Unlocking the potential of transdermal drug delivery

ABSTRACT

Transdermal drug delivery (TDD) has gained clinical approval over several decades, with extensive research dedicated to novel drug and device development. Despite notable research progress, the market adoption of TDD devices has not met anticipated levels, with oral administration and injection remaining predominant delivery methods. To maximize the potential of TDD, we identify bottlenecks hindering its widespread clinical application and propose promising research avenues. We begin by analyzing stringent demands necessary to truly benefit patients, addressing significant challenges in biomechanics, nanomedicine, and flexible electronics. Subsequently, we delve into skin anatomy, enhancement strategies, nano-carriers, and their underlining mechanisms, highlighting the importance and framework of quantitative modeling. Based on these discussions, we highlight the core strength of TDD, such as automatic precise administration based on feedback and high delivery efficiencies, especially applicable to localized conditions (e.g., central nervous system diseases, tumors). Finally, we envision the future of intelligent TDD device and its operation scenario, aiming to steer research efforts toward faster translation of laboratory innovations into widely used products for sufferers.

GRAPHICAL ABSTRACT

KEYWORDS:

• Transdermal drug delivery
• biomechanics
• nanomedicine
• flexible electronics

For thousands of years, drug therapy has served as a fundamental pillar of medical treatment [1]. The predominant modalities for drug delivery today are oral administration and injection (Figure 1) [2–5]. However, oral administration often exhibits diminished bioavailability owing to the first-pass effect, while injection involves trauma and often requires professional operation; both posing challenges in sustaining a sustained and stable blood drug concentration [3,6]. In order to overcome the above limitations, transdermal drug delivery (TDD), which involves drug absorption through the skin, has emerged as a viable approach for localized or systemic therapeutic interventions [4]. Since the skin inherently acts as a barrier [7] against external agents and lacks the absorptive properties of the gastrointestinal tract, physical or chemical enhancement techniques are indispensable for facilitating drug permeation through this barrier [3,4,8]. Numerous investigations have been devoted to innovative physical or chemical enhancement strategies (e.g., sonophoresis [9–13], iontophoresis [14–18], microneedles [19–27], and electroporation [28–34]) and their synergistic combinations (e.g., iontophoresis & sonophoresis [35,36], and iontophoresis & microneedles [37,38]), as well as the application of various diseases (e.g., tumors [39–42], heart disease [43,44], hypertension [45,46], diabetes [21,47–51], and arthritis [52]).

Figure 1. Three strategies for drug delivery. Left: oral administration; from the mouth to the gastrointestinal tract, to the liver, and finally to the vascular system. Top right: injection administration including intramuscular (IM) injection, subcutaneous (SC) injection, intravenous (IV) injection, and intradermal (ID) injection; quickly reaching the vascular system. Bottom right: TDD; transporting locally for a period of time before reaching the vascular system.

Despite significant research achievements, the market adoption of TDD devices falls short of predicted levels. Up to now, oral administration and injection remain the dominant drug delivery methods [2,3]. The primary reasons for this discrepancy can be summarized as follows. On the one hand, for most drugs, the rate of drug delivery with existing commercial devices often fails to reach levels that ensure effective treatment without causing pain and tissue damage [3,4]. On the other hand, the existing commercial devices are often bulky and not portable [4,53]. These limitations highlight the considerable distance these devices have yet to cover to meet the stringent demands required for optimal patient care. An ideal TDD device should fulfill the following criteria. 1) Sufficient rate of drug delivery. The delivery rate should be adequate for effective treatment. 2) Low skin damage. Dermal cells should not undergo extensive apoptosis, with minor skin damage healing within a few days to avoid infection. 3) Pain-free. Painless treatment can improve the patient compliance. 4) Wearable capability. Devices wearability is crucial for improving patients’ quality of life and treatment efficacy. 5) Intelligent management capability. Intelligent management capability is essential for accurately controlling drug concentration according to physiological indexes and reducing the burden of patients. 6) Low cost. The above requirements should be implemented within an acceptable cost range. Addressing these scientific and technological challenges and meeting these requirements necessitates collaborative efforts from researchers in the fields of biomechanics, flexible electronics, and nanomedicine are essential. For example, transforming the skin from a barrier that blocks external substances into an efficient drug absorption pathway, without causing tissue damage, requires an in-depth understanding of the biomechanics of TDD [54]. This understanding becomes even more critical when considering the bio-chemo-physical coupling phenomena [55]. To avoid the toxicity of certain drugs to the skin and improve the drug delivery efficiency, nanomedicine technology, involving encapsulating nanoscale drug particles in a specially designed shell and releasing them upon reaching the target site [56–58], is frequently necessary. Wearable capability and intelligence require the integration and improvement of the existing flexible electronic technologies.

In this review, we aim to address the challenges associated with TDD and propose promising research routes. As a basis for understanding the process of TDD, we discuss the detailed anatomy of the skin and various types of pathways for drug absorption from the skin. We then delve into a discussion of different enhancement strategies, nano-carriers and elucidate the underlying mechanisms, based on which we further discuss the quantitative modeling of the process of TDD. The pharmacokinetic model is also discussed here to construct a complete theory from transdermal absorption to metabolism of the drugs. We highlight its efficacy in treating systemic diseases such as diabetes and hypertension, as well as its potential for addressing localized conditions like central nervous system disorders and tumors across different anatomical regions. Based on the above discussion, we point out the core competence of TDD, that is, high delivery efficiencies (especially for localized disease) and automatic precise administration based on feedback. We then discuss recent developments in wearable TDD devices and biosensors, which collectively contribute to the development of intelligent and wearable drug delivery systems. Finally, we predict the future intelligent TDD device and its working scenario, and summarize the achievements and trends into a technology roadmap. Ultimately, we hope to steer and to accelerate research efforts toward faster translation of laboratory innovations into widely used products.

Anatomy of the skin and pathways of drug absorption

To understand the mechanisms of drug absorption through the skin, we begin by delineating the intricate anatomy of the skin and the diverse pathways involved in drug uptake. The human skin, encompassing approximately 1.5 − 2.0 m², serves as the body’s largest organ and plays a crucial role in protecting the body from external environmental influences [59]. As shown in Figure 2, the outermost layer of human skin is the epidermis with a total thickness of approximately 50–100 µm [60]. The constituent cells of the epidermis include keratinocytes, melanocytes, Langerhans cells, and Merkel cells. Keratinocytes are the main constituent cells of the epidermis, accounting for over 80% of the total number of epidermal cells. According to the differentiation stage, keratinocytes can be divided into five layers, which are the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum (SC) from inside to outside.

Figure 2. Schematic illustration of the anatomy of the skin and pathways of drug absorption.

