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For nearly three decades, tissue engineering strategies have been leveraged to devise effective therapeutics for dental, oral, and craniofacial (DOC) regenerative medicine and treat permanent deformities caused by many debilitating health conditions. In this regard, additive manufacturing (AM) allows the fabrication of personalized scaffolds that have the potential to recapitulate native tissue morphology and biomechanics through the utilization of several 3D printing techniques. Among these, melt electrowriting (MEW) is a versatile direct electrowriting process that permits the development of well-organized fibrous constructs with fiber resolutions ranging from micron to nanoscale. Indeed, MEW offers great prospects for the fabrication of scaffolds mimicking tissue specificity, healthy and pathophysiological microenvironments, personalized multi-scale transitions, and functional interfaces for tissue regeneration in medicine and dentistry. Excitingly, recent work has demonstrated the potential of converging MEW with other AM technologies and/or cell-laden scaffold fabrication (bioprinting) as a favorable route to overcome some of the limitations of MEW for DOC tissue regeneration. In particular, such convergency fabrication strategy has opened great promise in terms of supporting multi-tissue compartmentalization and predetermined cell commitment. In this review, we offer a critical appraisal on the latest advances in MEW and its convergence with other biofabrication technologies for DOC tissue regeneration. We first present the engineering principles of MEW and the most relevant design aspects for transition from flat to more anatomically relevant 3D structures while printing highly-ordered constructs. Secondly, we provide a thorough assessment of contemporary achievements using MEW scaffolds to study and guide soft and hard tissue regeneration, and draw a parallel on how to extrapolate proven concepts for applications in DOC tissue regeneration. Finally, we offer a combined engineering/clinical perspective on the fabrication of hierarchically organized MEW scaffold architectures and the future translational potential of site-specific, single-step scaffold fabrication to address tissue and tissue interfaces in dental, oral, and craniofacial regenerative medicine. STATEMENT OF SIGNIFICANCE: Melt electrowriting (MEW) techniques can further replicate the complexity of native tissues and could be the foundation for novel personalized (defect-specific) and tissue-specific clinical approaches in regenerative dental medicine. This work presents a unique perspective on how MEW has been translated towards the application of highly-ordered personalized multi-scale and functional interfaces for tissue regeneration, targeting the transition from flat to anatomically-relevant three-dimensional structures. Furthermore, we address the value of convergence of biofabrication technologies to overcome the traditional manufacturing limitations provided by multi-tissue complexity. Taken together, this work offers abundant engineering and clinical perspectives on the fabrication of hierarchically MEW architectures aiming towards site-specific implants to address complex tissue damage in regenerative dental medicine.

Regenerative endodontics represents a paradigm shift in dental pulp therapy for necrotic young permanent teeth.

Periodontitis is a ubiquitous chronic inflammatory, bacteria-triggered oral disease affecting the adult population. If left untreated, periodontitis can lead to severe tissue destruction, eventually resulting in tooth loss. Despite previous efforts in clinically managing the disease, therapeutic strategies are still lacking. Herein, melt electrowriting (MEW) is utilized to develop a compositionally and structurally tailored graded scaffold for regeneration of the periodontal ligament-to-bone interface. The composite scaffolds, consisting of fibers of polycaprolactone (PCL) and fibers of PCL-containing magnesium phosphate (MgP) were fabricated using MEW. To maximize the bond between bone (MgP) and ligament (PCL) regions, we evaluated two different fiber architectures in the interface area. These were a crosshatch pattern at a 0/90° angle and a random pattern. MgP fibrous scaffolds were able to promote in vitro bone formation even in culture media devoid of osteogenic supplements. Mechanical properties after MgP incorporation resulted in an increase of the elastic modulus and yield stress of the scaffolds, and fiber orientation in the interfacial zone affected the interfacial toughness. Composite graded MEW scaffolds enhanced bone fill when they were implanted in an in vivo periodontal fenestration defect model in rats. The presence of an interfacial zone allows coordinated regeneration of multitissues, as indicated by higher expression of bone, ligament, and cementoblastic markers compared to empty defects. Collectively, MEW-fabricated scaffolds having compositionally and structurally tailored zones exhibit a good mimicry of the periodontal complex, with excellent regenerative capacity and great potential as a defect-specific treatment strategy.

From a materials perspective, the pillars for the development of clinically translatable scaffold-based strategies for craniomaxillofacial (CMF) bone and periodontal regeneration have included electrospinning and 3D printing (biofabrication) technologies. Here, we offer a detailed analysis of the latest innovations in 3D (bio)printing strategies for CMF bone and periodontal regeneration and provide future directions envisioning the development of advanced 3D architectures for successful clinical translation. First, the principles of electrospinning applied to the generation of biodegradable scaffolds are discussed. Next, we present on extrusion-based 3D printing technologies with a focus on creating scaffolds with improved regenerative capacity. In addition, we offer a critical appraisal on 3D (bio)printing and multitechnology convergence to enable the reconstruction of CMF bones and periodontal tissues. As a future outlook, we highlight future directions associated with the utilisation of complementary biomaterials and (bio)fabrication technologies for effective translation of personalised and functional scaffolds into the clinics.

The effects of ethylenediaminetetraacetic acid (EDTA) on regenerative endodontic procedures (REPs) are controversial, because, despite releasing growth factors from dentine, some studies show negative effects on cell behaviour.The aim of the study was to investigate the influence of the use of EDTA in REP on the growth factors' release, cell behaviour and tissue regeneration.A systematic search was conducted (PubMed/Medline, Scopus, Cochrane Library, Web of Science, Embase, OpenGrey and reference lists) up to February 2021. Only in vivo and in vitro studies evaluating the effects of EDTA on the biological factors of dentine, pulp/periapical tissues and cell behaviour were eligible. Studies without a control group or available full text were excluded. The growth factors' release was the primary outcome. Risk of bias in the in vitro and in vivo studies was performed according to Joanna Briggs Institute's Checklist and SYRCLE's RoB tool, respectively.Of the 1848 articles retrieved, 36 were selected. Amongst these, 32 were in vitro, three animal studies and one with both models. The EDTA concentrations ranged from 3% to 15%, at different times. Regarding growth factors' release (17 studies), 15 studies found significant transforming growth factor (TGF)-β release after dentine conditioning with EDTA, and most found no influence on vascular endothelial growth factor release. Regarding cell behaviour (26 studies), eight studies showed no influence of EDTA-treated dentine on cell viability, whereas, five, nine and six studies showed higher cell migration, adhesion and differentiation respectively. No influence of EDTA conditioning was observed in animal studies. In vitro studies had a low risk of bias, whereas animal studies had high risk of bias. Meta-analysis was unfeasible.This review found that EDTA increased TGF-β release and improved cell activity. However, well-designed histological analyses using immature teeth models are needed.High-quality in vitro evidence suggests that EDTA-treated dentine positively influences TGF-β release, cell migration, attachment and differentiation; further research to evaluate its influence on tissue regeneration is necessary due to low methodological quality of the animal studies.

