Faculty Bibliography

Literature has reported that up to 50% of dental implants may be affected by peri-implantitis, a bacteria-induced chronic inflammatory process, which promotes osteoclast-mediated bone resorption and inhibits bone formation, leading to progressive bone loss around implants. Current evidence points toward an increased risk for the development of peri-implantitis in both obesity/metabolic syndrome (MetS) and diabetes mellitus (DM) conditions relative to the healthy population. Currently, there is no effective treatment for peri-implantitis and the 50% prevalence in MetS and DM, along with its predicted increase in the worldwide population, presents a major concern in implant dentistry as hyperglycemic conditions are associated with bone-healing impairment; this may be through dysfunction of osteocalcin-induced glucose metabolism. The MetS/DM proinflammatory systemic condition and altered immune/microbiome response affect both catabolic and anabolic events of bone-healing that include increased osteoclastogenesis and compromised osteoblast activity, which could be explained by the dysfunction of insulin receptor that led to activation of signals related with osteoblast differentiation. Furthermore, chronic hyperglycemia along with associated micro- and macro-vascular ailments leads to delayed/impaired wound healing due to activation of pathways that are particularly important in initiating events linked to inflammation, oxidative stress, and cell apoptosis; this may be through deactivation of AKT/PKB protein, which possesses a pivotal role in drive survival and eNOS signaling. This review presents an overview of the local and systemic mechanisms synergistically affecting bone-healing impairment in MetS/DM individuals, as well as a rationale for hierarchical animal model selection, in an effort to characterize peri-implantitis disease and treatment.

Lumbar fusion is a procedure associated with several indications, but screw failure remains a major complication, with an incidence ranging 10% to 50%. Several solutions have been proposed, ranging from more efficient screw geometry to enhance bone quality, conversely, drilling instrumentation have not been thoroughly explored. The conventional instrumentation (regular [R]) techniques render the bony spicules excavated impractical, while additive techniques (osseodensification [OD]) compact them against the osteotomy walls and predispose them as nucleating surfaces/sites for new bone. This work presents a case-controlled split model for in vivo/ex vivo comparison of R vs OD osteotomy instrumentation in posterior lumbar fixation in an ovine model to determine feasibility and potential advantages of the OD drilling technique in terms of mechanical and histomorphology outcomes. Eight pedicle screws measuring 4.5 mm × 45 mm were installed in each lumbar spine of eight adult sheep (four per side). The left side underwent R instrumentation, while the right underwent OD drilling. The animals were killed at 6- and 12-week and the vertebrae removed. Pullout strength and non-decalcified histologic analysis were performed. Significant mechanical stability differences were observed between OD and R groups at 6- (387 N vs 292 N) and 12-week (312 N vs 212 N) time points. Morphometric analysis did not detect significant differences in bone area fraction occupancy between R and OD groups, while it is to note that OD showed increased presence of bone spiculae. Mechanical pullout testing demonstrated that OD drilling provided higher degrees of implant anchoring as a function of time, whereas a significant reduction was observed for the R group.

BACKGROUND:Three-dimensionally-printed bioceramic scaffolds composed of β-tricalcium phosphate delivering the osteogenic agent dipyridamole can heal critically sized calvarial defects in skeletally mature translational models. However, this construct has yet to be applied to growing craniofacial models. In this study, the authors implanted three-dimensionally-printed bioceramic/dipyridamole scaffolds in a growing calvaria animal model and evaluated bone growth as a function of geometric scaffold design and dipyridamole concentration. Potential adverse effects on the growing suture were also evaluated. METHODS:Bilateral calvarial defects (10 mm) were created in 5-week-old (approximately 1.1 kg) New Zealand White rabbits (n = 16 analyzed). Three-dimensionally-printed bioceramic scaffolds were constructed in quadrant form composed of varying pore dimensions (220, 330, and 500 μm). Each scaffold was coated with collagen and soaked in varying concentrations of dipyridamole (100, 1000, and 10,000 μM). Controls consisted of empty defects. Animals were killed 8 weeks postoperatively. Calvariae were analyzed using micro-computed tomography, three-dimensional reconstruction, and nondecalcified histologic sectioning. RESULTS:Scaffold-induced bone growth was statistically greater than bone growth in empty defects (p = 0.02). Large scaffold pores, 500 μm, coated in 1000 μM dipyridamole yielded the most bone growth and lowest degree of scaffold presence within the defect. Histology showed vascularized woven and lamellar bone along with initial formation of vascular canals within the scaffold lattice. Micro-computed tomographic and histologic analysis revealed patent calvarial sutures without evidence of ectopic bone formation across all dipyridamole concentrations. CONCLUSION/CONCLUSIONS:The authors present an effective pediatric bone tissue-engineering scaffold design and dipyridamole concentration that is effective in augmentation of calvarial bone generation while preserving cranial suture patency.

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: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.

Adenosine receptor activation has been investigated as a potential therapeutic approach to heal bone. Bone has enhanced regenerative potential when influenced by either direct or indirect adenosine receptor agonism. As investigators continue to elucidate how adenosine influences bone cell homeostasis at the cellular and molecular levels, a small but growing body of literature has reported successful in vivo applications of adenosine delivery. This review summarizes the role adenosine receptor ligation plays in osteoblast and osteoclast biology and remodeling/regeneration. It also reports on all the modalities described in the literature at this point for delivery of adenosine through in vivo models for bone healing and regeneration.

