Faculty Bibliography

This study investigates a comprehensive model of bone regeneration capacity of dypiridamole-loaded 3D-printed bioceramic (DIPY-3DPBC) scaffolds composed of 100% beta-tricalcium phosphate (β -TCP) in an immature rabbit model through the time of facial maturity. The efficacy of this construct was compared to autologous bone graft, the clinical standard of care in pediatric craniofacial reconstruction, with attention paid to volume of regenerated bone by 3D reconstruction, histologic and mechanical properties of regenerated bone, and long-term safety regarding potential craniofacial growth restriction. Additionally, long-term degradation of scaffold constructs was evaluated. At 24 weeks in vivo, DIPY-3DPBC scaffolds demonstrated volumetrically significant osteogenic regeneration of calvarial and alveolar defects comparable to autogenous bone graft with favorable biodegradation of the bioactive ceramic component in vivo. Characterization of regenerated bone reveals osteogenesis of organized, vascularized bone with histologic and mechanical characteristics comparable to native bone. Radiographic and histologic analyses were consistent with patent craniofacial sutures. Lastly, through application of 3D morphometric facial surface analysis, our results support that DIPY-3DPBC scaffolds do not cause premature closure of sutures and preserve normal craniofacial growth. Based on this novel evaluation model, this DIPY-3DPBC scaffold strategy is a promising candidate as a safe, efficacious pediatric bone tissue engineering strategy.

There are over 2 million long bone defects treated in the USA annually, of which ~5% will not heal without significant surgical intervention. While autogenous grafting is standard of care in simple defects, a customized scaffold for large defects in unlimited quantities is not available. Recently, a three-dimensionally (3D) printed bioactive ceramic (3DPBC) scaffold has been successfully utilized in the of repair critical sized long bone defects in vivo. In this study, 3DPBC scaffolds were augmented with Dipyridamole, an adenosine A2A receptor (A_2A R) indirect agonist, because of its known effect to enhance bone formation. Critical-sized full thickness segmental defects (~11mm x full thickness) defects were created in the radial diaphysis in New Zealand White rabbits (n=24). A customized 3DPBC scaffold composed of β-tricalcium phosphate was placed into the defect site. Groups included scaffolds that were collagen-coated (COLL), or immersed in 10μM, 100μM, or 1000μM Dipyridamole solution. Animals were euthanized 8 weeks post-operatively and the radii/ulna-scaffold complex retrieved, en bloc, for micro-CT, histological and mechanical analysis. Bone growth was assessed exclusively within scaffold pores and evaluated by microCT and advanced reconstruction software. Biomechanical properties were evaluated utilizing nanoindentation to assess the newly regenerated bone for elastic modulus (E) and hardness (H). MicroCT reconstructions illustrated bone in-growth throughout the scaffold, with an increase in bone volume dependent on the Dipyridamole dosage. Histological evaluation did not indicate any adverse immune response while revealing progressive remodeling of bone. These customized biologic 3DPBC scaffolds have the potential of repairing and regenerating bone. This article is protected by copyright. All rights reserved.

BACKGROUND:Surgical fixation of implants into bone for the correction of bone deformities or defects is a traditional approach for skeletal stabilization. Important measures of efficacy of implants include implant stability and osseointegration-the direct interaction between living bone and an implant. Osseointegration depends on successful implant placement and subsequent bone remodeling. This study utilized osseodensification drilling (OD) in a low bone density model using trabecular metal (TM) implants. MATERIAL AND METHODS/METHODS:Three osteotomy sites, Regular, OD-CW (clockwise), and OD-CCW (counterclockwise), were prepared in each ilium of three female sheep. Drilling was performed at 1100rpm with saline irrigation. Trabecular metal (TM) (Zimmer, Parsippany, NJ, USA) implants measuring 3.7mm in diameter x 10mm length were placed into respective osteotomies. A three-week period post-surgery was given to allow for healing to take place after which all three sheep were euthanized and the ilia were collected. Samples were prepared, qualitatively and quantitatively analyzed using histology micrographs and image analysis software (ImageJ, NIH, Bethesda, MD). Bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO) were quantified to evaluate the osseointegration parameters. RESULTS:All implants exhibit successful bone formation in the peri-implant environment as well as within the open spaces of the trabecular network. Osseointegration within the TM (quantified by %BIC) as a function of drilling technique was more pronounced in OD samples(p>0.05). The %BAFO however shows a significant difference (p=0.036) between the CCW and R samples. Greater bone volume and frequency of bone chips are observed in OD samples. CONCLUSION/CONCLUSIONS:The utilization of OD as a design for improved fixation of hardware was supported by increased levels of stability, both primary and secondary. Histological data with OD provided notably different results from those of the regular drilling method.

