Additive Manufacturing Technologies for Fabrication of Biomaterials for Surgical Procedures in Dentistry: A Narrative Review

PURPOSE: To screen and critically appraise available literature regarding additive manufacturing technologies for bone graft material fabrication in dentistry. MATERIAL AND METHODS: PubMed and Scopus were searched up to May 2021. Studies reporting the additive manufacturing techniques to manufacture scaffolds for intraoral bone defect reconstruction were considered eligible. A narrative review was synthesized to discuss the techniques for bone graft material fabrication in dentistry and the biomaterials used. RESULTS: The databases search resulted in 933 articles. After removing duplicate articles (128 articles), the titles and abstracts of the remaining articles (805 articles) were evaluated. A total of 89 articles were included in this review. Reading these articles, 5 categories of additive manufacturing techniques were identified: material jetting, powder bed fusion, vat photopolymerization, binder jetting, and material extrusion. CONCLUSIONS: Additive manufacturing technologies for bone graft material fabrication in dentistry, especially 3D bioprinting approaches, have been successfully used to fabricate bone graft material with distinct compositions

Derivatized nanoparticles for CNS-targeted drug delivery

Neurodegenerative and cerebrovascular diseases exert a growing impact from the societal and economic point of view. Therefore the development of strategies for early detection as well as for effective and safe treatments of such diseases is becoming more important than ever. For these reasons, research the targeting of active molecules to CNS represents one of the most challenging drawbacks. The selectivity of blood-brain barrier (BBB) highly limits therapies for the cerebral diseases and in the recent years a great deal of efforts to develop strategies that aid drug passage across the BBB have been made. Nanotechnology-based approaches have gained increasing attention as the most promising strategies for CNS targeted drug delivery. Such approach involves the use of at least two components, one of which is a nanoparticle (NP), which serves as a carrier (nanocarrier), and the other is the therapeutic agent (cargo). Among NPs, those made of poly(lactic-co-glycolic acid) (PLGA) hold an uncommon biocompatibility and, when conjugated with an heptapeptide (g7) able to cross the BBB, they reach at high rate the cerebral tissue. Using in vitro cell models of lysosomal storage diseases, an heterogeneous group of rare inherited disorders characterized by the lysosomal accumulation of undigested or partially digested macromolecules, which ultimately results in cellular dysfunction and clinical abnormalities, with a strong neurological involvement, we demonstrate that PLGA-NPs loaded with the missing enzyme were able to reach lysosomes and to rescue 50% of the enzymatic deficiency after a single administration. Moreover the conjugation of the enzyme with NPs also might contribute to improve the stability/integrity of the enzyme thus prolonging its life span. Thus, g7-NPs seem to represent a promising tool for the treatment of diseases with neurological involvement. Work supported by ELA Foundation (Agreement n. 2011-037C1B: “Leading nanomedicine into the therapy for Leukodystrophies: nanoparticles overcoming the blood−brain barrier to treat the mouse model of Krabbe Disease”) and Fondazione Cassa di Risparmio di Perugia (Project n. 2010.011.0434: “Effetto sulla salute umana dell’esposizione a materiale nano strutturato: impiego di modelli cellulari per lo studio della nanotossicità”

Use of Polylactide-Co-Glycolide-Nanoparticles for Lysosomal Delivery of a Therapeutic Enzyme in Glycogenosis Type II Fibroblasts

Glycogenosis type II, or Pompe Disease, is a lysosomal storage disease caused by the deficiency of acid alpha-glucosidase (GAA), leading to glycogen accumulation in muscles. A recombinant human GAA (rhGAA, Myozyme\uae) is currently used for enzyme replacement therapy. Despite its efficacy in most of patients, some of them show a diminished response to the treatment with rapidly progressive clinical deterioration, due to immuno-mediated enzyme inactivation. To demonstrate that Nanoparticles (NPs) could be profitably exploited to carry macromolecules, PLGA NPs loaded with rhGAA (GAA-NPs) were prepared by double emulsion solvent evaporation. Their surface morphology, particle size, zeta-potential and biochemical activity were assessed. "Pulse and chase" experiments were made by administrating GAA-NPs on patients' fibroblasts. Biochemical activity tests showed a more efficient cellular uptake of rhGAA loaded to NPs and a more significant stability of the enzyme (up to 7 days) in vitro, if compared to the same amount of rhGAA free enzyme. This data allows to envision in vivo experiments, in significant animal models, to further characterize lysosomal enzyme loaded-NPs' efficacy and toxicity

The ENDOTRIAL Study: A spontaneous, open-label, randomized, multicenter, crossover study on the efficacy of sildenafil, tadalafil, and vardenafil in the treatment of erectile dysfunction