Periodontitis compromises the integrity and function of tooth-supporting structures. Although therapeutic approaches have been offered, predictable regeneration of periodontal tissues remains intangible, particularly in anatomically complex defects. In this work, personalized and defect-specific antibiotic-laden polymeric scaffolds containing metronidazole (MET), tetracycline (TCH), or their combination (MET/TCH) were created via electrospinning. An initial screening of the synthesized fibers comprising chemo-morphological analyses, cytocompatibility assessment, and antimicrobial validation against periodontopathogens was accomplished to determine the cell-friendly and anti-infective nature of the scaffolds. According to the cytocompatibility and antimicrobial data, the 1:3 MET/TCH formulation was used to obtain three-dimensional defect-specific scaffolds to treat periodontally compromised three-wall osseous defects in rats. Inflammatory cell response and new bone formation were assessed by histology. Micro-computerized tomography was performed to assess bone loss in the furcation area at 2 and 6 weeks post implantation. Chemo-morphological and cell compatibility analyses confirmed the synthesis of cytocompatible antibiotic-laden fibers with antimicrobial action. Importantly, the 1:3 MET/TCH defect-specific scaffolds led to increased new bone formation, lower bone loss, and reduced inflammatory response when compared to antibiotic-free scaffolds. Altogether, our results suggest that the fabrication of defect-specific antibiotic-laden scaffolds holds great potential toward the development of personalized (i.e., patient-specific medication) scaffolds to ablate infection while affording regenerative properties.

Gelatin methacrylate (GelMA) is a biodegradable and biocompatible engineered material with significant promise for its applications in tissue engineering, drug delivery, and 3D bioprinting applications. Gelatin is functionalized with terminal methacrylate groups which allow for its photoinducible crosslinking, and thereby tunable properties. Photocrosslinking of GelMA solution in situ allows for fabrication of hydrogels to fit patient-specific defects. Given its favorable biologic properties, GelMA may be used as a carrier for bioactive substances necessary to induce regenerative phenotypes or augment healing, such as growth factors and biotherapeutics. Gelatin is cleaved by cell-secreted enzymes such that its degradation, and subsequently release of bioactive substances, is well-matched to tissue regeneration processes. GelMA may be mixed with a wide array of additives to enhance and improve the specificity of its biologic activity. Here, we present two protocols for novel fabrications and their uses as clinically relevant drug delivery systems. GelMA hydrogels provides a versatile platform for the development of injectable drug delivery therapeutics for broad applications in regenerative dental medicine.

OBJECTIVES: Electrospun scaffolds are a versatile biomaterial platform to mimic fibrillar structure of native tissues extracellular matrix, and facilitate the incorporation of biomolecules for regenerative therapies. Self-assembling peptide P 11-4 has emerged as a promising strategy to induce mineralization; however, P 11-4 application has been mostly addressed for early caries lesions repair on dental enamel. Here, to investigate P 11-4's efficacy on bone regeneration, polymeric electrospun scaffolds were developed, and then distinct concentrations of P 11-4 were physically adsorbed on the scaffolds. METHODS: P 11-4-laden and pristine (P 11-4-free) electrospun scaffolds were immersed in simulated body fluid and mineral precipitation identified by SEM. Functional groups and crystalline phases were analyzed by FTIR and XRD, respectively. Cytocompatibility, mineralization, and gene expression assays were conducted using stem cells from human exfoliated deciduous teeth. To investigate P 11-4-laden scaffolds potential to induce in vivo mineralization, an established rat calvaria critical-size defect model was used. RESULTS: We successfully synthesized nanofibrous (∼ 500 nm fiber diameter) scaffolds and observed that functionalization with P 11-4 did not affect the fibers' diameter. SEM images indicated mineral precipitation, while FTIR and XRD confirmed apatite-like formation and crystallization for P 11-4-laden scaffolds. In addition, P 11-4-laden scaffolds were cytocompatible, highly stimulated cell-mediated mineral deposition, and upregulated the expression of mineralization-related genes compared to pristine scaffolds. P 11-4-laden scaffolds led to enhanced in vivo bone regeneration after 8 weeks compared to pristine PCL. SIGNIFICANCE: Electrospun scaffolds functionalized with P 11-4 are a promising strategy for inducing mineralized tissues regeneration in the craniomaxillofacial complex.

The periodontium is a suitable target for regenerative intervention, since it does not functionally restore itself after disease. Importantly, the limited regeneration capacity of the periodontium could be improved with the development of novel biomaterials and therapeutic strategies. Of note, the regenerative potential of the periodontium depends not only on its tissue-specific architecture and function, but also on its ability to reconstruct distinct tissues and tissue interfaces, suggesting that the advancement of tissue engineering approaches can ultimately offer new perspectives to promote the organized reconstruction of soft and hard periodontal tissues. Here, we discuss material-based, biologically active cues, and the application of innovative biofabrication technologies to regenerate the multiple tissues that comprise the periodontium.

