Sustainable Polylactic Acid-Derived Polyurethane/MXene Microneedles for Stimulus-Responsive Transdermal Delivery

Abstract

The convergence of sustainability and advanced functionality is critical in the design of next-generation biomedical materials. Here, we report a biodegradable microneedle (MN) platform composed of polyurethane (PU) synthesized by the chemical recycling of polylactic acid (PLA). This green strategy upcycles PLA waste to produce a flexible, mechanically robust matrix suitable for transdermal applications. Incorporation of a trace amount (∼0.005 wt %) of delaminated Ti₃C₂T _x MXene imparts photothermal responsiveness under near-infrared (NIR) irradiation, antioxidant capacity (demonstrated using in vitro radical-scavenging assays), and improved mechanical strength. These features enable heat-triggered model drug release and suggest the potential for managing local oxidative stress in wound environments. In vitro assessments confirmed effective skin penetration, photothermal cycling stability, and acceptable cytocompatibility. This proof-of-concept study establishes a sustainable, multifunctional MN platform that integrates circular polymer design with stimuli-responsive performance, supporting future development for advanced transdermal drug delivery applications.

1. Introduction

Microneedles (MNs) have emerged as promising transdermal platforms for minimally invasive drug delivery and diagnostics, offering advantages such as pain-free administration, improved patient compliance, and bypassing of first-pass metabolism. Their clinical applications span vaccination, insulin delivery, and chronic disease or physical wound management. − However, the long-term success and translation of MN technologies into clinically and commercially viable systems are strongly dependent on the materials used. Metals and ceramics, though mechanically robust, are nonbiodegradable and cost-prohibitive. Recently, the field of biomaterials has undergone an important shift, transitioning from the application of passive and inert substances to the creation of advanced ″smart nanomaterials″ that actively interact with biological systems and respond to external stimuli. As a foundational matrix for these advanced systems, synthetic polymers derived from renewable resources such as polylactic acid (PLA) offer improved biocompatibility, processability, and environmental appeal. − PLA is particularly attractive due to its tunable degradation profile and regulatory acceptance. Yet, its intrinsic brittleness and lack of flexibility often lead to tip fracture or insertion failure during skin penetration, posing considerable limitations for MN applications. − To address these shortcomings, physical blending of PLA with flexible polymers like poly­(lactic-co-glycolic acid) (PLGA) or polycaprolactone (PCL) has been widely attempted. However, these blends often exhibit poor interfacial compatibility, unpredictable degradation behavior, and inconsistent mechanical performance. −

A more promising approach involves chemically converting PLA into polyurethane (PU), producing a new class of elastomeric materials with tailored flexibility, enhanced mechanical strength, and retained biodegradability. − This method effectively repurposes PLA into a distinct polymer matrix, offering superior structural and mechanical characteristics essential for MN performance. , In this study, virgin PLA resin was used as a model feedstock to simulate the feasibility of the chemical recycling pathway under controlled conditions suitable for biomedical applications. While the valorization of postconsumer PLA would enhance sustainability, its direct application in healthcare would require rigorous purification and safety validation. Nevertheless, the underlying recycling strategy remains broadly applicable to both recycled and virgin sources.

Recent innovations in MNs have also focused on hydrogel-based platforms and stimuli-responsive systems. For instance, hydrogel MNs constructed from zwitterionic polymers have shown promise for protein delivery by minimizing aggregation and preserving bioactivity. Other systems have explored polysaccharide–synthetic polymer hybrids, such as PVA blends, to improve mechanical integrity via cross-linking and facilitate controlled drug release. However, these hydrogel systems often exhibit poor insertion capability, limited structural stability under load, and challenges in long-term durability in physiological environments, particularly for applications requiring heat responsiveness or extended skin contact. Similarly, dissolvable MNs composed of sugars, polymers, or surfactant-based matrices enable transient delivery without requiring patch removal but often exhibit limited mechanical strength and inadequate thermal responsiveness for multifunctional use. In contrast, PU has been used as a MN matrix due to its favorable elasticity, toughness, and biocompatibility. − Yet, the use of PU derived from chemically recycled PLA is underexplored, particularly in combination with multifunctional fillers for stimuli-responsive delivery. Given its elastomeric nature and adjustable network architecture, PLA-based PU offers an attractive platform for dissolvable yet mechanically robust MNs, capable of heat-triggered drug release and reliable performance.

To impart these precise heat-triggered capabilities and elevate the PU matrix into a multifunctional transdermal platform, delaminated Ti₃C₂T _x MXene was selected as the ideal functional additive. 2D MXenes possess exceptional photothermal conversion efficiencies, making them highly promising for generating localized, near-infrared (NIR)-triggered heat. Incorporating MXene not only acts as a photothermal trigger for on-demand, stimulus-responsive drug delivery but also reinforces the mechanical strength necessary for reliable transdermal insertion. Furthermore, the localized mild heat and intrinsic properties of MXene provide additional benefits, such as managing local oxidative stress and offering antibacterial effects within wound environments, making it well-suited for inflammation-responsive delivery and wound healing applications. −

Despite these advances, current microneedle systems typically rely on either conventional petroleum-derived polymers or biodegradable materials that lack sufficient mechanical robustness and multifunctionality. Moreover, while MXene-based microneedles have recently been explored, these systems generally depend on relatively high filler loadings, where the accumulation of nanomaterials in tissues raises significant concerns regarding cytotoxicity, oxidative stress, and long-term biocompatibility. Furthermore, excessive MXene concentrations and high laser power can cause severe thermal elevation, leading to unintended burns or thermal damage to surrounding healthy tissue. Beyond these safety concerns, existing MXene-based microneedles are rarely integrated with sustainable polymer design strategies. While PU has been investigated as a microneedle matrix, the use of chemically recycled PLA-derived PU for biomedical microneedle applications remains largely unexplored.

In this context, the present study introduces a distinct material design strategy that integrates (i) chemical recycling of PLA into a functional PU matrix, (ii) incorporation of an ultralow concentration of MXene (∼0.005 wt %) to achieve efficient photothermal response without compromising structural integrity, and (iii) realization of multifunctionality, including mechanical robustness, antioxidant activity, and stimulus-responsive drug release, within a single platform. This combination represents an underexplored approach that bridges sustainable polymer chemistry with advanced functional microneedle design, going beyond incremental material modifications. By leveraging PLA-derived PU and delaminated Ti₃C₂T _x MXene, this platform integrates material circularity with the mechanical tunability and NIR-mediated responsiveness required for reliable transdermal performance. The resulting MNs demonstrate effective skin insertion, antioxidant activity, and high cytocompatibility, supporting their potential for next-generation wound management and therapeutic delivery systems.

