Jellyfish-Inspired Microneedles Dissolve in Minutes to Heal Oral Ulcers

Oral ulcers are among the most common lesions of the human body, yet treating them remains surprisingly difficult. The mouth is a hostile environment for medicine: saliva continuously washes away applied drugs, the swallowing reflex clears whatever survives, and the tough stratum corneum of the oral epithelium blocks hydrophilic compounds from penetrating. Adhesive patches can partly resist wash-away, but they cannot force drugs through the epithelial barrier, and conventional microneedle systems built from slowly degrading polymers such as PLGA or chitosan often take hours to days to dissolve, prolonging inflammation and leaving behind fragments that can trigger foreign-body reactions. A team of researchers at Xi’an Jiaotong University has now unveiled a radically different solution: a dissolving microneedle patch that borrows its release mechanism from the stinging cells of jellyfish and delivers more than 85 percent of its therapeutic payload within just 20 minutes of insertion.

The new platform, described in the journal Materials Today Bio, is built from hyaluronic acid, a naturally occurring polysaccharide already familiar from cosmetic and biomedical applications. The key insight lies in the chemistry of crosslinking. Hyaluronic acid, with its abundant carboxyl groups, readily coordinates with multivalent cations such as calcium ions, forming a three-dimensional hydrogel network reinforced by hydrogen bonds in humid conditions. But when the gel encounters tissue fluid rich in monovalent sodium and potassium ions, ligand exchange displaces the pre-chelated calcium and the network rapidly falls apart. This dynamic, switchable coordination network gives the microneedles a rare combination of properties: enough mechanical strength to pierce the oral epithelium when dry, and near-instant disintegration once exposed to the salty microenvironment of ulcerated tissue.

The design inspiration came from nematocysts, the microscopic harpoon-like organelles that jellyfish use to discharge venom in response to osmotic pressure. To mimic this triggered-release strategy, the researchers first constructed drug-loaded nanofibers from glycyrrhizic acid, a natural saponin that self-assembles into long-range ordered structures with internal hydrophobic domains. Using a low-frequency acoustic resonance technique operating at 55 hertz, they co-assembled glycyrrhizic acid with two complementary plant-derived therapeutics: baicalein, a flavonoid that disrupts bacterial cell walls and inhibits bacterial DNA synthesis, and astaxanthin, a potent carotenoid antioxidant that scavenges reactive oxygen species and promotes tissue repair. The resulting nanofibers measured just 3 to 4 nanometers in diameter but stretched up to 5 micrometers in length, an extraordinary aspect ratio of 1250, with surface zeta potentials exceeding 40 millivolts that keep the suspensions physically stable.

Encapsulation within the nanofibers solved one of the most stubborn problems in phytochemical medicine: poor water solubility. Free baicalein and astaxanthin barely dissolve in aqueous media, but once loaded into the glycyrrhizic acid fibers their apparent solubilities rose to 775.50 and 95.16 micrograms per milliliter, corresponding to enhancements of 127.5-fold and 213.7-fold respectively. Because the nanofibers carry abundant surface carboxyl groups, they behave like anionic polymers and can themselves participate in calcium-mediated gelation, becoming woven into the hyaluronic acid matrix rather than merely suspended within it. When calcium chloride solution was added, a stable, self-healing gel formed within one minute, confirmed by scanning electron microscopy and rheological testing that revealed the characteristic thixotropic behavior of an electrostatically crosslinked network.

The finished microneedle patch, designated GA@BA&Ast MNs, was cast in polydimethylsiloxane molds using vacuum centrifugal casting. Each 10 by 10 millimeter patch carries a 15 by 15 array of needles, 600 micrometers tall with 300-micrometer bases, dimensions chosen to match the anatomy of the oral epithelium so the tips cross the stratum corneum without damaging deeper tissue. Mechanical testing showed the composite needles were 1.56 times stronger than pure hyaluronic acid microneedles, comfortably exceeding the 0.15-newton threshold required for epithelial penetration. Confocal imaging of fluorescently labeled patches confirmed uniform drug distribution throughout the tips, and in rat tissue the needles delivered their cargo to depths of at least 220 micrometers, reaching the deep epithelial layers that topical formulations cannot access.