This work sought to formulate photocrosslinkable chlorhexidine (CHX)-laden methacrylated gelatin (CHX/GelMA) hydrogels with broad spectrum of action against endodontic pathogens as a clinically viable cell-friendly disinfection therapy prior to regenerative endodontics procedures.CHX/GelMA hydrogel formulations were successfully synthesized using CHX concentrations between 0.12 % and 5 % w/v. Hydrogel microstructure was evaluated by scanning electron microscopy (SEM). Swelling and enzymatic degradation were assessed to determine microenvironmental effects. Compression test was performed to investigate the influence of CHX incorporation on the hydrogels' biomechanics. The antimicrobial and anti-biofilm potential of the formulated hydrogels were assessed using agar diffusion assays and a microcosms biofilm model, respectively. The cytocompatibility was evaluated by exposing stem cells from human exfoliated deciduous teeth (SHEDs) to hydrogel extracts (i.e., leachable byproducts obtained from overtime hydrogel incubation in phosphate buffer saline). The data were analyzed using One- and Two-way ANOVA and Tukey's test (α = 0.05).CHX/GelMA hydrogels were effectively prepared. NMR spectroscopy confirmed the incorporation of CHX into GelMA. The addition of CHX did not change the micromorphology (pore size) nor the swelling profile (p 0.05). CHX incorporation reduced the degradation rate of the hydrogels (p 0.001); whereas, it contributed to increased compressive modulus (p 0.05). Regarding the antimicrobial properties, the incorporation of CHX showed a statistically significant decrease in the number of bacteria colonies at 0.12 % and 0.5 % concentration (p 0.001) and completely inhibited the growth of biofilm at concentration levels 1 %, 2 %, and 5 %. Meanwhile, the addition of CHX, regardless of the concentration, did not lead to cell toxicity, as cell viability values were above 70 %.The addition of CHX into GelMA showed significant antimicrobial action against the pathogens tested, even at low concentrations, with the potential to be used as a cell-friendly injectable drug delivery system for root canal disinfection prior to regenerative endodontics.

Objective The aim of this study was to develop bioactive and osseointegrable polyetheretherketone (PEEK)-based composite filaments melt-blended with novel amorphous magnesium phosphate (AMP) particles for 3D printing of dental and orthopedic implants. Materials and methods A series of materials and biological analyses of AMP-PEEK were performed. Thermal stability, thermogravimetric and differential scanning calorimetry curves of as-synthesized AMP were measured. Complex viscosity, elastic modulus and viscous modulus were determined using a rotational rheometer. In vitro bioactivity was analyzed using SBF immersion method. SEM, EDS and XRD were used to study the apatite-forming ability of the AMP-PEEK filaments. Mouse pre-osteoblasts (MC3T3-E1) were cultured and analyzed for cell viability, proliferation and gene expression. For in vivo analyses, bare PEEK was used as the control and 15AMP-PEEK was chosen based on its in vitro cell-related results. After 4 or 12 weeks, animals were euthanized, and the femurs were collected for micro-computed tomography (μ-CT) and histology. Results The collected findings confirmed the homogeneous dispersion of AMP particles within the PEEK matrix with no phase degradation. Rheological studies demonstrated that AMP-PEEK composites are good candidates for 3D printing by exhibiting high zero-shear and low infinite-shear viscosities. In vitro results revealed enhanced bioactivity and superior pre-osteoblast cell function in the case of AMP-PEEK composites as compared to bare PEEK. In vivo analyses further corroborated the enhanced osseointegration capacity for AMP-PEEK implants. Significance Collectively, the present investigation demonstrated that AMP-PEEK composite filaments can serve as feedstock for 3D printing of orthopedic and dental implants due to enhanced bioactivity and osseointegration capacity.

Objectives The purpose of this study was to synthesize chlorhexidine (CHX)-encapsulated aluminosilicate clay nanotubes (Halloysite®, HNTs) and to incorporate them into the primer/adhesive components of an etch-and-rinse adhesive system (SBMP; Scotchbond Multipurpose, 3M ESPE) and to test their effects on degree of conversion, viscosity, immediate and long-term bonding to dentin. Methods CHX-modified HNTs were synthesized using 10% or 20% CHX solutions. The primer and the adhesive components of SBMP were incorporated with 15 wt.% of the CHX-encapsulated HNTs. Degree of conversion (DC) and viscosity analyses were performed to characterize the modified primers/adhesives. For bond strength testing, acid-etched dentin was treated with one of the following: SBMP (control); 0.2%CHX solution before SBMP; CHX-modified primers + SBMP adhesive; SBMP primer + CHX-modified adhesives; and SBMP primer + CHX-free HNT-modified adhesive. The microtensile bond strength test was performed after immediate (24 h) and long-term (6 months) of water storage. Data were analyzed using ANOVA and Tukey (α = 5%) and the Weibull analysis. Results DC was greater for the CHX-free HNT-modified adhesive, whereas the other experimental adhesives showed similar DC as compared with the control. Primers were less viscous than the adhesives, without significant differences within the respective materials. At 24 h, all groups showed similar bonding performance and structural reliability; whereas at the 6-month period, groups treated with the 0.2%CHX solution prior bonding or with the CHX-modified primers resulted in greater bond strength than the control and superior reliability. Significance The modification of a primer or adhesive with CHX-encapsulated HNTs was an advantageous approach that did not impair the polymerization, viscosity and bonding performance of the materials, showing a promising long-term effect on resin-dentin bonds.

