Abstract

Against the backdrop of rapid advances in precision medicine and non-invasive diagnostics, microneedles (MNs) have emerged as a novel drug delivery system that bridges the gap between conventional hypodermic injection and traditional transdermal patches. With their unique structural design and versatile functional integration capabilities, MNs have demonstrated tremendous potential across a wide spectrum of biomedical applications-ranging from controlled drug release and biosensing to vaccine delivery. This article provides a systematic overview of MN technology from four key perspectives: basic definition and classification, biomedical applications, biomaterials and their properties, and mainstream fabrication strategies, culminating in a forward-looking discussion on the challenges and future trajectories of this rapidly evolving field.

1. What Are Microneedles? Structural Features and Working Mechanisms

Microneedles are microscale needle-like array structures with a height ranging from 50 to 2000 μm​ and a tip diameter of less than 100 μm. Typically arranged at high density on a substrate to form a patch-like device, MNs operate on a deceptively simple yet powerful principle: mechanical penetration of the stratum corneum-the skin's outermost barrier layer. By creating transient microchannels within the epidermis without stimulating dermal nociceptors (pain receptors) or blood vessels, MNs enable efficient transdermal delivery of macromolecular drugs, nucleic acids, vaccines, and other therapeutic agents that conventional patches cannot reach.

1.1 Classification by Functional Response

Based on their structural design and drug release mechanisms, MNs are broadly categorized into five major types:

Figure 1.​ Classification of microneedles and their respective drug delivery mechanisms. [1]

This classification framework underscores the high degree of flexibility in structure-function integrated design​ that MNs offer, enabling researchers to tailor devices for specific clinical scenarios.

2. Application Progress of Microneedles in Biomedical Engineering

2.1 Transdermal Drug Delivery

Traditional transdermal drug delivery is severely limited by the impermeable nature of the stratum corneum, rendering it ineffective for macromolecules such as proteins, peptides, and siRNA. MNs effectively circumvent this barrier. To date, they have been successfully employed for the percutaneous delivery of insulin, monoclonal antibodies, growth hormones, and other biologics-significantly improving bioavailability while eliminating the need for repeated injections.

2.2 Vaccine Delivery Systems

MN patches offer a compelling advantage in vaccine logistics: antigens and adjuvants can be stabilized at room temperature, eliminating cold-chain dependence-a critical bottleneck in global vaccine distribution. Furthermore, MNs naturally target the skin's dense population of antigen-presenting cells (APCs), particularly Langerhans cells in the epidermis, eliciting stronger and more durable immune responses​ compared to intramuscular injection.

2.3 Biosensing and Point-of-Care Testing (POCT)

Integrated MN sensors can extract interstitial fluid (ISF)-a rich source of biomarkers-for real-time, continuous monitoring of physiological indicators such as glucose, lactate, and inflammatory cytokines, offering a minimally invasive alternative to repeated blood draws. This convergence of sampling and sensing in a single device is paving the way for wearable closed-loop diagnostic systems.

2.4 Oncology and Localized Intervention

Locally implanted drug-loaded MNs are being explored for targeted chemotherapy and immunomodulation​ in skin cancers and post-surgical residual breast cancer lesions. Additionally, stimuli-responsive MNs​ incorporating photothermal or magnetic hyperthermia agents are under active investigation, enabling spatiotemporally controlled therapeutic activation.

2.5 Medical Aesthetics and Dermatological Repair

Encapsulating bioactive ingredients such as hyaluronic acid and collagen​ within dissolving MNs promotes dermal regeneration, effectively addressing acne scars, hyperpigmentation, and skin aging. These systems combine excellent safety profiles with proven clinical efficacy, driving rapid commercial adoption in the aesthetic medicine sector.

Figure 2.​ Representative applications of microneedles across biomedical fields. [2]

3. Biomaterials for Microneedles: Properties and Selection Criteria

Material selection is a determining factor​ in MN performance, directly influencing mechanical strength, degradation behavior, drug-loading efficiency, and biocompatibility. Current MN materials are primarily classified into four categories:

⚠️ Regulatory Note: All MN materials must comply with ISO 10993 biocompatibility standards, ensuring the absence of cytotoxicity, sensitization, and irritation.

Furthermore, composite material strategies-such as PLGA/HA blends or polymer-ceramic hybrids-are emerging as a powerful approach to synergistically enhance mechanical robustness, drug retention, and release controllability.

4. Fabrication Methods: From Microfabrication to Additive Manufacturing

MN manufacturing integrates techniques from micro-electromechanical systems (MEMS), soft lithography, template replication, and advanced printing technologies. The typical fabrication pipeline includes the following key methods:

4.1 Silicon Photolithography + Deep Reactive Ion Etching (DRIE)

Produces high-precision silicon master molds

Process is mature and well-characterized

Limitation: High cost; primarily suited for prototyping and research-scale production

4.2 PDMS Soft Molding

Polymer solutions are cast into silicon masters, cured, and demolded

Low cost, high reproducibility, and scalable-the dominant industrial pathway

Compatible with a wide range of polymeric materials

4.3 3D Printing Technologies

Includes inkjet printing, stereolithography (SLA), and digital light processing (DLP)

Enables personalized customization and complex 3D geometries

Resolution has progressively improved to ±10 μm, approaching MEMS-level precision

4.4 Near-Field Electrospinning

Constructs nanofiber-based MN structures

Provides ultra-high specific surface area, ideal for high-capacity drug loading

Particularly suited for bioactive molecule encapsulation

Current Manufacturing Challenges

The field faces ongoing challenges in balancing resolution, production throughput, and batch-to-batch consistency-especially for GMP-compliant clinical-grade manufacturing. Achieving scalable, reproducible production while maintaining sub-100 μm feature fidelity remains a key engineering hurdle.

5. Future Perspectives and Challenges

Despite the rapid technological evolution of MNs, several critical bottlenecks persist on the path to widespread clinical translation:

However, the convergence of flexible electronics, smart materials, and AI-assisted design​ is accelerating the arrival of next-generation Smart Microneedle Systems (SMS). These integrated platforms-capable of sensing, responding, and providing feedback​ within a single closed-loop device-are no longer a distant vision but an emerging reality.

6. Concluding Remarks

Microneedles are far more than a drug delivery tool. They represent a cross-disciplinary innovation platform​ at the intersection of materials science, micro/nano-manufacturing, biomedical engineering, and artificial intelligence. Ultimately, MNs embody a future healthcare paradigm defined by three core principles: minimal invasiveness, high efficacy, and patient-centric design.