Tough Adhesive Hydrogel for Intraoral Adhesion and Drug Delivery.

Oral lichen planus (OLP) and recurrent aphthous stomatitis (RAS) are common chronic inflammatory conditions, manifesting as painful oral lesions that negatively affect patients' quality of life. Current treatment approaches are mainly palliative and often ineffective due to inadequate contact time of the therapeutic agent with the lesions. Here, we developed the Dental Tough Adhesive (DenTAl), a bioinspired adhesive patch with robust mechanical properties, capable of strong adhesion against diverse wet and dynamically moving intraoral tissues, and extended drug delivery of clobetasol-17-propionate, a first-line drug for treating OLP and RAS. DenTAl was found to have superior physical and adhesive properties compared to existing oral technologies, with ~2 to 100× adhesion to porcine keratinized gingiva and ~3 to 15× stretchability. Clobetasol-17-propionate incorporated into the DenTAl was released in a tunable sustained manner for at least 3 wk and demonstrated immunomodulatory capabilities in vitro, evidenced by reductions in several cytokines, including TNF-α, IL-6, IL-10, MCP-5, MIP-2, and TIMP-1. Our findings suggest that DenTAl may be a promising device for intraoral delivery of small-molecule drugs applicable to the management of painful oral lesions associated with chronic inflammatory conditions.

Neurturin-containing laminin matrices support innervated branching epithelium from adult epithelial salispheres.

Cell transplantation of autologous adult biopsies, grown ex vivo as epithelial organoids or expanded as spheroids, are proposed treatments to regenerate damaged branching organs. However, it is not clear whether transplantation of adult organoids or spheroids alone is sufficient to initiate a fetal-like program of branching morphogenesis in which coordinated branching of multiple cell types including nerves, mesenchyme and blood vessels occurs. Yet this is an essential concept for the regeneration of branching organs such as lung, pancreas, and lacrimal and salivary glands. Here, we used factors identified from fetal organogenesis to maintain and expand adult murine and human epithelial salivary gland progenitors in non-adherent spheroid cultures, called salispheres. These factors stimulated critical developmental pathways, and increased expression of epithelial progenitor markers such as Keratin5, Keratin14, FGFR2b and KIT. Moreover, physical recombination of adult salispheres in a laminin-111 extracellular matrix with fetal salivary mesenchyme, containing endothelial and neuronal cells, only induced branching morphogenesis when neurturin, a neurotrophic factor, was added to the matrix. Neurturin was essential to improve neuronal survival, axon outgrowth, innervation of the salispheres, and resulted in the formation of branching structures with a proximal-distal axis that mimicked fetal branching morphogenesis, thus recapitulating organogenesis. Epithelial progenitors were also maintained, and developmental differentiation programs were initiated, showing that the fetal microenvironment provides a template for adult epithelial progenitors to initiate branching and differentiation. Further delineation of secreted and physical cues from the fetal niche will be useful to develop novel regenerative therapies that instruct adult salispheres to resume a developmental-like program in vitro and to regenerate branching organs in vivo.

FGF2 Enhances Odontoblast Differentiation by αSMA+ Progenitors In Vivo.

The goal of this study was to examine the effects of early and limited exposure of perivascular cells expressing α (αSMA) to fibroblast growth factor 2 (FGF2) in vivo. We performed in vivo fate mapping by inducible Cre-loxP and experimental pulp injury in molars to induce reparative dentinogenesis. Our results demonstrate that early delivery of exogenous FGF2 to exposed pulp led to proliferative expansion of αSMA-tdTomato+ cells and their accelerated differentiation into odontoblasts. In vivo lineage-tracing experiments showed that the calcified bridge/reparative dentin in FGF2-treated pulps were lined with an increased number of Dspp+ odontoblasts and devoid of BSP+ osteoblasts. The increased number of odontoblasts derived from αSMA-tdTomato+ cells and the formation of reparative dentin devoid of osteoblasts provide in vivo evidence for the stimulatory effects of FGF signaling on odontoblast differentiation from early progenitors in dental pulp.