2. Materials and Methods

2.1. Materials

Polylactic acid (PLA 4043D) (M _w = 1.2–1.5 × 10⁵ g/mol) was obtained from NatureWorks LLC (Minnetonka, Minnesota, USA). Lithium fluoride (LiF), 2,2-bis­(hydroxymethyl)­propionic acid (DMPA), isophorone diisocyanate (IPDI), and 1,4-butanediol (BDO) were purchased from Acros Organics (Fair Lawn, New Jersey, USA). Ethanol was obtained from Merck Millipore (Darmstadt, Germany). Tetrathylene glycol (TEG), tin­(II) 2-ethylhexanoate (Sn­(Oct)₂), poly­(ethylene oxide) (PEO) (M _w = 100 000 g/mol), and rhodamine B were sourced from Sigma-Aldrich (St. Louis, Missouri, USA). Pentaerythritol, polyethylene glycol (PEG)-400 (M _w = 550–650 g/mol), PEG-600 (M _w = 380–420 g/mol), 1,1-diphenyl-2-picrylhydrazyl (DPPH), and 2-phenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl (PTIO) free radicals were acquired from Tokyo Chemical Industry (Tokyo, Japan). Glycerol, methanol, and 2-amino-2-(hydroxymethyl)-1,3-propanediol were purchased from Fujifilm Wako Pure Chemical Industries (Osaka, Japan). Chloroform, dimethyl sulfoxide (DMSO), acetone, triethylamine (TEA), and hydrochloric acid (HCl) were supplied by Carlo Erba Chemicals (Milan, Italy). A Ti₃AlC₂ MAX phase (99.5%) was purchased from Luoyang Tongrun Nano Technology Co. Ltd. (Luoyang, China), and a Sylgard 184 silicone elastomer kit (PDMS) was acquired from Dow Corning (Midland, Michigan, USA). All materials were used as received without further purification.

2.2. Synthesis of Delaminated Ti₃C₂T _x MXene

Ti₃C₂T _x MXene was synthesized by etching the aluminum layer from the Ti₃AlC₂ MAX phase using a LiF/HCl mixture. Briefly, LiF (1.9 g) was dissolved in 10 mL of 9 M HCl and stirred at approximately 25 °C for 10 min in a Teflon vessel before gradually adding Ti₃AlC₂ powder (1.0 g) under continuous stirring. The reaction proceeded at 50 °C for 24 h to complete the etching. The suspension was repeatedly washed with deionized water by centrifugation (∼2300g, 5000 rpm, 5 min per cycle) until the supernatant reached pH 5–6. The etched material was then vacuum-dried at 60 °C for 24 h. To obtain delaminated MXene, the dried Ti₃C₂T _x powder was dispersed in DMSO (1:12 w/v) and stirred for 24 h at room temperature. Delaminated nanosheets were separated by using centrifugation (5000 rpm, 5 min) and stored at 4 °C until use. Successful etching and delamination were confirmed by using X-ray diffraction (XRD) and scanning electron microscopy (SEM) analyses. XRD indicated a shift of the (002) peak from approximately 2θ = 6–5.64°, corresponding to an increase in interlayer d-spacing from ∼1.47 nm to ∼1.56 nm, as calculated using Bragg’s Law. Transmission electron microscopy (TEM) imaging confirmed this expansion, indicating a delaminated flake morphology with increased interlayer distances, consistent with XRD results (Figure S1).

2.3. Chemical Recycling of PLA Using Alcohol Acidolysis

The alcohol acidolysis of PLA was carried out in a microwave reactor (Discover SP series, CEM Matthews, North Carolina, USA). PLA pellets and DMPA were added to a 35 mL vessel tube equipped with a magnetic stir bar. The ratio of PLA to DMPA was maintained at 6:1 (w/w). The reaction was carried out at 180 °C for 15 min under self-generated pressure (<100 psi). The resulting PLA-DMPA oligomer product was purified by dissolving it in hot acetone followed by precipitation in an excess volume of water/ethanol. The acidolysis products were then vacuum-filtered and dried overnight in an oven at 60 °C.

The chemical structure and molecular weight of the resulting PLA-DMPA oligomer were characterized by using Fourier transform infrared spectroscopy (FTIR) and gel permeation chromatography (GPC). The FTIR spectrum exhibited strong ester carbonyl stretching at approximately 1746 cm^–1 and broad O–H stretching bands between ∼ 3200 and 3500 cm^–1, consistent with carboxylic acid end-group formation (Figure S2a). GPC analysis indicated a number-average molecular weight (Mn) of 4899 g/mol and a weight-average molecular weight (M _w ) of 5637 g/mol for the PLA-DMPA oligomer (Figure S2b and Table S1). This confirmed significant chain scission relative to the starting PLA (M _w ∼ 100 000 g/mol), yielding oligomers suitable for PU synthesis. Although nuclear magnetic resonance (NMR) analysis was not performed, FTIR and GPC data confirmed the incorporation of DMPA-derived functional groups and oligomer formation, although precise quantification of end-group conversion remains an inherent limitation of this approach.

2.4. Synthesis of Polyurethane

The synthesis of PLA-based PU is illustrated in Figure . The PLA-DMPA oligomer and 1 wt % tin­(II) 2-ethylhexanoate [Sn­(Oct)₂] catalyst were dissolved in chloroform in a three-neck round-bottom flask. Isophorone diisocyanate (IPDI) was added under mechanical stirring, and the reaction mixture was heated to 90 °C for 3 h under reflux to form the PU prepolymer. Subsequently, a chain extender, selected from TEG, PEG-400, PEG-600, 1,4-butanediol (BDO), 2-amino-2-(hydroxymethyl)-1,3-propanediol (NH₂–CE), glycerol, or penta-erythritol, was introduced and reacted for an additional 1 h to complete chain extension. Upon cooling to 30 °C, triethylamine was added dropwise to adjust the solution to a neutral pH (∼7) followed by stirring for 30 min. The resulting PU solution was stored at room temperature prior to emulsification.

1.

Schematic illustration of polyurethane (PU) synthesis by emulsification. PU, polyurethane; PLA, polylactic acid; DMPA, 2,2-bis­(hydroxymethyl)­propionic acid; IPDI, isophorone diisocyanate; BDO, 1,4-butanediol; PEG, polyethylene glycol; TEG, tetrathylene glycol; MNs, microneedles.

For the preparation of PU/MXene emulsions, an aqueous dispersion of delaminated Ti₃C₂T _x MXene was added to the PU solution in chloroform (oil phase) at a volume ratio of 1:2 (aqueous:organic). The mixture was emulsified using a probe sonicator operating at 70% amplitude for 2 min followed by overnight stirring at 500 rpm and approximately 25 °C to ensure solvent evaporation. A schematic representation of PU synthesis using BDO as the chain extender is provided in Figure , and detailed formulation compositions are summarized in Table .

2.

Reaction pathway of polyurethane (PU) synthesis from polylactic acid (PLA)-2,2-bis­(hydroxymethyl)­propionic acid (DMPA) oligomer and isophorone diisocyanate (IPDI), with chain extension using 1,4-butanediol (BDO).

1. Composition of Polyurethane (PU) Formulations Synthesized with Varying Chain Extenders and NCO/OH Ratios .

			chain extender (mmol)
sample	PLA-DMPA (mmol)	IPDI (mmol)	TEG	PEG-400	PEG-600	BDO	NH2–CE	glycerol	pentaerythritol	NCO/OH
PU/TEG	1	5.2	2.5	−	−​	−​	−​	−​	−​	1.50
	1	5.2	3.2	−​	−​	−​	−​	−​	−​	1.24
	1	5.2	4.2	−​	−​	−​	−​	−​	−​	1.00
	1	4.5	3.5	−​	−​	−​	−​	−​	−​	1.00
PU/PEG-400	1	4.5	−​	3.5	−​	−​	−​	−​	−​	1.00
PU/PEG-600	1	4.5	−​	−​	3.5	−​	−​	−​	−​	1.00
PU/BDO	1	5.2	−​	−​	−​	3.2	−​	−​	−​	1.24
PU/NH2–CE	1	4.5	−​	−​	−​	−​	3.5	−​	−​	1.00
PU/glycerol	1	4.5	−​	−​	−​	−​	−​	3.5	−​	1.00
PU/pentaerythritol	1	4.5	−​	−​	−​	−​	−​	−​	3.5	1.00

^aPU, polyurethane; PLA, polylactic acid; DMPA, 2,2-bis­(hydroxymethyl)­propionic acid; IPDI, isophorone diisocyanate; BDO, 1,4-butanediol; PEG, polyethylene glycol; TEG, tetrathylene glycol.

