Recent Advances in Electronic Skin Technologies for Transdermal Drug Delivery Applications

The skin serves as the largest interface between the human body and the external environment and plays a critical role in regulating the substances that enter and exit the body. Under normal physiological conditions, the skin is designed to permit minimal penetration, as other tissues—such as the highly permeable epithelia of the gastrointestinal tract and lungs—are primarily responsible for controlled substance entry. In parallel, the skin functions to prevent excessive loss of water and essential endogenous components, thereby maintaining homeostasis. The exceptional barrier function of the skin is largely attributed to the stratum corneum, the thin outermost layer of the epidermis. Unlike other tissues, the stratum corneum is composed of terminally differentiated corneocytes, which consist mainly of aggregated keratin filaments enclosed within a cornified protein envelope. These corneocytes are embedded in an extracellular lipid matrix arranged in multiple lamellar bilayers. This unique lipid organization effectively restricts trans epidermal water loss while simultaneously impeding the penetration of most topically applied substances. As a result, only drugs that are sufficiently lipophilic and possess low molecular weight can readily permeate the skin, presenting a major challenge for transdermal drug delivery intended for either local or systemic therapeutic effects.

Stratum Corneum Structure and Organization

The stratum corneum is a highly specialized composite structure composed of proteins and lipids arranged in a characteristic “brick-and-mortar” architecture. In this model, the corneocytes act as the “bricks,” while the intercellular lipid matrix functions as the “mortar.” Rather than being uniformly distributed, the hydrophobic lipids of the stratum corneum are confined to the extracellular domains, where they are organized into well-defined lamellar membranes that envelop the corneocytes. Consequently, variations in skin permeability across different anatomical sites are not primarily determined by stratum corneum thickness but instead arise from differences in the number of lamellar layers, lipid content, membrane organization, and lipid composition. These structural and biochemical factors collectively govern the barrier properties of the skin and its permeability behavior.

Fig. 1. Anatomy and physiology of the skin show the potential targets or site of action for cosmetics and drugs (reprinted by permission of Pearson Education, Inc. from Marieb 1997).

Human stratum corneum is typically comprised of about 20 corneocyte cell layers, which differ in their thickness, packing of keratin fila- ments, filaggrin content, and number of Corne desmosomes, depending on body site. Corneocytes are surrounded by a highly cross-linked, resilient sheath, the cornified envelope, while the cell interior is packed with keratin filaments embedded in a matrix composed mainly of flag- grin and its breakdown products (the latter are also referred to as “natural moisturizing factors”). As noted above, individual corneocytes, in turn, are surrounded by a lipid-enriched extracellular matrix, organized largely into lamellar membranes, which derive from secreted lamellar body precursor lipids.

Fig.2. Pathways into the skin for transdermal drug delivery.

A. Transdermal transport via a tortuous pathway largely within extracellular lipids. This pathway is utilized during drug absorption in association with chemical, biochemical and some physical enhancers. B. Transport through hair follicles and sweat ducts can be enhanced by iontophoresis and certain particulate formulations. C. Transport directly across the stratum corneum is enabled by electroporation. D. Stripping, ablation, abrasion and microneedles remove stratum corneum to make micron-scale (or larger) pathways into the skin. Reproduced with permission from Prausnitz MR, et al. Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov. 2004; 3:115–24.

Fig. 3. Two-compartment “bricks and mortar “system and “pore” pathway.

A. The stratum corneum is a unique two-compartment system, analogous to a brick wall. Whereas lipids are sequestered extracellularly within the stratum corneum, the corneocyte is lipid-depleted but protein-enriched. B. The degradation of Corne desmosomes results in discontinuous lacunar domains, which represent the likely aqueous “pore” pathway. These lacunae can enlarge and extend, forming a continuous but collapsible network under certain conditions, e.g. occlusion, prolonged hydration, sonophoresis

Electronic skin (e-skin)

