Hyaluronic acid-based microneedles: materials design, fabrication strategies, challenges, and solutions for...

Hyaluronic acid (HA)-based microneedles have emerged as highly promising minimally invasive platforms for transdermal and transmucosal drug delivery, overcoming the limitations of conventional oral, topical, and injectable therapies. Owing to its excellent biocompatibility, biodegradability, hydrophilicity, non-immunogenicity, and intrinsic bioactivity, HA functions not only as a structural biomaterial but also as a therapeutic component that enhances tissue hydration, wound healing, immune modulation, and drug bioavailability. This review provides a comprehensive overview of the major fabrication strategies used for HA-based microneedles, including micro-molding, photolithography, centrifugal lithography, droplet-born air blowing, and additive manufacturing approaches. The effects of these techniques on microneedle geometry, mechanical strength, drug-loading capacity, dissolution behavior, and controlled-release performance are critically discussed. Recent biomedical applications of HA-based microneedles are systematically summarized, including transdermal drug delivery, vaccination and immunotherapy, diabetic and burn wound healing, oral ulcer treatment, allergy desensitization, alopecia areata therapy, ophthalmic delivery, and photodynamic therapy for oral leukoplakia. Particular emphasis is placed on multifunctional systems integrating nanoparticles, liposomes, antimicrobial agents, growth factors, antioxidants, and immunomodulatory compounds to achieve synergistic therapeutic effects. The review also highlights the mechanisms through which HA-mediated swelling, hydration, and biodegradation facilitate efficient and sustained drug release after microneedle insertion into biological tissues. Despite significant progress, challenges related to large-scale manufacturing, long-term stability, sterilization, dose reproducibility, and regulatory approval remain barriers to clinical translation. Overall, HA-based microneedles represent versatile next-generation platforms with strong potential for safe, effective, and patient-compliant biomedical applications.