models Consortium (GHBMC) human body model (HBM) roof impacts were performed to investigate the most severe cases from the MADYMO simulations to generate a distribution of head-to-roof impact energies. RESULTS: From the multiparameter design of experiment and experimental study, kinematics and energy output were extracted and analyzed. Based on dummy-to-roof impact force and dummy-to-roof impact velocity, the most severe rollover scenarios were identified. In the DRoTS experiments followed by the drop tests, the range of identified impact velocities was between 2 and 5.8 m/s. However, computational simulations of the rollover crashes showed higher impact velocities and similar effective masses. The largest dummy-to-roof impact velocity was 11 m/s. CONCLUSIONS: This study combined computational and experimental analyses to determine a range of possible unbelted occupant-to-roof impact energies. These results can be used to determine design parameters for an impactor for the assessment of the risk of roof glazing ejection for unbelted occupants in rollover crashes.