The SC serves as the major barrier against external substances [61]. It is composed of 15–30 layers of corneocyte cells with a total thickness of 10–20 µm. [62,63] The main components of the SC are keratin proteins derived from dead keratinocyte cells in the deeper layers [64] and lipids including ceramides (30–40%) [65,66], cholesterols, cholesterols esters, free fatty acids, squalene, wax esters and triglycerides [67]. The corneocyte cells are interconnected by corneodesmosomes, ensuring the structural integrity of the SC [68]. Beneath the SC, stratum lucidum is a clear and thin layer that consists of 2–3 layers of keratinocyte cells, primarily present in palms, soles and digits [69,70]. The subsequent layer is the stratum granulosum, where the cells have a thicker membrane compared to the first two layers. Below this layer is the stratum spinosum, consisting of 5–10 layers of keratinocytes [59], and hosting Langerhans cells, accounting for 3–5% of epidermal cells [71]. Langerhans cells, characterized by dendritic morphology, are an important type of immune cells with phagocytic function (engulfing bacteria, exogenous particles and damaged cells), capable of recognizing, processing, and presenting antigens [72]. The stratum basale directly contacts the dermis via interconnecting collagen fibers. In the stratum basale, the cells proliferate and become primary cells for keratinocytes that are present in the upper epidermal layers [73]. Epidermal turnover occurs about 28 days, with new cells from the stratum basale migrating upwards to replace cells in the stratum corneum, which are subsequently shed. Merkel cells are considered to be a type of neuroendocrine cell that forms a cellular axonal complex with sensory nerve fibers [74,75], enabling the perception of pain.

The dermis, located beneath the epidermis and intricately linked to the epidermal stratum basale via the basal membrane, plays a supporting role for the epidermis [4]. It is mainly composed of fibrous protein (collagen fibers, elastic fibers, and reticular fibers), matrix and cells. The dermis contains several types of functional cells, among which fibroblasts play a pivotal role in synthesizing collagen, elastic, and reticular fibers, thereby contributing significantly to the skin’s elasticity and tensile strength [59]. The matrix is an amorphous substance that fills the gaps between fiber bundles such as collagen fibers and elastic fibers, playing an important role in the connection, nutrition, and protection. It contains mucopolysaccharides such as hyaluronic acid that can bind with water to prevent water loss. There are two layers in the dermis, namely the papillary layer and the reticular layer [59]. The papillary layer is shallow and thin, hosting fine fibers, abundant capillaries, lymphatic vessels, nerve endings and tactile bodies. In contrast, the reticular layer is deep and thick, with interwoven dense fibers, and larger blood vessels, lymphatic vessels and nerves [76]. Due to the presence of phagocytes, fibroblasts, leucocytes, and mast cells, the dermis plays a crucial role in immune function [77]. In addition, there are numerous hair follicles, sebaceous glands, and sweat glands in the dermis for sweating and sebum secretion [78]. The layer below the dermis is the subcutaneous layer, which serves to connect the skin, muscles, and bones [79].

The possible pathways for drugs pass through the skin can be divided into transcellular route, intercellular route and appendageal route [80]. In the transcellular route, drugs navigate across membranes composed of lipid bilayers [81]. This route is mainly taken by hydrophobic drugs because of the hydrophobic properties of lipid complex in the cell membranes of the SC [29]. In the intercellular route, the drugs diffuse through the intercellular space of residing keratinocytes in the SC [82]. The intercellular route is the predominant pathway for drug absorption, particularly for hydrophilic compounds [83,84]. Several models have been developed to predict permeability of the stratum corneum to hydrophobic drugs [85–87]. For example, one equation formulated by Potts and Guy [87] correlates skin permeability (P) with solute molecular mass (M) and octanol – water partition coefficient (K_o/w):

(1) $log\mathit{P}\approx -2.7+0.71\times log{K}_{\mathit{o}/w}-0.0061\times \mathit{M}$(1)

The appendageal route refers to drug delivery through hair follicles or sweat ducts within the skin [80]. This route is particularly advantageous for transport of large macromolecules that are difficult to penetrate the epidermal cells [29]. Nevertheless, the effectiveness of this route is somewhat limited due to the smaller absorption area (~0.1% of skin area) [53]. Overall, the skin is originally a barrier that protects against external substances and does not have a good absorption effect like the gastric mucosa or intestinal mucosa. Therefore, the utilization of physical or chemical enhancement techniques becomes necessary to facilitate drug permeation through this barrier.

Enhancement strategies and underlying mechanisms

The physical or chemical enhancement strategies for TDD include chemical enhancers [88–94], iontophoresis [14–18], microneedles [19–27], sonophoresis [9–13,95], electroporation [28–34], laser radiation [96–103], etc., each with different underlying mechanisms. For example, chemical enhancers disrupt the structure of lipid bilayer of the stratum corneum by extracting lipids using solvents and surfactants to generate nanoscale lipid stacking defects [3]. Iontophoresis provides a motive force for drug molecule transport through sustained low electrical current (0.5 to 20 mA [104,105]), as shown in Figure 3a. Anionic drugs are placed beneath the cathode, while cationic drugs are placed beneath the anode. In the skin, anions move toward the anode, while cations move oppositely. Iontophoresis is mainly used for ionized drugs delivery, although it can also deliver weak charged or neutral molecules through electroosmosis [3]. The factors that affect efficiency include physicochemical characteristics of the drugs, current magnitude, duration, and physiology of the application site. The molecular weight of the drug is suggested to be less than 10,000 Da, [106] and the examples include nonsteroidal anti-inflammatory drugs (ibuprofen, aspirin, etc.) [107], granisetron [108], almotriptan [109], donepezil [110], sodium nonivamide acetate [111] and insulin [112]. Microneedle technology utilizes very short needles to penetrate the stratum corneum and deliver drugs into the skin in a minimally invasive manner (Figure 3b). Microneedles are typically made of biocompatible substances or biodegradable polymers [26]. The factors that affect efficiency include physicochemical characteristics of the drugs, size and density of microneedles. Microneedle technology can promote the delivery of both small and large molecules. It has been shown to be useful in the delivery of corona virus 2019 (Covid-19) vaccines [25,27,113,114], long-acting antiretroviral drugs for human immunodeficiency virus (HIV) (e.g., rilpivirine [115,116]) and contraceptives [23] (e.g., estradiol, levonorgestrel [117–119], ethynyl estradiol, and etonogestrel [24]).

Figure 3. Schematic illustrations of the underlying mechanisms of typical enhancement strategies. a) Iontophoresis; b) microneedle; c) sonophoresis; d) electroporation.

