Two-Photon Polymerisation 3D Printing of Microneedle Array Templates with Versatile Designs: Application in the Development of Polymeric Drug Delivery Systems

Abstract

Purpose: To apply a simple and flexible manufacturing technique, two-photon polymerisation (2PP), to the fabrication of microneedle (MN) array templates with high precision and low cost in a short time.

Methods: Seven different MN array templates were produced by 2PP 3D printing, varying needle height (900-1300 μm), shape (conical, pyramidal, cross-shaped and with pedestal), base width (300-500 μm) and interspacing (100-500 μm). Silicone MN array moulds were fabricated from these templates and used to produce dissolving and hydrogel-forming MN arrays. These polymeric MN arrays were evaluated for their insertion in skin models and their ability to deliver model drugs (cabotegravir sodium and ibuprofen sodium) to viable layers of the skin (ex vivo and in vitro) for subsequent controlled release and/or absorption.

Results: The various templates obtained with 2PP 3D printing allowed the reproducible fabrication of multiple MN array moulds. The polymeric MN arrays produced were efficiently inserted into two different skin models, with sharp conical and pyramidal needles showing the highest insertion depth values (64-90% of needle height). These results correlated generally with ex vivo and in vitro drug delivery results, where the same designs showed higher drug delivery rates after 24 h of application.

Conclusion: This work highlights the benefits of using 2PP 3D printing to prototype variable MN array designs in a simple and reproducible manner, for their application in drug delivery.

Keywords: 3D printing; dissolving; hydrogel-forming; microneedle array; two-photon polymerisation.

Fig. 1

Optimisation of different 3D printing parameters (Describe software settings): (a) (i) distance between layers (“slicing”); (ii) shell parameters (distance between hatching lines within a layer – “hatching distance”, shell contour count, and number of filled slices at the bottom of the shell – “base slice count”); (iii) scaffold parameters (spacing between scaffold walls and floors, thickness of scaffold walls and scaffold floor); and (iv) “splitting” mode (block width in X and Y direction, block height and block offset in X, Y and Z direction); (b) effect of block size and position in printing the needle tip with (i) two blocks, (ii) one short block in Z direction, and (iii) one single and large block [(iv), printed example]; (c) Two-step 3D printing of long MN master templates (1.3 mm high needles) and additional baseplate; (d) cavities introduced in the MN, pedestal and baseplate designs.

Fig. 2

Final CAD-assisted image of all MN array designs developed with the dimensions of individual needles, (a) D1 to (g) D7.

Fig. 3

(a) Schematic representation of the method used to assemble master templates produced by 2PP 3D printing to fabricate silicone MN array moulds. (b) Representative light microscope images of the different steps of the manufacturing process (D7 design shown as an example): (i) master template, (ii) master template mounted on PLA holder and (iii) silicone MN array mould.

Fig. 4

Light microscope (left) and scanning electron microscope (right) images of the seven MN array designs prepared with dissolving formulation (a, D1 to f, D6).

Fig. 5

Insertion of the different DMN arrays into Parafilm M®. (a) Percentage of holes created by each MN array in Parafilm M® layers (each 127 μm in height) in relation with the total number of MN per array. Upon application of different forces, as measured by (a) light microscope and (b) OCT images. All results shown as means ± SD, n = 3.

Fig. 6

Light microscope images of CAB Na-loaded DMN arrays (a, D1 to f, D6). (g) CAB Na content per array area in each of the developed DMN array designs (means ± SD, n ≥ 3).

Fig. 7

Amount of CAB Na (in μg/0.5 cm²) deposited in neonatal porcine skin following DMN array insertion (means ± SD, n ≥ 3).

Fig. 8

(a) Light microscope images of the two different HFMN array designs (D6, left; D7, right). (b) Swelling profile of the hydrogel-forming formulation. (c) Insertion of HFMN arrays into Parafilm M®, upon application of different forces. (d) Representative optical coherence tomography (OCT) images of the insertion of HFMN arrays into full thickness porcine skin. Images artificially coloured to facilitate visualisation (skin is seen in green and HFMN arrays in blue). All results shown as means ± SD, n ≥ 3.

Fig. 9

In vitro permeation of IBU Na across dermatomed porcine skin (350 μm in thickness) using 5 × 5 conical and 5 × 3 cross-shaped MN arrays and a lyophilised wafer-like reservoir (means ± SD, n ≥ 3).