Introduction. The three effective, commercially available drugs for the treatment of erectile dysfunction-sildenafil, vardenafil, and tadalafil-inhibit the same substrate, the erectolytic enzyme phosphodiesterase type 5 (PDE5). Although there are pharmacological differences between these three compounds, few comparative studies have been conducted to date. Aim. The aim of this study was to determine the efficacy of sildenafil, tadalafil, and vardenafil in a randomly assigned 8-week fixed regimen. Methods. This was a spontaneous, open-label, randomized, multicenter, crossover study where the patients were randomized to receive sildenafil 50 mg, sildenafil 100 mg, tadalafil 20 mg, or vardenafil 20 mg. Main Outcome Measures. The primary outcome included the posttreatment analysis of erectile function domains of the abridged International Index of Erectile Function (IIEF5+1). The secondary objectives included the analysis of peak-systolic velocities (PSVs), end-diastolic velocities (EDVs), and resistive index (RI), and the estimate of the percentage of men with normal penile hemodynamic parameters after each treatment. Results. In all groups of patients taking sildenafil 50 mg, sildenafil 100 mg, tadalafil 20 mg, and vardenafil 20 mg at a frequency reflecting the common treatment regimens in real life, there was a statistically significant baseline-to-end point improvement in subjective perception of erectile function measured by IIEF5+1. When the four groups were compared, the treatments were not different in modifying IIEF5+1 and penile flow parameters. However, the within-group analysis showed that PSV improved in the sildenafil 50 mg group and that PSV together with RI significantly ameliorated in patients receiving 100 mg of sildenafil. Regression analysis confirmed an independent effect of sildenafil on hemodynamic efficacy parameters. Conclusions. An overall equivalence was demonstrated in the subjective perception of treatment benefits for all the PDE5i tested. However, sildenafil, in a dose-dependent manner, was the unique PDE5i able to ameliorate some of the penile flow parameters within the 8-week treatment period. These findings should be interpreted conservatively because of the observational nature of the study. Jannini EA, Isidori AM, Gravina GL, Aversa A, Balercia G, Bocchio M, Boscaro M, Carani C, Corona G, Fabbri A, Foresta C, Forti G, Francavilla S, Granata ARM, Maggi M, Mansani R, Palego P, Spera G, Vetri M, and Lenzi A on behalf of the Endotrial Study Group. The ENDOTRIAL study: A spontaneous, open-label, randomized, multicenter, crossover study on the efficacy of sildenafil, tadalafil, and vardenafil in the treatment of erectile dysfunction. J Sex Med 2009;6:2547-2560

Exercise oscillatory ventilation and prognosis in heart failure patients with reduced and mid-range ejection fraction

Aims Exercise oscillatory ventilation (EOV) is a pivotal cardiopulmonary exercise test parameter for the prognostic evaluation of patients with chronic heart failure (HF). It has been described in patients with HF with reduced ejection fraction (<40%, HFrEF) and with HF with preserved ejection fraction (>50%, HFpEF), but no data are available for patients with HF with mid-range ejection fraction (40-49%, HFmrEF). The aim of the study was to evaluate the prognostic role of EOV in HFmrEF patients. Methods and results We analysed 1239 patients with HFmrEF and 4482 patients with HFrEF, enrolled in the MECKI score database, with a 2-year follow-up. The study endpoint was the composite of cardiovascular death, urgent heart transplant, and ventricular assist device implantation. We identified EOV in 968 cases (16% and 17% of cases in HFmrEF and HFrEF, respectively). HFrEF EOV+ patients were significantly older, and their parameters suggested a more severe HF than HFrEF EOV- patients. A similar behaviour was found in HFmrEF EOV+ vs. EOV- patients. Kaplan-Meier analysis, irrespective of ejection fraction, showed that EOV is associated with a worse survival, and that patients with HFrEF and HFmrEF EOV+ had a significantly worse outcome than the EOV- of the same ejection fraction groups. EOV-associated survival differences in HFmrEF patients started after 18 months of follow-up. Conclusion Exercise oscillatory ventilation has a similar prevalence and ominous prognostic value in both HFmrEF and HFrEF patients, indicating a group of patients in need of a more intensive follow-up and a more aggressive therapy. In HFmrEF, the survival curves between EOV+ and EOV- patients diverged only after 18 months

Revisiting a Prognosticating Algorithm from Cardiopulmonary Exercise Testing in Chronic Heart Failure (from the MECKI Score Population)

Cardiopulmonary exercise testing is a prognostic tool in heart failure with reduced left ventricular ejection fraction (HFrEF). Prognosticating algorithms have been proposed, but none has been validated. In 2017, a predictive algorithm, based on peak oxygen consumption (VO2), ventilatory response to exercise (ventilation [VE] carbon dioxide production [VCO2], the VE/VCO2 slope), exertional oscillatory ventilation (EOV), and peak respiratory exchange ratio, was recommended, according treatment with β blockers: patients with HFrEF registered in the metabolic exercise test data combined with cardiac and kidney indexes (MECKIs) database were used to validated this algorithm. According to the inclusion/exclusion criteria, 4,683 MECKI patients with HFrEF were enrolled. At 3 years follow-up, the end point was cardiovascular death and urgent heart transplantation (cardiovascular events [CV]). CV events occurred in 25% in patients without β blockers, whereas those with β-blockers had 11% (p <0.0001). In patients without β blockers, 36%, 24%, and 7% CV events were observed in those with peak VO2 ≤10, with peak VO2 >10 <18, and with peak VO2 ≥18 ml/kg/min (p = 0.0001), respectively; in MECKI patients with peak VO2 ≤10 and patients with intermediate exercise capacity, a peak respiratory exchange ratio (≥1.15) and VE/VCO2 slope (≥35) were diriment, respectively (p = 0.0001). EOV, when occurred, increased risk. In MECKI patients on β blockers, 29%, 17%, and 8% CV events were noticed in those with a peak VO2 ≤8, with peak VO2 = 8 to 12, and patients with peak VO2 ≥12 ml/kg/min, respectively (p = 0.0000); when EOV was monitored an increment of risk was witnessed. In conclusion, the outcome of this algorithm was confirmed with the MECKI cohort