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Obesity/Metabolic Syndrome and Diabetes Mellitus on Peri-implantitis

de Oliveira, Paula Gabriela Faciola Pessôa; Bonfante, Estevam A; Bergamo, Edmara T P; de Souza, Sérgio Luis Scombatti; Riella, Leonardo; Torroni, Andrea; Benalcazar Jalkh, Ernesto B; Witek, Lukasz; Lopez, Christopher D; Zambuzzi, Willian Fernando; Coelho, Paulo G
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.
PMID: 32591106
ISSN: 1879-3061
CID: 4510852

Osseodensification drilling vs conventional manual instrumentation technique for posterior lumbar fixation: Ex-vivo mechanical and histomorphological analysis in an ovine model

Torroni, Andrea; Lima Parente, Paulo Eduardo; Witek, Lukasz; Hacquebord, Jacques Henri; Coelho, Paulo G
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.
PMID: 32369220
ISSN: 1554-527x
CID: 4439042

Bone Tissue Engineering in the Growing Calvaria Using Dipyridamole-Coated, Three-Dimensionally-Printed Bioceramic Scaffolds: Construct Optimization and Effects on Cranial Suture Patency

Maliha, Samantha G; Lopez, Christopher D; Coelho, Paulo G; Witek, Lukasz; Cox, Madison; Meskin, Alan; Rusi, Sejndi; Torroni, Andrea; Cronstein, Bruce N; Flores, Roberto L
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.
PMID: 31985634
ISSN: 1529-4242
CID: 4293882

Dipyridamole-loaded 3D-printed bioceramic scaffolds stimulate pediatric bone regeneration in vivo without disruption of craniofacial growth through facial maturity

Wang, Maxime M; Flores, Roberto L; Witek, Lukasz; Torroni, Andrea; Ibrahim, Amel; Wang, Zhong; Liss, Hannah A; Cronstein, Bruce N; Lopez, Christopher D; Maliha, Samantha G; Coelho, Paulo G
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.
PMID: 31804544
ISSN: 2045-2322
CID: 4218802

Repair of Critical-Sized Long Bone Defects Using Dipyridamole-Augmented 3D Printed Bioactive Ceramic Scaffolds

Witek, Lukasz; Alifarag, Adham M; Tovar, Nick; Lopez, Christopher D; Cronstein, Bruce; Rodriguez, Eduardo D; Coelho, Paulo G
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 (A2A 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.
PMID: 31334868
ISSN: 1554-527x
CID: 3986952

Regeneration of a Pediatric Alveolar Cleft Model Using Three-Dimensionally Printed Bioceramic Scaffolds and Osteogenic Agents: Comparison of Dipyridamole and rhBMP-2

Lopez, Christopher D; Coelho, Paulo G; Witek, Lukasz; Torroni, Andrea; Greenberg, Michael I; Cuadrado, Dean L; Guarino, Audrey M; Bekisz, Jonathan M; Cronstein, Bruce N; Flores, Roberto L
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.
PMID: 31348344
ISSN: 1529-4242
CID: 3988322

Local delivery of adenosine receptor agonists to promote bone regeneration and defect healing

Lopez, Christopher D; Bekisz, Jonathan M; Corciulo, Carmen; Mediero, Aranzazu; Coelho, Paulo G; Witek, Lukasz; Flores, Roberto L; Cronstein, Bruce N
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.
PMID: 29913176
ISSN: 1872-8294
CID: 3157852

Temporary materials used in prosthodontics: The effect of composition, fabrication mode, and aging on mechanical properties

Bergamo, Edmara T P; Campos, Tiago M B; Piza, Mariana M T; Gutierrez, Eliezer; Lopes, Adolfo C O; Witek, Lukasz; Coelho, Paulo G; Celestrino, Marcos; Carvalho, Laura F de; Benalcázar Jalkh, Ernesto B; Bonfante, Estevam A
PURPOSE/OBJECTIVE:To evaluate the effect of composition, fabrication mode, and thermal cycling on the mechanical properties of different polymeric systems used for temporary dental prostheses. MATERIALS AND METHODS/METHODS:Standard bar-shaped specimens (25 × 2 × 2 mm) were fabricated of six polymeric systems of varying compositions and fabrication modes (n = 10/group): conventional PMMA (Alike, GC) - group CGC; conventional PMMA (Dêncor, Clássico) - group CD; bis-acryl (Tempsmart, GC) - group BGC; bis-acryl (Yprov, Yller) - group BY; milled PMMA (TelioCAD, Ivoclar) - group MI; 3D printed bis-acryl - (Cosmos Temp, Yller) group PY. Half of the specimens were subjected to 5000 thermal cycles (5 °C to 55 °C). Three-point bending tests were performed using a universal testing machine with a crosshead speed set to 0.5 mm/min. Flexural strength and elastic modulus were calculated from the collected data. FTIR spectra were recorded pre and post curing and after thermal cycling to evaluate material composition and degree of conversion. Energy-dispersive spectroscopy (EDS) and scanning electron microscope (SEM) were utilized to examine the composition and micromorphology of the systems, respectively. Data were analyzed using two-analysis of variance and Tukey tests (α = 0.05). RESULTS:FTIR spectra indicated that BGC, BY and PY groups corresponded to urethane dimethacrylate systems (bis-acryl), while CGC, CD, and MI groups corresponded to monomethacrylate systems, polymethyl methacrylate (PMMA). Bis-acryl BGC system yeilded the highest flexural strength (80 MPa), followed by the milled PMMA MI system (71 MPa), both statistically significant different relative to other groups. Bis-acryl BY exhibited the lowest flexural strength (27 MPa). Thermocycling significantly increased the flexural strength of all polymeric systems (∼10-15 MPa), except for the 3D-printed PY group. Bis-acryl BGC (1.89 GPa) and conventional PMMA CGC (1.66 GPa) groups exhibited the highest elastic modulus, followed by milled PMMA MI group (1.51 GPa) and conventional PMMA CD (1.45 GPa) systems, with significant difference detected between BGC group and MI and CD groups. The 3D printed PY (0.78 GPa) and bis-acryl BY (0.47 GPa) systems presented the lowest elastic modulus. Thermocycling did not have a significant influence on the elastic modulus. FTIR spectra indicate water sorption and release of unreacted monomers as well as increased degree of conversion (∼5-12%) after thermal cycling. CONCLUSION/CONCLUSIONS:Composition and fabrication mode and thermal cycling significantly affected the mechanical properties of polymeric systems used for temporary dental prostheses.
PMID: 35839630
ISSN: 1878-0180
CID: 5269552

