Ez4 d

MNs were designed by TinkerCAD (Autodesk, San Francisco, USA), an online computer-aided design software. The patch with MNs was designed as a square of 15 × 15 × 2 mm (Fig. 1). Each patch contained 36 conical MNs which were of 1 mm in diameter and 1.5 mm in height after printing (the dimensions of final patch are described in Chap. 3.1). The design was converted to.stl format and uploaded to LumenX (Cellink, Göteborg, Sweden) 3D printer. The resin used for the printing consisted of VP, PEGDA, photoiniciator-LAP (1 wt%), and distilled water as the solvent. The printing resolution was 50 μm and intensity of UV light was 22.5 mW/cm 2 per layer.
After the printing process, the patch was gently removed, washed in 70% ethanol, and put in the UV-chamber (Asiga, Alexandria, Australia) for 1 min. Finally, the patch was dried at room temperature for 2 days, when the moisture in the patch stabilized. In the case of IMQ loaded patches, the freeze-dried IMQ NCs were added to resin and stirred for 15 min (500 rpm). The patches were visualized by optical microscopy Leica EZ4D (Leica Microsystems, Milton Keynes, UK) at room temperature.

Fabrication and characterisation of HMNs.
The HMN arrays were designed using Shapr3D. The arrays consist of 5 × 5 HMNs that have a pyramidal shape with 1 mm height, 0.75 mm width, 2 mm tip-to-tip interspacing, and 100 μm hole diameter (Fig. 2A). The HMN arrays were fabricated from polyether ether ketone (PEEK) sheets which were machined using a nanosecond-pulse, diode-pumped, solid-state laser operating at a wavelength of 355 nm (Fig. S1 †). The drilling of the holes was performed by the same laser system. The morphology and dimensions of the HMN arrays were assessed and measured using a digital light microscope (Leica EZ4 D, Leica Microsystems, Milton Keynes, UK). Moreover, a MN holder for fluid delivery was built to prove the HMN array allows fluids to pass through it (Fig. S2 †). The information on the reagents, instrumentation, fabrication of the holder and methodology used for the mechanical testing are described in the ESI. †

The architecture and appearance of the MAPs were observed using an optical microscope (Leica EZ4 D, Leica Microsystems, Milton Keynes, UK). Differential scanning calorimetry (DSC) was conducted on the neat drug and respective formulations. This was done using DSC Q100 (TA Instruments, Elstree, Hertfordshire, UK). The resistance of the needles under compression was ascertained using a TA-TX2 Texture Analyser (TA) (Stable Microsystems, Haslemere, UK) using the same parameters which have been previously reported. 35, 36 Upon exposure to a compressive force of 32 N, changes in needle height was estimated using eqn (1).
MAPs height reduction ð%Þ ¼
where H initial is the original needle height and H after is the needle height post compression.
The insertion profile of the MAPs into Parafilm® M and ex vivo neonatal porcine skin (with a thickness of approximately 600 µm) was investigated using an EX-101 optical coherence tomography (OCT) microscope (Michelson Diagnostics Ltd, Kent, UK), as reported previously. 37 Upon acquiring the OCT images, the insertion depth of the needles was visualised and calculated using ImageJ® software (National Institutes of Health, Bethesda, MD, USA).

Fractured surfaces of the specimens were examined with a stereomicroscope (Leica EZ4D, Leica Microsystems, Heerbrugg, Switzerland) at 35× magnification, and the fracture modes were identified. Modes of failure were classified as follows: adhesive failure, the failure occurred entirely within the adhesive area; cohesive failure in resin composite, the failure occurred exclusively within the resin composite area; cohesive failure in dentin, the failure occurred exclusively within the dentin area; and mixed failure, the failure extended from the adhesive into either the resin composite or dentin area.