Faculty Bibliography

Adenosine receptor activation has been explored as a modulator of the inflammatory process that propagates osteoarthritis. It has been reported that cartilage has enhanced regenerative potential when influenced by adenosine receptor activation. As adenosine's role in maintaining chondrocyte homeostasis at the cellular and molecular levels is explored, successful in vivo applications of adenosine delivery for cartilage repair continue to be reported. This review summarizes the role adenosine receptor ligation plays in chondrocyte homeostasis and regeneration of articular cartilage damaged in osteoarthritis. It also reports on all the modalities reported for delivery of adenosine through in vivo applications.

PURPOSE/OBJECTIVE:The increasing prevalence of obesity and/or metabolic syndrome (O/MS) and diabetes mellitus (DM) remains a global health concern. Clinically relevant and practical translational models mimicking human characteristics of these conditions are lacking. This study aimed to demonstrate proof of concept of the induction of stable O/MS and type 2 DM in a Göttingen minipig model and validate both of these disease-adjusted Göttingen minipig models as impaired healing models for the testing of dental implants. MATERIALS AND METHODS/METHODS:Nine minipigs were split into 3 groups-control (normal diet), obese (cafeteria diet), and diabetic (cafeteria diet plus streptozotocin)-followed by placement of dental implants. Inflammatory markers including tumor necrosis factor α, C-reactive protein, and cortisol were recorded for each study group. Removal torque was measured, and histomorphometric analysis (bone-to-implant contact and bone area fraction occupancy) was performed. RESULTS:O/MS pigs showed, on average, a 2-fold increase in plasma C-reactive protein (P < .05) and cortisol (P < .09) concentrations compared with controls; DM pigs showed, on average, a 40-fold increase in plasma tumor necrosis factor α levels (P < .05) and a 2-fold increase in cortisol concentrations (P < .05) compared with controls. The impact of O/MS and DM on implants was determined. The torque to interface failure was highest in the control group (200 N-cm) and significantly lower in the O/MS (90 N-cm) and DM (60 N-cm) groups (P < .01). Bone formation around implants was significantly greater in the control group than in the O/MS and DM groups (P < .02). CONCLUSIONS:Both O/MS and DM minipigs express a human-like disease phenotype, and both presented bone-healing impairment around dental implants. Our finding of no significant difference between type 2 DM and O/MS in bone formation around implants provides evidence that further investigation of the impact of O/MS is warranted.

Angiogenesis is a critical aspect of wound healing. We investigated the role of keratinocytes in promoting angiogenesis in mice with lineage specific deletion of the transcription factor FOXO1. The results indicate that keratinocyte-specific deletion of Foxo1 reduces VEGFA expression in mucosal and skin wounds and leads to the reduced endothelial cell proliferation, reduced angiogenesis and impaired re-epithelialization and granulation tissue formation. In vitro FOXO1 was needed for VEGFA transcription and expression. In a porcine dermal wound healing model that closely resembles healing in humans, local application of a FOXO1 inhibitor reduced angiogenesis. This is the first report that FOXO1 directly regulates VEGFA expression and that FOXO1 is needed for normal angiogenesis during wound healing.

This study evaluated the influence of polishing protocols on the surface roughness of flowable and regular bulk fill composites. Five bulk fill composites were tested: SureFil SDR Flow (SDR), Tetric EvoFlow Bulk fill (TEF), Filtek Bulk Fill Flowable (FIF), Tetric EvoCeram Bulk Fill (TEC), and Filtek Bulk Fill Posterior (FIP). Two polishing protocols were tested: Sof-Lex and Astropol. Astropol created a smoother surface for FIP (P < .05); however, the polishing protocol did not influence surface roughness on TEC (P > .05). SDR, TEF, and FIF exhibited rougher surfaces when polished. Sof-Lex created rougher surfaces for bulk fill composites. It was concluded that surface roughness was related to material composition rather than the polishing system.