2.5. Synthesis of PU/MXene Films and MNs

PU/MXene emulsions with a solid content of 35% (w/w) were cast into silicone molds and dried overnight at 60 °C to fabricate the PU/MXene composite films. For MN fabrication, two formulation strategies were explored to optimize the structural integrity and mechanical performance (Figure ). In the first approach, the PU/MXene emulsion was directly cast into a PDMS mold, vacuum-degassed for 5 min to remove air bubbles, and then air-dried at room temperature for 72 h before demolding the solidified MN patches. In the second approach, the PU/MXene emulsion was blended with a 15% (w/v) aqueous PEO solution at a volume ratio of 2:1 (PU/MXene:PEO). PEO was incorporated as a hydrophilic and film-forming polymer to enhance mechanical flexibility, promote uniform drying, and facilitate mold filling by reducing the surface tension and increasing the viscosity. The blended mixture was similarly cast into a PDMS mold, vacuum-treated for 5 min, and air-dried at ambient temperature for 72 h before carefully removing the fully solidified MN patches from the mold. For drug release studies, 2.66 μg of Rhodamine B (RhB) was incorporated into 300 μL of the PU/MXene–PEO casting mixture, corresponding to a concentration of approximately 8.87 μg/mL. The MXene concentration used in this study (∼0.005 wt %) was determined based on preliminary optimization experiments, which indicated that higher MXene loadings resulted in excessive photothermal heating and structural instability of the microneedles under NIR irradiation.

3.

Overview of polyurethane (PU)/MXene microneedle (MN) preparation methods: (a) direct casting of PU/MXene emulsion onto a Sylgard 184 silicone elastomer kit (PDMS) mold and (b) PU/MXene emulsion mixed with poly­(ethylene oxide) (PEO) solution before casting into a PDMS mold.

2.6. Characterization of PU/MXene Composites

The physicochemical and structural properties of PU/MXene emulsions and MN patches were characterized by using a suite of analytical techniques. Particle size distribution and zeta potential of the emulsions were measured with a Zetasizer Nano-ZS (Malvern Instruments, Malvern, UK). Chemical composition and molecular interactions were analyzed using FTIR spectroscopy (Nicolet 8700, Thermo Scientific, Waltham, Massachusetts, USA) in attenuated total reflectance mode, averaging 32 scans at a resolution of 4 cm^–1. Morphological features of PU/MXene films and MN arrays were observed by using SEM (TM3030, Hitachi, Tokyo, Japan). The compressive mechanical properties of the MN patches were evaluated using a ZTA-1 digital force gauge (IMADA Inc., Northbrook, Illinois, USA). Patches containing 36 MNs arranged over a 6 cm × 6 cm area were mounted on a stationary platform, while the force sensor was attached to a vertically moving plate. Displacement was applied at incremental speeds of 30, 100, and 200 μm/s to determine the load-bearing capacity and structural deformation thresholds of the MNs. All mechanical tests were conducted under dry conditions to evaluate the intrinsic structural strength and load-bearing capacity of the microneedles. Dry-state testing has been widely adopted as a standard method for assessing microneedle robustness prior to insertion. Although hydration can influence polymer mechanical behavior, the dry mechanical data provide a conservative estimate of the structural integrity. In addition, functional insertion capability was independently evaluated using ex vivo porcine skin under physiologically relevant conditions, thereby complementing the dry mechanical assessment and providing a more comprehensive evaluation of microneedle performance. Thermal response during NIR stimulation was monitored in real time using an SK-8500 infrared thermal imaging system (Axel Global, Osaka, Japan), allowing temperature profiling across the microneedle patch during photothermal conversion tests.

2.7. Microneedle Penetration Test

The skin penetration ability of PU/MXene MN patches was evaluated using ex vivo porcine skin as a model due to its structural similarity to human skin. Freshly excised porcine skin was trimmed to 3 × 3 cm sections (thickness ∼ 5 mm) and stored at −20 °C until use. Prior to testing, the samples were equilibrated to room temperature for 30 min under sealed conditions to preserve moisture content. MN patches were manually applied using a consistent thumb pressure (∼30 s) to simulate real-world user application. Following patch removal, the skin surface was examined using SEM to identify puncture sites and assess insertion efficacy.

2.8. Photothermal Performance of PU and PU/MXene MN Patches

The photothermal response of the MN patches was evaluated under 808 nm NIR irradiation at a power density of 1 W/cm², using a light source positioned 30 cm from the sample. Surface temperature was monitored in real time using an infrared thermal camera, and thermal images were captured to assess the heat distribution across the patch. To evaluate the photothermal stability and repeatability, a cyclic irradiation protocol was conducted: samples were exposed to 808 nm NIR light for 60 s followed by a passive cooling period of 60 s. This on/off cycle was repeated for five consecutive rounds. Temperature profiles were analyzed across cycles to assess the peak temperature consistency, thermal decay rates, and photothermal conversion durability.

2.9. Antioxidant Activity of PU and PU/MXene Patches

The antioxidant capacity of the PU and PU/MXene MN patches was evaluated by using DPPH and PTIO radical scavenging assays. For each test, 200 μL of the MN extract solution was mixed with 800 μL of either the DPPH or PTIO solution. Parallel control mixtures containing phosphate-buffered saline (PBS) and the respective radical solutions were prepared under identical conditions. All samples were incubated at 37 °C for 30 min in the dark to prevent light-induced radical degradation. After incubation, the absorbance was measured at 517 nm for DPPH and 734 nm for PTIO using a microplate reader (Infinite 200 Pro, Tecan Group Ltd., Männedorf, Switzerland). The radical scavenging activity (%) was calculated using eq :

$$\mathrm{scavenging}\mathrm{ratio}(\%)=(A_{\mathrm{control}}-A_{\mathrm{sample}})/A_{\mathrm{control}}\times 100$$ 1

where A _control is the absorbance of the control solution and A _sample is the absorbance of the MN extract mixture.

2.10. Cytotoxicity Evaluation of PU and PU/MXene Patches

L929 fibroblast cells (American Type Culture Collection, Manassas, Virginia, USA) were cultured at 37 °C in a humidified atmosphere containing 5% CO₂ using Dulbecco’s modified Eagle’s medium (DMEM; Sigma-Aldrich, St. Louis, Missouri, USA) containing 10% fetal bovine serum. For cytotoxicity evaluation, MN extracts were prepared by immersing 20 mg of MN patches in 1 mL of culture medium and incubating at 37 °C for 24 h. The resulting stock solutions were serially diluted with fresh medium to generate a range of test concentrations. Cytotoxicity was evaluated using the MTT assay in a 96-well plate. In brief, L929 cells were seeded into each well at a density of 1 × 10³ cells in 100 μL of culture medium and incubated for 72 h to allow cell attachment and proliferation. Following this, 100 μL of each MN extract dilution was added to the wells, and the cells were incubated for an additional 24 h. After treatment, 100 μL of MTT solution (300 μg/mL) was added to each well, and the wells were incubated for 4 h to allow formazan crystal formation. The medium was then carefully removed, and 100 μL of DMSO was added to dissolve the crystals. Absorbance was measured at 540 nm by using a microplate reader, and cell viability was calculated relative to untreated control wells.