Sonophoresis, also known as phonophoresis, utilizes low-frequency (LFS, 20 − 100 kHz) or high-frequency (HFS, ≥0.7 MHz) ultrasound based on the cavitation effect (Figure 3c). For long-term use without damage to organs, the United States Food and Drug Administration (US FDA) recommends a maximum mechanical index (MI) of 1.9, which is calculated by dividing the peak pressure (MPa) measured in water by the square root of frequency (MHz).[120,121] The cavitation of LFS mainly occurs on the surface of the skin, and the expected mechanism is the oscillation and collapse of bubbles on the skin surface, resulting in local shock waves and liquid micro jets toward the stratum corneum, increasing skin permeability temporarily. HFS cavitation mainly occurs in skin, and bubbles are generated in the cavities among keratinocytes in the stratum corneum. Oscillating cavitation bubbles can cause disruption of the lipid bilayer in the stratum corneum, thereby increasing skin permeability [95]. The thermal effect may also play nonnegligible roles in some cases [9,10,95,122,123]. Factors affecting efficiency include the frequency, intensity, application time, coupling medium, and distance between the ultrasonic probe and the skin [124–126]. Sonophoresis can promote the delivery of hydrophobic and hydrophilic drugs, as well as for the delivery of small and large molecules, such as ketoprofen [126], vancomycin [127], fuocinolone acetonide [11], gemcitabine hydrochloride [128], and proteins (e.g., insulin, interferon γ, and erythropoietin) [129]. Ultrasound can not only generate microbubbles in situ, but also on-demand stimulate injected phase-changing nanodroplets loaded with drugs, transforming them into microbubbles and generating cavitation [130–139]. This cavitation can apply forces on cell connections in biological barrier membranes (such as the blood-brain barrier), triggering a transient and reversible increase in permeability. Electroporation creates aqueous pores in the lipid bilayer of the SC by applying high voltage (10–1000 V) for a brief duration (less than a few hundred milliseconds), enabling deeper drug penetration [33] (Figure 3d). Efficiency factors include the voltage magnitude, length of pulse, number of pulses and the physicochemical properties of the drug [33]. Electroporation can promote the delivery of both small and large molecules, such as alniditan [140], tetracaine [141], fentanyl [142], timolol [143], insulin [144], calcein [34], dextran and doxorubicin [145], yet high voltage poses a risk of cell damage [146,147]. Laser radiation can achieve controlled destruction and ablation of the SC with depth from tens to hundreds of micrometers, thereby accelerating drug delivery [96–100,102]. Efficiency factors include the laser type, intensity, length of pulse, number of pulses and the physicochemical properties of the drug [101,103]. Researchers have already demonstrated through animal experiments that laser radiation can facilitate the delivery of both small and large molecules, such as diclofenac, morphine, nalbuphine, buprenorphine, methotrexate, prednisone, and vaccines [96–103]. However, the laser equipment is typically expensive, limiting its potential applications [101]. The comparison of the advantages and disadvantages of the above typical enhancement strategies is shown in Table 1.

Although the utilization of aforementioned strategies can improve the rate of drug delivery, it is still challenging for numerous drugs to achieve an effective therapeutic dose. Simply increasing the intensity under a single strategy to increase drug delivery rate can lead to significant cellular stimulation, toxicity, and even cause serious skin damage. For example, traditional chemical enhancers and iontophoresis lack the precision to confine their effects to the stratum corneum, as high intensity can cause cytotoxicity and tissue damage. Sonophoresis and microneedles, while more adept at disrupting the stratum corneum for enhanced TDD without compromising deeper tissues, can still pose risks such as dermal damage at elevated intensities or larger pore sizes. To address these challenges, a judicious integration of multiple strategies in a coherent sequence without surpassing their safety thresholds can substantially boost drug delivery rates while upholding safety standards. In recent years, researchers in the field of biomedicine have conducted many experimental explorations in the combination of TDD strategies, confirming the advantages of multiple-strategy combinations over a single strategy [38], such as the combination of iontophoresis and sonophoresis, and the combination of iontophoresis and microneedles. Qualitative explanations for these combinations have also been proposed: iontophoresis can provide a motive force for drug molecule transport, while sonophoresis or microneedles can disrupt a part of the stratum corneum to improve the permeability, leading to a synergistic effect between these mechanisms.

Table 1. Comparison of advantages and disadvantages of typical enhancement strategies.

Strategies	Advantages	Disadvantages	References
Chemical enhancers	Low cost	Non-programmable Damaging deep tissue	[88–94]
Iontophoresis	Programmable control Easy circuit design	Only enabling small molecule Slow delivery rate	[14–18]
Microneedles	Low cost Enabling large molecular weight	Non-programmable Risk of bacterial infection	[19–27]
Sonophoresis	Programmable control Enabling large molecular weight	Complex circuit design Minor thermal irritation	[9–13,95]
Electroporation	Programmable control Enabling large molecular weight	Tingling Risk of damaging deep tissue	[28–34]
Laser radiation	Programmable control Enabling large molecular weight	High cost Non-wearable Skin irritation and dyspigmentation	[96–103]

Quantitative modeling of the process of TDD

The development of a quantitative theory to access the efficacy of various combinations of drug delivery strategies are of great guiding significance in advancing TDD technology. The key factors involved in the aforementioned strategies include stress fields, electric fields, chemical reactions, and biological feedback, operating molecular, cellular, and macroscopic organizational scales [55,148–154]. However, quantitative models for such multi-physical field coupling are still relatively limited. The existing theoretical models for TDD mainly include continuum mechanics models and equivalent circuit models. For example, Mitragotri et al. [54] proposed a continuum mechanics model for sonophoresis, in which the skin is simplified as a homogeneous block to calculate the strain and the damaged pore caused by ultrasound induced bubbles or micro-jets (Figure 4a). Chizmadzhev et al. [155] established an equivalent circuit model for electroporation, as depicted in Figure 4b. The resistance of bulk solution R_b is in series with the skin resistance, which includes two parallel branches: The resistance R_x refers to the main pathways of background electrolyte going through the appendages and stratum corneum; The resistance R_c corresponds to the inner part of each compartment and R_l to lipid bilayers, forming boundaries between the compartments. In addition, numerical simulations combining microneedles and iontophoresis often employ the Nernst-Planck equation from electrochemistry as a control equation [156,157]. While these models offer insights for single-strategy TDD, they fall short in guiding combinations of multiple strategies. Simple superposition is inadequate due to differing spatial scales and strong coupling effects among strategies.

Figure 4. Existing theoretical models for TDD. a) Theoretical model for sonophoresis [54]. Left: three possible modes through which inertial cavitation may enhance the permeability of stratum corneum. Right: a schematic illustration of a spherical shock wave propagating through the surface of stratum corneum. b) Theoretical model for electroporation [155]. Left: structure and transport model of stratum corneum where the corneocytes are shown by the shaded area and are surrounded by the lipid domain. The lipid and lipid-corneocyte routes of ion transport are denominated as t and s, respectively. The inset shows the multi-lamellar lipid domain after formation of electropores. Right: the equivalent electrical scheme of stratum corneum. U, U_s and U_l are the voltage drop on the corresponding resistances.