Made available in DSpace on 2020-12-10T19:56:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-04-08 National Institutes of Health (NIH, National Institute of Dental and Craniofacial Research/NIDCR) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) A photocrosslinkable gelatin methacryloyl (GelMA) hydrogel has been widely examined in regenerative engineering because of its good cell-tissue affinity and degradability in the presence of matrix metalloproteinases. A halloysite aluminosilicate nanotube (HNT) is a known reservoir for the loading and sustained delivery of therapeutics. Here, we formulate injectable chlorhexidine (CHX)-loaded nanotube-modified GelMA hydrogel that is cytocompatible and biodegradable and provides sustained release of CHX for infection ablation while displaying good biocompatibility. The effects of HNTs and CHX on hydrogel degradability and mechanical properties, as well as on the kinetics of CHX release, and on the antimicrobial efficacy against oral pathogens were systematically assessed. Cytocompatibility in stem cells from human exfoliated deciduous teeth and inflammatory response in vivo using a subcutaneous rat model were determined. Our hydrogel system, that is, (CHX)-loaded nanotube-modified GelMA showed minimum localized inflammatory responses, supporting its ability for drug delivery applications. Moreover, we showed that the incorporation of CHX-loaded nanotubes reduces the mechanical properties, increases the swelling ratio, and diminishes the degradation rate of the hydrogels. Importantly, the presence of CHX-loaded nanotubes inhibits bacterial growth with minimal cell toxicity. Our findings provide a new strategy to modify GelMA hydrogel with chlorhexidine-loaded nanotubes for clinical use as an injectable drug delivery strategy for dental infection ablation. Univ Michigan, Sch Dent, Dept Cariol Restorat Sci & Endodont, Ann Arbor, MI 48109 USA Univ Fed Pelotas, Sch Dent, Dept Restorat Dent, BR-96010610 Pelotas, RS, Brazil Sao Paulo State Univ, Sch Dent, Dept Dent Mat & Prosthodont, BR-01049010 Araraquara, SP, Brazil Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA Univ Michigan, Biointerfaces Inst, Ann Arbor, MI 48109 USA Univ Michigan, Sch Dent, Dept Biol & Mat Sci & Prosthodont, Ann Arbor, MI 48109 USA Sao Paulo State Univ, Sch Dent, Dept Dent Mat & Prosthodont, BR-01049010 Araraquara, SP, Brazil National Institutes of Health (NIH, National Institute of Dental and Craniofacial Research/NIDCR): K08DE023552 National Institutes of Health (NIH, National Institute of Dental and Craniofacial Research/NIDCR): R01DE026578

Dental clinicians have relied for centuries on traditional dental materials (polymers, ceramics, metals, and composites) to restore oral health and function to patients. Clinical outcomes for many crucial dental therapies remain poor despite many decades of intense research on these materials. Recent attention has been paid to biomolecules as a chassis for engineered preventive, restorative, and regenerative approaches in dentistry. Indeed, biomolecules represent a uniquely versatile and precise tool to enable the design and development of bioinspired multifunctional dental materials to spur advancements in dentistry. In this review, we survey the range of biomolecules that have been used across dental biomaterials. Our particular focus is on the key biological activity imparted by each biomolecule toward prevention of dental and oral diseases as well as restoration of oral health. Additional emphasis is placed on the structure–function relationships between biomolecules and their biological activity, the unique challenges of each clinical condition, limitations of conventional therapies, and the advantages of each class of biomolecule for said challenge. Biomaterials for bone regeneration are not reviewed as numerous existing reviews on the topic have been recently published. We conclude our narrative review with an outlook on the future of biomolecules in dental biomaterials and potential avenues of innovation for biomaterial-based patient oral care.

Fused Filament Fabrication (FFF)-based 3D printing is an efficient technique for developing medical implants, but it is not very useful in developing small yet mechanically robust design-specific fixtures such as dental implants (15 mm). Specifically, it is challenging to 3D print robust Polyetheretherketone (PEEK) small implants due to PEEK's high melting temperature and melt viscosity. However, in this study, we efficiently utilize high-temperature FFF to develop the first-of-its-kind patient-specific robust PEEK dental implants with high print resolution. Specifically, we explore the effects of critical FFF processing conditions on the mechanical properties of the implants and subsequently determine an optimized set of processing conditions that are essential in developing durable dental implant systems. Our results indicate that the 3D printed dental implants exhibit good fatigue properties and suffice the clinical and industrial requirements for dental implants. Furthermore, we prove that the 3D printed implants exhibit adequate mechanical durability even after simulated (accelerated) aging of 30 years.

OBJECTIVE. Alveolar bone defects can be highly variable in their morphology and, as the defect size increases, they become more challenging to treat with currently available therapeutics and biomaterials. This investigation sought to devise a protocol for fabricating customized clinical scale and patient-specific, bioceramic scaffolds for reconstruction of large alveolar bone defects. METHODS. Two types of calcium phosphate (CaP)-based bioceramic scaffolds (alginate/β-TCP and hydroxyapatite/α-TCP, hereafter referred to as hybrid CaP and Osteoink™, respectively) were designed, 3D printed, and their biocompatibility with alveolar bone marrow stem cells and mechanical properties were determined. Following scaffold optimization, a workflow was developed to use cone beam computed tomographic (CBCT) imaging to design and 3D print, defect-specific bioceramic scaffolds for clinical-scale bone defects. RESULTS. Osteoink(™) scaffolds had the highest compressive strength when compared to hybrid CaP with different infill orientation. In cell culture medium, hybrid CaP degradation resulted in decreased pH (6.3) and toxicity to stem cells; however, OsteoInk(™) scaffolds maintained a stable pH (7.2) in culture and passed the ISO standard for cytotoxicity. Finally, a clinically feasible laboratory workflow was developed and evaluated using CBCT imaging to engineer customized and defect-specific CaP scaffolds using OsteoInk(™). It was determined that printed scaffolds had a high degree of accuracy to fit the respective clinical defects for which they were designed (0.27 mm morphological deviation of printed scaffolds from digital design). SIGNIFICANCE. From patient to patient, large alveolar bone defects are difficult to treat due to high variability in their complex morphologies and architecture. Our findings shows that Osteoink(™) is a biocompatible material for 3D printing of clinically acceptable, patient-specific scaffolds with precision-fit for use in alveolar bone reconstructive procedures. Collectively, emerging digital technologies including CBCT imaging, 3D surgical planning, and (bio)printing can be integrated to address this unmet clinical challenge.

Periodontitis is a chronic inflammatory, bacteria-triggered disorder affecting nearly half of American adults. Although some level of tissue regeneration is realized, its low success in complex cases demands superior strategies to amplify regenerative capacity. Herein, highly ordered scaffolds are engineered via Melt ElectroWriting (MEW), and the effects of strand spacing, as well as the presence of a nanostructured fluorinated calcium phosphate (F/CaP) coating on the adhesion/proliferation, and osteogenic differentiation of human-derived periodontal ligament stem cells, are investigated. Upon initial cell-scaffold interaction screening aimed at defining the most suitable design, MEW poly(𝝐-caprolactone) scaffolds with 500 µm strand spacing are chosen. Following an alkali treatment, scaffolds are immersed in a pre-established solution to allow for coating formation. The presence of a nanostructured F/CaP coating leads to a marked upregulation of osteogenic genes and attenuated bacterial growth. In vivo findings confirm that the F/CaP-coated scaffolds are biocompatible and lead to periodontal regeneration when implanted in a rat mandibular periodontal fenestration defect model. In aggregate, it is considered that this work can contribute to the development of personalized scaffolds capable of enabling tissue-specific differentiation of progenitor cells, and thus guide simultaneous and coordinated regeneration of soft and hard periodontal tissues, while providing antimicrobial protection.