2.11. Biocompatibility Evaluation In Vivo of PU and PU/MXene Patches

All animal experiments were conducted in strict accordance with protocols approved by the Institutional Animal Care and Use Committee of the Japan Advanced Institute of Science and Technology (JAIST) (Approval No. 07–007) and followed ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines.

Biocompatibility of biodegradable PU and PU/MXene MNs was evaluated using BALB/c-nu/nu mice (female, 6 weeks old, n = 6, average body weight of 18 g; BALB/c CrSIc-nu/nu; Japan SLC, Shizuoka, Japan). Under anesthesia, PU or PU/MXene MN patches were applied to the right dorsal skin of each mouse using a medical adhesive bandage. After recovery from anesthesia, the mice were kept awake with MN patches attached for 3 h. The patches were then carefully removed, and the dissolution of the MN was visually confirmed. In the case of PU/MXene MN, a slight black coloration was observed at the insertion sites, indicating the presence of MXene.

At 168 h (7 days) after MN application, blood samples were collected from the inferior vena cava. Complete blood count (CBC) analysis was performed using an automated clinical hematology analyzer (Celltac α MEK6558; Nihon Kohden, Tokyo, Japan). Blood biochemical parameters were analyzed by Oriental Yeast Co. (Tokyo, Japan). Following blood collection, major organs including the heart, lungs, liver, spleen, and kidneys were harvested, fixed, and subjected to hematoxylin and eosin (H&E) staining for histological evaluation. Control experiments were performed using mice without MN application (nontreatment group). Overall health indicators (viability and body weight) were monitored every single day.

2.12. Statistical Analysis

All quantitative results are presented as mean ± standard deviation (SD) based on at least three independent experiments (n ≥ 3). Statistical comparisons between two groups were performed using unpaired two-tailed t-tests with Welch’s correction to account for unequal variances. Differences were considered statistically significant at p < 0.05 or p < 0.001, as indicated. All statistical analyses and data visualization were conducted using OriginPro 2022 (OriginLab Corporation, Northampton, Massachusetts, USA; Academic Version).

3. Results and Discussion

3.1. Selection of Chain Extender for PU Synthesis

The choice of chain extenders plays a critical role in determining the properties of PLA-based PU systems for MN fabrication. Chain extender chemistry directly influences the cross-linking density, hydrogen bonding interactions, and phase morphology of the polymer network, which in turn govern the mechanical integrity, flexibility, and processing behavior essential for reliable MN performance. To identify the most suitable chain extender, a range of candidates, including linear diols (TEG, PEG-400, PEG-600, BDO), trifunctional alcohols (glycerol, pentaerythritol), and an amino-functional triol (NH₂–CE), was systematically evaluated. The screening strategy integrated particle size and zeta potential measurements of PU emulsions, FTIR spectroscopic analysis of cured films, and macroscopic film property assessment to ensure a comprehensive understanding of the impact of each chain extender on the final material performance.

3.1.1. Particle Size Distribution and Zeta Potential of PLA-Based PU Emulsions

Emulsion stability is a critical parameter for casting uniform, defect-free MNs. Figure S3a–d shows the particle size distributions of PU emulsions prepared with different chain extenders. TEG- and BDO-based emulsions exhibited relatively narrow and uniform particle size ranges 20–800 nm and 70–700 nm, respectively, indicative of good colloidal stability and consistent dispersion. In contrast, PEG-400 and PEG-600 systems displayed much broader distributions extending up to 5 μm, likely due to increased micelle formation and phase separation driven by their high molecular weights and hydrophilic nature.

Zeta potential measurements (Figure S3e) provided additional insights into the colloidal stability. Most formulations maintained zeta potentials below −30 mV, suggesting sufficient electrostatic repulsion for emulsion stability. Of these, TEG and BDO emulsions showed the most stable and uniform profiles, reflecting their compatibility with the PU prepolymer and optimal chain lengths for controlled network formation. In contrast, emulsions containing glycerol, pentaerythritol, or NH₂–CE precipitated rapidly during solvent evaporation, indicating excessive cross-linking and poor miscibility, which disqualified them from further consideration for MN fabrication.

3.1.2. FTIR Analysis of the PLA-based PU Network Structure

FTIR spectroscopy was used to analyze the molecular architecture of PU films synthesized with various chain extenders, providing insights into cross-linking behavior, hydrogen bonding, and urethane linkage formation, all of which are critical for MN mechanical performance. Using TEG as a model system, variations in the NCO/OH ratio (Figure S4a) indicated increased urethane cross-linking with higher isocyanate content, demonstrated by broadening of the carbonyl stretching band (∼1750 cm^–1) and the appearance of a shoulder near 1720 cm^–1. Enhanced hydrogen bonding was also evident from intensified N–H bending (∼1540 cm^–1) and C–H stretching (∼2900 cm^–1) bands. − Although increased cross-linking can improve rigidity, excessive cross-linking compromises flexibility, which is essential for MNs that must undergo controlled deformation during insertion without fracturing.

A comparative FTIR analysis (Figure S4b) of films prepared with TEG, BDO, PEG-400, and PEG-600 confirmed characteristic urethane peaks at ∼1750 cm^–1 (CO stretching), ∼1540 cm^–1 (N–H bending), and ∼2900 cm^–1 (C–H stretching). PEG-based formulations showed broader carbonyl bands, reflecting increased hydrogen bonding and potential microphase separation associated with their higher molecular weights and hydrophilicity. However, this also suggested an uncontrolled network structure prone to moisture absorption and mechanical instability. TEG-based films displayed narrower carbonyl bands consistent with moderate cross-linking and better flexibility. BDO-based PUs exhibited more pronounced N–H and CO bands, indicative of stronger hydrogen bonding and a cohesive urethane network that balances mechanical strength with sufficient flexibility for MN fabrication.

Trifunctional extenders, such as glycerol and pentaerythritol, led to substantially broader carbonyl peaks (Figure S4c), suggesting highly cross-linked networks. Although such cross-linking can increase structural integrity in some contexts, it produced rigid, brittle films incompatible with MN fabrication, where conformability is essential. The amino-functional triol, NH₂–CE, failed to produce a coherent film as rapid precipitation on solvent evaporation indicated poor miscibility with the PU prepolymer matrix.

3.1.3. Correlation with Macroscopic Film Properties

Macroscopic film characteristics supported these molecular-level findings. Qualitative evaluation indicated that TEG- and BDO-based films formed smooth, flexible, and moldable sheets, essential for replicating fine MN features in molds. BDO-derived films, in particular, exhibited slightly higher stiffness while maintaining flexibility without brittleness, achieving the necessary balance to resist deformation during insertion while avoiding fracture. In contrast, PEG-400 and PEG-600 films were overly hydrophilic and sticky, making them difficult to demold and handle reliably. Films prepared with glycerol, pentaerythritol, or NH₂–CE were brittle and prone to fracture upon bending, consistent with the excessive cross-linking observed in FTIR spectra. Although photographic documentation is not presented here, these macroscopic properties were systematically evaluated across batches and aligned with the structural and spectroscopic analyses.

