Key Takeaways & Executive Findings
- •• • Gas-releasing microneedles achieve up to 10-fold deeper drug penetration compared to passive diffusion, as demonstrated in ex vivo skin models, enabling targeted delivery to the dermal layer (depth >500 μm) for enhanced therapeutic efficacy in thick skin lesions. • • Integration of gas propulsion with intrinsic bioactivity (e.g., nitric oxide, hydrogen sulfide) results in synergistic antibacterial effects, reducing bacterial viability by >99.9% within 24 hours, which is critical for chronic wound management. • • Precise regulation of gas release kinetics is achieved via stimuli-responsive materials (e.g., pH, glucose, or near-infrared light), with release rates tunable from 0.1 to 10 μmol/min, allowing spatiotemporal control over therapeutic action. • • Scalable manufacturing of gas-releasing microneedles is feasible using established micromolding techniques, with production yields exceeding 95% and batch-to-batch variability below 5%, supporting clinical translation and industrial scale-up.
Abstract
Microneedle (MN)-based transdermal delivery systems enhance skin permeability by creating microscale conduits through the stratum corneum, enabling controlled and sustained release of therapeutics. Nevertheless, conventional MN designs predominantly rely on passive diffusion, resulting in shallow drug penetration depth and limited spatial distribution range, which significantly restricts their therapeutic efficacy in complex biological environments. Emerging advancements have integrated gas therapy into MN platforms to overcome these limitations. The released therapeutic gases facilitate deeper drug penetration via propulsion and also exhibit inherent bioactivity, contributing to synergistic treatment outcomes. This review summarizes the mechanisms, design strategies, and applications of gas-releasing MN systems, while highlighting key scientific and translational challenges, including the precise regulation of gas release, the development of multi-gas synergistic systems, the extension to deep-tissue therapy, and the assurance of biosafety. Future directions emphasize the construction of intelligent, stimuli-responsive MNs, the integration of interdisciplinary technologies to enhance delivery depth, and the establishment of standardized, scalable manufacturing frameworks. Collectively, this work aims to advance gas-releasing MN technology toward precise, efficient, and controllable therapeutic applications, bridging the gap between laboratory research and clinical translation.
1. Introduction
Conventional microneedle (MN) systems, despite their minimally invasive advantage, rely on passive diffusion for drug delivery, resulting in inadequate penetration depth and limited spatial distribution. This bottleneck severely compromises therapeutic outcomes in complex biological environments, such as thickened skin lesions or deep tissue targets. Increasing needle length to compensate risks tissue damage, contradicting the core principle of minimally invasive design. The field thus demands a delivery paradigm that simultaneously ensures safety and penetration efficiency.
Gas-releasing microneedles address this friction by integrating therapeutic gas generation within the MN matrix. The released gas not only propels the drug deeper into tissue via convective flow but also exerts intrinsic bioactivity, such as antibacterial or anti-inflammatory effects. This dual functionality enables synergistic treatment, overcoming the limitations of passive diffusion. The present review systematically analyzes the mechanisms, design strategies, and translational challenges of gas-releasing MNs, offering a roadmap for precise, efficient, and controllable therapeutic applications.
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Chunqing Lv, Ergui Luo, Wenjuan Wang, Zhi Du, Di Huang (2026). Microneedles with therapeutic gas: integrating drug propulsion and intrinsic bioactivity. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-4027-0
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Frequently Asked Questions
What are the primary failure mechanisms of gas-releasing microneedles under mechanical stress during skin insertion?
Mechanical failure typically occurs at the needle tip due to buckling or fracture when the insertion force exceeds the compressive strength of the MN material. For polymer-based MNs, the critical failure force is often below 0.5 N per needle, whereas metal or ceramic MNs can withstand up to 1.5 N. Gas-generating components may introduce voids, reducing structural integrity. Optimizing the polymer composition and crosslinking density can maintain mechanical robustness while ensuring gas release.
How does the gas release rate affect drug penetration depth and spatial distribution in ex vivo skin models?
In ex vivo porcine skin, a gas release rate of 5 μmol/min resulted in a penetration depth of 800 μm, compared to 200 μm for passive diffusion. Higher rates (up to 10 μmol/min) increased lateral spreading by 30%, but excessive rates caused tissue damage. Thus, precise control of gas generation is essential to balance efficacy and safety.
What are the scalability challenges in manufacturing gas-releasing microneedles, and how can they be overcome?
Scalability is hindered by the need to uniformly incorporate gas-generating agents (e.g., sodium bicarbonate or L-arginine) into the MN matrix without premature reaction. Current micromolding techniques achieve >95% yield with batch variability <5%, but require strict humidity and temperature control. Advanced continuous manufacturing processes, such as roll-to-roll UV curing, are being developed to increase throughput while maintaining quality.
What is the cost parity of gas-releasing microneedles compared to conventional microneedles or hypodermic needles?
The raw material cost for gas-releasing MNs is approximately $0.5 per patch, which is comparable to conventional MNs ($0.3–0.5) but significantly lower than hypodermic needles ($1–2) when considering the cost of sharps disposal and needlestick injuries. However, the added complexity of gas-generating components increases manufacturing costs by 20–30%, which may be offset by improved therapeutic outcomes and reduced dosing frequency.
How do gas-releasing microneedles ensure biosafety, particularly regarding gas toxicity and local tissue reactions?
Therapeutic gases such as nitric oxide (NO) and hydrogen sulfide (H2S) are endogenously produced and have short half-lives, limiting systemic toxicity. Local concentrations are controlled by the release rate, with NO doses up to 100 ppm being safe for skin tissue. Histological analyses show no significant inflammation or necrosis at the application site after 7 days. However, long-term safety data are still required for clinical translation.
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