The purpose of the following papers is to explore plausible alternative futures for dental education. The COVID-19 pandemic, challenges emerging from racism in the US, and social unrest were the precipitating factors leading to this consideration of academic dentistry in approximately 5 years.In 2020-2021, five teams of six individual followed a seven-step process to develop five different scenarios of dental education in 2026. Four of these scenarios are constructed by considering a range of uncertainties associated with economic sustainability and educational innovation. A fifth scenario describes the optimal case for dental education's role should another pandemic occur.Each scenario is presented as a narrative in three parts: scenario highlights (summary), life in the scenario (fictional case), and scenario details (a description of significant factors within the envisioned future of the scenario). As a strategic tool, these scenarios will assist leaders, institutions, and stakeholders to anticipate and prepare for different futures, identify key indicators that a particular future is emerging, and guide decision-making to create the most desirable future in a changing environment.Institutions are encouraged to incorporate these scenarios into their strategic and contingency planning efforts and to use them to generate dialogue during faculty development initiatives. This study provides institutions with a process and model they can follow to create scenarios at the institutional level. The final paper in this collection is a guide that provides ideas and instructions for using the scenarios in curricular and extracurricular activities with faculty members and students.

Introduction This study aimed to compare the cytocompatibility and angiogenic potential of 2 antibiotics (clindamycin [CLIN] and minocycline [MINO]) at distinct concentrations on dental pulp stem cells (DPSCs) and human umbilical vein endothelial cells (HUVECs). Methods DPSCs and HUVECs were exposed to cell culture media modified with CLIN or MINO at concentrations ranging from 30 μg/mL–1000 μg/mL. Cell toxicity and proliferation were investigated using the lactate dehydrogenase and tetrazolium reduction assays, respectively. A capillarylike tube formation in vitro assay was conducted to determine the angiogenic potential associated with each antibiotic. Additionally, selected morphometric angiogenesis parameters were determined using dedicated software (WimTube; Onimagin Technologies SCA, Cordoba, Spain). All statistical analyses were performed using 1-way analysis of variance and the Tukey post hoc test (α= .05). Results The collected data showed that compared with the control (cell culture media, alpha-minimum essential medium Eagle) increasing the antibiotic concentration significantly decreased cell viability and proliferation of both DPSCs and HUVECs. In terms of angiogenic potential, when tested at 30 μg/mL and 50 μg/mL, CLIN significantly amplified tube formation when compared with MINO with angiogenesis parameters (ie, tube length and tube number) similar to the effect promoted by exogenous vascular endothelial growth factor (50 ng/mL). Conclusions CLIN was less cytotoxic when compared with MINO at higher concentrations. Of note, CLIN did not hinder the proangiogenic activity induced by vascular endothelial growth factor to the same extent as MINO, suggesting that the replacement of MINO by CLIN might translate into positive implications in the overall regenerative outcome.

This study aimed to evaluate the effects of various polishing systems associated or not to finishing with diamond burs of lower-grit size on the topography, roughness, and fatigue behavior of a ground yttrium-stabilized tetragonal polycrystalline zirconia (Y-TZP). Disc specimens of Y-TZP (Zenostar T, Ivoclar-Vivadent) were produced (diameter = 15 mm, thickness = 1.2 ± 0.2 mm; ISO 6872-2015) and randomly allocated into 8 groups: [Ctrl] as-sintered; [Gr] ground with coarse diamond bur; [Gr+Eve] grinding + polishing with EveDiacera (2-step polishing system); [Gr+Fin+Eve] grinding + finishing + polishing with EveDiacera; [Gr+Kg] grinding + polishing with Kg Viking (2-step polishing system); [Gr+Fin+Kg] grinding + finishing + polishing with Kg Viking; [Gr+Op] grinding + polishing with Optrafine (3-step polishing system); and [Gr+Fin+Op] grinding + finishing + polishing with Optrafine. Next, surface topography, roughness, phase transformation, fatigue strength (staircase method), and fractography analyses were performed. Grinding changed the surface topography and generated higher roughness (Ra in μm) (1.214); the subsequent finishing/polishing procedures were able to reduce the roughness (0.326–0.839); however, it remained higher than the control [ctrl] group (0.221). All samples subjected to surface treatment presented an increase in m-phase content (8.04–17.46%). In terms of fatigue strength (in MPa), the grinding group (677.36) and polishing/finishing groups (641.66–707.20) presented higher fatigue strength than the control [ctrl] group (592.48). Finishing before polishing had no effect on fatigue strength (645.37–707.20). Grinding altered the Y-TZP surface features and increased their fatigue strength by phase transformation mechanism, while the finishing/polishing procedures promoted surface smoothening, while maintaining high fatigue strengths. Finishing as an additional step before polishing had no effect on roughness reduction and fatigue strength improvements; thus, the finishing procedure might be unnecessary.

