The COVID-19 pandemic highlighted the urgent need for effective and accessible vaccination strategies. While intramuscular (IM) injection is the standard, it suffers from drawbacks such as needle phobia and procedural pain. Transdermal vaccination offers an attractive alternative due to the skin's rich immune cell network. However, the stratum corneum (SC) barrier limits the permeation of macromolecular vaccines. Microneedles (MNs) can overcome this barrier by creating microchannels, but passive diffusion through these channels is inefficient. Iontophoresis, which uses a mild electric current to enhance transdermal delivery, is effective for small molecules but struggles with macromolecules. This research aimed to combine the advantages of MNs and iontophoresis to create a system for efficient transdermal delivery of macromolecular vaccines. The authors hypothesized that the synergistic action of MNs and iontophoresis would significantly improve transdermal vaccine delivery efficiency and elicit a strong immune response.

The introduction section reviews existing transdermal vaccination strategies, highlighting the limitations of using microneedles alone (inefficient passive diffusion) and iontophoresis alone (ineffective for macromolecules). It establishes the rationale for combining these two methods to achieve enhanced transdermal delivery of macromolecular vaccines. The review implicitly suggests a gap in the literature—a lack of effective systems for transdermal delivery of this class of vaccines—which this research aims to address.

The researchers developed a wearable iontophoresis-driven MN patch consisting of: Ag/AgCl electrodes on a flexible poly(lactic-co-glycolic acid) (PLGA) substrate; solid microneedles; a polyacrylamide/chitosan hydrogel for vaccine storage; and an impermeable gasket. The system's functionality involves three steps: 1) "Press and poke": the patch is pressed onto the skin, inserting the MNs and creating microchannels; 2) Iontophoresis-driven delivery: a mild electric current drives the vaccine through the microchannels via electromigration and electroosmosis; and 3) Immune response: the delivered vaccine is captured by antigen-presenting cells (APCs) in the skin, initiating an immune response. The fabrication process involved micromachining of stainless steel 316L microneedles, hydrogel preparation, and assembly of the patch components. The iontophoresis device included a rechargeable lithium battery, boost module, and constant current output module to ensure stable current delivery (0.5 mA). In vitro studies assessed ovalbumin delivery using the patch, and in vivo experiments in BALB/c mice evaluated the immune response compared to intramuscular injection. The physiological effects of the patch on the skin were also examined.

In vitro experiments showed that the amount of ovalbumin delivered transdermally could be controlled by adjusting the iontophoresis current. In vivo studies in BALB/c mice demonstrated that the iontophoresis-driven MN patch induced a robust immune response to ovalbumin, exceeding that of intramuscular injection. The authors observed a synergistic effect between MN puncture and iontophoresis, significantly enhancing transdermal delivery efficiency. The wearable device was small, lightweight (18g), and capable of delivering a stable current for an hour. The polyacrylamide/chitosan hydrogel provided effective vaccine storage and maintained consistent conductivity during iontophoresis. The MN patch was shown to be safe and well-tolerated by the skin. Specific data points regarding the quantity of ovalbumin delivered, antibody titers, and cytokine levels are likely presented within the full paper but are omitted in this summary due to the availability of only the abstract.

The successful combination of MNs and iontophoresis resulted in a highly effective transdermal vaccine delivery system. The superior immune response compared to intramuscular injection suggests the potential of this technology to replace traditional needle-based vaccination. The controlled delivery and ease of use makes the system suitable for at-home self-administration, enhancing vaccine accessibility, particularly in remote areas or during pandemics. The use of a biocompatible hydrogel avoids the limitations of dissolvable MNs. The study’s findings support the development of a painless, user-friendly, and effective alternative to traditional vaccination methods.

This research successfully demonstrated a novel iontophoresis-driven microneedle patch for efficient transdermal delivery of macromolecular vaccines. The system’s superior performance compared to traditional methods and its user-friendly design hold great promise for improving vaccine accessibility and uptake. Future research could explore the use of different vaccine antigens and optimization of the hydrogel formulation for enhanced delivery and immune response. Investigations into the long-term effects and safety profile of the system are also warranted.

While the study demonstrated efficacy in mice, further research is needed to validate the results in humans. The long-term effects of repeated patch application and potential skin irritation should be investigated. The study focused on ovalbumin as a model antigen; additional research should evaluate the efficacy with other vaccine types. The specific parameters of the applied current and the duration of the treatment may need further optimization for different vaccines and populations.