On the other hand, due to the large molecular weight, the transmembrane transport of nanomedicine especially including nano-carriers involves endocytosis and exocytosis, which needs to be considered and modeled on a smaller scale. This process is significantly different from the transport of ions and small molecules. Over the past few decades, the forms of nano-carriers have evolved from liposomes [158,159] to polymer nanoparticles [160–167] and metal nanoparticles [168–171], then to lipid nanoparticles [172–174], nanostructured lipid carriers [175–180] and phase-changing nanodroplets [130–139], and recently to metal-organic frameworks [181–183] and biomimetic nanocarriers [184] (extracellular vesicles inspired [185–187], viruses inspired [188], bacteria inspired [189,190], etc.), as shown in Figure 5a. The size, shape, stiffness, surface chemical properties, and biological functions of the nano-carriers can all affect the performance of transmembrane transport. There are many models describing the transmembrane transport of nanomedicine. For example, Deserno proposed a model for the elastic deformation of a fluid membrane upon colloid binding, and found a line of continuous binding transitions and a second line of discontinuous envelopment transitions, which meet at an unusual triple point (Figure 5b) [191]. Gao et al. established a model for receptor-mediated endocytosis, showing that the particles in the size range of tens to hundreds of nanometers can enter or exit cells via wrapping even in the absence of clathrin or caveolin coats, and an optimal particles size exists for the smallest wrapping time, which broadly agrees with experimental observations [192]. Afterward, Yi et al. investigated the adhesive wrapping of a soft elastic vesicle by a lipid membrane, showing that there exist a maximum of five distinct wrapping phases, which depend on the vesicle size, adhesion energy, surface tension of the membrane, and bending rigidity ratio between vesicle and membrane [193]. Wang et al. presented a theoretical analysis regarding the cooperative entry of nanoparticles into cells, demonstrating that oblate ellipsoidal nanoparticles exhibit greater energy compensation during cooperative entry compared to individual nanoparticles or spherical nanoparticles (Figure 5c) [194]. Yi et al. further investigated the incorporation of soft particles into lipid vesicles, considering the global deformation of the vesicles (Figure 5d) [195]. However, the above models rarely consider the important role of the biological functions of nanomedicine and cells in endocytosis and exocytosis, and cannot explain the advantages of the biomimetic carriers found in the experiments.

Figure 5. Structures and mechanical models of nano-carriers. a) Schematic diagram of the structures of various nano-carriers: from the traditional to the most advanced. b) the model for elastic deformation of a fluid membrane upon colloid binding [191]. c) the model for cooperative entry of nanoparticles into the cell [194]. d) the model for incorporation of soft particles into lipid vesicles [195].

Now we consider the bio-chemo-physical coupling phenomena in TDD (Figure 6), which could inspire a new theoretical framework for quantitative TDD. Chemical factors include concentrations, molecular weights, ionizability and hydrophilicity of the delivered drugs, types, and concentrations of other ions, pH value, hydrophilicity and other chemical properties of the nano-carriers (liposomes, polymers, vesicles, etc.), and concentrations of nutrients (blood glucose, blood oxygen, etc.). Physical factors include stress field, temperature field, and potential field inside the skin, ultrasound field inside and outside the skin, mechanical and electrical properties of the skin, stiffnesses, sizes, and shapes of the nano-carriers, and geometric constraints provided by the devices. Biological functions include effects of enzymes, endocytosis and exocytosis, differentiation, proliferation and apoptosis of cells, and nerve action. The mutual coupling relationships between them are mainly reflected in the following aspects. (1) Absorption and metabolism of drugs are affected by chemical factors (drugs, enhancers, nano-carriers, skin tissue); Drugs/nano-carriers can cause cytotoxicity and pain perception; The rate of wound healing is influenced by nutrition. (2) Absorption and metabolism of drugs are affected by environmental physical factors (stress, temperature, etc.) and physical factors of drugs/nano-carriers (stiffness, size, shape, etc.); Physical factors (excessive stress, temperature, etc.) can cause damages of tissues; Physical factors (excessive stress, temperature, etc.) can also cause pain sense. (3) The mass transport and charge movement of drug molecules are coupled, involving electrochemical reactions, convection, and diffusion. For specific application situations, some of the above coupling relationships can be reasonably selected for theoretical modeling. Detailed process of the theoretical modeling can refer to some models that have been developed to describe bio-chemo-mechanical processes at the molecular, cellular, and tissular levels [55,148–154]. According to different mathematical methods, they can be roughly divided into three categories: continuum mechanics models, discrete models, and multi-scale models [55]. The continuum field equations maintain unity in mathematical description and convenience in numerical solution [149,196]. For discrete models, some detailed physical mechanisms at the cellular and subcellular scales can be considered [148,197]. Multi-scale models facilitate the understanding of how macroscopic mechanical properties and biological functions depend on complex physical mechanisms at different length and time scales [198,199]. By combining hierarchical structures with various models, multi-scale models can share the advantages of different modeling methods and reflect the synergistic effects of different levels of size.

Figure 6. Bio-chemo-physical coupling phenomena in TDD.

Pharmacokinetic models

To construct a comprehensive theory from transdermal absorption to metabolism of the drugs, it’s essential to incorporate the pharmacokinetic models. These models aim to study the changes in the amount of substances with time during the absorption, distribution, metabolism, and excretion of drugs through various pathways [200]. To facilitate research and application, complex physiological systems are commonly simplified, and the established pharmacokinetic models include compartment models [201,202], noncompartment models based on statistical moment principle [203–205], physiologically based pharmacokinetic models [206,207], etc. Among them, the compartment models are the most classic pharmacokinetic models, which were first proposed by Widmark and Tandberg [208] on the basis of the kinetic study of Michaelis and Menten [209], and developed by Teorell et al. [201,202] The compartment model treats the body as a system, dividing it into several compartments according to the drug transport rate characteristics, and assuming that the drugs entering the compartments can be evenly distributed throughout the compartments in an instant [210]. The mathematical modeling process of single-compartment models and two-compartment models for intravenous administration and extravascular administration is discussed below.

If the drugs are rapidly distributed in the body after intravenous administration, the single-compartment model can be used to describe this process, as shown in Figure 6a. The elimination of drugs is assumed to obey first-order rate kinetics, that is, the elimination rate is proportional to the amount of drugs in the body at this time. Then, the differential equation about the amount of drugs can be established as

(2) $-\frac{\mathrm{d}X}{\mathrm{d}t}=K_{\mathrm{e}}\mathit{X},$(2)

where $\mathit{X}$ is the amount of drugs in the body at time $\mathit{t}$, and $K_{\mathrm{e}}$ is the first-order elimination rate constant. Compared with intravascular administration, there is an additional absorption process for extravascular administration, such as oral administration (Figure 7a) and TDD (Figure 7b). When the drugs deliver through the skin, the absorption site (the local skin) can be considered as a ‘compartment.’ The processes of absorption and elimination for extravascular administration also typically obey first-order rate kinetics. Based on this, the differential equations for the amount of drugs at the absorption site and the amount of drugs in the body can be established respectively:

Figure 7. Existing pharmacokinetic models (the compartment models). a) one-compartment model for oral and injection. b) two-compartment model for oral and injection. c) two-compartment model for TDD. d) three-compartment model for TDD.