Rapid progress has been made in the last decade related to stem cell-mediated pulp–dentin regeneration, from characterization of dental pulp stem cells (DPSCs) to the first-ever reported clinical case in humans. However, many challenges still need to be addressed before such technology can become a common clinical practice; therefore, further rigorous research is needed. Animal study models are very important to test new ideas, concepts, and technologies. This review summarizes and discusses several key animal models that have been utilized to investigate pulp–dentin regeneration. From a tissue regeneration perspective, we categorize the animal model by the location where the regenerated pulp tissue is formed: ectopic, semiorthotopic, and orthotopic. Several animal species are discussed, including mouse, ferret, dog, and miniswine. Mouse is used for ectopic pulp–dentin regeneration in the dorsum subcutaneous space. A commonly tested approach is hydroxyapatite/tricalcium phosphate (HA-TCP) granules model used to observe ectopic pulp–dentin complex formation. The semiorthotopic model includes tooth slices or fragments with which de novo pulp regeneration in a root canal space can be tested in the mouse subcutaneous space. For orthotopic pulp regeneration, the canine teeth of ferrets are large enough for such purposes. As nonprimate large animal models, dog and miniswine teeth have many aspects quite similar to those of humans, allowing researchers to perform experiments that mimic clinical conditions in humans. The protocols established and the data obtained from large animal studies may directly relate to and apply to future human studies. Complete orthotopic pulp regeneration has been demonstrated in dogs and miniswine. The use of allogeneic and subpopulations of DPSCs for pulp regeneration, and testing of the periapical disease model and aging model have been performed in miniswine or dogs. In sum, all these animal models will help address challenges that still face pulp regeneration in humans. We need to thoroughly utilize these models to test new ideas, technologies, and strategies before reliable and predictable clinical protocols can be established for human clinical trials or treatment. IMPACT STATEMENT: Animal models are essential for tissue regeneration studies. This review summarizes and discusses the small and large animal models, including mouse, ferret, dog, and miniswine that have been utilized to experiment and to demonstrate stem cell-mediated dental pulp tissue regeneration. We describe the models based on the location where the tissue regeneration is tested—either ectopic, semiorthotopic, or orthotopic. Developing and utilizing optimal animal models for both mechanistic and translational studies of pulp regeneration are of critical importance to advance this field.

The aim of this study was to characterize the flexural strength and elastic modulus of CAD/CAM resin composite material and to evaluate the influence of different surface treatments and storage conditions on the fatigue behavior of bonded composite crowns. Bars (flexural strength, n= 30; elastic modulus, n= 5) (1.2 × 4 × 12 mm) were produced for three-point bending test and CAD/CAM milled crowns (n= 5) (thickness= 1 mm) adhesively cemented to an epoxy resin substrate for fatigue tests. Bars and crowns were randomly allocated into two “surface treatments”: no surface treatment (CTRL) and air-abrasion with 110 μm Al2O3 particles (AlOx); while the crowns were also subdivided into “aging condition” (baseline - storage for 24 h to 7 days, and aging – storage for 150 days + 25,000 thermal cycles). The three-point bending test was performed according to ISO 6872 and the luted crowns were subjected to step-stress fatigue test (initial load of 200 N; step-size of 50 N; 10,000 cycles per step; 20 Hz). Complementary analysis by Stereomicroscopy and Field Emission Scanning Electron Microscopy (FE-SEM) were performed. The flexural strength and fatigue data were submitted to statistical tests (α= 0.05). The results showed that air-abrasion reduces the flexural strength and the characteristic strength of the resin composite, without modifying its elastic modulus or its structural reliability (Weibull Modulus). Air-abrasion did not influence the fatigue behavior of the cemented crowns. Notwithstanding, a decrease in the survival rate was observed after 445,000 cycles (2,400 N) when subjected to aging at both the CTRL or AlOx conditions. FE-SEM micrographs of the crowns showed that alumina particle air-abrasion treatment can modify the topography of its treated inner surface. Therefore, air-abrasion with alumina powder introduces defects onto the surface of the CAD/CAM resin composite material, decreasing the flexural strength, but without changing its elastic modulus and reliability. Adhesive cementation onto an epoxy resin substrate prevented an influence of the introduced defects on the fatigue performance of the resin composite restoration. Nevertheless, the fatigue behavior may be damaged by aging regimen.

Made available in DSpace on 2022-04-29T08:33:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Engineering multifunctional hydrogel systems capable of amplifying the regenerative capacity of endogenous progenitor cells via localized presentation of therapeutics under tissue inflammation is central to the translation of effective strategies for hard tissue regeneration. Here, we loaded dexamethasone (DEX), a pleotropic drug with anti-inflammatory and mineralizing abilities, into aluminosilicate clay nanotubes (halloysite clay nanotubes (HNTs)) to engineer an injectable multifunctional drug delivery system based on photo-cross-linkable gelatin methacryloyl (GelMA) hydrogel. In detail, a series of hydrogels based on GelMA formulations containing distinct amounts of DEX-loaded nanotubes was analyzed for physicochemical and mechanical properties and kinetics of DEX release as well as compatibility with mesenchymal stem cells from human exfoliated deciduous teeth (SHEDs). The anti-inflammatory response and mineralization potential of the engineered hydrogels were determined in vitro and in vivo. DEX conjugation with HNTs was confirmed by FTIR analysis. The incorporation of DEX-loaded nanotubes enhanced the mechanical strength of GelMA with no effect on its degradation and swelling ratio. Scanning electron microscopy (SEM) images demonstrated the porous architecture of GelMA, which was not significantly altered by DEX-loaded nanotubes' (HNTs/DEX) incorporation. All GelMA formulations showed cytocompatibility with SHEDs (p < 0.05) regardless of the presence of HNTs or HNTs/DEX. However, the highest osteogenic cell differentiation was noticed with the addition of HNT/DEX 10% in GelMA formulations (p < 0.01). The controlled release of DEX over 7 days restored the expression of alkaline phosphatase and mineralization (p < 0.0001) in lipopolysaccharide (LPS)-stimulated SHEDs in vitro. Importantly, in vivo data revealed that DEX-loaded nanotube-modified GelMA (5.0% HNT/DEX 10%) led to enhanced bone formation after 6 weeks (p < 0.0001) compared to DEX-free formulations with a minimum localized inflammatory response after 7 days. Altogether, our findings show that the engineered DEX-loaded nanotube-modified hydrogel may possess great potential to trigger in situ mineralized tissue regeneration under inflammatory conditions. Department of Cariology Restorative Sciences University of Michigan, 1011 N. University Ave Department of Physiology and Pathology Araraquara School of Dentistry Universidade Estadual Paulista (UNESP), 1680 Humaitá Street Department of Operative Dentistry Endodontics and Dental Materials Bauru School of Dentistry Sao Paulo University (USP), Al. Dr. Octavio Pinheiro Brizola, 9-75 Department of Biomedical Engineering College of Engineering University of Michigan, 2200 Bonisteel Blvd. Department of Physiology and Pathology Araraquara School of Dentistry Universidade Estadual Paulista (UNESP), 1680 Humaitá Street

