(W0930-02-07) Revolutionising Microneedle-Based Transdermal Delivery: A Colourful Approach to Efficiency Feedback and User Navigation

Purpose: Dissolving microneedle technology represents an innovative approach to minimally invasive transdermal drug delivery, demonstrating efficacy in delivering both micro and macro therapeutic molecules. However, concerns raised in end-user surveys and requirements proposed by regulatory authorities based on the ease and reliability of dissolving microneedles applications have impeded their commercialisation efforts, where the lack of clear indicators for successful patch insertion and removal time was highlighted^[1]. To tackle this challenge, a colour-change-based feedback system was devised to provide indications and navigate end-users along the administration process. The colour alteration indicates interstitial fluid infiltration into the baseplate from the skin, indirectly confirming needle dissolution and cargo delivery, thereby addressing the aforementioned problems associated with dissolving microneedles.

Methods: The dissolving microneedles were constructed with two layers, the first layer was composed of hydrophilic polymers loaded with model drugs (FITC-dextran and fluorescein sodium), representing small and large therapeutic molecules and the second baseplate layer was made from hydrophobic poly(lactic acid) (PLA) infused with moisture-sensitive silica particles to establish a biphase dissolving microneedle feedback system. The progressive colour change was devised to be aligned with the needle dissolution with rationalised PLA: silica ratio (w/w) and silica particle size (below 180 µm M180 and 50 µm M50). Comprehensive evaluations encompassing physicochemical attributes and biocompatibility of the system, microneedle integrity and mechanical strength were conducted, alongside ex vivo dissolution and permeation studies of the model drugs. Initial trials on rats were undertaken to assess the practical viability of this approach in vivo.

Results: The baseplate materials were characterised in terms of tensile strength and cytotoxicity on human dermal fibroblasts, where desirable mechanical strength and acceptable biocompatibility were confirmed (Figure 1).The microneedles produced in this study exhibited well-defined shapes, consistent heights, and precisely controlled interspacing, resulting from the uniform geometry of the micro-moulds. The insertion of dissolving microneedles into the skin was indicated by a colour change discernible to the human eye in 5 min. A distinct colour change from buff to red-purple (FITC-dextran loaded microneedles) and blue-purple (fluorescein sodium loaded microneedles) could be observed within the respective dissolving microneedle baseplates during the dissolution process. Prior to dissolution, the needles of the patch presented a sharp tip and, post-dissolution, the cone-shaped pedestals on which the needle tips were mounted remained on the backing layer where silica gel particles were seen inlaid and dispersed (Figure 2). The colour change of the baseplate aligned with the dissolution of the needles and in vitro delivery, suggesting that keeping the patches after colour change had no added benefits in terms of cargo consignment (Figure 3). Additionally, the preliminary application of this system on rats demonstrated obvious colour shifts due to the infiltration of interstitial fluid into the baseplate, which could be further investigated with the pharmacokinetics of the administration.

Conclusion: A novel delivery efficiency feedback system for biphasic dissolving microneedles based on a PLA baseplate containing crystal violet dye encapsulated within silica was successfully developed. Additionally, complete dissolution of the needles from dissolving microneedles and subsequent drug release could be aligned with the obvious colour change of the backing layer, thereby prompting the correct time to remove the patches. This not only addresses the concerns and requirements raised by end-users and regulators but also enhances the user experience, promoting the broader acceptance and utilisation of microneedles for self-administration of medication, particularly in the critical context of vaccination during a global health crisis.

References: [1] A. Hutton., et al. Drug Deliv. Transl. Res. 2022, 12, 838.

Acknowledgements: This work was supported by China Scholarship Council (202106370014) and EPSRC grant EP/V047221/1.


Figure 1. Morphology and tomography of the films made of PLA (a, d), PLA+M180 (b, e) and PLA+M50 (c, f) obtained by optical microscope and SEM. Representative stress/strain curves (g), elongation at break (h), elastic modulus (i), ultimate tensile strength (j)  for films made of PLA, PLA+M180 and PLA+M50. **** represents (p < 0.0001) (Means + SD, n=3). The percentage of viable cells after 72 h of culture with PLA+M180 and PLA+M50 DMAPs in MTT assay (Means + SD, n=6) (k). Alive/dead staining of fibroblastic cells on control, PLA+M180 and PLA+M50 treated samples (l) (Green represented alive and red represented dead). Total DNA content of cells on control, PLA+M180 and PLA+M50 cultured for 72 h in PicoGreen assay (Means + SD, n=6) (m). ** represents p < 0.001.


Figure 2. Schematic illustration of the fabrication process of DMAPs (a0). Morphology of dissolving microneedles of FITC-dextran (a-f) and fluorescein sodium (g-l) before (a-c&g-i) and after (d-f&j-l) needle dissolution obtained by optical microscopy and SEM. Representative fluorescence images and Z-stack images of DMAP of FITC-dextran 150 kDa (m, n, o) and fluorescein sodium (p, q, r) obtained by fluorescence microscope and multiphoton microscopy.


Figure 3. Ex vivo dissolution (a, c) and baseplate colour change (b,d) for FITC-dextran (a, b) and fluorescein sodium (c, d) dissolving microneedle. Ex vivo delivery of the two dissolving microneedles (e) and distribution of the analytes (mean±SD, n = 3) (f). Preliminary result from dissolving microneedles with the feedback system on rats (g).