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Keeping sodium hypochlorite (NaOCl) within the root canal is challenging in regenerative endodontics. In this study, we developed a drug delivery system using a gelatin methacryloyl (GelMA) hydrogel incorporated with aluminosilicate clay nanotubes (HNTs) loaded with NaOCl. Pure GelMA, pure HNTs, and NaOCl-loaded HNTs carrying varying concentrations were assessed for chemo-mechanical properties, degradability, swelling capacity, cytocompatibility, antimicrobial and antibiofilm activities, and in vivo for inflammatory response and degradation. SEM images revealed consistent pore sizes of 70–80 µm for all samples, irrespective of the HNT and NaOCl concentration, while HNT-loaded hydrogels exhibited rougher surfaces. The hydrogel's compressive modulus remained between 100 and 200 kPa, with no significant variations. All hydrogels demonstrated a 6–7-fold mass increase and complete degradation by the seventh day. Despite an initial decrease in cell viability, all groups recovered to 65–80% compared to the control. Regarding antibacterial and antibiofilm properties, 12.5 HNT(Double) showed the highest inhibition zone on agar plates and the most significant reduction in biofilm compared to other groups. In vivo, the 12.5 HNT(Double) group displayed partial degradation after 21 days, with mild localized inflammatory responses but no tissue necrosis. In conclusion, the HNT-NaOCl-loaded GelMA hydrogel retains the disinfectant properties, providing a safer option for endodontic procedures without harmful potential. [ABSTRACT FROM AUTHOR]

This study was aimed at engineering photocrosslinkable azithromycin (AZ)-laden gelatin methacryloyl fibers via electrospinning to serve as a localized and biodegradable drug delivery system for endodontic infection control. AZ at three distinct amounts was mixed with solubilized gelatin methacryloyl and the photoinitiator to obtain the following fibers: GelMA+5%AZ, GelMA+10%AZ, and GelMA+15%AZ. Fiber morphology, diameter, AZ incorporation, mechanical properties, degradation profile, and antimicrobial action against Aggregatibacter actinomycetemcomitans and Actinomyces naeslundii were also studied. In vitro compatibility with human-derived dental pulp stem cells and inflammatory response in vivo using a subcutaneous rat model were also determined. A bead-free fibrous microstructure with interconnected pores was observed for all groups. GelMA and GelMA+10%AZ had the highest fiber diameter means. The tensile strength of the GelMA-based fibers was reduced upon AZ addition. A similar pattern was observed for the degradation profile in vitro. GelMA+15%AZ fibers led to the highest bacterial inhibition. The presence of AZ, regardless of the concentration, did not pose significant toxicity. In vivo findings indicated higher blood vessel formation, mild inflammation, and mature and thick well-oriented collagen fibers interweaving with the engineered fibers. Altogether, AZ-laden photocrosslinkable GelMA fibers had adequate mechanical and degradation properties, with 15%AZ displaying significant antimicrobial activity without compromising biocompatibility. [ABSTRACT FROM AUTHOR]

This study evaluated the biocompatibility of degradable polydioxanone (PDS) electrospun drug delivery systems (hereafter referred as matrices) containing metronidazole (MET) or ciprofloxacin (CIP) after subcutaneous implantation in rats. Sixty adult male rats were randomized into six groups: SHAM (sham surgery); PDS (antibiotic‐free matrix); 1MET (one 25 wt% MET matrix); 1CIP (one 25 wt% CIP matrix); 2MET (two 25 wt% MET matrices); and 2CIP (two 25 wt% CIP matrices). At 3 and 30 days, animals were assessed for inflammatory cell response (ICR), collagen fibers degradation, and oxidative profile (reactive oxygen species [ROS]; lipid peroxidation [LP]; and protein carbonyl [PC]). At 3 days, percentages of no/discrete ICR were 100, 93.3, 86.7, 76.7, 50, and 66.6 for SHAM, PDS, 1MET, 1CIP, 2MET, and 2CIP, respectively. At 30 days, percentages of no/discrete ICR were 100% for SHAM, PDS, 1MET, and 1CIP and 93.3% for 2MET and 2CIP. Between 3 and 30 days, SHAM, 1CIP, and 2CIP produced collagen, while 1MET and 2MET were unchanged. At 30 days, the collagen fiber means percentages for SHAM, PDS, 1MET, 1CIP, 2MET, and 2CIP were 63.7, 60.7, 56.6, 62.6, 51.8, and 61.7, respectively. Antibiotic‐eluting matrices showed similar or better oxidative behavior when compared to PDS, except for CIP‐eluting matrices, which showed higher levels of PC compared to SHAM or PDS at 30 days. Collectively, our findings indicate that antibiotic‐eluting matrices may be an attractive biocompatible drug delivery system to fight periodontopathogens. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B, 2019. [ABSTRACT FROM AUTHOR]