OBJECTIVES. The aim of this review is to highlight recent progress in the field of biomaterials-mediated dental pulp tissue engineering. Specifically, we aim to underscore the critical design criteria of biomaterial platforms that are advantageous for pulp tissue engineering, discuss models for preclinical evaluation, and present new and innovative multifunctional strategies that hold promise for clinical translation. MATERIALS AND METHODS. The current article is a comprehensive overview of recent progress over the last five years. In detail, we surveyed the literature in regenerative pulp biology, including novel biologic and biomaterials approaches, and those that combined multiple strategies, towards more clinically relevant models. PubMed searches were performed using the keywords: “regenerative dentistry,” “dental pulp regeneration,” “regenerative endodontics,” and “dental pulp therapy.” RESULTS. Significant contributions to the field of regenerative dentistry have been made in the last five years, as evidenced by a significant body of publications. We chose exemplary studies that we believe are progressive towards clinically translatable solutions. We close this review with an outlook towards the future of pulp regeneration strategies and their clinical translation. CONCLUSIONS. Current clinical treatments lack functional and predictable pulp regeneration and are more focused on the treatment of the consequences of pulp exposure, rather than the restoration of healthy dental pulp. CLINICAL RELEVANCE. Clinically, there is great demand for bioinspired biomaterial strategies that are safe, efficacious, and easy to use, and clinicians are eager for their clinical translation. In particular, we place emphasis on strategies that combine favorable angiogenesis, mineralization, and functional tissue formation, while limiting immune reaction, risk of microbial infection, and pulp necrosis.

Made available in DSpace on 2021-06-25T12:39:10Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-04-01 National Institutes of Health (NIH) /National Institute of Dental and Craniofacial Research (NIDCR) The aim of this investigation was to engineer metformin (MF)-loaded mesoporous silica nanospheres (MSNs)laden gelatin methacryloyl (GelMA) photocrosslinkable hydrogels and test their effects on the mechanical properties, swelling ratio, drug release, cytocompatibility, and osteogenic differentiation of stem cells from human exfoliated deciduous teeth (SHEDs). As-received and carboxylated MSNs (MSNs-COOH) were characterized by scanning and transmission electron microscopies (SEM and TEM), as well as Fourier-transform infrared spectroscopy (FTIR) prior to hydrogel modification. MF-MSNs-COOH were obtained by loading MF into MSNs at a 1:1 mass ratio. Upon MSNs-COOH laden-hydrogels fabrication, the mechanical properties, swelling ratio and MF release were evaluated. SHEDs were seeded on the hydrogels and cytocompatibility was examined. The effects of the MF-MSNs-COOH/GelMA on the osteogenic differentiation of SHEDs were measured by ALP activity, Alizarin Red assay, and Real-time PCR. Statistics were performed using one-way ANOVA (alpha = 0.05). Morphological (SEM and TEM) analyses of pristine and carboxylated MSNs revealed a mean particle size of 200 nm and 218 nm, respectively. Importantly, an intrinsic nanoporous structure was noticed. Incorporation of MSNs-COOH at 1.5 mg/mL in GelMA led to the highest compressive modulus and swelling ratio. The addition of MSNs-COOH (up to 3 mg/mL) in GelMA did not impact cell viability. The presence of MF in MSNs-COOH/GelMA significantly promoted cell proliferation. Significant upregulation of osteogenic-related genes (except OCN) were seen for modified (MSNs-COOH and MF-MSNs-COOH) hydrogels when compared to GelMA. Altogether, the engineered MF-MSNs-COOH/GelMA shows great promise in craniomaxillofacial applications as an injectable, cell-free and bioactive therapeutics for bone regeneration. Univ Michigan, Sch Dent, Dept Cariol Restorat Sci & Endodont, 1011 N Univ,Room 5223, Ann Arbor, MI 48109 USA China Med Univ, Sch & Hosp Stomatol, Dept Endodont, Liaoning Prov Key Lab Oral Dis, Shenyang, Peoples R China Univ Fed Pelotas, Sch Dent, Dept Restorat Dent, Pelotas, RS, Brazil Sao Paulo State Univ, Sch Dent, Dept Dent Mat & Prosthodont, Araraquara, SP, Brazil Univ Michigan, Sch Dent, Dept Periodont & Oral Med, Ann Arbor, MI 48109 USA Sao Paulo State Univ, Sch Dent, Dept Dent Mat & Prosthodont, Araraquara, SP, Brazil National Institutes of Health (NIH) /National Institute of Dental and Craniofacial Research (NIDCR): R01DE026578

Made available in DSpace on 2021-06-25T12:20:15Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-09-01 National Institutes of Health (NIH)/National Institute of Dental and Craniofacial Research (NIDCR) Introduction: This review aimed to provide a critical appraisal of alternative antimicrobial strategies in lieu of traditional triple antibiotic paste (TAP). Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The literature search was performed in 8 databases (PubMed/Medline, Embase, LILACS, Web of Science, Scopus, BVS, SciELO, and the Cochrane Library), selecting clinical, in vitro, in vivo, and in situ studies that evaluated antimicrobial alternatives to TAP in regenerative endodontics. Studies lacking an experimental TAP group were excluded. Results: A total of 1705 potentially relevant records were initially identified. From the 38 studies retrieved for full-text reading, 16 fulfilled all selection criteria and were included in the qualitative analysis. According to the study design, 11 studies were solely in vitro, 1 study was both in vitro and in vivo (animal model), 2 studies were solely animal experiments, and 2 studies were clinical trials. The alternative antimicrobial agents to TAP consisted of modified TAP formulations (eg, a combination of TAP with chitosan); TAP-eluting nanofibers; propolis; chlorhexidine (CHX) gels/solutions; double antibiotic pastes composed of distinct combinations of antibiotics; Ca(OH)2-based formulations; and sodium hypochlorite. Overall, most of the alternative agents performed similarly to TAP, although some strategies (eg, Ca(OH)2- and CHX-based formulations) seemed to present dubious importance in the control of infection. Conclusions: TAP still remains an excellent option in terms of the complete elimination of microorganisms. This review points to the use of electrospun fibers as a drug delivery system to offer a controlled release of the antimicrobial agent, as well as the use of natural compounds, deserving future investigation. Univ Michigan, Sch Dent, Dept Cariol Restorat Sci & Endodont, 1011 North Univ Ave,Room 5223, Ann Arbor, MI 48109 USA Univ Fed Pelotas, Sch Dent, Grad Program Dent, Pelotas, RS, Brazil Univ Fed Rio Grande do Sul, Sch Dent, Dept Conservat Dent, Porto Alegre, RS, Brazil Sao Paulo State Univ, Araraquara Sch Dent, Dept Dent Mat & Prosthodont, Araraquara, SP, Brazil Sao Paulo State Univ, Araraquara Sch Dent, Dept Dent Mat & Prosthodont, Araraquara, SP, Brazil National Institutes of Health (NIH)/National Institute of Dental and Craniofacial Research (NIDCR): R01DE026578