Achieving the appropriate primary stability for immediate or early loading in areas with low-density bone, such as the posterior maxilla, is challenging. A three-dimensional (3D) stabilization implant design featuring a tapered body with continuous cutting flutes along the length of the external thread form, with a combination of curved and linear geometric surfaces on the thread's crest, has the capacity to enhance early biomechanical and osseointegration outcomes compared to implants with traditional buttressed thread profiles. Commercially available implants with a buttress thread design (TP), and an experimental implant that incorporated the 3D stabilization trimmed-thread design (TP 3DS) were used in this study. Six osteotomies were surgically created in the ilium of adult sheep (N = 14). Osteotomy sites were randomized to receive either the TP or TP 3DS implant to reduce site bias. Subjects were allowed to heal for either 3 or 12 weeks (N = 7 sheep/time point), after which samples were collected en bloc (including the implants and surrounding bone) and implants were either subjected to bench-top biomechanical testing (e.g., lateral loading), histological/histomorphometric analysis, or nanoindentation testing. Both implant designs yielded high insertion torque (ITV ≥ 30 N⋅cm) and implant stability quotient (ISQ ≥ 70) values, indicative of high primary stability. Qualitative histomorphological analysis revealed that the TP 3DS group exhibited a continuous bone-implant interface along the threaded region, in contrast to the TP group at the early, 3-week, healing time point. Furthermore, TP 3DS's cutting flutes along the entire length of the implant permitted the distribution of autologous bone chips within the healing chambers. Histological evaluation at 12 weeks revealed an increase in woven bone containing a greater presence of lacunae within the healing chambers in both groups, consistent with an intramembranous-like healing pattern and absence of bone dieback. The TP 3DS macrogeometry yielded a ~66% increase in average lateral load during pushout testing at baseline (T = 0 weeks, p = 0.036) and significantly higher bone-to-implant contact (BIC) values at 3 weeks post-implantation (p = 0.006), relative to the traditional TP implant. In a low-density (Type IV) bone model, the TP 3DS implant demonstrated improved performance compared to the conventional TP, as evidenced by an increase in baseline lateral loading capacity and increased BIC during the early stages of osseointegration. These findings indicate that the modified implant configuration of the TP 3DS facilitates more favorable biomechanical integration and may promote more rapid and stable bone anchorage under compromised bone quality conditions. Therefore, such improvements could have important clinical implications for the success and longevity of dental implants placed in regions with low bone density.

The aim of the study was to assess the effect of bulk material on the reliability and failure modes of narrow-diameter implants. Narrow implants (Ø3.5 × 10 mm - 11° internal conical connection) were manufactured from three different bulk materials: commercially pure titanium grade-IV (CP4), cold-worked titanium (CW), and 4Titude (4Ti), and were evaluated under fatigue testing. Eighteen samples per group were tested under step-stress accelerated life testing through 30° off-axis load application in mild, moderate, and aggressive loading profiles. The number of cycles and load at failure were used to calculate use-level probability curves and reliability for missions of 100,000 cycles up to 200 N, followed by fractographic analyses. Beta values suggested that damage accumulation dictated failures. Reliability analyses at 80, 120, and 150 N evidenced high reliability for narrow implants independent of bulk material. At 200 N, a decrease in reliability was observed for all groups (∼46%). Failure mode analysis depicted similar failures for all groups and comprised implant fracture, abutment fracture, and implant + abutment fractures. Narrow implants presented high reliability for physiologic masticatory forces in the anterior region. Characteristic strength, reliability, and failure modes were similar regardless of bulk material, suggesting that fatigue damage accumulation at thin wall implants dictated failure over bulk material strength.

Guided bone regeneration (GBR) procedures have been indicated to enhance bone response, reliably regenerate lost tissue, and create an anatomically pleasing ridge contour for biomechanically favorable and prosthetically driven implant placement. The aim of the current study was to evaluate and compare the bone regenerative performance of deproteinized bovine bone (DBB) and deproteinized porcine bone (DPB) grafts in a beagle mandibular model for the purposes of GBR. Four bilateral defects of 10 mm × 10 mm were induced through the mandibular thickness in each of the 10 adult beagle dogs being studied. Two of the defects were filled with DPB, while the other two were filled with DBB, after which they were covered with collagen-based membranes to allow compartmentalized healing. Animals were euthanized after 6, 12, 24, or 48 weeks postoperatively. Bone regenerative capacity was evaluated by qualitative histological and quantitative microtomographic analyses. Microcomputed tomography data of the bone (%), graft (%), and space (%) were compared using a mixed model analysis. Qualitatively, no histomorphological differences in healing were observed between the DBB and DPB grafts at any time point. By 48 weeks, the xenografts (DBB and DPB) were observed to have osseointegrated with regenerating spongy bone and a close resemblance to native bone morphology. Quantitatively, a higher amount of bone (%) and a corresponding reduction in empty space (space (%)) were observed in defects treated by DBB and DPB grafts over time. However, no statistically significant differences in bone (%)were observed between DBB (71.04 ± 8.41 at 48 weeks) and DPB grafts (68.38 ± 10.30 at 48 weeks) (p > 0.05). GBR with DBB and DPB showed no signs of adverse immune response and led to similar trends in bone regeneration over 48 weeks of permitted healing.