Electronic skin (e-skin) is a flexible, ultra-thin, and wearable electronic platform capable of environmental sensing and controlled response. E-skin systems utilize stretchable, bendable, and deformable materials, achieved through advanced mechanical and material engineering, to replace conventional rigid electronic components. This design enables e-skin devices to closely replicate the mechanical behavior of human skin, ensuring high mechanical compliance and conformability. As a result, e-skin devices can intimately interface with the skin surface, allowing efficient exploitation of skin mechanics for diverse biomedical applications, including physiological monitoring, transdermal drug delivery, and controlled drug release. The conceptual foundation of e-skin technology originates from flexible electronic components developed for devices such as e-readers and curved display systems, which rely on conductive polymers and carbon-based materials. Beyond standalone functionality, e-skins are capable of integrating with intelligent devices and networked systems, enabling real-time data acquisition, processing, and feedback. This connectivity significantly broadens their potential applications in healthcare monitoring, human–computer interaction, and therapeutic management. From a structural perspective, e-skin devices are composed of three principal components: sensing units, signal conversion and transmission circuits, and bioinspired interfaces analogous to neural networks. Together, these elements facilitate the detection, processing, and transmission of tactile and physiological signals. Sensor components form the core of e-skin systems and are tailored to detect specific environmental stimuli. For instance, pressure sensors translate mechanical forces into electrical signals and are commonly designed using capacitive or resistive mechanisms. Capacitive pressure sensors operate by modulating capacitance through changes in the distance between parallel electrodes, offering high sensitivity and linear response; polymeric materials, microstructured elastomers, or air gaps may serve as dielectric layers. In contrast, resistive pressure sensors function through either intrinsic piezoresistive effects within materials or changes in contact resistance between structured conductors and electrodes. While conventional piezoresistive polymer composites often exhibit limitations such as hysteresis, temperature sensitivity, and reduced pressure responsiveness, contact-resistance–based designs have demonstrated improved stability and reduced thermal interference. Following signal detection, integrated conversion and transmission circuits transform sensor outputs into electrical pulse signals, enabling quantitative interpretation of stimulus intensity. In such systems, increasing pressure results in higher pulse frequencies, while pulse amplitude and waveform modulation allow control over signal strength and spatial resolution. Flexible data transmission modules further support signal amplification, processing, and communication with external devices or biological tissues. Collectively, these integrated components establish e-skin as a promising multifunctional platform for advanced biomedical sensing and pharmaceutical drug delivery applications. Electronic skin (e-skin) technologies have emerged as innovative platforms engineered to emulate the tactile, mechanical, and physiological characteristics of human skin. These advanced systems have gained considerable attention due to their broad applicability across diverse fields, including robotics, prosthetics, and wearable healthcare technologies. The fundamental aim of e-skin development is to enable sophisticated sensory feedback and interactive capabilities, thereby promoting more intuitive, efficient, and responsive interfaces between humans and machines. In the context of wearable healthcare devices, e-skins offer significant potential by enabling continuous, non-invasive monitoring of key physiological parameters such as body temperature, pressure, and skin deformation. This capability supports improved personal health assessment and disease management. Within robotic applications, e-skins that replicate human tactile sensation enhance operational precision, adaptability, and safety during human–robot interactions. Similarly, in prosthetic systems, the integration of e-skin technologies can restore tactile perception in amputees, thereby improving functional performance and overall quality of life. Collectively, these advancements position e-skin technology as a transformative tool with substantial implications for biomedical and pharmaceutical sciences.

Fig4. Functions of E-SKIN

Types and Permeation Mechanisms of Transdermal Drug Delivery Systems

The success of transdermal drug delivery systems (TDDS) is largely governed by the chosen delivery strategy. To achieve efficient transdermal transport of bioactive compounds, numerous conventional and advanced approaches have been developed to overcome the skin’s barrier function. These strategies include the use of chemical permeation enhancers, ointments, transdermal patches, injections, microneedles, sonophoresis, electroporation, and iontophoresis, all of which aim to improve drug permeation across the skin. In addition to formulation strategies, the permeation mechanism itself plays a pivotal role in determining drug absorption and therapeutic efficacy. Therefore, a comprehensive understanding of the various TDDS types and their associated permeation pathways is essential for the rational design of safe and effective transdermal delivery platforms. The primary routes by which active pharmaceutical ingredients traverse the skin barrier are illustrated in Fig

Ointments

Ointments represent one of the most commonly employed dosage forms in transdermal drug delivery. These formulations typically comprise an active drug, a semi-solid base or gel matrix, and penetration enhancers. Ointments facilitate localized drug delivery by enabling direct drug action at the site of application, offering advantages such as ease of use, rapid onset of action, and sustained therapeutic effects. However, their limited skin permeability can restrict drug flux, potentially compromising therapeutic outcomes. Furthermore, due to gradual drug release kinetics, repeated or prolonged application of ointments, creams, and gels may be required to maintain optimal drug concentrations at the target site.

Transdermal Patches

Transdermal patches constitute a major class of TDDS and are designed to exploit the mechanical flexibility, stretchability, and sensory properties of human skin. The polymer matrix serves as the core component of these systems and plays a critical role in drug loading, release kinetics, and mechanical performance. Advances in patch technology are closely linked to the development of novel polymeric materials and fabrication techniques that enable high tensile strength, excellent electrical conductivity, mechanical flexibility, and cost-effectiveness. Synthetic polymers are widely used in patch fabrication due to their favorable physicochemical properties, including chemical inertness, thermal stability, transparency, tunable mechanical behavior, and low Young’s modulus. These materials are commonly employed in both transdermal patches and stretchable electronic devices. However, their inherent limitations—such as poor hydrophilicity, weak adhesion to biological surfaces, limited biocompatibility, and lack of biodegradability—significantly restrict their biomedical applications. To address these challenges, natural polymers such as polysaccharides, proteins, and lipids have gained increasing attention owing to their excellent biocompatibility, biodegradability, and ease of chemical modification. Additionally, biodegradable and bioabsorbable synthetic polymers, including polylactides and polyglycolides, can degrade into physiologically acceptable metabolites that are readily eliminated by the body. Nevertheless, natural polymers often exhibit suboptimal mechanical strength, durability, electrical conductivity, and structural consistency, which can negatively affect drug release profiles, transport efficiency, and skin-integrated health monitoring. To overcome these limitations, semi-synthetic polymers—produced through chemical modification of natural polymers—have been developed. These materials combine the favorable biological properties of natural polymers with enhanced mechanical strength, stability, and functional versatility. Semi-synthetic polymers are typically low-cost, non-toxic, and biodegradable, while functional groups such as hydroxyl and carboxyl moieties enable further biofunctionalization and controlled crosslinking with other polymer systems. A summary of commonly used polymers in TDDS is provided.

