Oral mucositis is a painful inflammation and ulceration of the oral mucosa that frequently occurs as a side effect of radiation and chemotherapy that impairs patients' quality of life, making eating and drinking challenging. Local anesthetics applied directly to lesions can provide temporary pain relief without substantial systemic exposure. Buccal films are a promising delivery platform because they protect the sore area while releasing anesthetics locally to the inflamed mucosa. In this work, the mucoadhesive and swelling properties of chitosan were exploited as a backing layer in bilayer films whose inner drug-loaded layer comprised hydroxypropyl methyl cellulose (HPMC). Formulations containing HPMC of two molecular weights (low and high Mw) at concentrations chosen to give similar viscosity in solution (9% and 2.8% w/w, respectively), were tested with chitosan at 2% and 3% w/w. Interactions between chitosan and HPMC were confirmed by QCM-D. Tetracaine and bupivacaine served as model drugs. Films containing 5-10 mg drug were transparent and non-crystalline; higher drug loads produced crystallization on drying. Drug release was monitored simultaneously from the drug-containing layer and the chitosan backing layer in a side-by-side setup, and the best formulation was able to limit the drug release through the backing layer by about 70% for one hour. This early-stage study shows that chitosan is a promising backing layer for bilayer films, reducing the amount of drug released into the oral cavity. Additionally, it may improve mouthfeel and mucosal residence time while enhancing therapeutic efficacy and patient comfort.

Background and Objectives: Anal fissures are a common condition in the general population, for which there are multiple treatment options. It is essential to select the most appropriate treatment for the right patient. This study aimed to observe and evaluate the effect of topical antibiotherapy, which is widely used in the management of wounds and chronic infections, on the healing of acute and chronic anal fissures. Materials and Methods: Hospital records of 625 individuals diagnosed with an anal fissure were reviewed. Previous treatments, including 0.4% glyceryl trinitrate and 5% lidocaine, were recorded. A total of 118 patients were included: 49 patients who received additional topical metronidazole due to inflammation, induration and minimal purulent discharge, in the absence of an abscess; and 69 uncomplicated patients who received only standard treatment, as per the exclusion criteria. Results: The mean age of the participants was 41.06 ± 10.70 years. No significant differences were found between the groups regarding age or sex (p = 0.616 and p = 0.665, respectively). However, prior treatment history and mucosal healing differed significantly between the two groups (p = 0.001 and p = 0.024, respectively). There were no significant differences in follow-up intervals, additional treatment requirements or improvement in VAS scores (p = 0.546, 0.904 and 0.154, respectively). Conclusions: Topical metronidazole may be associated with improved mucosal healing in selected patients with acute anal fissures presenting with clinical features such as local inflammation, minimal discharge or incision-related changes. However, the observed benefit does not appear to be uniform across all patients, and, in the absence of microbiological data, the extent of microbial involvement remains uncertain. Accordingly, topical metronidazole may be considered for carefully selected cases of acute anal fissure based on clinical judgement, while avoiding routine or indiscriminate antibiotic use.

Tetrodotoxin (TTX), widely known as pufferfish venom, is a low-molecular-weight guanidinium neurotoxin. It can accumulate to extremely high concentrations in certain animals, including pufferfish, blue-ringed octopuses, flatworms, and nemerteans. However, the origin of TTX and the mechanisms that enable such extreme accumulation in these animals remain poorly understood. In this study, using confocal laser scanning microscopy combined with electron immunocytochemistry and ultrastructural analysis, we demonstrate the presence of TTX-positive bacteria associated with specialized cellular structures-type II phagosomes of gut enterocytes-in the highly toxic nemertean Cephalothrix cf. simula. We hypothesize that TTX production in C. cf. simula results from interactions between the nemertean host and its endosymbionts. These findings clarify the origin and accumulation of the toxin in nemerteans and have broader implications for other TTX-bearing species.

Endoscopic submucosal dissection (ESD), a minimally invasive procedure, is constrained by the rapid dissipation of conventional submucosal cushions and the absence of sustained postoperative therapeutic support. Herein, we develop a multifunctional hydrogel integrating mucosal elevating, sustained local analgesia, wound protection, antibacterial and antioxidant capabilities for perioperative management of ESD. The hydrogel is formed via Schiff base reactions between carboxymethyl chitosan and oxidized dextran, incorporates methylene blue for intraoperative visualization, and integrates mesoporous silica nanoparticles loaded with Bupivacaine (BUP@MSNs) to enable local sustained-release analgesia. Targeting critical limitations of conventional mucosal elevating agents, the hydrogel rapidly forms a stable submucosal cushion through in situ gelation, enhancing ESD procedural efficiency and safety while enabling immediate wound sealing and protection. Under physiological conditions, the hydrogel exhibits excellent injectability, self-healing capacity, and tissue adhesion at the lesion site. It also exerts potent antioxidant and antibacterial activities, fulfilling requirements for perioperative microenvironment modulation. Furthermore, the hydrogel delivers early postoperative analgesia that persists for over 48 h, effectively covering the peak pain phase post-ESD. Comprehensive in vitro and in vivo safety evaluations confirm its favorable biocompatibility and tolerability. Collectively, the hydrogel represents an integrated, clinically operable, and cost-effective candidate for gastrointestinal endoscopic minimally invasive therapies.