(3) $\left\{\begin{array}{c}-\frac{\mathrm{d}{\mathit{X}}_{\mathrm{a}}}{\mathrm{d}\mathit{t}}=K_{\mathrm{a}}{X}_{\mathrm{a}},\\ \frac{\mathrm{d}X}{\mathrm{d}t}=K_{\mathrm{a}}{X}_{\mathrm{a}}-K_{\mathrm{e}}\mathit{X},\end{array}\right.$(3)

where $X_{\mathrm{a}}$ is the amount of drugs in absorption site at time $\mathit{t}$, and $K_{\mathrm{a}}$ is the first-order absorption rate constant.

Upon absorption, many drugs are rapidly distributed across various tissues, organs, and body fluids. Approximately, these components together with the blood system form a compartment, constitute what is known as the central compartment. Conversely, areas where drug distribution occurs at a slower pace are referred to as peripheral compartments. Thus, a two-compartment model can be formed, as shown in Figure 7c. When administered intravenously, there is no absorption process. The drugs first enter the system through the central compartment. While being eliminated in the central compartment, the drugs undergo reversible transport between the central compartment and the peripheral compartment. Generally, the processes of elimination and transport obey first-order rate kinetics, based on which the differential equations for the amount of drugs in each compartment are established as:

(4) $\left\{\begin{array}{c}\frac{\mathrm{d}{\mathit{X}}_{\mathrm{C}}}{\mathrm{d}\mathit{t}}=K_{\mathrm{PC}}{X}_{\mathrm{P}}-K_{\mathrm{CP}}{X}_{\mathrm{C}}-K_{\mathrm{e}}{X}_{\mathrm{C}},\\ \\ \frac{\mathrm{d}{\mathit{X}}_{\mathrm{P}}}{\mathrm{d}\mathit{t}}=K_{\mathrm{CP}}{X}_{\mathrm{C}}-K_{\mathrm{PC}}{X}_{\mathrm{P}},\end{array}\right.$(4)

where $X_{\mathrm{C}}$ is the amount of drugs in the central compartment at time $\mathit{t}$; $X_{\mathrm{P}}$ is the amount of drugs in the peripheral compartment at time $\mathit{t}$; $K_{\mathrm{PC}}$ is the first-order rate constant for transport from the peripheral compartment to the central compartment; $K_{\mathrm{CP}}$ is the first-order rate constant for transport from the central compartment to the peripheral compartment; $K_{\mathrm{e}}$ is the first-order rate constant for drug elimination from the central compartment. When the drugs deliver through the skin, there is an additional absorption process (Figure 7d). Assuming the absorption and the elimination of the drugs obey first-order rate kinetics, the amount of drugs in each compartment satisfies the following relationship.

(5) $\left\{\begin{array}{c}\begin{array}{c}\frac{\mathrm{d}{\mathit{X}}_{\mathrm{a}}}{\mathrm{d}\mathit{t}}=-K_{\mathrm{a}}{X}_{\mathrm{a}},\\ \frac{\mathrm{d}{\mathit{X}}_{\mathrm{C}}}{\mathrm{d}\mathit{t}}=K_{\mathrm{a}}{X}_{\mathrm{a}}-\left(K_{\mathrm{CP}}+K_{\mathrm{e}}\right)X_{\mathrm{C}}+K_{\mathrm{PC}}{X}_{\mathrm{P}},\end{array}\\ \frac{\mathrm{d}{\mathit{X}}_{\mathrm{P}}}{\mathrm{d}\mathit{t}}=K_{\mathrm{CP}}{X}_{\mathrm{C}}-K_{\mathrm{PC}}{X}_{\mathrm{P}},\end{array}\right.$(5)

The aforementioned models can be employed to calculate pharmacokinetic parameters such as rate constant, biological half-life, apparent volume of distribution, clearance rate, area under the curve, etc. These parameters are valuable for guiding the development of new drugs and facilitating rational clinical drug use.

By combining the above pharmacokinetic models with the TDD models mentioned in the previous section, we can assess the delivery efficiency across various drug delivery methods. Figure 8a illustrates the transport pathways of drug transport within the body. For the oral administration, drugs are delivered from the mouth to the gastrointestinal tract, then to the liver, and eventually to the vascular system. For the intravenous injection, drugs quickly reach the vascular system. For the TDD, drugs are transported locally for a period of time before reaching the vascular system. Correspondingly, drug concentration distribution in the body can be calculated after some simplification. Here, we present a schematic diagram only for qualitative explanation (Figure 8b). Due to the first-pass effect, the drug concentration under oral administration is usually lower than that under intravenous injection. In fact, the drug efficiency under intravenous injection is still not high enough for local diseases. A recent work reveals that the typical delivery efficiency of anti-tumor drugs through intravenous injection is only about one out of one million (Figure 8c) [211]. After the drugs are administered intravenously, they have to transport through the bloodstream to reach the final target site. Many of the drugs are taken up by the liver, spleen, and other reticuloendothelial organs. After entering the solid tumor, they have to cross the blood vessel, extracellular matrix, and other non-tumor cells before reaching the tumor cells. Then the drugs have to cross the cell membrane, vesicles, and other subcellular structures before reaching the target in the nucleus. However, for the TDD, the drug concentration in the body near the patch is much higher than that in other locations, and the drug concentration in other locations could be close to that of intravenous injection conditions. This distinguishing feature makes TDD more efficient in treating superficial local diseases compared to intravenous injection, and far more effective than oral administration.

Figure 8. Delivery efficiency under different methods of drug delivery. a) Illustration of the drug transport pathways in the body under different methods of drug delivery. b) Schematic diagram of the distribution of drug concentration under different methods of drug delivery. c) Typical delivery efficiency (about one out of one million) of anti-tumor drugs through intravenous injection [211].

Application of TDD in diseases of different body parts

After years of development, TDD technology has been applied to treat various diseases of different body parts. These diseases generally fall into two categories: systemic diseases and localized diseases, as shown in Figure 9a,b and Table 2. Systemic diseases treated by TDD mainly include heart disease, hypertension, diabetes, etc. Nitroglycerin patches were approved by the US FDA for the treatment of angina in 1981 [4]. Clonidine patches were approved by the US FDA for the treatment of hypertension in 1990 [4]. These nitroglycerin and clonidine patches exhibit fewer adverse effects than conventional oral dosage forms. Insulin patches have been widely studied for the treatment of diabetes since 1991 [49], and there are still a lot of new progress in recent years.[21,47,48,50,51,212,213] TDD also has great potential in providing long-acting contraceptives, such as the sustained release of levonorgestrel (one month to one year).[23,117,119,214] The main advantage of TDD for systemic diseases is to achieve programmable and precise administration based on disease feedback or in a fixed manner. Localized diseases treated by TDD mainly include central nervous system diseases (e.g., Parkinson’s disease [215], Alzheimer’s disease [216,217], depression [218,219]), glioblastoma [220], breast cancer [221], superficial tumors (e.g., melanoma [219,220], papilloma [222,223], T-cell lymphoma [224]), dermatosis [225], arthritis [52], etc. Transdermal delivery offers not only programmable and precise administration but also achieves high delivery efficiencies, making it a promising therapeutic approach.