Evoked bleeding (EB) clinical procedure, comprising a disinfection step followed by periapical tissue laceration to induce the ingrowth of undifferentiated stem cells from the periodontal ligament and alveolar bone, is currently the only regenerative‐based therapeutic approach to treating pulp tissue necrosis in undeveloped (immature) permanent teeth approved in the United States. Yet, the disinfection step using antibiotic‐based pastes leads to cytotoxic, warranting a biocompatible strategy to promote root canal disinfection with no or minimal side‐effects to maximize the regenerative outcomes. The purpose of this investigation was to develop a tubular three‐dimensional (3D) triple antibiotic‐eluting construct for intracanal drug delivery. Morphological (scanning electron microscopy), chemical (Fourier transform infrared spectroscopy), and mechanical (tensile testing) characteristics of the polydioxanone‐based triple antibiotic‐eluting fibers were assessed. The antimicrobial properties of the tubular 3D constructs were determined in vitro and in vivo using an infected (Actinomyces naeslundii) dentin tooth slice model and a canine method of periapical disease, respectively. The in vitro data indicated significant antimicrobial activity and the ability to eliminate bacterial biofilm inside dentinal tubules. In vivo histological findings demonstrated that, using the EB procedure, the tubular 3D triple antibiotic‐eluting construct allowed the formation of an appropriate environment that led to apex closure and the ingrowth of a thin layer of osteodentin‐like tissue into the root canal. Taken together, these findings indicate that our novel drug delivery construct is a promising biocompatible disinfection strategy for immature permanent teeth with necrotic pulps. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1576–1586, 2019. [ABSTRACT FROM AUTHOR]

Abstract: Periodontitis is a major chronic inflammatory disorder that can lead to the destruction of the periodontal tissues and, ultimately, tooth loss. To date, flap debridement and/or flap curettage and periodontal regenerative therapy with membranes and bone grafting materials have been employed with distinct levels of clinical success. Current resorbable and non-resorbable membranes act as a physical barrier to avoid connective and epithelial tissue down-growth into the defect, favoring the regeneration of periodontal tissues. These conventional membranes possess many structural, mechanical, and bio-functional limitations and the “ideal” membrane for use in periodontal regenerative therapy has yet to be developed. Based on a graded-biomaterials approach, we have hypothesized that the next-generation of guided tissue and guided bone regeneration (GTR/GBR) membranes for periodontal tissue engineering will be a biologically active, spatially designed and functionally graded nanofibrous biomaterial that closely mimics the native extra-cellular matrix (ECM). Objective: This review is presented in three major parts, including (1) a brief overview of the periodontium and its pathological conditions, (2) currently employed therapeutics used to regenerate the distinct periodontal tissues, and (3) a review of commercially available GTR/GBR membranes as well as the recent advances on the processing and characterization of GTR/GBR membranes from a materials perspective. Significance: Studies of spatially designed and functionally graded membranes (FGM) and in vitro antibacterial/cell-related research are addressed. Finally, as a future outlook, the use of hydrogels in combination with scaffold materials is highlighted as a promising approach for periodontal tissue engineering. [Copyright &y& Elsevier]

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. [Display omitted] • Chlorhexidine-laden gelatin methacrylate hydrogel (CHX/GelMA) was synthesized. • CHX/GelMA showed significant antimicrobial action against endodontic pathogens. • CHX/GelMA holds potential for infection eradication prior to regenerative procedures. [ABSTRACT FROM AUTHOR]

• A drug delivery system to afford sustained release of DEX was achieved by CD-IC. • DEX/CD-IC was successfully incorporated into PLGA fibers via electrospinning. • UPLC revealed the solubility enhancement and sustained release of DEX by CD-IC. • Cell compatibility and proliferation was more favorable in DEX/CD-IC fibers. • Odonto/osteogenic differentiation was enhanced in DEX/CD-IC electrospun fibers. Beta-cyclodextrin (β-CD) is an oligosaccharide commonly used to improve the aqueous solubility of lipophilic drugs (e.g., dexamethasone, DEX). Here we present the development of a drug delivery system to provide sustained release of DEX by β-CD-inclusion complex (IC) to amplify the mineralization capacity of stem cells from human-extracted deciduous teeth (SHEDs) as a potential direct pulp capping strategy. First, IC of DEX (DEX-CD-IC) was synthesized with β-CD. To confirm DEX-CD-IC complex formation, X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) analyses were performed. XRD data indicated that IC formation was achieved due to formation of a new crystalline structure, whereas FTIR revealed the presence of the IC from the shifting of the peaks of each component in DEX-CD-IC. Then, electrospun poly(lactic-co-glycolic acid, PLGA) fibers (PLGA/DEX-CD-IC) were processed by varying the concentration of DEX-CD-IC (5%, 10 %, and 15 %). The release of DEX from fibers was determined by ultraperformance liquid chromatography for 28 days. Thanks to the solubility enhancement of DEX by IC, electrospun PLGA/DEX-CD-IC fibers released DEX in a more sustained fashion compared to PLGA/DEX fibers. No deleterious effect was found in terms of SHEDs' proliferation when cultured with or on electrospun fibers, regardless of the IC presence. Importantly, a more pronounced odontogenic differentiation was stimulated by electrospun fibers loaded with the lowest DEX-CD-IC concentration (5%), as a result of the sustained DEX release. In sum, PLGA/DEX-CD-IC fibers have great potential in vital dental pulp therapy, owing to its sustained DEX release, cytocompatibility, and odontogenic differentiation capacity. [ABSTRACT FROM AUTHOR]