OBJECTIVES/OBJECTIVE:To evaluate the three-dimensional fit of abutments fabricated by the industry to those either milled or cast by a commercial laboratory and to correlate the implant-abutment connection fit with stress at fatigue failure of prostheses. Probability of survival (reliability) and fractography to characterize failure modes were also performed for cemented and screw-retained prostheses. METHODS:One-hundred and twenty-six maxillary central incisor crowns were milled to restore implants and divided in 3 cemented and 3 screwed-retained groups (n = 21/each), as follows: [Digital-Sc]: milled one-piece monolithic abutment/crown; [TiB-Sc]: milled crowns cemented onto Ti-base abutments; [UCLA]: screw-retained crown using UCLA abutments; [Digital-Ce]: milled two-piece assembly comprised by screwed monolithic abutment and a cemented crown; [TiB-Ce]: milled coping cemented onto Ti-base abutments to receive a cemented crown; [UCLA-Ce]: UCLA abutments that received an overcast coping and a cemented crown. Implant-abutment volume misfit was assessed by micro-computed tomography using the silicone replica technique. Implant/crown systems were subjected to step-stress accelerated life testing (SSALT) in water. The use-level probability Weibull curves and reliability for a mission of 50,000 cycles at calculated stress at failure of 2,300, 3300 and 4300 MPa were plotted. Fractographic analysis was performed with scanning electron microscopy. Internal misfit was analyzed through one-way ANOVA following post-hoc comparisons by Tukey test (p < 0.05). Correlation between misfit volume and the stress at fatigue failure was assessed by Pearson test. RESULTS:). The mean β values were: 1.68, 1.39, 1.48, 2.41, 2.27 and 0.71 for Digital-Sc, TiB-Sc, UCLA, Digital-Ce, TiB-Ce and UCLA-Ce, respectively, indicating that fatigue was an accelerating factor for failure of all groups. Higher stress at failure decreased the reliability of all groups, more significantly for screw compared to cement-retained groups, especially for Digital-Sc that demonstrated the lowest reliability. The failure mode was restricted to abutment screw fracture. A negative correlation was observed between misfit values and stress at failure (r = -0.302, p = 0.01). CONCLUSIONS:Abutments milled by a commercial lab presented higher misfit compared to those provided by the industry and a moderate correlation was observed between higher misfit and lower stress at failure during fatigue. Probability of survival decreased at higher stress, especially for screw compared to cement-retained groups, and failures were confined to abutment screws.

This paper is aimed to present a biomaterials perspective in implant therapy that fosters improved bone response and long-term biomechanical competence from surgical instrumentation to final prosthetic rehabilitation. Strategies to develop implant surface texturing will be presented and their role as an ad hoc treatment discussed in light of the interplay between surgical instrumentation and implant macrogeometric configuration. Evidence from human retrieved implants in service for several years and from in vivo studies will be used to show how the interplay between surgical instrumentation and implant macrogeometry design affect osseointegration healing pathways, and bone morphologic and long-term mechanical properties. Also, the planning of implant-supported prosthetic rehabilitations targeted at long-term performance will be appraised from a standpoint where personal preferences (eg, cementing or screwing a prosthesis) can very often fail to deliver the best patient care. Lastly, the acknowledgement that every rehabilitation will have its strength degraded over time once in function will be highlighted, since the potential occurrence of even minor failures is rarely presented to patients prior to treatment.