Based on this integrated analysis of emulsion stability, molecular structure, and macroscopic film properties, BDO was selected as the optimal chain extender for MN fabrication. Its balanced contribution to cross-linking density and hydrogen bonding yielded PU films with excellent mechanical integrity, flexibility, and processability. These properties ensured the formation of structurally robust MNs capable of precise molding, reliable demolding, and effective skin insertion without fracturing, supporting their application in transdermal drug delivery and biomedical device development.

3.2. PU/MXene Microneedle Fabrication and MXene Concentration Optimization

3.2.1. Microneedle Fabrication, Structural Characterization, and Thermal Stability

Microneedle arrays were fabricated by using two polyurethane-based formulations, which consisted of a neat PU/MXene emulsion and a PEO-modified PU/MXene system in which PEO acted as a hydrophilic and elastomeric additive to enhance matrix flexibility and facilitate demolding. These formulations were systematically studied to elucidate the effects of polymer network architecture and chain mobility on microstructure formation, dimensional integrity, and mechanical performance.

The neat PU/MXene emulsion, when cast into PDMS molds and dried under ambient conditions, produced MNs with sharp conical tips and well-aligned geometries. However, the resulting arrays exhibited considerable brittleness, particularly during demolding, often leading to a tip fracture or partial detachment. This mechanical fragility is attributed to the high cross-link density and intrinsic rigidity of the segmented polyurethane network, which limited molecular mobility and restricted the ability to relax internal stress during solvent evaporation and mold removal. Additionally, the presence of MXene nanosheets, although beneficial for mechanical reinforcement, may have further increased stiffness and contributed to localized stress concentration, promoting structural failure during mechanical handling.

In contrast, the PEO-modified PU/MXene formulation demonstrated markedly improved demolding behavior and structural preservation. The incorporation of PEO, a flexible and hydrophilic polymer, introduced elastomeric domains within the polyurethane matrix, thereby enhancing the chain flexibility and enabling internal stress dissipation. Furthermore, the lower surface tension of the PEO-containing emulsion facilitated improved wetting and cavity filling, particularly within the high-aspect-ratio features of the mold. SEM analysis (Figure a–c) confirmed the formation of MNs with uniform morphology, sharp tips, and continuous base regions. The observed geometric consistency and surface regularity indicated high molding conformity and preservation of dimensional integrity throughout the fabrication process. These features are essential for minimizing insertion force and ensuring structural integrity during skin penetration. Energy-dispersive spectroscopy (EDS) mapping (Figure d–f) verified the uniform distribution of MXene within the MN structure, demonstrating that the addition of PEO did not disrupt the filler dispersion or compromise compositional homogeneity.

4.

Morphological and structural characterization of PU/MXene MNs before and after incorporating minimal MXene content (0.005 wt.%). (a) Optical image of MNs fabricated with higher MXene content, (b–f) SEM images and EDS elemental maps showing needle geometry and uniform MXene distribution at higher content, (g) optical image of MNs with minimal MXene content, and (h–l) SEM images and EDS maps confirming structurally intact, defect-free needles with preserved tip sharpness, base integrity, and uniform MXene distribution at minimal filler content. PU, polyurethane; MNs, microneedles; SEM, scanning electron microscope; EDS, energy-dispersive spectroscopy.

In preliminary trials, MN patches with a higher MXene content showed visible surface degradation and discoloration under NIR irradiation, indicating thermal damage due to excessive photothermal conversion. This localized overheating exceeded the thermal stability of the polyurethane matrix, leading to softening, deformation, and, in some cases, structural failure. To prevent these effects while maintaining photothermal responsiveness, MXene was used at a minimal concentration (0.005 wt %). This design strategy follows a minimal-additive approach in which the lowest possible MXene content is used to maximize functional efficiency while preserving mechanical integrity and cytocompatibility. The results highlight that even trace amounts of MXene can provide significant functional enhancement when homogeneously dispersed within the polymer matrix. SEM imaging (Figure g–i) confirmed that this formulation maintained intact the needle architecture with no deformation or loss of tip sharpness. Elemental mapping (Figure j–l) showed a uniform MXene distribution, preserving functional performance despite the low filler content and highlighting the importance of nanosheet dispersion and matrix–filler interactions in maintaining dimensional integrity.

3.2.2. Mechanical Performance and Compression Behavior

The mechanical behavior of the MN arrays was evaluated through both stepwise and continuous compression testing. Microneedles fabricated from the neat PU/MXene emulsion demonstrated a progressive increase in force during stepwise compression, from 3.4 N at 0.5 mm to 33.9 N at 2.0 mm displacement (Figure a), which exceeds the insertion force threshold (∼0.058 N per needle) for human skin. In continuous compression (1.0 mm at 200 μm/s), a peak force of 9.24 N was recorded (Figure b). However, SEM analysis postcompression (Figure c,d) indicated substantial deformation, with approximately 33% tip height reduction, indicating limited shape recovery and poor resistance to mechanical loading.

5.

Mechanical characterization of PU/MXene MNs before and after reducing MXene content. (a–d) Results for MNs fabricated with the initial high MXene content: (a) Force–displacement profile under incremental compression, (b) comparison with continuous compression, and (c, d) SEM images after compression showing tip deformation and approximately 33% reduction in needle height. (e–i) Results for MNs fabricated with the optimized lower MXene concentration (0.005 wt %): (e) Force–displacement comparison between PU and PU/MXene MNs, (f, h) SEM images of PU MNs after compression, and (g, i) SEM images of PU/MXene MNs after compression showing improved shape retention and reduced permanent deformation. PU, polyurethane; MNs, microneedles; SEM, scanning electron microscopy.

In contrast, microneedles fabricated from the PEO-modified PU/MXene formulation containing 0.005 wt % MXene exhibited improved mechanical integrity. These MNs achieved a peak compression force of 6.25 N, in comparison to 3.88 N for unmodified PU-based microneedles (Figure e), suggesting enhanced stiffness and load-bearing capacity due to MXene reinforcement. Postcompression SEM images (Figure f–i) showed that PU/MXene MNs retained approximately 85% of their original height, whereas PU-only microneedles retained ∼70%, indicating superior shape recovery and reduced permanent deformation. This enhancement is attributed to efficient stress transfer at the MXene–PU interface and improved energy dissipation, facilitated by the elastomeric matrix network. The physical basis for this efficient stress transfer lies in the strong interfacial hydrogen bonding between the highly active surface terminations of MXene (−OH, – F, and O) and the polar urethane linkages (−NH and CO) of the PU matrix. As previously confirmed by the broad N–H and O–H stretching bands in FTIR analysis (Figure S4), this extensive hydrogen bonding network acts as a robust physical cross-link. Such interfacial bonding prevents MXene agglomeration and ensures that mechanical loads are effectively transferred from the flexible polymer to the rigid 2D nanosheets. These combined mechanisms result in a balanced formulation with sufficient elasticity and structural integrity for reliable microneedle performance. , Post-compression SEM analysis indicated localized tip deformation and minor blunting in higher-MXene-content samples, indicating stress concentration at the tip during loading. It should be noted that the mechanical properties reported here were obtained under dry conditions, which reflect the intrinsic stiffness and structural integrity of the microneedles. While hydration may reduce the modulus in polymeric systems, the measured forces significantly exceed the reported threshold required for skin penetration. Furthermore, successful insertion into porcine skin under physiologically relevant conditions confirms that the mechanical performance is sufficient for practical transdermal application.

