Mould-Free Microneedles in a Single Step: 3D Printing with Photopolymer Resins for Transdermal Delivery

Introduction

The skin, the body’s largest organ, serves as a multi-layered protective barrier against chemical, microbial, and mechanical challenges [1]. Anatomically, it comprises the epidermis, dermis, and hypodermis [2], but the outermost ~10–25 μm stratum corneum (SC) is the principal barrier to exogenous molecules. The SC “brick-and-mortar” structure of corneocytes embedded in a lipid matrix, effectively limits permeation that only a few drug compounds (<500 Da, log P ~2–4, high potency) can cross intact skin unaided [3]. As a result, most hydrophilic drugs, macromolecules, and vaccines still rely on hypodermic needle injection, an invasive approach associated with pain, needle-stick injuries, cold-chain storage requirements [4], and poor patient compliance. Various strategies (e.g., chemical enhancers, iontophoresis, ultrasound via sonophoresis [5,6]) have been explored to expand transdermal delivery, but offer only modest enhancement and can pose safety issues, limiting widespread use. MN arrays provide a promising physical means to bypass the superficial barrier of the skin. These devices consist of microscopic projections (typically ~150 μm to 1.5 mm in length) [7] that pierce the SC to create transient microchannels for drug or vaccine delivery, while avoiding nerves and blood vessels to minimise pain and bleeding. Ref. [8] MNs come in several designs (solid, coated, hollow, hydrogel-forming, and dissolving), among which dissolving microneedles (DMNs) are particularly attractive because they are made from water-soluble, biocompatible polymers that dissolve or biodegrade in the skin, eliminating sharps waste and allowing controlled drug release. Notably, DMN patches have successfully delivered biologics (e.g., peptides, proteins, nucleic acids) that would be unstable in the gastrointestinal tract or unable to cross intact skin [9,10]. However, an effective DMN must satisfy two opposing requirements: (i) sufficient mechanical rigidity to penetrate the SC, and (ii) rapid polymer dissolution to release the drug load shortly after insertion. Achieving this trade-off depends critically on both the polymer formulation and the fabrication method.

Conventional fabrication of DMNs relies on micro-moulding: a master mould is replicated in an elastomer like polydimethylsiloxane (PDMS), and a liquid polymer solution is cast into these cavities, then degassed, cured, and demoulded to yield MN arrays [11]. While straightforward, moulding can introduce geometric imperfections, blunted tips, tapered sidewalls, and incomplete filling that diminish insertion efficiency and batch uniformity. Moreover, the multi-step moulding workflow hinders rapid design iteration and complicates scale-up. These limitations have driven interest in additive manufacturing (3D printing) as a direct-write alternative to produce custom MN arrays on demand without moulds [12]. It is transforming healthcare by enabling the rapid production of highly personalised MNs with precisely tailored dimensions and drug loadings [13], while thinking about sustainability, its efficient, layer-by-layer production model simultaneously reduces material waste and simplifies scale-up compared to traditional moulding [14]. Among the 3D-printing methods, digital light processing (DLP) has emerged as a promising route for MN fabrication [15]. DLP uses a digital micromirror device to project patterned light onto a vat of photocurable resin, polymerising each layer in a single flash exposure. This parallel curing approach, unlike point-by-point laser stereolithography (SLA), achieves sub-50 μm feature resolution, uniform exposure across the layer, and build times of only seconds per layer [16] also new system can achieve higher resolution than this. Bottom-up DLP configurations further minimise peel forces during layer separation, enabling high-aspect-ratio structures with sharp tips. Indeed, DLP-printed polymer lattices have demonstrated higher strength-to-density ratios than moulded counterparts, attributed to more complete monomer conversion and lower porosity [17]. A major challenge for DLP-printed MNs is the limited biocompatibility of standard resins. Most commercial photopolymers use non-degradable acrylate matrices and toxic photo-initiators, rendering them unsuitable for DMNs. To address this, researchers have developed inks using degradable hydrophilic monomers like poly (ethylene glycol) diacrylate (PEGDA) and N-vinyl-2-pyrrolidone (VP) combined with water-soluble photoinitiators (e.g., LAP) [18]. However, the work from Petrova et al. [18]

