Microneedle-Mediated Vaccine Delivery to the Oral Mucosa

Abstract

The oral mucosa is a minimally invasive and immunologically rich site that is underutilized for vaccination due to physiological and immunological barriers. To develop effective oral mucosal vaccines, key questions regarding vaccine residence time, uptake, adjuvant formulation, dose, and delivery location must be answered. However, currently available dosage forms are insufficient to address all these questions. An ideal oral mucosal vaccine delivery system would improve both residence time and epithelial permeation while enabling efficient delivery of physicochemically diverse vaccine formulations. Microneedles have demonstrated these capabilities for dermal vaccine delivery. Additionally, microneedles enable precise control over delivery properties like depth, uniformity, and dosing, making them an ideal tool to study oral mucosal vaccination. Select studies have demonstrated the feasibility of microneedle-mediated oral mucosal vaccination, but they have only begun to explore the broad functionality of microneedles. This review describes the physiological and immunological challenges related to oral mucosal vaccine delivery and provides specific examples of how microneedles can be used to address these challenges. It summarizes and compares the few existing oral mucosal microneedle vaccine studies and offers a perspective for the future of the field.

Keywords: dosage forms; immune tolerance; mucosal immunization; sustained release.

Figure 1.

Schematic representation of the mucosal structure and select dendritic cell subsets present in the a) tonsils of the WTR, b) sublingual mucosa, c) buccal mucosa. The lingual and palatine tonsils are covered with ~100 μm thick stratified squamous epithelium and contain crypts lined by a non-uniform lymphoepithelium. The outer epithelium primarily contains Langerhans cells, while the crypt epithelium contains lympho-epithelial symbiosis DCs along with macrophages and lymphocytes (not depicted). Other DC populations including plasmacytoid DCs and interdigitating DCs densely populate the follicular region (F). Germinal center DCs are also present within germinal centers (not depicted). The sublingual epithelium ranges from 100–200 μm thick, while the buccal epithelium ranges from 500–800 μm thick. The buccal epithelium contains approximately 2.5 times the number of Langerhans cells in the sublingual epithelium. Submucosal DC subsets are not well characterized in humans, but evidence suggests that interstitial and myeloid DCs are present and plasmacytoid DCs may infiltrate during inflammation.

Figure 2.

Schematics of delivery for selected oral mucosal vaccine dosage forms depicting a) a thermo-responsive gel, b) a tablet, c) a film containing nanoparticles, d) MucoJet, e) electroporation, and f) a gene gun.

Figure 3.

Schematic of the microneedle design space and its potential to control various functions related to oral mucosal vaccine delivery. a) Relevant functions include: delivery uniformity, or equal tissue puncture by all needles in an array and equal delivery of vaccine components from each needle; mechanical properties, including needle strength and sharpness which are critical to easily puncture tissue; cell targeting, either actively or passively by designing the system to access a specific depth in tissue; dosing, specifically dosing efficiency, dose delivered per area of tissue, and dose per needle; and delivery kinetics, whether through design of the needle materials or integration of the vaccine with the needle. b) At the complete device scale, applicator devices may be designed to apply specific, repeatable forces across the microneedle array. c) Within a microneedle array, the backing material selection is an important consideration in ensuring close contact with the entire tissue, and interneedle spacing can affect the microneedle-tissue mechanical interactions. d) At the single needle level, needle geometry, dimensions, and materials all influence mechanical properties of the needles and resulting dose delivered after tissue puncture. Vaccines may be formulated as a coating, within the needle matrix, or encapsulated within a secondary delivery system like nanoparticles to achieve the desired dose and delivery kinetics.