Needle-insertion pain during dental local anesthesia remains one of the strongest triggers of dental anxiety. Conventional topical anesthetics show limited penetration through the thick palatal mucosa and often provide insufficient suppression of insertion pain. Microneedle (MN) patches have emerged as a minimally invasive drug-delivery platform capable of enhancing transmucosal permeability and topical anesthetic efficacy. This randomized, double-blind, crossover clinical trial evaluated the efficacy and safety of a benzocaine-loaded MN patch applied to the palatal mucosa prior to local anesthesia. Twenty adult patients requiring bilateral maxillary premolar scaling and root planing received MN or placebo patches in two study periods separated by a one-week washout. The primary outcome was the presence or absence of needle-insertion pain. Secondary outcomes included injection-phase pain assessed using a 100-mm visual analogue scale (VAS), numbness or discomfort at the application site, vital signs, and adverse events. Needle-insertion pain was reported in 2 of 20 cases (10%) under the MN patch condition, compared with 14 of 20 cases (70%) under the placebo patch condition, demonstrating a significantly lower incidence with the MN patch (p = 0.00049). In contrast, VAS scores for injection-phase pain did not differ significantly between conditions. No clinically relevant numbness, mucosal irritation, or MN-related adverse events were observed, and vital signs remained stable throughout both study periods. The benzocaine-loaded MN patch selectively attenuated superficial needle-insertion pain while maintaining an excellent safety profile. The absence of an effect on deeper injection-phase pain is likely attributable to the substantial thickness of the palatal mucosa. These findings support the clinical utility of MN-assisted transmucosal anesthesia as a novel drug-delivery modality in dentistry and provide a foundation for the development of minimally invasive analgesic systems.

A major weakness in the field of neurogastroenterology research has been a lack of technology to determine the spatial and temporal coordination of electrical activity along the gastrointestinal (GI) tract in-vivo, without requiring a surgical procedure. To overcome this weakness, we developed a miniaturized endoscope consisting of 128 iridium oxide recording sensors that allowed us to make high resolution intraluminal electrophysiological recordings in-vivo from the mucosal surface of the terminal large intestine of anesthetized mice. Recordings revealed discharges of smooth muscle action potentials organized into complex spatiotemporal patterns. The patterns were modified by pharmacological agents donepezil and atropine that stimulated or suppressed cholinergic neurotransmission, respectively. The patterns were also ablated by benzalkonium chloride, known to disrupt the function of the enteric nervous system. The endoscope was further validated under ex-vivo recording conditions, where blocking enteric neural activity with tetrodotoxin (TTX) again altered spontaneously occurring action potential patterns. This approach offers a unique opportunity to easily characterize normal and dysfunctional patterns of GI electrical activity in genetically modified and/or diseased mouse models, including drug discovery and high-throughput studies.

Gel-based depots are increasingly recognized as platforms to extend the intratissue residence of local anesthetics (LAs) while reducing systemic exposure. Hydrogels, organogels, and emerging bigels represent three distinct architectures defined by their continuous phases and drug-matrix interactions. Hydrogels provide hydrated polymer networks with predictable injectability, tunable degradation, and diffusion- or stimulus-responsive release, enabling sustained analgesia in perineural, peri-incisional, intra-articular, and implant-adjacent settings. Organogels, formed by supramolecular assembly of low-molecular-weight gelators in lipids or semi-polar solvents, strongly solubilize lipophilic LA bases and enhance barrier partitioning, making them suitable for dermal, transdermal, and mucosal applications in outpatient or chronic pain care. Bigels integrate aqueous and lipid domains within biphasic matrices, improving rheology, spreadability, and dual-solubilization capacity, although their use in LA delivery remains at the formulation stage, with no validated in vivo pharmacology. This narrative review synthesizes the design principles, release mechanisms, and translational evidence across these platforms, highlighting domain-specific advantages and barriers related to mechanical robustness, sterilization, reproducibility, and regulatory feasibility. We propose a platform-level framework in which depot selection is aligned with LA chemistry, anatomical context, and clinical objectives to guide the development of workflow-compatible next-generation LA depots.