Primarily addressed drug loading and release, without systematically examining the rheological behaviour or cure kinetics of the resin, evaluating monomer conversion, assessing the mechanical performance of the MNs, or exploring multiple geometrical designs. In contrast, the present study comprehensively investigates these parameters to establish a deeper understanding of formulation–process–performance relationships in PEGDA/VP-based DMNs fabricated via DLP printing. Co-monomers such as VP can be added to lower resin viscosity and improve print fidelity [13]. Adjusting the PEGDA/VP ratio and photoinitiator loading allows tuning of viscosity, crosslink density, mechanical strength, and dissolution rate, though these parameters have yet to be systematically optimised for DMNs. Only isolated studies have so far attempted to fabricate DMNs directly via DLP printing [12,13,18], often using proprietary resin formulations and providing limited mechanical data. As a result, the relationships between resin composition, print fidelity and device performance remain poorly understood. Therefore, a comprehensive investigation is needed that (i) specifies the printable formulation window for degradable PEGDA/VP resins, (ii) correlates formulation and exposure parameters with MN geometry and mechanical performance, and (iii) benchmarks DLP-printed DMNs against conventional mould-cast analogues. Addressing these gaps will determine whether vat photopolymerisation can produce MN patches with the required precision, mechanical robustness, and fast dissolution for clinical applications. In the current study, these questions are tackled by formulating a range of biodegradable PEGDA/VP resin blends (PEGDA/VP with LAP photoinitiator) and evaluating their viscosity, photo-reactivity, and printability. Using these resins, designed DMN arrays (conical and pyramidal, different heights as well as base radius) and printed them on a desktop DLP system under optimised conditions to limit dimensional deviation of the computer-aided design (CAD). The printed MNs were comprehensively characterised using a range of microscopic, spectroscopic, and thermal analysis techniques. Real-time spectroscopic monitoring was employed to track the progression of photopolymerisation, while optical and scanning electron microscopy were utilised to characterise microneedle geometry and surface morphology. Rheological analysis was conducted to determine the appropriate shear-rate conditions for stable bottom-up printing, and axial compression testing was applied to assess mechanical strength relative to reported skin-insertion thresholds. Dissolution studies in physiological buffer were further undertaken to examine crosslink density and matrix stability. Collectively, these methodologies were selected to provide a comprehensive evaluation of the DLP process and to establish its potential advantages over traditional mould-based fabrication for producing uniform, mechanically reliable MNs. By elucidating these formulation-process, performance relationships, this study establishes DLP 3D printing as a robust single-step platform for on-demand production of DMN patches for transdermal delivery.

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Materials

N-vinyl-2-pyrrolidone (VP, ≥98%), polyethylene glycol diacrylate (PEGDA) with a molecular weight of 700 g/mol, and lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP, ≥95%) were obtained from Sigma Aldrich, part of Merck KGaA (Darmstadt, Germany). Phosphate-buffered saline (PBS) tablets, at pH 7.4, were also included. Deuterated dimethyl sulfoxide-D6 + 0.03% 1,3,5 trioxane (DMSO-d6; ≥98%; Sigma-Aldrich, St. Louis, MO, USA), purchased from VWR International (Lutterworth, UK), was used as supplied. Commercial resin for DLP printer PlasCLEAR® 3DP (Poly (methyl methacrylate) PMMAs) Polymers were purchased from iMakr (London, UK). Isopropyl alcohol (IPA) was purchased from Sigma Aldrich (St. Louis, MO, USA). Methylene blue (≥97%) was obtained from Merck KGaA (Darmstadt, Germany). The water used in the experiments was deionised, distilled, and subsequently filtered through a Millipore Q purification system.

Meshram, R.N.; Lamprou, D.A. Mould-Free Microneedles in a Single Step: 3D Printing with Photopolymer Resins for Transdermal Delivery. Pharmaceutics 2025, 17, 1498. https://doi.org/10.3390/pharmaceutics17111498

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