Effects of local single dose administration of parathormone on the early stages of osseointegration: A pre-clinical study

Grossi, João Ricardo Almeida; Deliberador, Tatiana Miranda; Giovanini, Allan Fernando; Zielak, João César; Sebstiani, Aline Monise; Gonzaga, Carla Castiglia; Coelho, Paulo G; Zétola, André Luis; Weiss, Fernando P; Benalcázar Jalkh, Ernesto B; Storrer, Carmen Lucia Mueller; Witek, Lukasz
The present study aimed to evaluate the effect of parathormone (PTH) administered directly to the implant's surface prior to insertion, using a large translational animal model. Sixty titanium implants were divided into four groups: (i) Collagen, control group, where implants were coated with Type-I Bovine-collagen, and three experimental groups, where implants received varying doses of PTH: (ii) 12.5, (iii) 25, and (iv) 50 μg, prior to placement. Fifteen female sheep (~2 years old, weighing ~65 kg) received four implants in an interpolated fashion in C3, C4 or C5 vertebral bodies. After 3-, 6- and 12-weeks, samples were harvested, histologically processed, qualitatively and quantitatively assessed for bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO). BIC yielded lower values at 6-weeks for 50 μg relative to the control group, with no significant differences, when compared to the 12.5- and 25-μg. No significant differences were detected at 6-weeks between collagen, 12.5- and 25-μg groups. At 3- and 12-weeks, no differences were detected for BIC among PTH groups. With respect to BAFO, no significant differences were observed between the control and experimental groups independent of PTH concentration and time in vivo. Qualitative observations at 3-weeks indicated the presence of a more mature bone near the implant's surface with the application of PTH, however, no significant differences in new bone formation or healing patterns were observed at 6- and 12-weeks. Single local application of different concentrations of PTH on titanium implant's surface did not influence the osseointegration at any time-point evaluation in low-density bone.
PMID: 35218605
ISSN: 1552-4981
CID: 5172632

Laddec® versus Bio-Oss®: The effect on the healing of critical-sized defect - Calvaria rabbit model

Gil, Luiz Fernando; Nayak, Vasudev Vivekanand; Benalcázar Jalkh, Ernesto B; Tovar, Nick; Chiu, Kai-Jen; Salas, Jaime Campos; Marin, Charles; Bowers, Michelle; Freitas, Gileade; Mbe Fokam, Dejolie Christelle; Coelho, Paulo G; Witek, Lukasz
The aim of this study was to evaluate the in vivo performance of two different deproteinized bovine bone (DBB) grafting materials: DBBB (Bio-Oss®) and DBBL (Laddec®), for the regeneration of critically sized (8 mm) defects in rabbit's calvaria. Three round-shaped defects were surgically created in the calvaria of 13 New Zealand White rabbits proximal to the coronal suture in the parietal bone. Two of the defects were filled with one of the grafting materials while a third was left empty to serve as a negative control. Bone regeneration properties were evaluated at 4- and 8-weeks after implantation by means of histological and histomorphometrical analyses. Statistical analyses were performed through a mixed model analysis with fixed factors of time and material. Histological evaluation of the control group evidenced a lack of bridging bone formation across the defect sites at both evaluation time points. For the experimental groups, new bone formation was observed around the defect periphery and to progress radially inwards to the center of the defect site, regardless of the grafting material. Histomorphometric analyses at 4 weeks demonstrated higher amount of bone formation through the defect for DBBB group. However, at 8 weeks, DBBL and DBBB demonstrated osteoconductivity and low resorption rates with evidence of statistically similar bone regeneration through the complete boney defect. Finally, DBBB presented lower soft tissue migration within the defect when compared to DBBL at both evaluation time points. DBBB and DBBL presented similar bone regeneration performance and slow resorption rates. Although both materials promoted bone regeneration through the complete defect, DBBB presented lower soft tissue migration within the defects at 4- and 8-weeks.
PMID: 35857711
ISSN: 1552-4981
CID: 5279162