3.3. Photothermal Response, Thermal Stability, and Stimulus-Responsive Drug Release under NIR Irradiation

The photothermal performance of the PU/MXene MNs with minimal MXene content (∼0.005 wt %) was assessed under NIR irradiation and compared to PU MNs. PU/MXene MNs exhibited a rapid and sustained temperature increase, confirming that even very low MXene loading is sufficient for effective photothermal conversion (Figure a). Within the first 10 s of exposure, PU/MXene MNs reached 38 °C, compared to 30 °C for PU MNs. The temperature continued to rise to 56 °C after 60 s, eventually stabilizing at approximately 62 °C after 180 s, whereas PU MNs plateaued at 46 °C. Figure b presents the temperature–time profiles of both systems, highlighting the superior photothermal conversion efficiency of PU/MXene MNs. Both showed an initial rapid temperature rise, but only the MXene-containing formulation reached the threshold required to induce matrix softening and polymer chain relaxation, conditions conducive to thermally triggered drug release.

6.

Photothermal response, thermal stability, and NIR-triggered drug release of PU/MXene MNs. (a) Infrared thermal images during 808 nm irradiation, (b) temperature–time profiles (mean ± SD, n = 3), (c) DSC curves showing thermal transitions, (d) temperature cycling over five NIR on/off cycles, and (e) RhB release profiles with and without NIR irradiation (mean ± SD, n = 3). Statistical significance determined using Welch’s two-sample t-test; **p < 0.05; ***p < 0.001; ns indicates not significant. NIR, near-infrared; PU, polyurethane; SD, standard deviation; DSC, differential scanning calorimetry; RhB, Rhodamine B.

To investigate these thermal transitions, differential scanning calorimetry (DSC) was performed on neat PU, PU MNs, and PU/MXene MNs (Figure c). The DSC curve of neat PU lacked a visible glass transition temperature (T _g ) within the tested range, consistent with its predominantly amorphous structure and limited thermal responsiveness. PU MNs incorporating PEO displayed a distinct melting peak at ∼53 °C, corresponding to crystalline domains that partially contributed to the thermal response during NIR exposure. The PU/MXene MNs retained this melting peak (∼54 °C), indicating that PEO crystallinity was preserved despite MXene incorporation. The presence of MXene enhanced overall heat distribution and energy conversion within the matrix due to its high thermal conductivity and NIR absorption. Furthermore, the tightly bound hydrogen-bonded interface between MXene and the PU matrix (Figure S4) minimizes the interfacial thermal resistance. This seamless physical connection prevents phonon scattering, allowing the rapid, localized heat generated by MXene to dissipate efficiently throughout the surrounding polymer. This enables the MNs to exceed the softening point of the matrix and promote thermally induced polymer chain mobility.

Thermal cycling tests evaluated the stability and repeatability of the photothermal response. PU/MXene MNs were subjected to five on/off NIR irradiation cycles of 1 min intervals. The MNs consistently reached peak temperatures of ∼62 °C in each cycle with minimal baseline drift, demonstrating excellent thermal stability and reliable reusability under repeated activation (Figure d). The photothermal performance was confirmed by evaluating its ability to trigger a stimulus-responsive drug release. Rhodamine B (RhB) release from PU/MXene MNs was analyzed under NIR irradiation compared to passive conditions (Figure e). In the initial phase (0–10 min), both irradiated and nonirradiated samples showed similar release profiles dominated by passive diffusion. The stimulus-responsive drug release observed in the PU/MXene system is primarily attributed to the photothermal effect of MXene under NIR irradiation. The localized heat generated by MXene increases the polymer chain mobility and induces partial softening of the PU/PEO matrix, thereby accelerating the diffusion of encapsulated molecules. This mechanism is best described as thermally enhanced diffusion rather than a discrete structural phase transition or chemical degradation, highlighting the role of MXene as an efficient photothermal transducer within the polymer network. Statistical analysis using Welch’s two-sample t-test indicated that NIR irradiation resulted in higher release at 1, 15, and 30 min (p < 0.05), confirming photothermal-triggered diffusion acceleration due to localized matrix heating. ,

To further verify this, the mechanism of stimulus-responsive drug release was quantitatively analyzed by using the Higuchi and Korsmeyer–Peppas kinetic models (Figure ). Fitting the release data to the Higuchi model demonstrated good linear fits (R ² ≥ 0.94), indicating that diffusion plays a major role in the release profile. Notably, the Higuchi release rate constant (k _H ) increased significantly from 7.41 under passive conditions to 8.89 under NIR irradiation, mathematically confirming that the photothermal effect accelerates the overall release rate. Furthermore, the release mechanism was evaluated using the Korsmeyer–Peppas equation. The diffusional exponent (n) was calculated to be 0.65 for the passive group and 0.62 for the NIR-irradiated group. Because these values fall between 0.45 and 0.89, they indicate an anomalous (non-Fickian) transport mechanism, wherein drug release is governed by a combination of both diffusion and polymer matrix swelling/relaxation. The consistency of the n values between the two groups confirms that NIR irradiation does not alter this fundamental dual mechanism. Instead, localized photothermal heating accelerates the kinetic rate of diffusion and facilitates polymer chain relaxation without degrading the matrix.

7.

Kinetic modeling of the in vitro stimulus-responsive drug release profiles from PU/MXene microneedles. (a) Linear fitting of the release data using the Higuchi model to evaluate the diffusion rate under passive conditions (without NIR) and photothermal activation (with NIR), and (b) linear fitting of the release data using the Korsmeyer–Peppas model to determine the fundamental transport mechanism. The linear regression equations and corresponding correlation coefficients (R ²) are provided in the inset for each condition. Data are presented as mean ± SD (n = 3).

While the incorporation of PEO is essential for improving the moldability and flexibility of the microneedle arrays, its contribution to the release kinetics is functionally different from the photothermal trigger. Because PEO is highly hydrophilic, it establishes the baseline environment for passive diffusion by promoting water uptake and matrix swelling. However, the exact same PEO-modified PU/MXene formulation was used for both passive and NIR-irradiated release studies. Therefore, the baseline swelling contribution of PEO is constant across both conditions. The significant acceleration in drug release observed under NIR irradiation cannot be attributed to PEO, but it is exclusively driven by the localized photothermal conversion of the MXene nanosheets. MXene provides the dynamic thermal energy required to increase the polymer free volume, acting as the active stimulus-responsive trigger beyond the permissive baseline established by PEO.

Complete in vitro dissolution of the MNs within 30 min supported the potential for applications requiring rapid or complete drug release. RhB was selected as a widely used model compound to establish a proof of concept for NIR-triggered release thanks to its compatibility with optical tracking and consistent diffusion behavior. Future work will build on this foundation by exploring clinically relevant therapeutic agents with varied physicochemical properties to demonstrate broader applicability. This dual mechanism of passive diffusion followed by thermally enhanced release demonstrates the potential of PU/MXene MNs to enable on-demand, stimulus-responsive delivery suitable for controlled and localized biomedical applications.

3.4. Functional Evaluation of PU and PU/MXene MNs

3.4.1. Skin Penetration Capability

The skin insertion performance of PU and PU/MXene MNs was assessed using porcine skin, a widely accepted model for human skin due to its similarity in structure and elasticity to human skin. Whereas optical microscopy offered limited resolution, SEM imaging clearly indicated puncture marks in the form of distinct circular depressions (Figure ), confirming a successful breach of the stratum corneum. This is a critical criterion for effective transdermal drug delivery. The dissolvable nature of the MNs offered added benefit by facilitating sustained release of therapeutic agents through gradual matrix degradation in the interstitial fluid. This property eliminates the risk of needle residue and enhances safety by enabling complete dissolution post-insertion.