AIM/OBJECTIVE:To evaluate the influence of brain-derived neurotrophic factor (BDNF) in combination with collagen sponges on periodontal tissue regeneration. METHODS:Unilateral, "box-type" (4x5mm), one-wall intrabony defects were surgically created at posterior mandibular teeth in 14 Beagle dogs. Animals received all experimental groups and the defects were randomly treated as follow: Emdogain® (positive control) [EMD]; HeliPlug®+BDNF [H/B]; RCP®+BDNF [R/B]; negative control [Control]; TeruPlug®+BDNF [Tp/B] and TeruPlug®+BDNF2 [Ts/B]. Periodontal wound healing was observed every 2 weeks by computed tomography. The animals were euthanized at 8 weeks post-surgery for microcomputed tomography and histomorphometric evaluation. RESULTS:All groups presented ∼1mm apical epithelial attachment relative to cementoenamel junction. Although linear measurements did not demonstrate significant differences between groups for cementum and periodontal ligament regeneration, semi-quantitative analysis depicted higher percentage of samples with mineralized cementum and functional PDL for Ts/B, R/B and H/B groups relative to EMD and Control (p<0.046). Irrespective of quantification method (2D or 3D), Ts/B, Control, Tp/B and H/B groups presented the highest mean percentage of new bone (not significantly different), followed by R/B and EMD groups. CONCLUSION/CONCLUSIONS:While no significant differences were detected in quantitative analyses, Ts/B combination results in significantly more samples with full periodontal tissue regeneration relative to control groups.

OBJECTIVE:To compare hard-tissue healing after 3 exodontia approaches. MATERIALS AND METHODS/METHODS:Premolars of dogs were extracted: (1) flapless, (2) flap, and (3) flap + socket coverage with polytetrafluoroethylene (dPTFE) nonresorbable membrane (flap + dPTFE). Animals were euthanized at 1 and 4 weeks. Amount of bone formation within socket and socket total area were measured. RESULTS:Amount of bone formation revealed significant difference between 1 and 4 weeks; however, there was no differences among groups. Socket total area decreased after 4 weeks, and the flap + dPTFE group showed significantly higher socket total area. As a function of time and group, flap + dPTFE 4 weeks presented similar socket total area values relative to flap + dPTFE at 1 week, and significantly higher socket total area than flapless and flap. The histological sections revealed almost no bone formation within socket after 1 week, which increased for all groups at 4 weeks. CONCLUSION/CONCLUSIONS:Socket coverage with polytetrafluoroethylene (dPTFE) membrane showed to effectively preserve bone architecture. Bone formation within sockets was not influenced by tooth extraction technique.

BACKGROUND:Alveolar clefts are traditionally treated with secondary bone grafting, but this is associated with morbidity and graft resorption. Although recombinant human bone morphogenetic protein-2 (rhBMP-2) is under investigation for alveolar cleft repair, safety concerns remain. Dipyridamole is an adenosine receptor indirect agonist with known osteogenic potential. This study compared dipyridamole to rhBMP-2 at alveolar cleft defects delivered using bioceramic scaffolds. METHODS:Skeletally immature New Zealand White rabbits underwent unilateral, 3.5 × 3.5-mm alveolar resection adjacent to the growing suture. Five served as negative controls. The remaining defects were reconstructed with three-dimensionally printed bioceramic scaffolds coated with 1000 μm of dipyridamole (n = 6), 10,000 μm of dipyridamole (n = 7), or 0.2 mg/ml of rhBMP-2 (n = 5). At 8 weeks, new bone was quantified. Nondecalcified histologic evaluation was performed, and new bone was evaluated mechanically. Statistical analysis was performed using a generalized linear mixed model and the Wilcoxon rank sum test. RESULTS:Negative controls did not heal, whereas new bone formation bridged all three-dimensionally printed bioceramic treatment groups. The 1000-μm dipyridamole scaffolds regenerated 28.03 ± 7.38 percent, 10,000-μm dipyridamole scaffolds regenerated 36.18 ± 6.83 percent (1000 μm versus 10,000 μm dipyridamole; p = 0.104), and rhBMP-2-coated scaffolds regenerated 37.17 ± 16.69 percent bone (p = 0.124 versus 1000 μm dipyridamole, and p = 0.938 versus 10,000 μm dipyridamole). On histology/electron microscopy, no changes in suture biology were evident for dipyridamole, whereas rhBMP-2 demonstrated early signs of suture fusion. Healing was highly cellular and vascularized across all groups. No statistical differences in mechanical properties were observed between either dipyridamole or rhBMP-2 compared with native bone. CONCLUSION/CONCLUSIONS:Dipyridamole generates new bone without osteolysis and early suture fusion associated with rhBMP-2 in skeletally immature bone defects.

