Eoin D. O’ Cearbhaill

Buccal administration of peptide therapeutics offers a noninvasive alternative to injections but remains constrained by limited peptide epithelial permeability and physicochemical instability. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are important therapeutics with limited noninvasive administration options. Here, we present a buccal peptide delivery platform integrating electrostatic nanocomplexation, design of experiments (DoE)-guided optimization, and solid-state stabilization. Chitosan oligosaccharide (COS) was complexed with a model GLP-1 RA peptide molecule to generate monodisperse nanocomplexes (∼100 nm) with low polydispersity and a positive surface charge (∼+20 mV). Lyophilization preserved nanocomplex integrity during storage at 4 °C for at least one month, enabling dispersibility and retention of colloidal characteristics and GLP-1 RA secondary structure. Nanocomplexes exhibited minimal cytotoxicity in TR-146 cells at 1 mg/mL over 180 min. Mechanistic analyses demonstrated membrane lipid remodelling, dynamin-dependent endocytic involvement, and redistribution of tight junction and desmosomal proteins, supporting a model involving nanocomplex uptake leading to modulation of epithelial barrier properties. The nanocomplexes were then incorporated into a bilayer film composed of a pullulan/sodium carboxymethyl cellulose mucoadhesive layer and an Eudragit RLPO backing layer. GLP-1 RA permeation across porcine buccal mucosae from the nanocomplexes in solution reached ∼13% at 3 h (P_app ∼3.8 × 10^–6 cm/s) while incorporation of complexes in bilayers yielded ∼3.4% permeation (P_app ∼1.2 × 10^–6 cm/s) compared to the absence of flux for the GLP-1 RA in solution. These findings demonstrate that peptide nanocomplexes can be successfully incorporated into mucoadhesive films. This approach offers advantages over films comprising permeation enhancers.

Large animal models, while valuable, are expensive, time-consuming, and limited to discrete interventional or terminal timepoints, while existing benchtop models do not offer an accurate representation of the esophageal environment. Moreover, current pre-clinical models cannot effectively simulate swallowing dysfunction (dysphagia), restricting progress in understanding motility disorders like achalasia and hindering evidence-based dietary recommendations. In response, we present RoboGullet, a biomimetic soft-robotic model with independent localized longitudinal and circumferential muscle actuation, enabling, for the first time, simulation of both normal and diseased esophageal motility. We further enhance realism with a biohybrid variant, RoboGullet + , incorporating porcine esophageal mucosa/submucosa. We demonstrate this platform’s versatility through three key applications: assessing stent migration, simulating achalasia I-III within clinical diagnostic criteria, and analyzing bolus swallowing. Our findings reveal that: (1) stent migration increases over fivefold when incorporating longitudinal muscle movement versus isolated circumferential; (2) using a viscous non-Newtonian bolus improves high-resolution manometry diagnostic sensitivity of Achalasia III through increasing the Distal Latency diagnostic metric by 20.83%; and (3) stirring Greek-style yoghurt (common non-Newtonian dietary recommendation) significantly improves bolus transit versus unstirred for Achalasia Types I-II patients. This establishes RoboGullet+ as a powerful translational tool, advancing our understanding of esophageal motility and its therapeutic interventions.

Islet encapsulation has the potential to enable transplantation without requirement for life-long immunosuppression. The period between implantation and revascularisation is most harmful for encapsulated islets as they receive nutrients and oxygen exclusively via diffusion. This critical time gap must be bridged with a temporary oxygen supply to prevent inflammation and apoptosis. Hence, we compared the efficiency of individual components of an oxygen-delivering matrix (hyaluronic acid (HA); HA + perfluorodecalin nanoemulsion; HA + perfluorodecalin nanoemulsion + oxygen) to provide a substitute for the extracellular matrix and to facilitate human islet survival. The islets were loaded into silicone-based macroencapsulation devices with multi-scale porous membranes designed to optimise revascularisation. Four to five days of normoxic culture revealed that non-oxygen-charged nanoemulsion prevented islet disintegration but did not reduce necrosis or apoptosis. Oxygen supply decreased the generation of reactive oxygen species and chemokines, thereby increasing islet yield. Stimulated insulin secretion of encapsulated islets was marginal and severely delayed. Islets incubated in oxygen-precharged nanoemulsion were characterised by the highest stimulation index. These data suggest that islet survival in macroencapsulation devices can be optimised with a multi-functional matrix providing mechanical support and temporary oxygen supply to reduce the production of pro-inflammatory mediators. Suitable oxygen delivery systems with an extended life span must identified before in vivo experiments can be undertaken.