OBJECTIVE:To characterize the mechanical properties of different coating methods of DLC (diamond-like carbon) onto dental implant abutment screws, and their effect on the probability of survival (reliability). METHODS:Seventy-five abutment screws were allocated into three groups according to the coating method: control (no coating); UMS - DLC applied through unbalanced magnetron sputtering; RFPA-DLC applied through radio frequency plasma-activated (n=25/group). Twelve screws (n=4) were used to determine the hardness and Young's modulus (YM). A 3D finite element model composed of titanium substrate, DLC-layer and a counterpart were constructed. The deformation (μm) and shear stress (MPa) were calculated. The remaining screws of each group were torqued into external hexagon abutments and subjected to step-stress accelerated life-testing (SSALT) (n=21/group). The probability Weibull curves and reliability (probability survival) were calculated considering the mission of 100, 150 and 200N at 50,000 and 100,000 cycles. RESULTS:DLC-coated experimental groups evidenced higher hardness than control (p<0.05). In silico analysis depicted that the higher the surface Young's modulus, the higher the shear stress. Control and RFPA showed β<1, indicating that failures were attributed to materials strength; UMS showed β>1 indicating that fatigue contributed to failure. High reliability was depicted at a mission of 100N. At 200N a significant decrease in reliability was detected for all groups (ranging from 39% to 66%). No significant difference was observed among groups regardless of mission. Screw fracture was the chief failure mode. SIGNIFICANCE/CONCLUSIONS:DLC-coating have been used to improve titanium's mechanical properties and increase the reliability of dental implant-supported restorations.

OBJECTIVES/HYPOTHESIS: Although the primary goal of medialization laryngoplasty is to improve glottic closure, implant placement is also likely to alter the biomechanical properties of the vocal fold (VF). We sought to employ novel, nanoscale technology to quantify these properties following medialization based on the hypothesis that different medialization materials will likely yield differential biomechanical effects. STUDY DESIGN: Ex vivo. METHODS: Nine pig larynges were divided into three groups: control, Silastic (Dow Corning, Midland, Michigan, U.S.A.) block medialization, or Gore-Tex (W.L. Gore & Associates, Newark, Delaware) medialization. Laryngoplasty was performed on excised, intact larynges. The larynges were then bisected in the sagittal plane and each subjected to dynamic nanomechanical analysis (nano-DMA) at nine locations using a 250-mum flat-tip punch and frequency sweep-load profile across the free edge of the VF and inferiorly along the conus elasticus. RESULTS: Silastic block and Gore-Tex implant introduced increased storage and loss moduli. Overall, storage moduli mean (maximum) increased from 38 kilopascals (kPa) (119) to 72 kPa (422) and 129 kPa (978) in control, Gore-Tex, and Silastic implants, respectively. Similarly, loss moduli increased from 13 kPa (43) to 22 kPa (201) and 31 kPa (165), respectively. Moduli values varied widely by location in the Silastic block and Gore-Tex groups. At the free VF edge, mean (maximum) storage moduli were lowest in the Gore-Tex group, 20 kPa (44); compared to control, 34.5 kPa (86); and Silastic, 157.9 kPa (978), with similar loss and complex moduli trends. CONCLUSION: Medialization laryngoplasty altered VF structure biomechanical properties; Silastic and Gore-Tex implants differentially impact these properties. LEVEL OF EVIDENCE: NA. Laryngoscope, 2017.

Periodontal furcation defects are usually addressed by the placement of a physical barrier which may limit the regenerative potential of periodontal wounds. This study morphometrically quantified the regenerative effect of brain-derived neurotrophic factor (BDNF) in furcation defects in a non-human primate model. Grade II furcation defects (with and without induced inflammation prior to surgery) were created on the first and second molars of eight non-human primates. Defects were treated with open flap debridement and subsequently filled with either: Group A; BDNF (500 microg mL-1 ) in high-molecular weight-hyaluronic acid (HMW-HA), Group B; BDNF (50 microg mL-1 ) in HMW-HA, Group C; HMW-HA acid only, Group D; unfilled defect, or Group E; BDNF (500 microg mL-1 ) in saline. Periodontal wound healing was observed every 2 weeks by computed-tomography. At 11 weeks all animals were sacrificed and maxillary and mandibular block biopsies were referred for nondecalcified histology. Linear measurements of new cementum (cellular and acellular) and periodontal ligament (PDL) formation were performed. Computerized-tomography reconstruction and software quantification demonstrated successful bone fill for all groups. However, histometric assessment demonstrated significantly higher level of total periodontal regeneration for the 500 microg mL-1 BDNF HMW-HA relative to all other groups. No significant differences in cementogenesis were observed among groups. Significantly higher acellular cementum formation was observed for sites where inflammation was not induced prior to surgical procedures. While all groups experienced similar bone fill and cementogenesis, the 500 microg mL-1 BDNF HMW-HA appeared to most effectively repair PDL (minimum increase of approximately 22% relative to all groups; over 200% relative to unfilled defects). (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2017.