The core objective of pain management is to effectively alleviate pain while ensuring safety, sustainability, and personalization. Local anesthetics demonstrate significant advantages in analgesia, yet their clinical application is constrained by short half-lives and the risk of cardiotoxicity and neurotoxicity when administered in high doses. The development of long-acting local anesthetics with sustained-release formulations has become a research focus. Traditional carriers like liposomes often suffer from rapid initial release and drug diffusion, leading to limited analgesic duration and low drug loading capacity. Natural polymers, however, offer distinct advantages as drug delivery systems. They exhibit excellent biocompatibility and biodegradability, breaking down into harmless byproducts in the body to prevent tissue accumulation and immune reactions. With natural origins and cost-effectiveness, polymers such as chitosan and sodium alginate also demonstrate mucosal adhesion properties to prolong drug retention at injection sites. Their highly modifiable molecular structures allow chemical adaptation to different local anesthetics. Recent advancements in microfluidics and 3D printing have optimized drug loading and controlled-release performance in natural polymer composite systems, showcasing significant clinical translation potential. This review summarizes all studies on natural polymer-based local anesthetic delivery systems that include experimental validation, animal experiments, and clinical trials, sourced from PubMed and the ClinicalTrials.gov database over the past 5 years and outlines future application prospects, providing innovative approaches for long-acting analgesia.

Pluronic® gels loaded with Bupivacaine salt of linolenic acid (Bup-γL) were successfully developed in the past for oral mucositis pain control. The mechanisms of drug release from such Pluronic® gels have not yet been fully understood. The objective of this study was to explore the underlying mechanisms of drug release from Pluronic® gels with or without interference by sodium lauryl sulfate (SLS). The in vitro release of the hydrophilic bupivacaine salt (bupivacaine hydrochloride, BupHCl) as well as two hydrophobic bupivacaine salts (bupivacaine salt of linolenic acid, Bup-γL; and bupivacaine salt of linoleic acid, Bup-L) formulated in Pluronic® gels was performed. The liquid crystalline structure, the rheological properties and the thermal properties of these Pluronic® formulations were analyzed using small-angle X-ray scattering (SAXS), rheology and nano differential scanning calorimetry (nano DSC), respectively. The release of hydrophobic Bup-γL and Bup-L was significantly slowed down in SLS induced body-centered cubic (bcc) and face-centered cubic (fcc) structures in the Pluronic® gels, compared with the hexagonal structure in the Pluronic® gels without SLS. On the other hand, the release of BupHCl from the Pluronic® gels was not significantly different in the SLS induced lamellar structure and in the hexagonal structure (without SLS). In brief, the liquid crystalline structure in the Pluronic® gels did not influence the release of the hydrophilic drug yet significantly affected the release of the hydrophobic drugs. This is the first report revealing the release mechanisms of bupivacaine salts from Pluronic® gels through exploring their liquid crystalline structures. The findings not only provide an in-depth understanding of the drug release from the Pluronic® gels developed previously for oral mucositis pain control, but more importantly, offer valuable insight to assist future Pluronic® based formulation design for drug release control.

For more than sixty years, the piperidinopropiophenone derivative dyclonine is used as a local anesthetic in human and veterinary medicines. Dyclonine-containing drugs (Dyclone, DycloPro) have been developed as anti-itching medications and pain relievers in dermatology and dentistry. The product is used also as a protectant of mucosal surfaces to facilitate endoscopic examination. In the present review, the history of dyclonine is retraced and its multiple pharmaceutical usages are discussed. Synthetic strategies to obtain dyclonine are summarized. The goal of this study was also to analyze all pharmacological activities of the drug and its molecular targets. Dyclonine is considered a potent and selective antagonist of TRPV3 channels but it inhibits also histone methyltransferase G9a, aldehyde dehydrogenase 2 (ALDH2) and a few other proteins. The contribution of these targets to the drug activities is discussed. The better knowledge of the pharmacology of dyclonine has raised novel opportunities to use the drug for the treatment of neurodegenerative diseases, notably Parkinson disease and Friedreich's ataxia, and to combat drug-resistant cancers, such as chemo-resistant head and neck squamous cell carcinoma and glioblastoma. Preliminary evidence for the activity of dyclonine-containing drug combinations to treat multiple myeloma and solid tumors are discussed. An overview of dyclonine pharmacology is offered. This unsung drug has not finished talked about it.