8.

Scanning electron microscopy images exposing distinct circular punctures on porcine skin showing the penetration achieved using PU/MXene MNs and their ability to penetrate the stratum corneum.

The observed shallow penetration is consistent with the expected behavior of dissolvable MNs and aligns with applications, such as cosmetic treatment or vaccination, where deep penetration is unnecessary. Quantitative depth measurements were not performed, as they were beyond the scope of this study. SEM-confirmed skin penetration, combined with axial compression testing, supports the mechanical suitability of the PU/MXene MNs for transdermal drug delivery. The measured peak compression forces, exceeding 6 N for optimized formulations, provide a strong safety margin over the typical ∼0.058 N per needle insertion threshold. This indicates that the design achieves sufficient mechanical strength and balanced deformability for reliable skin insertion while minimizing structural failure. Advanced imaging techniques such as fluorescence microscopy or optical coherence tomography (OCT) could be useful in future studies focused on deep-tissue delivery or precise dissolution kinetics, but they fall outside the current scope of early stage functional validation. In addition to SEM-based visualization of puncture sites, the mechanical data further support effective skin penetration as the measured insertion forces exceed the commonly reported threshold required to breach the stratum corneum. Porcine skin, used in this study, is widely accepted as a reliable model for human skin due to its comparable structure and mechanical properties. Together, these results provide sufficient functional evidence of successful microneedle insertion for transdermal delivery applications within the scope of this study.

3.4.2. Antioxidant Capacity

The antioxidant properties of PU and PU/MXene MNs were evaluated by using DPPH and PTIO radical scavenging assays. The PU/MXene MNs exhibited substantially improved scavenging capacity, with 21.74 and 20.37% inhibition for DPPH and PTIO, respectively, compared to only 1.06 and 0.46% for PU MNs (Figure ). This finding was corroborated by the assay images showing marked color fading upon exposure to PU/MXene extracts, reflecting effective radical scavenging. This behavior is attributed to MXene’s surface chemistry, with oxygen-containing functional groups enabling antioxidant activity. These chemical assays provide evidence of the intrinsic radical-scavenging capacity in the PU/MXene MNs. DPPH and PTIO assays are standard methods for assessing such capacity in biomaterials, suggesting their potential relevance for managing oxidative stress in wound care applications. The incorporation of MXene at minimal loading (∼0.005 wt %) achieved this antioxidant functionality while preserving both cytocompatibility and mechanical integrity of the MNs. This balance supports their intended role as multifunctional systems. They enable NIR-triggered therapeutic delivery while also offering complementary antioxidant activity that may help control local oxidative stress in wound environments. Future studies using cell-based oxidative stress models or in vivo wound-healing assays will be valuable to confirm the biological relevance and therapeutic efficacy of the observed antioxidant properties to advance the multifunctional potential of this sustainable MN platform.

9.

Antioxidant activity of polyurethane (PU) and PU/MXene microneedles measured using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2-phenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl (PTIO) assays. Results are shown as mean ± SD (n ≥ 3), with ***p < 0.001 indicating significant differences. Assay images display color fading that reflects radical-scavenging activity, with PU/MXene microneedles demonstrating stronger antioxidant performance than PU and control samples.

3.4.3. Cytocompatibility Assessment

Cytocompatibility of the PU and PU/MXene MN formulations was assessed using the MTT assay across a range of extract concentrations (Figure ). This provides a reliable preliminary assessment of cytotoxicity for biomedical materials. Both PU and PU/MXene MN formulations maintained high cell viability, with values >80% at concentrations up to 288 μg/mL. This indicates low cytotoxicity and satisfies standard criteria for materials intended for transdermal or subcutaneous use. Statistical analysis indicated that only the PU/MXene group at 576 μg/mL exhibited a reduction in viability compared to the control (***p < 0.001), whereas all other groups, including PU and lower concentrations of PU/MXene, were similar in this respect. These findings indicate that MXene, when incorporated at minimal levels (∼0.005 wt %), does not impair cytocompatibility under typical application conditions. The observed decrease at 576 μg/mL may be attributed to dose-dependent cytotoxicity mechanisms associated with MXene materials, including reactive oxygen species (ROS) generation, membrane disruption, or intracellular uptake leading to stress signaling. Previous studies have reported similar threshold behaviors, where MXene cytotoxicity becomes more apparent only at higher loadings or prolonged exposure durations. , Thus, the results here reinforce the strategic benefit of using MXene at minimal concentrations sufficient for photothermal activity while staying below cytotoxic thresholds.

10.

Cytocompatibility of polyurethane (PU) and PU/MXene microneedles at various extract concentrations was assessed using the MTT assay. Data are presented as mean ± standard deviation (n = 7). Statistical comparisons were performed against the control group using Welch’s two-sample t-test. A reduction in viability was observed only for PU/MXene at 576 μg/mL (***p < 0.001). All other groups showed no significant difference from the control (ns).

The mode of administration for MNs, a localized and minimally invasive route, further reduces the risk of systemic toxicity. Unlike systemic injections, MN-mediated drug delivery confines material exposure to superficial dermal layers, where local clearance and biocompatibility are more relevant than systemic accumulation. This localized context supports the applicability of PU/MXene MNs, especially when functional enhancements, such as NIR responsiveness and antioxidant activity, are achieved with minimal filler loading. Whereas the MTT assay provides valuable insights, it represents only one aspect of biological evaluation. Mitochondrial metabolism, though sensitive, may not fully capture membrane integrity, cell morphology, or the inflammatory response. While these findings confirm low cytotoxicity, complementary assessments such as intracellular ROS assays could further delineate specific cellular interaction mechanisms. To validate these in vitro results within a complex physiological environment, the in vivo biocompatibility and systemic safety of the MNs were subsequently evaluated as detailed in the following section.

3.4.4. In Vivo Biocompatibility Assessment

The in vivo biocompatibility of PU and PU/MXene MNs was assessed by using BALB/c-nu/nu mice. Both types of MN patches were successfully applied to the dorsal skin under anesthesia and remained attached for 3 h in conscious mice. Upon removal of the patches, complete dissolution of the microneedles was confirmed, indicating efficient degradation of the PU-based MNs in the skin. In the PU/MXene group, slight black coloration was observed at the MN insertion sites, suggesting successful delivery of MXene into the skin (Figure a–c). Comprehensive safety evaluation revealed that body weights of mice in all treatment groups remained stable throughout the experimental period, indicating the absence of significant adverse effects (Figure S5).

11.

In vivo application and biocompatibility evaluation of PU and PU/MXene MNs. (a) Photographs of PU and PU/MXene microneedle patches immediately after application to the dorsal skin of BALB/c-nu/nu mice under anesthesia, (b) representative image of microneedle patches attached to the dorsal skin during the application period, (c) photographs taken immediately after removal of the microneedle patches following 3 h of application, showing successful attachment and subsequent removal, and (d) hematoxylin and eosin (H&E) staining of major organs sectioned after intravenous injection of PU, PU/MXene, or PBS after 7 d.