Background/Purpose: 3D-printed bioactive ceramic (3DPBC) scaffolds composed of beta-tricalcium phosphate (b-TCP) and coated in the osteogenic agent dipyridamole have been previously shown to heal critically sized calvarial defects in an adult animal model. This bone tissue engineering construct has yet to be applied in a pediatric craniofacial model and there has been evidence that other osteogenic agents such as BMP-2 can prematurely fuse growing sutures. 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 (DIPY) concentration for the growing calvarium; and 3) characterize the effects of this bone tissue engineering construct on the growing suture. Methods/Description: Bilateral calvarial defects (10 mm) were created in 5-week-old New Zealand White rabbits (n = 14) 2 mm posterior and lateral to the coronal suture and sagittal sutures, respectively. 3DPBC scaffolds were constructed in quadrant form composed by varying pore dimensions (220, 330, and 500 mum). Each scaffold was collagen coated and soaked in varying concentrations of DIPY (100, 1000, and 10 000 muM). 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 postoperatively. 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).
Result(s): Scaffold group healing presented bone formation throughout the scaffold structure (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. No significant difference in bone formation was detected when experimental groups were collapsed over pore size (P > .40). When pore size was collapsed over DIPY concentration, higher mean values were observed for the DIPYimmersed groups, and significance was shown between the 1000-muM and collagen groups (P < .05). Pore size and DIPY interaction was more pronounced for the 330-mum pore size where both the 100-and 1000-mum dosages presented significantly higher bone formation compared to collagen (P < .05). Across all concentrations of DIPY, including 10 000 mM (10 times greater than the experimental concentration, yielding the highest bone formation), sutures remained patent.
Conclusion(s):We present an effective bone tissue engineering scaffold design and dipyridamole concentration that significantly improve bone growth in a pediatric growing calvarial model and preserves cranial suture patency

PURPOSE/OBJECTIVE:To evaluate the probability of survival and failure modes of different external hexagon connection systems restored with anterior cement-retained single-unit crowns. The postulated null hypothesis was that there would be no differences under accelerated life testing. MATERIALS AND METHODS/METHODS:Fifty-four external hexagon dental implants (∼4 mm diameter) were used for single cement-retained crown replacement and divided into 3 groups: (3i) Full OSSEOTITE, Biomet 3i (n = 18); (OL) OEX P4, Osseolife Implants (n = 18); and (IL) Unihex, Intra-Lock International (n = 18). Abutments were torqued to the implants, and maxillary central incisor crowns were cemented and subjected to step-stress-accelerated life testing in water. Use-level probability Weibull curves and probability of survival for a mission of 100,000 cycles at 200 N (95% 2-sided confidence intervals) were calculated. Stereo and scanning electron microscopes were used for failure inspection. RESULTS:The beta values for 3i, OL, and IL (1.60, 1.69, and 1.23, respectively) indicated that fatigue accelerated the failure of the 3 groups. Reliability for the 3i and OL (41% and 68%, respectively) was not different between each other, but both were significantly lower than IL group (98%). Abutment screw fracture was the failure mode consistently observed in all groups. CONCLUSION/CONCLUSIONS:Because the reliability was significantly different between the 3 groups, our postulated null hypothesis was rejected.

This study evaluated comparatively two configurations (powder and putty) of a composite biomaterial based on PLGA (Poly(lactide-co-glycolide)/nanoescale hydroxyapatite (ReOss®, Intra-Lock International) through microscopic morphology, in vitro cytotoxicity, biocompatibility and in vivo response as a bone substitute. SEM and EDS characterized the biomaterials before/after grafting. Cytocompatibility was assessed with murine pre-osteoblasts. Osteoconductivity and biocompatibility were evaluated in White New Zealand rabbits. Both configurations were implanted in the calvaria of eighteen animals in non-critical size defects, with blood clot as the control group. After 30, 60 and 90 days, the animals were euthanized and the fragments containing the biomaterials and controls were harvested. Bone blocks were embedded in paraffin (n=15) aiming at histological and histomorphometric analysis, and in resin (n=3) aiming at SEM and EDS. Before implantation, the putty configuration showed both a porous and a fibrous morphological phase. Powder revealed porous particles with variable granulometry. EDS showed calcium, carbon, and oxygen in putty configuration, while powder also showed phosphorus. After implantation EDS revealed calcium, carbon, and oxygen in both configurations. The materials were considered cytotoxic by the XTT test. Histological analysis showed new bone formation and no inflammatory reaction at implant sites. However, the histomorphometric analysis indicated that the amount of newly formed bone was not statistically different between experimental groups. Although both materials presented in vitro cytotoxicity, they were biocompatible and osteoconductive. The configuration of ReOss® affected morphological characteristics and the in vitro cytocompatibility but did not impact on the in vivo biological response, as measured by the present model.