Bioabsorbable stents offer a significant advantage over metallic stents by providing temporary mechanical support to blood vessels and gradually degrading, thereby reducing the risk of long-term complications and restenosis. Polymeric stents, particularly those made from poly(l-lactic acid), have attracted attention for below-the-knee artery interventions because of their biocompatibility and potential for customized geometries and mechanical properties. However, challenges remain in the development of efficient and scalable fabrication techniques for such devices. This study aimed to develop and evaluate a rotational-axis fused filament fabrication method for the fabrication of bioabsorbable polymeric stents with improved mechanical and biological performance. A rotating-mandrel-based multiaxis system was used to print stents with a conventional closed-cell design while exploring variations in seam line overlaps and ring joint formations. Box-Behnken method was employed to systematically study the influence of key printing parameters─extrusion temperature, printing speed, and extrusion flow rate─on critical stent performance metrics: strut width, radial force, and flexural force. Microscopic analysis, radial compression, and three-point bending tests were performed for performance evaluation. Regression models and analysis of variance (ANOVA) revealed that the extrusion temperature and flow rate significantly influenced the mechanical properties. A multiobjective optimization approach was used to minimize the strut width while maximizing the radial and flexural strengths, resulting in a strut width of 205 μm and radial and flexural forces of 2.5 and 0.19 N, respectively, with an extrusion temperature, speed, and value of 200 °C, 90 mm/min, and 120%, respectively. Further characterization using microtomography and surface profilometry confirmed the structural integrity, consistent strut morphology, and surface quality. Accelerated degradation tests and in vitro biocompatibility assessments demonstrated favorable degradation profiles and cytotoxicity. A 95% mass change was observed in the printed stent after 10 d of accelerated degradation. This study presents a robust rotational-axis FFF method for scalable, bioabsorbable, and patient-specific stent fabrication.

Due to an incomplete understanding of the biomechanics of microneedle skin insertion for therapeutic delivery, translating microneedle device performance to clinical use remains challenging. For drug‐coated microneedles, it is hypothesized that the mode of skin insertion plays a significant role in how efficiently the drug is released and diffuses. By modeling application pressure magnitude and duration, both computationally and experimentally, the influence of both factors on drug delivery is evaluated. Building on the previously described computational modeling approaches, the development of a Franz Diffusion Cell assay customized with 3D‐printed components for use with microneedle patches with adjustable boundary conditions that capture strain‐dependent drug diffusion in porcine skin is described. Findings demonstrate that the modified Franz Diffusion Cells accurately simulate microneedle‐skin interactions under load, correlating with computational trends. Specifically, leaving microneedle patches in situ for 10 h reduced drug diffusion by ≈14%, compared to removal after 6 h. Prolonged application pressure may negatively impact on diffusion of the drug from the coated patch due to localized strain on surrounding skin tissue. These findings enhance understanding of how microneedle application mode influences drug delivery and the reliability of ex vivo transdermal testing, enabling more effective predictive pre‐clinical assessment of microneedle performance.

Low-temperature additive manufacturing of magnesium (Mg) alloy implants is considered a promising technique for biomedical applications due to Mg’s inherent biocompatibility and 3D printing’s capability for patient-specific design. This study explores the influence of powder volume content, size, and morphology on the mechanical properties and viscosity of polylactic acid (PLA) matrix composite filaments containing in-house-produced magnesium–calcium (Mg-Ca) particles, with a focus on their application towards low-temperature additive manufacturing. We investigated the effects of varying the Mg-Ca particle content in a PLA matrix, revealing a direct correlation between volume content and bending strength. Particle size analysis demonstrated that smaller particles (D50: 57 μm) achieved a bending strength of 63.7 MPa, whereas larger particles (D50: 105 μm) exhibited 49.6 MPa at 20 vol.%. Morphologically, the filament containing spherical particles at 20 vol.% showed a bending strength that was 11.5 MPa higher than that of the filament with irregular particles. These findings highlight the critical role of particle content, size, and shape in determining the mechanical and rheological properties of Mg-Ca/PLA composite filaments for use in material extrusion additive manufacturing.