Figure 9. The application of TDD in diseases of different body parts. a) Systemic diseases. b) Localized diseases.

Table 2. Application of TDD in systemic diseases and localized diseases.

Categories	Diseases	Drugs	Delivery efficiencies	References
Systemic diseases	Heart disease	Nitroglycerin	Lower than injection; Higher than oral administration	[4]
	Hypertension	Clonidine	Lower than injection; Higher than oral administration	[4]
	Diabetes	Insulin	Lower than injection; Higher than oral administration	[21,47–51,212,213]
Localized diseases	Alzheimer’s disease	Donepezil hydrochloride	2.4-fold higher than oral administration	[216,217]
	Depression	Esketamine, duloxetine	Higher than oral administration	[218,219]
	Parkinson’s disease	Silagilan	18-fold higher than intravenous injection	[215]
	Glioblastoma	Model nanoparticles	Higher than intravenous injection	[220]
	Breast cancer	Doxorubicin hydrochloride and docetaxel	Higher than oral administration	[221]
	Melanoma	Doxorubicin and celecoxib, or doxorubicin and trametinib	Higher than oral administration	[227,228]
	Papilloma	Temozolomide, ketorolac	Higher than oral administration	[222,223]
	T-cell lymphoma	Vorinostat	Higher than oral administration	[224]
	Dermatosis	Baicalein	Higher than injection; Higher than oral administration	[225]
	Arthritis	Diclofenac sodium and teriflunomide, brucine, triptolide, hydroxytyrosol, etc.	Higher than oral administration	[52]

Here we focus on discussing central nervous system diseases and superficial tumors. The delivery efficiency of drugs for central nervous system diseases is typically low, both orally and intravenously, due to the presence of the blood-brain barrier and blood-tumor barrier [226]. Kim et al. [216] prepared microneedles containing donepezil hydrochloride using a micro-molding method based on a hydroxypropyl methylcellulose-ethanol/water mixture and a carboxymethyl cellulose water solution, and administered them through the back skin of mice. Pharmacokinetic studies have shown that, at a dosage of 692 μg·kg⁻¹, the bioavailability of microneedles is 2.4 times that of oral administration, and the peak concentration (C_max) of the same dose of microneedle administration is 4 times that of oral administration. Similarly, Zhao et al. [217] prepared microneedles based on methacryl gelatin for the delivery of donepezil hydrochloride. After the microneedles puncture into the subcutaneous area, the polyvinyl alcohol in the backing layer dissolves and wraps around the needle body to achieve controlled drug release. Courtenay et al. [218] constructed hydrogel microneedles for transdermal delivery of esketamine. Experimental results have shown that microneedles can continuously release esketamine for more than 24 hours in rats, and the blood drug concentration within 24 hours is higher than 0.15–0.3 μg·mL⁻¹. In addition, Kumar et al. [219] prepared a transdermal patch composed of duloxetine and sulfobutyl ether-β-cyclodextrin. After transdermal delivery of the patch to rats, autonomous activity was measured using a digital photoelectric velocimeter, showing a notable antidepressant effect. Bali et al. [215] developed a kind of polymer nanoparticles loaded with Silagilan (SGN-PNP) for the transdermal treatment of Parkinson’s disease. The brain drug concentration of the SGN-PNP after intravenous injection reaches 7.7 times that of only the SGN, confirming the targeting ability of the SGN-PNP; Meanwhile, compared to intravenous injection of the SGN-PNP, transdermal delivery of the SGN-PNP prolongs the time to peak (T_max) of brain drug from 0.5 h to 36 h, and increases the concentration of brain drug from 1401.3 ng·h·mL⁻¹ to 25,451.6 ng·h·mL⁻¹, demonstrating excellent ability of sustained-release drug delivery. A recent study [220] found that the meningeal lymphatic vessels can connect to the deep cervical lymph nodes, so the drugs can directly flow into the meningeal lymphatic vessels through the deep cervical lymph nodes, which can be used for the treatment of brain diseases.

For tumor treatment, the efficiency of oral and intravenous delivery is also very low due to the absorption of drugs by other organs in the body, while the combination of transdermal delivery and nanomedicine holds promise for improving delivery efficiency and reducing toxic side effects. There are three main types of drug therapy for tumors: chemotherapy, gene therapy, and immunotherapy. Chemotherapy drugs widely used in clinical superficial tumors include doxorubicin, cisplatin, paclitaxel, etc. Ahmed et al. [227] used liposomes loaded with doxorubicin and celecoxib for transdermal melanoma treatment, demonstrating significant anti-tumor effects. Bhatnagar et al. [221] delivered doxorubicin hydrochloride and docetaxel, resulting in a notable improvement in survival rates compared to intratumoral chemotherapy drugs. Lan et al. [39] delivered cisplatin encapsulated with lipid nanoparticles, leading to significantly increased tumor cell apoptosis without serum platinum or organ toxicity in vivo. Huang et al. [228] achieved sustained release of doxorubicin and trametinib, overcoming P-glycoprotein-mediated multidrug resistance and reducing systemic toxic side effects.

Abnormal gene expression influences the occurrence and progression of tumors. Gene-based therapies primarily involve delivering nucleic acids into the body, such as plasmid DNA (pDNA), small interfering RNA (siRNA), and oligonucleotides. These nucleic acids are usually encapsulated in polymers, liposomes, nanoparticles, or cell penetrating peptides for transdermal delivery. Li et al. [40] developed pH-responsive polycaprolactone microneedles loaded with the p53 expression plasmid (p53 DNA), which demonstrated an efficiency of 90.1% in inhibiting subcutaneous tumors. Ruan et al. [229] delivered a nanocomposite consisting of cell-penetrating peptide (octaarginine) and B-Raf proto-oncogene serine/threonine protein kinase siRNA for the treatment of melanoma, inducing tumor cell apoptosis and inhibiting tumor cell proliferation. The combination of transdermal delivery and gene therapy exhibits significant tissue permeability and minimal side effects, along with advantages in enhancing gene stability and promoting gene expression [230–232].