To evaluate systemic toxicity, blood samples were collected 7 d after MN application. Complete blood count and biochemical analyses revealed no significant abnormalities in mice treated with either PU or PU/MXene MNs compared with the nontreatment group. All measured parameters remained within normal ranges, indicating no detectable hematological or biochemical toxicity (Table ). Specifically, the stability of hepatic enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and renal markers such as creatinine (CREA) and blood urea nitrogen (BUN) suggests that the metabolic clearance of the dissolved MN components did not induce acute stress on the liver or kidneys, which are the primary clearance pathways for nanomaterials. , Furthermore, histological examination of major organs, including the heart, lungs, liver, spleen, and kidneys, showed no pathological abnormalities in either treatment group (Figure d). The H&E-stained tissue sections from MN-treated mice were comparable to those from the nontreatment group, demonstrating the absence of observable tissue damage or inflammatory responses. The lack of inflammatory cell infiltration or granuloma formation in the liver and spleen is particularly encouraging, as these organs are common sequestration sites where inorganic nanomaterials can accumulate and cause toxicity. , These results collectively indicate that both PU and PU/MXene MNs exhibit excellent in vivo biocompatibility and do not induce systemic toxicity under the conditions tested, confirming their potential suitability for safe transdermal drug delivery applications.

2. CBCs and Biochemical Parameters of the Mice Treated with PBS or Microneedles after 7 days .

measured value	entry	unit	PBS (n = 6)	PU (n = 6)	PU/MXene (n = 6)	p value
CBC	WBC	×102 /μL	48.8 ± 6.00	45.2 ± 1.64	43.0 ± 4.37	>0.05
	RBC	×104 /μL	856.0 ± 6.70	890.7 ± 9.93	872.3 ± 8.88	>0.05
	HGB	g/dL	15.3 ± 0.14	15.8 ± 0.17	15.6 ± 0.16	>0.05
	HCT	%	45.0 ± 0.41	45.9 ± 0.53	45.5 ± 0.48	>0.05
	MCV	fL	53.1 ± 0.76	51.6 ± 0.09	52.1 ± 0.19	>0.05
	MCH	pg	18.1 ± 0.23	17.7 ± 0.05	17.8 ± 0.07	>0.05
	MCHC	g/dL	34.1 ± 0.08	34.2 ± 0.10	34.1 ± 0.07	>0.05
	PLT	×104 /μL	76.5 ± 2.79	85.1 ± 1.50	84.6 ± 4.48	>0.05
biochemical parameters	TP	g/dL	4.4 ± 0.06	4.8 ± 0.08	4.6 ± 0.14	>0.05
	ALB	g/dL	3.0 ± 0.06	3.1 ± 0.03	3.1 ± 0.04	>0.05
	BUN	mg/dL	28.4 ± 1.04	28.6 ± 2.01	27.0 ± 0.58	>0.05
	CRE	mg/dL	0.1 ± 0.01	0.1 ± 0.01	0.1 ± 0.01	>0.05
	Na	mEq/L	144.2 ± 0.80	145.2 ± 0.55	144.0 ± 0.24	>0.05
	K	mEq/L	22.6 ± 0.28	22.3 ± 0.49	22.3 ± 0.25	>0.05
	Cl	mEq/L	106.0 ± 0.62	106.0 ± 0.41	105.8 ± 0.44	>0.05
	AST	IU/L	56.8 ± 1.55	55.5 ± 1.54	56.7 ± 1.74	>0.05
	ALT	IU/L	27.0 ± 0.82	26.7 ± 0.73	30.0 ± 1.25	>0.05
	LDH	IU/L	273.7 ± 13.49	257.3 ± 12.25	245.3 ± 17.74	>0.05
	AMY	IU/L	2536.8 ± 236.04	2555.8 ± 155.86	2653.0 ± 132.07	>0.05
	CK	IU/L	74.7 ± 4.28	72.2 ± 8.16	70.2 ± 5.91	>0.05

^aData are represented as means ± standard errors of the mean (SEM.); n = 6 biologically independent mice. Statistical analyses comprise Student’s two-sided t-test. Abbreviations: ALB, albumin; ALT, alanine transaminase; AMY, amylase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Cl, chlorine; CK, creatine kinase; CRE, creatinine; HCT, hematocrit; HGB, hemoglobin; K, potassium; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; Na, sodium; PLT, platelet; RBC, red blood cell; TP, total protein; WBC, white blood cell.

4. Conclusions

This work presents a sustainable and multifunctional MN platform based on PU derived from chemically recycled PLA, offering a sustainable material solution for advanced transdermal drug delivery. The use of recycled PLA provides a biodegradable and biocompatible polymer matrix, aligning green circularity principles with biomedical innovation. Functional enhancement through MXene incorporation imparts photothermal responsiveness, antioxidant activity, and improved mechanical strength, achieving both structural performance and therapeutic functionality. The MNs successfully penetrated porcine skin, confirming their suitability for transdermal applications and enabled controlled drug release triggered by NIR irradiation. The antioxidant functionality of MXene may serve a supporting role in managing oxidative stress relevant to wound care. These advanced features were achieved with minimal MXene loading and without compromising cytocompatibility, emphasizing the system’s safety and efficiency. This study establishes a promising framework for dissolvable MNs that integrates sustainability with clinical potential. Building upon these findings, in vivo assessments in mice demonstrated excellent biocompatibility, with no observable systemic toxicity or adverse inflammatory responses in major organs following MN application. Recognizing the proof-of-concept nature of this work, future work will focus on long-term biodegradation profiles and the evaluation of clinically relevant therapeutic agents to demonstrate performance with drugs of diverse physicochemical properties under physiological conditions.

Glossary

Abbreviations

BDO

1,4-butanediol

PEO

poly­(ethylene oxide)

DMPA

2,2-bis­(hydroxymethyl)­propionic acid

DSC

differential scanning calorimetry

EDS

energy-dispersive spectroscopy

IPDI

isophorone diisocyanate

MNs

microneedles

PU

polyurethane

NIR

near-infrared

PEG

polyethylene glycol

PLA

polylactic acid

PU

polyurethane

RhB

Rhodamine B

SD

standard deviation

TEG

tetrathylene glycol

The data that support the findings of this study are available within this article and its Supporting Information and from the corresponding author(s) upon request.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acspolymersau.6c00060.

• XRD patterns and TEM images confirming delamination of Ti₃C₂T _x MXene (Figure S1); FTIR spectrum and GPC data of PLA–DMPA polyol (Figure S2, Table S1); particle size distributions and zeta potential of PU emulsions with different chain extenders (Figure S3); FTIR spectra of PU formulations with various chain extenders and NCO/OH ratios (Figure S4); Average mouse body weight after each treatment (Figure S5) (PDF)

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Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-0813, Japan

O.D.P.: Experimentation, data collection, and writing of the original draft. A.P.: Methodology, visualization, and editing. K. A.: Conducted the experiments. N. Y.: Experimentation. E. M.: Methodology, visualization, and supervision. P.O.: Conceptualization, methodology, visualization, and supervision. K.M.: Conceptualization, methodology, visualization, review, editing, and supervision.

This work was supported in part by the research grant from the Thailand Science Research and Innovation Fundamental Fund and the Center of Excellence in Functional Advanced Materials Engineering (CoE FAME), Thammasat University; and by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (A) (Grant Number 23H00551), JSPS KAKENHI Grant-in-Aid for Challenging Research (Pioneering) (Grant Number 25K21827), JSPS Program for Forming Japan's Peak Research Universities (J-PEAKS) (Grant Number JPJS00420230006), and the Japan Science and Technology Agency (JST) Program for Co-creating Startup Ecosystem (Grant Number JPMJSF2318).

The authors declare no competing financial interest.