OBJECTIVE:To evaluate the reliability and failure mode of zirconia-reinforced lithium silicate (ZLS) molar crowns of different thicknesses. METHODS:Monolithic ZLS molar crowns (0.5mm, 1.0mm, and 1.5 mm thickness) were modeled and milled using a CAD/CAM system (n = 21/group). Crowns were cemented on dentin-like epoxy resin replicas with a resin cement. The specimens were subjected to single load-to-failure test for step-stress profiles designing. Mouth-motion step-stress accelerated-life test was performed under water by sliding an indenter 0.7 mm lingually down on the distobuccal cusp until specimen fracture or suspension. Use level probability Weibull curves and reliability were calculated and plotted. Polarized-light optical microscope and scanning electron microscope (SEM) were used to characterize fracture patterns. RESULTS:Irrespective of crown thickness, beta (β) values were higher than 1 and fatigue accelerated failures. While 0.5 mm ZLS crowns exhibited a significant reduction in the probability of survival at 200N, 300N and 400 N mission loads (69%, 41% and 19%, respectively), no significant difference was observed between 1.0 mm and 1.5 mm crowns. Both thicknesses have maintained the survivability at approximately 90%. Failure primarily comprised bulk fracture where radial cracks originated from the cementation surface beneath the indenter loading trail and propagated towards the cervical margin. SIGNIFICANCE/CONCLUSIONS:1.5 mm- and 1.0 mm-thickness monolithic ZLS crowns presented higher probability of survival compared to 0.5 mm crowns. Bulk fracture was the chief failure mode, regardless of thickness.

The study evaluated the effects of a Supercritical CO₂ (scCO₂ ) on a commercially available decellularized/delipidized naturally derived porcine pericardium collagen membrane, Vitala®. The Vitala® and scCO₂ treated experimental membranes were evaluated for guided tissue regeneration (GTR) of periodontal tissue in class III furcation defects utilizing a dog model. Physical material characterization was performed by scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The in vivo portion of the study was allocated to three-time points (6, 12, and 24-weeks) using standardized class III furcation defects created in the upper second and third premolars. The experimental defects (n = 5) were covered with either a collagen membrane (positive control), scCO₂ -treated collagen membrane (experimental) or no membrane (negative control). Following sacrifice, histologic serial sections were performed from cervical to apical for morphologic/morphometric evaluation. Morphometric evaluation was carried out by ranking the presence of collagen membrane, amount of bone formation within the defect site and inflammatory cell infiltrate content. SEM showed the experimental scCO₂ -treated membrane to have a similar gross fibrous appearance and chemical structure in comparison to the Vitala® Collagen membrane. A significant increase in membrane thickness was noted in the scCO₂ -treated membranes (366 ± 54 μm) vs non-treated membranes (265 ± 75 μm). TGA and DSC spectra indicated no significant qualitative differences between the two membranes. For the in vivo results, both membranes indicated significantly greater amounts of newly formed bone (scCO₂ : 2.85 ± 1.1; Vitala®: 2.80 ± 1.0) within the covered defects relative to uncovered controls (0.8 ± 0.27) at 24 weeks. Both membrane types gradually degraded as time elapsed in vivo from 6 to 12 weeks, and presented nearly complete resorption at 24 weeks. The inflammatory infiltrate at regions in proximity with the membranes was commensurate with healthy tissue levels from 6 weeks in vivo on, and periodontal ligament regeneration onset was detected at 12 weeks in vivo. The effect of the supplementary scCO₂ treatment step on the collagen membrane was demonstrated to be biocompatible, allowing for the infiltration of cells and degradation over time. The treated membranes presented similar performance in GTR to non-treated samples in Class III furcation lesions. Defects treated without membranes failed to achieve regeneration of the native periodontium. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B: Appl Biomater 00B: 000-000, 2018.