Immunotherapy, which stimulates the innate immune system of the body to recognize and eliminate tumors, possesses the characteristics of high specificity, high efficacy, and long-lasting effects. As a result, it has emerged as a first-line treatment for melanoma and lung cancer [233]. The primary approach involves delivering antigen vaccines, immune checkpoint inhibitors, genetic vaccines, antibodies, cytokines, etc [41,234]. The skin, being a robust immune organ, harbors a substantial population of dermal dendritic cells and Langerhans cells, which contribute significantly to immune defense mechanisms. When the microenvironment is disturbed, these dendritic cells become activated, initiating a series of immune reactions and activating the immune system. However, the stratum corneum greatly hinders the transdermal delivery of macromolecules such as antigens and antibodies. Therefore, immunotherapy based on the technology of TDD has shown great advantages [235]. Chen et al. [236] developed chitosan microneedles for continuous delivery of the model antigen ovalbumin. After delivering low-dose ovalbumin through microneedles, antibody levels can persist for 18 weeks, which is 2.5 times higher than the full dose of ovalbumin injected into muscles. Additionally, Ye et al. [42] developed a B16-F10 melanoma vaccine patch, which transdermally delivers tumor lysates bound to melanin, directly targeting antigen-presenting cells, and releasing the drug under near-infrared light irradiation, thereby promoting antigen uptake. The release of local cytokines greatly improves the survival rate of mice and has a significant inhibitory effect on both in situ and distal tumors. However, the translation of skin tumor immunotherapy from animals to clinical application still faces significant hurdles, such as limited vaccines immunogenicity, insufficient skin dendritic cell antigenicity, immune suppression, immune evasion, etc. A comprehensive understanding of skin immune physiology and tumor immune mechanisms is imperative. Designing efficient and safe TDD is essential to realize the clinical potential of these therapies.

Wearable TDD devices and biosensors

Wearable TDD devices and biosensors together are fundamental to the wearability and intelligence of the systems, a domain that has experienced rapid development in recent years. Up to now, enhancement strategies for wearable TDD devices have included sonophoresis [237,238], iontophoresis [38,157], microneedles [23–25,27,113–119], and electroporation [237], as shown in Table 3. For instance, Li et al. [238] presented a stretchable electronic facial mask (SEFM) for sonophoresis (Figure 10a). This work addresses the technical challenges associated with sonophoresis on large and complex human facial surfaces by introducing a single-side structure for piezoelectric components, ensuring low bending stiffness and high bendability to conform comfortably to the human face. Additionally, they introduced the single-side soft pressing (SSSP) technique for encapsulation. The animal experiments and human facial experiments have demonstrated the enormous potential of the developed SEFM in facial healthcare applications. Afterward, Yu et al. developed a conformable ultrasound patch (cUSP) utilizing intermediate-frequency sonophoresis (IFS) for effective cavitation-enhanced transdermal delivery of cosmeceuticals (Figure 10b) [239]. This study demonstrated the cUSP’s suitability for short-exposure, targeted transdermal delivery for patients and consumers suffering from skin conditions. Iontophoresis and microneedles are frequently combined to enhance delivery efficiency in the wearable TDD devices. The primary structural difference lies in the design of microneedles, such as solid polymer-based ion-conductive porous microneedles (Figure 10c) [38] and animal masticatory system bio-inspired microneedles (Figure 10d) [157]. More recently, the electroporation mechanism has also been applied to stretchable electronic facial mask to achieve cost-effective TDD (Figure 10e) [237].

Table 3. Representative wearable TDD devices.

Strategies	Parameters	Drugs	Enhancement	References
Microneedles	Needle diameter: tens to hundreds of micrometers; Needle length: hundreds of micrometers	Covid-19 vaccines, long-acting antiretroviral drugs for HIV, contraceptives, etc.	Several orders of magnitude	[23–25,27,113–119]
Iontophoresis & microneedles	Needle diameter: tens to hundreds of micrometers; Needle length: hundreds of micrometers Voltage: not exceeding 5 V	Dextran, insulin	Superior to microneedles alone	[38,157]
Sonophoresis	Frequency: 220–1000 kHz; Power: not exceeding 6 W	Hyaluronic acid, niacinamide, etc.	Up to 26 times	[238,239]
Electroporation	Pulse amplitude: 100 V; Pulse width: 200 μs; Interval: 60 ms	Niacinamide	3–4 times	[237]

Figure 10. Representative applications of wearable TDD devices and biosensors. a) a stretchable electronic facial mask for sonophoresis [238]. b) a conformable ultrasound patch for cavitation-enhanced transdermal cosmeceutical delivery [239]. c) Solid polymer-based ion-conductive porous microneedles for improving iontophoresis [38]. d) a biomimetic microneedle theranostic platform for intelligent and precise management of diabetes [157]. e) a stretchable electronic facial mask for skin electroporation [237]. f) Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis [245]. Top: photograph of the wearable device on a subject’s wrist, integrating the sensor array and the wireless flexible printed circuit board (FPCB). Bottom: schematic of the sensor array (including glucose, lactate, potassium, sodium and temperature sensors). g) Wearable ultrasound systems. Top: a fully integrated wearable ultrasound system to monitor deep tissues in moving subjects [242]. Bottom: a wearable cardiac ultrasound imager [241]. h) Skin-interfaced biosensors for wireless physiological monitoring in neonatal and pediatric intensive-care units [244]. Top: placement of a soft, wireless limb unit on a neonate at the ankle-to-base of the foot. Bottom: exploded-view illustration of the limb unit. IC: integrated circuit; Li-po: lithium polymer battery; LMS: low-modulus silicone; PCB: printed circuit board.

Physiological data of the body is crucial for precise medical treatment. Up to now, various wearable biosensors including wearable ultrasound systems [240–243], multifunctional intensive-care biosensors [244], multi-channel sweat-analysis sensors [245], strain sensors [246–250], pressure sensors [251,252], temperature sensors [253,254], pulse sensors [254,255], blood oxygen sensors [256,257], etc. have been developed, as shown in Table 4. For instance, Gao et al. [245] proposed fully integrated wearable sensor arrays for multi-channel in situ sweat analysis, providing monitoring of glucose, lactate, potassium, sodium and temperature (Figure 10f). Wearable ultrasound systems are quite helpful for measuring physiological data of deep tissues [240–243] (Figure 10g). On the basis of their previous work on a wearable cardiac ultrasound imager [241], Xu et al. developed a fully integrated autonomous wearable ultrasound system [242], which can monitor physiological signals (central blood pressure, heart rate, cardiac output, tidal volume, etc.) of deep tissues in real time during exercise, demonstrating huge application prospects. Rogers et al. [244] developed noninvasive skin-interfaced biosensors for wireless physiological monitoring in neonatal and pediatric intensive-care units (Figure 10h). These sensors not only match existing clinical standards for heart rate, respiration rate, blood oxygenation and temperature, but also provides additional important features, such as tracking movements and body orientation, capturing acoustic signatures of cardiac activity, and recording tonality characteristics of crying, which demonstrates their potential to greatly enhance the quality of neonatal and pediatric critical care. Pulse sensors are usually composed of highly sensitive strain sensors [246–250] or pressure sensors [251,252,254,255]. Bao et al. [255] developed a bioinspired microhairy pressure sensor, enabling ultraconformability on nonflat surfaces and significant enhancement in the signal-to-noise ratio. The sensor can measure weak pulsations of internal jugular venous pulses stemming from a human neck, which is beneficial for rapid diagnosis of cardiovascular and cardiac diseases.

