In Vivo Intradermal Delivery of Bacteria by Using Microneedle Arrays

Abstract

Infectious diseases propagated by arthropod vectors, such as tularemia, are commonly initiated via dermal infection of the skin. However, due to the technical difficulties in achieving accurate and reproducible dermal deposition, intradermal models are less commonly used. To overcome these limitations, we used microneedle arrays (MNAs), which are micron-scale polymeric structures, to temporarily disrupt the barrier function of the skin and deliver a bacterial inoculum directly to the dermis of an animal. MNAs increase reliability by eliminating leakage of the inoculum or blood from the injection site, thereby providing a biologically relevant model for arthropod-initiated disease. Here, we validate the use of MNAs as a means to induce intradermal infection using a murine model of tularemia initiated by We demonstrate targeted delivery of the MNA bolus to the dermal layer of the skin, which subsequently led to innate immune cell infiltration. Additionally,-coated MNAs were used to achieve lethality in a dose-dependent manner in C57BL/6 mice. The immune profile of infected mice mirrored that of established infection models, consisting of markedly increased serum levels of interleukin-6 and keratinocyte chemoattractant, splenic T-cell depletion, and an increase in splenic granulocytes, together confirming that MNAs can be used to reproducibly induce tularemia-like pathogenesis in mice. When MNAs were used to immunize mice using an attenuated mutant ( Δ), all immunized mice survived a lethal subcutaneous challenge. Thus, MNAs can be used to effectively deliver viable bacteria and provide a novel avenue to study intradermally induced microbial diseases in animal models.

Materials for Immunotherapy

“…Here, the microneedles were coated with up to 200 alternating layers of positively charged melanoma antigens and negatively charged CpG ODNs as adjuvants, resulting in the effective expansion of tumor‐specific CD8 + T cells. Recently, Jewell and co‐workers developed a similar PLA microneedle system to deliver a bacterial inoculum as a model for arthropod‐initiated disease . Overall, dissolvable microneedle arrays are an exciting frontier of immunotherapeutic research.…”

Optimisation of Design and Manufacturing Parameters of 3D Printed Solid Microneedles for Improved Strength, Sharpness, and Drug Delivery

“…Amongst the key criteria that render a coating process effective are uniformity and reproducibility, accuracy so the drug is only deposited on the MNs, low process temperatures to avoid drug degradation, and a strong bonding of the coating film on the MN surface to reassure that drug will not remain on the skin surface upon piercing [ 11 ]. Numerous methods have been applied for this purpose, such as immersion of the whole patch [ 12 ], drop coating [ 13 ], and spray coating [ 14 ], which are prone to allow contamination of the MN substrate by the coating material. The prominent coating techniques that reassure localized coating formation exclusively on the MN bodies with no drug deposition on the substrate, are dip-coating and inkjet printing [ 7 ].…”

Microneedle Coating Methods: A Review with a Perspective

“…It should be noted that in this approach, both the back and the front sides of the base of the array also get coated. This was the first technique reported in literature to coat microneedles (Matriano et al, 2002) and has also been used by others (Raja et al, 2013;van der Maaden et al, 2014;Zeng et al, 2017;Chandler et al, 2018). This is the simplest of all coating techniques, but it leads to significant wastage of the active molecule since coatings are produced on the entire microneedle patch.…”