Microneedle-Based Transdermal Systems for Vaccines and Biologics: A Review

Abstract

Traditional vaccine and biologic delivery via intramuscular or subcutaneous injections is often limited by pain, needle-related anxiety, infection risk, and the requirement for trained healthcare personnel. Microneedle-based transdermal systems have emerged as a promising alternative, offering a minimally invasive, painless, and patient-friendly approach for administering macromolecules. These systems employ tiny projections that penetrate the stratum corneum to deliver therapeutic agents directly into the dermis, a layer abundant in immune cells and vascular networks. A variety of microneedle designs—including solid, coated, dissolving, hollow, and hydrogel-forming types—have been engineered to deliver vaccines, peptides, proteins, and nucleic acid-based biologics. Both preclinical and clinical studies have demonstrated their potential to elicit strong immune responses while enhancing patient compliance. Despite these advantages, challenges such as large-scale manufacturing, biologic stability, and regulatory approval continue to hinder widespread implementation. This review focuses on the recent advances, applications, obstacles, and future directions of microneedle-based transdermal delivery systems for vaccines and biologics.

Keywords

Microneedle delivery systems; Transdermal vaccination; Biologics; Minimally invasive drug delivery; Immunization; Patient compliance; Vaccine stability

Introduction

Each microneedle type offers specific advantages and limitations, which depend on the physicochemical properties of the biologic and the intended therapeutic outcome (Larrañeta et al., 2016).

Mechanism of Transdermal Delivery:

The human skin serves as a robust barrier, with the stratum corneum restricting the penetration of most hydrophilic and large molecules. Microneedles bypass this barrier by forming microchannels that reach the viable epidermis or dermis. This allows direct interaction with antigen-presenting cells (APCs), including Langerhans cells and dermal dendritic cells, which play a pivotal role in initiating immune responses (van der Maaden et al., 2012). Targeted delivery to these immune-rich layers enhances vaccine immunogenicity while reducing systemic exposure.

Applications in Vaccines and Biologics:

Vaccines:

• Influenza Vaccines: Clinical studies have shown that microneedle patches delivering influenza antigens can elicit immune responses that are comparable or superior to those achieved with intramuscular injections (Rouphael et al., 2017).
• COVID-19 Vaccines: Experimental microneedle platforms have been investigated for both mRNA and protein-based COVID-19 vaccines, offering advantages such as improved thermostability and potential for self-administration.
• Polio and Measles Vaccines: Preclinical studies indicate promising immunogenicity with enhanced thermostability, which may help overcome storage challenges in resource-limited settings.

Biologics:

• Insulin: Dissolving microneedles loaded with insulin have demonstrated effective glycemic control in diabetic animal models.
• Monoclonal Antibodies: Early research suggests potential for both localized and systemic delivery using microneedles.
• Nucleic Acid Therapeutics: Microneedles have been employed for DNA- and RNA-based vaccines, enhancing gene expression and immune responses compared to traditional injection methods.

Challenges and Limitations:

While microneedle-based transdermal delivery systems have shown considerable promise in both preclinical and clinical studies, their adoption as widely used therapeutic products remains limited. The barriers to translation include challenges in formulation development, device engineering, large-scale manufacturing, regulatory approval, and user acceptance.

1. Formulation Stability:

Biologics, including proteins, peptides, and nucleic acids, are inherently unstable and susceptible to degradation under stress conditions such as heat, moisture, or mechanical pressure. During microneedle fabrication, processes like casting, drying, or coating can expose these biologics to harsh conditions, potentially compromising their structural integrity and biological activity. For instance, dissolving microneedles composed of sugars or polymers may absorb atmospheric moisture, reducing mechanical strength and diminishing drug stability. Maintaining biologic activity throughout the shelf life of microneedle products remains a significant and unresolved challenge.

2. Dose Uniformity and Loading Capacity:

Achieving accurate and consistent drug loading in microneedles remains a technical challenge. Coated microneedles can exhibit variability in coating thickness, whereas dissolving microneedles are limited in drug capacity due to size constraints. These limitations are particularly critical for biologics that require higher therapeutic doses, such as monoclonal antibodies. Inconsistent or insufficient dosing may lead to suboptimal therapeutic effects or variability in patient responses.

3. Mechanical Strength and Penetration Consistency:

Effective microneedle delivery requires adequate mechanical strength to penetrate the stratum corneum without fracturing. Microneedles composed of biodegradable polymers or sugars can be fragile, risking breakage during insertion, which may result in incomplete drug delivery or safety concerns from retained fragments in the skin. Additionally, penetration depth and consistency can be influenced by factors such as skin thickness, elasticity, and insertion force, raising challenges for dose reproducibility across diverse patient populations.

4. Manufacturing and Scalability:

Scaling microneedle production from laboratory to industrial levels remains a major challenge. Techniques such as micromolding, laser cutting, and photolithography require specialized equipment and can be expensive when applied at large scale. Ensuring consistent quality, sterility, and performance across mass-produced batches is difficult. Additionally, incorporating biologics into microneedle systems without compromising their stability during large-scale manufacturing continues to be an area of active research.