Once inserted, the transformation was dramatic. In dissolution experiments simulating the oral environment at 37 degrees Celsius and high humidity, the needle tips vanished within 2 minutes, and quantitative analysis showed that more than 85 percent of the microneedle volume had decomposed within 20 minutes, leaving minimal remnants. Spectroscopic analysis with ATR-FTIR and X-ray photoelectron spectroscopy traced the mechanism: sodium ions from the tissue fluid infiltrate the matrix and associate with the hyaluronic acid carboxylates, initiating network rearrangement, while hyperosmotic conditions further drive hydration, swelling and diffusion. Compared with chitosan-based microneedles, the release rates of astaxanthin and baicalein were enhanced by factors of 15.49 and 596.31 respectively. Crucially, the released nanofibers were then rapidly taken up by surrounding cells: within 30 minutes, the absolute amounts of astaxanthin and baicalein absorbed by oral tissue exceeded those from chitosan microneedles by 91.71-fold and 401.47-fold.

Laboratory assays revealed how the two drugs divide the therapeutic labor. In endothelial cell models, the combined nanofibers drove a scratch-wound closure rate of 87.8 percent within 24 hours, significantly outperforming astaxanthin alone at 56.4 percent, and promoted the formation of orderly tubular networks on Matrigel, indicating robust pro-angiogenic activity. The dual-drug formulation also showed the strongest scavenging of reactive oxygen species in inflamed macrophages. On the antimicrobial front, baicalein proved to be the core active component: plate assays confirmed that the released nanofibers killed and inhibited both Escherichia coli and Staphylococcus aureus, while neither hyaluronic acid nor glycyrrhizic acid alone had significant effect. In lipopolysaccharide-stimulated macrophages, the combination produced the greatest reductions in the pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha among all tested groups.

The decisive test came in a rat model of oral ulceration induced by acetic acid chemical burn. Over a seven-day treatment period, ulcers treated with the full microneedle system achieved 77.3 percent wound closure, compared with just 25.5 percent natural healing in untreated animals, 34.9 percent with blank microneedles and 54.3 percent with baicalein-only patches. Macroscopically, the treated ulcers regained a healthy pink color, a sign of rapid revascularization absent in the controls. Histological examination told the same story: while untreated animals remained at the early granulation stage, the combination-treated tissue showed a smooth, continuous epithelial layer covering the wound with minimal inflammatory infiltration, hallmarks of the final maturation and remodeling phase of healing. Masson’s trichrome staining revealed uniformly organized collagen fibers resembling normal mucosa, and immunohistochemistry showed collagen deposition enhanced by 41 percent and vascular endothelial growth factor expression boosted by 47 percent relative to model controls, alongside elevated phosphorylation of PI3K and Akt, suggesting the pro-angiogenic effect runs through this well-known signaling pathway.

Safety results were equally encouraging. Major organs from treated animals showed intact architecture without inflammation, necrosis or fibrosis, the hemolysis rate stayed below the 5 percent acceptance criterion, and endothelial cell viability remained above 90 percent after exposure to patch extracts. Because the formulation relies on plant-derived compounds rather than antibiotics or corticosteroids, it sidesteps the side effects and resistance concerns associated with conventional pharmacological treatments. The researchers position the platform as a universal delivery system for hydrophobic small-molecule drugs, one whose osmolality-triggered disintegration requires no external stimulus and is tailored specifically to the wet, hyperosmotic and mechanically active environment of the mouth. If the approach translates to the clinic, the humble jellyfish sting, refined over hundreds of millions of years of evolution, may offer relief to the millions of people who suffer each year from the raw, painful lesions of oral ulcers, and potentially to patients with oral fibrosis and oral cancer as well.

Subject of Research: Osmolality-responsive dissolving microneedles for oral ulcer drug delivery

Article Title: Hyaluronic acid-based osmolality-responsive immediate-release microneedles co-loading baicalein and astaxanthin for oral ulcer therapy

Article References: Yang, J., Shi, K., Wang, J., Liu, H., Zhang, Y., Guang, X., Wang, S., Lei, W., Wang, Y., Tan, M., Ma, X., & Wu, H. (2026). Hyaluronic acid-based osmolality-responsive immediate-release microneedles co-loading baicalein and astaxanthin for oral ulcer therapy. Materials Today Bio, 41, Article 103702. https://doi.org/10.1016/j.mtbio.2026.103702

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103702

Keywords: microneedles, oral ulcers, hyaluronic acid, drug delivery, baicalein, astaxanthin, glycyrrhizic acid, nanofibers, biomimetic, osmolality-responsive, wound healing, anti-inflammatory