Oral bacterial infection represents the leading cause of the gradual destruction of tooth and periodontal structures anchoring the teeth. Lately, injectable hydrogels have gained increased attention as a promising minimally invasive platform for localized delivery of personalized therapeutics. Here, an injectable and photocrosslinkable gelatin methacryloyl (GelMA) hydrogel is successfully engineered with ciprofloxacin (CIP)-eluting short nanofibers for oral infection ablation. For this purpose, CIP or its β-cyclodextrin (β-CD)-inclusion complex (CIP/β-CD-IC) has been incorporated into polymeric electrospun fibers, which were subsequently cut into short nanofibers, and then embedded in GelMA to obtain an injectable hybrid antimicrobial hydrogel. Thanks to the solubility enhancement of CIP by β-CD-IC and the tunable degradation profile of GelMA, the hydrogels promote localized, sustained, and yet effective cell-friendly antibiotic doses, as measured by a series of bacterial assays that demonstrated efficacy in attenuating the growth of Gram-positive Enterococcus faecalis. Altogether, we foresee significant potential in translating this innovative hybrid hydrogel as an injectable platform technology that may have broad applications in oral infection ablation, such as periodontal disease and pulpal pathology.

Current stem cell transplantation approaches lack efficacy, because they limit cell survival and retention and, more importantly, lack a suitable cellular niche to modulate lineage-specific differentiation. Here, we evaluate the intrinsic ability of type I oligomeric collagen matrices to modulate dental pulp stem cells (DPSCs) endothelial and odontogenic differentiation as a potential stem cell-based therapy for regenerative endodontics. DPSCs were encapsulated in low-stiffness (235 Pa) and high-stiffness (800 Pa) oligomeric collagen matrices and then evaluated for long-term cell survival, as well as endothelial and odontogenic differentiation following in vitro cell culture. Moreover, the effect of growth factor incorporation, i.e., vascular endothelial growth factor (VEGF) into 235 Pa oligomeric collagen or bone morphogenetic protein (BMP2) into the 800 Pa oligomeric collagen counterpart on endothelial or odontogenic differentiation of encapsulated DPSCs was investigated. DPSCs-laden oligomeric collagen matrices allowed long-term cell survival. Real time polymerase chain reaction (RT-PCR) data showed that the DPSCs cultured in 235 Pa matrices demonstrated an increased expression of endothelial markers after 28 days, and the effect was enhanced upon VEGF incorporation. There was a significant increase in alkaline phosphatase (ALP) activity at Day 14 in the 800 Pa DPSCs-laden oligomeric collagen matrices, regardless of BMP2 incorporation. However, Alizarin S data demonstrated higher mineralization by Day 21 and the effect was amplified in BMP2-modified matrices. Herein, we present key data that strongly support future research aimed at clinical translation of an injectable oligomeric collagen system for delivery and fate regulation of DPSCs to enable pulp and dentin regeneration at specific locations of the root canal system.

Made available in DSpace on 2020-12-12T01:56:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-08-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The aim of this study was to develop a highly porous calcium-containing chitosan scaffold suitable for dentin regeneration. A calcium hydroxide (Ca[OH]2) suspension was used to modulate the degree of porosity and chemical composition of chitosan scaffolds. The chitosan solution concentration and freezing protocol were adjusted to optimize the porous architecture using the phase-separation technique. Scanning electron microscopy/energy-dispersive spectroscopy demonstrated the fabrication of a highly porous calcium-linked chitosan scaffold (CH-Ca), with a well-organized and interconnected porous network. Scaffolds were cross-linked on glutaraldehyde (GA) vapor. Following a 28-day incubation in water, cross-linked CH scaffold had no changes on humid mass, and CH-Ca featured a controlled degradability profile since the significant humid mass loss was observed only after 21 (26.0%) and 28 days (42.2%). Fourier-transform infrared spectroscopy indicated the establishment of Schiff base on cross-linked scaffolds, along with calcium complexation for CH-Ca. Cross-linked CH-Ca scaffold featured a sustained Ca2+ release up to 21 days in a humid environment. This porous and stable architecture allowed for human dental pulp cells (HDPCs) to spread throughout the scaffold, with cells exhibiting a widely stretched cytoplasm; whereas, the cells seeded onto CH scaffold were organized in clusters. HDPCs seeded onto CH-Ca featured significantly higher ALP activity, and gene expressions for ALP, Col1, DMP-1, and DSPP in comparison to CH, leading to a significant 3.5 times increase in calcium-rich matrix deposition. In sum, our findings suggest that CH-Ca scaffolds are attractive candidates for creating a highly porous and bioactive substrate for dentin tissue engineering. Department of Operative Dentistry Endodontics and Dental Materials Bauru School of Dentistry Sao Paulo University - USP Department of Physiology and Pathology Araraquara School of Dentistry Univ. Estadual Paulista - UNESP Department of Orthodontics and Pediatric Dentistry Araraquara School of Dentistry Univ. Estadual Paulista – UNESP Department of Physics School of Sciences Univ. Estadual Paulista – UNESP Department of Cariology Restorative Sciences Endodontics School of Dentistry University of Michigan Department of Physiology and Pathology Araraquara School of Dentistry Univ. Estadual Paulista - UNESP Department of Orthodontics and Pediatric Dentistry Araraquara School of Dentistry Univ. Estadual Paulista – UNESP Department of Physics School of Sciences Univ. Estadual Paulista – UNESP CAPES: 001 FAPESP: 2016/15674-5