Microneedle Systems for Transdermal Drug Delivery

Microneedle systems (MNS) consist of micron-scale needle arrays, typically ranging up to 1000 μm in length, which are integrated into a supporting substrate to enable transdermal drug delivery without causing damage to the dermis or underlying nerve tissues. Upon application, microneedles create transient micropores in the stratum corneum, allowing water-soluble and poorly permeable drugs to diffuse into the viable epidermis and dermis, from where they can enter systemic circulation. Based on their structural design and mode of drug release, microneedles are commonly classified into five categories: solid, coated, dissolving, hollow, and hydrogel-forming microneedles. The selection of materials for microneedle fabrication plays a crucial role in determining their mechanical strength, biocompatibility, drug-loading capacity, and release behavior. Polymeric microneedles, in particular, offer a minimally invasive alternative to conventional injections by effectively breaching the stratum corneum with significantly reduced pain and tissue trauma. Microneedle-based delivery systems have been successfully employed for the administration of a wide range of therapeutic agents, including small-molecule drugs, peptides, proteins, and vaccines, demonstrating their versatility in treating various medical conditions. However, the efficient transdermal delivery of biotherapeutics remains challenging due to their large molecular size, hydrophilic nature, limited stability, and poor skin permeability, which collectively restrict drug uptake. To address these limitations and improve patient comfort, ongoing research focuses on optimizing microneedle design, material composition, and drug delivery strategies. For instance, hydrogel-forming microneedles enable sustained and controlled drug release, thereby reducing dosing frequency and enhancing therapeutic efficacy. Additionally, advanced surface coatings such as chitosan and silicon dioxide have been explored to improve drug stability, enhance permeation, and increase absorption efficiency. These innovations highlight the growing potential of microneedle systems as effective and patient-friendly platforms for transdermal delivery of both conventional drugs and biotherapeutics.

Electroporation

Electroporation is an active, physically driven transdermal delivery technique that employs high-voltage electrical pulses, typically ranging from 5 to 500 V, applied over microsecond- to millisecond-scale durations to enhance the transport of therapeutic agents across biological membranes. The efficiency of electroporation-mediated transdermal permeation is influenced by the physicochemical characteristics of the drug, as well as formulation and electrical parameters. Increases in pulse voltage, duration, and frequency have been shown to significantly enhance drug transport across the skin. During electroporation, brief high-intensity electrical pulses disrupt the highly ordered lipid bilayers of the stratum corneum, leading to the formation of transient aqueous pores. These temporary pathways facilitate the permeation of hydrophilic and high–molecular weight compounds, including biomacromolecules, which would otherwise exhibit poor skin permeability. As a result, electroporated skin serves as an effective conduit for enhanced drug absorption. Despite its therapeutic potential, electroporation is associated with several limitations. The application of high-voltage electrical fields may induce localized adverse effects, such as tissue cavitation, bleeding, and an increased risk of infection. The procedure can also cause patient discomfort or pain and requires precise control of electrical parameters and skilled operation. Furthermore, the relatively high cost of electroporation equipment compared with conventional transdermal delivery devices may restrict its widespread clinical adoption.

Iontophoresis

Iontophoresis is a non-invasive, electrically assisted transdermal drug delivery technique that utilizes a low-intensity electric current to promote the transport of both charged and uncharged molecules across the skin, primarily through hair follicles and sweat glands. Drug permeation during iontophoresis occurs through two principal mechanisms: electro repulsion and electroosmosis. Electro repulsion involves the application of an electric field that drives charged drug molecules away from an electrode of the same charge, thereby enhancing their movement across the skin. Electroosmosis, on the other hand, results from the convective solvent flow induced by the applied electric field, which facilitates the transport of neutral and positively charged molecules across the negatively charged skin barrier. Together, these mechanisms significantly improve drug flux and allow controlled, site-specific delivery, making iontophoresis a promising strategy for transdermal administration of a wide range of therapeutic agents.

Fig4. Approaches of TDDDS

Table 1. Classification of polymers used in transdermal drug delivery systems (TDDS) based on their origin