5. Regulatory and Quality Control Challenges:

Unlike traditional injections or oral dosage forms, microneedle patches are considered combination drug-device products, which adds complexity to regulatory approval. Agencies such as the FDA and EMA have limited specific guidelines for microneedle systems, creating uncertainties in clinical trial design, quality control, and approval pathways. Furthermore, establishing long-term safety, skin tolerability, and equivalence to conventional delivery methods requires extensive data, which can further extend development timelines.

6. Cost and Accessibility:

While microneedle systems are intended to lower healthcare costs by reducing the need for trained personnel, their initial production and specialized fabrication equipment can make them more expensive than conventional injections in the short term. For large-scale vaccination programs in low- and middle-income countries, affordability and supply chain logistics remain significant challenges.

7. Patient Acceptance and Human Factors:

Although microneedles are typically painless, patient perception and acceptance can vary. Some individuals may hesitate to adopt novel delivery technologies due to unfamiliarity or concerns about their effectiveness compared to conventional injections. Furthermore, successful self-administration requires clear instructions, training, and confidence to ensure proper patch adhesion and accurate drug delivery. Improper application could result in incomplete penetration and diminished therapeutic efficacy.

8. Limited Clinical Data:

Although numerous preclinical studies and early-stage clinical trials have demonstrated promising outcomes, large-scale, long-term clinical data remain limited. Comprehensive information on immunogenicity, durability of protection, and safety across diverse populations is necessary before widespread regulatory approval and commercialization can be achieved.

Microneedle-based transdermal systems continue to face technical, regulatory, and social challenges that impede their rapid transition from research laboratories to routine clinical practice. Addressing these obstacles will require advancements in biologic stabilization, reliable manufacturing processes, standardized regulatory frameworks, cost-effective production strategies, and enhanced patient education. Collaborative efforts among academia, industry, and regulatory authorities are critical to accelerate clinical adoption and fully realize the potential of this innovative technology.

FUTURE PERSPECTIVES:

Microneedle-based transdermal systems have the potential to revolutionize vaccine and biologic delivery, but realizing their full impact depends on progress in several areas, including materials science, device engineering, formulation development, clinical application, and regulatory pathways. Key future directions include:

1. Thermostable and Long-Term Formulations:

A major challenge for vaccines and biologics is their reliance on the cold chain. Many protein- and nucleic acid-based vaccines require refrigeration, restricting global accessibility, especially in low-resource settings.

Future research is focusing on developing thermostable microneedle formulations that remain stable at ambient temperatures for extended periods, thereby lowering storage and transportation costs.

Examples include sugar-based dissolving microneedles and polymeric encapsulation methods, both of which help protect the therapeutic payload from degradation.

2. Smart and Responsive Microneedles:

Emerging microneedle designs can be engineered to respond to physiological stimuli, including pH, glucose levels, temperature, or enzymatic activity. Smart micro needles could enable on-demand drug release, for instance: 

Anti-inflammatory peptides released at sites of localized inflammation. Insulin is secreted in response to increased blood glucose levels. Integration with biosensors could enable closed-loop systems, connecting real-time monitoring with automatic, responsive drug release.

3. Integration with Wearable and Digital Health Devices :

The combination of microneedle patches with wearable electronics enables continuous biomarker monitoring alongside controlled biologic delivery. Future designs may incorporate IoT-connected patches, allowing remote monitoring by healthcare providers and adherence tracking for chronic therapies. This approach holds particular promise for diabetes management, long-term vaccination, and hormone replacement therapy.

4. Expanding Therapeutic Applications:

Beyond vaccines, microneedles show potential applications in cancer immunotherapy, gene therapy, and biologic-based therapies. For example:

• Cancer vaccines delivered transdermally to activate local immune cells.
• mRNA therapies delivered directly to the skin to reduce systemic toxicity.  
• Monoclonal antibody delivery via microneedles to reduce injection frequency.

5. Advanced Fabrication and 3D Printing:

Current micro needle manufacturing commonly relies on micromolding and lithography, methods that can be costly and challenging to scale.

3D printing and laser-assisted fabrication are emerging as scalable alternatives, enabling:

• Complex geometries care being developed to enhance skin penetration and optimize drug release.
• Customizable microneedle patches can be customized to suit individual patients or specific therapeutic agents.
• Rapid prototyping enables the development and testing of experimental vaccines and biologics.

6. Regulatory Harmonization and Standardization:

Regulatory approval continues to be a key barrier to the widespread clinical adoption of microneedles. Future efforts should focus on establishing global guidelines for their safety, efficacy, and quality control. Standardization will support faster clinical trials, promote global adoption of microneedle vaccines in mass immunization programs, and ensure consistency in manufacturing, drug loading, and mechanical performance.

7. Patient-Centric Design and Acceptability:

Future microneedle systems will prioritize usability, convenience, and aesthetics to improve patient compliance. Potential features include painless self-administration, minimal training requirements, and compact patch designs that still provide sufficient drug capacity for multi-dose delivery.

CONCLUSION:

Microneedle-based transdermal systems represent a transformative approach for delivering vaccines and biologics. By enabling painless administration, enhancing immunogenicity, and supporting potential self-application, they overcome many limitations associated with traditional injections. While technical, manufacturing, and regulatory challenges persist, ongoing advances in materials science, device engineering, and clinical evaluation are poised to establish microneedles as a mainstream drug delivery platform in the near future.

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