Table 4. Representative wearable biosensors.

Categories	Physiological data	Mechanical performance	References
Wearable ultrasound systems	Central blood pressure, heart rate, cardiac output, tidal volume, etc.	Stretchable and bendable	[240–243]
Multifunctional intensive-care biosensors	Heart rate, respiration rate, blood oxygenation, temperature, movements, acoustic signatures, etc.	Stretchable and bendable	[244]
Multi-channel sweat-analysis sensors	Glucose, lactate, potassium, sodium and temperature	Bendable	[245]
Strain sensors	Pulse	Stretchable and bendable	[246–250]
Pressure sensors	Pulse	Stretchable and bendable	[251,252,254,255]
Temperature sensors	Temperature	Stretchable and bendable	[253,254]
Blood oxygen sensors	Blood oxygen	Bendable	[256,257]

Future intelligent TDD device

As illustrated in Figure 11, the future intelligent TDD device should consist of wearable transdermal patches, wearable biosensors, an integrated micro-circuit for local computing and storage, and a wireless communication micro-module. Firstly, the biosensors monitor the necessary physiological signals, after which the local micro-circuit computes an appropriate dosage or wirelessly transmits this data to a smartphone for calculation. Subsequently, the drug release from the transdermal patch is regulated through the calculation results. Doctors can oversee and intervene in the treatment process using the cloud application. This approach enables precise spatiotemporal control and feedback regulation of drug delivery, which is crucial for precision medicine. Such a drug delivery system is versatile, being applicable not only to systemic diseases like diabetes and hypertension for automatic precise administration based on feedback, but also to localized diseases such as central nervous system diseases (Parkinson’s disease, Alzheimer’s disease, etc.), superficial tumors (melanoma, papilloma, etc.), glioblastoma, breast cancer and dermatosis, ensuring automatic precise administration and high delivery efficiencies. We also illustrated several typical application scenarios of TDD, depicted in the bottom right corner of Figure 11. It is suitable for continuous treatment during daily work without interruption and allows for automatic continuous treatment without the need for personnel on duty at night. Furthermore, it is appropriate for emergency treatment during the onset of cardiovascular and cerebrovascular diseases, particularly as patients may lose consciousness. At such critical moments, the drug delivery rate can be increased while disregarding potential skin damage. Additionally, it is well-suited for self-support treatment for astronauts, given the limited availability of space medical resources.

Figure 11. A vision of an intelligent wearable TDD device and its operation scenario.

To achieve the above goals, it is necessary to overcome the three major challenges of science and technology, mainly involving biomechanics, nanomedicine, and flexible electronics. We summarize the achievements and trends of development into a technology roadmap to guide development strategies, as depicted in Figure 12. In terms of biomechanics, theoretical models and numerical simulations have evolved from early circuit equivalence related to iontophoresis and electroporation to continuum mechanics models and electrochemical models. At the current stage, multi-physics coupling models are urgently needed to guide the processes of drug delivery. In the future, it will be necessary to establish multi-scale models to thoroughly understand these processes and achieve more efficient drug delivery. For the development of devices, the enhanced delivery strategy has gradually evolved from chemical enhancement to iontophoresis, sonophoresis, and microneedles, and more recently to combination strategy. The form of commercial devices has gradually evolved from bulky boxes and probes in the early days to integrated and portable circuit boards. Flexible patches, even soft patches, have been developed in the laboratory, and they will continue to evolve into intelligent patches in the future. The upper rate limit of drug delivery for typical drugs (medium molecular weight) has developed from 0.01 mg·cm⁻²·day⁻¹ to 10 mg·cm⁻²·day⁻¹, and in the future, it needs to reach hundreds of mg·cm⁻²·day⁻¹. Finally, we summarize the technological progress and prospects in nanomedicine. Initially, only small lipophilic molecules comprised the drug category. Subsequently, small hydrophilic molecules were added to the range, followed by polypeptides and proteins, and most recently, mRNA and DNA. Transdermal delivery of mRNA and DNA is still in its early stages. Correspondingly, the molecular weight has increased from the order of 10² Da to the order of 10⁷ Da. The design of nanocarriers is crucial for improving delivery efficiency, which has evolved from liposomes to polymer nanoparticles, nanoemulsions, lipid nanoparticles, and nanostructured lipid carriers, and most recently to biomimetic nanocarriers [184] (extracellular vesicles inspired [185–187], viruses inspired [188], bacteria inspired [189,190], etc.). We hope that collaborative efforts among researchers in biomechanics, nanomedicine, and flexible electronics will drive forward relevant research and pave the way for widespread clinical applications of TDD in the near future.

Figure 12. A technology roadmap for the achievements and trends of the development of TDD.

Conclusion and perspective

In summary, TDD has gained clinical approval over several decades, with extensive research dedicated to novel drug and device development. The developed enhancement strategies include sonophoresis, iontophoresis, microneedles, and electroporation, and their synergistic combinations (e.g., iontophoresis & sonophoresis, and iontophoresis & microneedles). The diseases treated by TDD mainly include heart disease, hypertension, diabetes, central nervous system diseases (e.g., Parkinson’s disease, Alzheimer’s disease, depression), glioblastoma, breast cancer, superficial tumors (e.g., melanoma, papilloma, T-cell lymphoma), dermatosis, arthritis, etc. Despite notable research progress, the market adoption of TDD devices has not met anticipated levels, with oral administration and injection remaining predominant delivery methods. The bottlenecks hindering its widespread clinical application mainly lies in two aspects: 1) Current technology has not yet resolved the contradiction between drug delivery rate and tissue damage; 2) Most existing demonstration scenarios cannot fully leverage its pivotal strengths: feedback-based automatic precise administration and high delivery efficiency (especially applicable to localized diseases).

Based on these bottlenecks, we identify three major challenges in science and technology, primarily involving biomechanics, nanomedicine, and flexible electronics, and propose specific research routes to address these challenges. The most lacking and crucial aspect currently is the bio-chemo-mechanical coupling modeling and related experiments, aiming to find methods to improve drug delivery rate without damaging deep tissues and ensuring rapid recovery of skin damage. Researchers in the field of flexible electronics can develop advanced wearable TDD devices with combinations of enhancement strategies based on these methods. Another primary goal for researchers in the field of flexible electronics is to identify the most suitable application scenarios, especially prioritizing localized diseases. Focus on these application scenarios, specific technical requirements need to be refined to reverse-engineer device structures, circuits, and low-cost fabrication processes. Unfortunately, much of the current research is merely demonstrations aimed at showcasing delivery enhancement effects. For researchers in the field of nanomedicine, there is a need to develop more nanomedicines suitable for TDD, considering the differences between crossing the barrier of the skin and the barrier to target tissues from blood vessels. We anticipate that collaborative efforts among researchers in biomechanics, nanomedicine, and flexible electronics will propel relevant research and ultimately lead to widespread clinical applications of TDD in the near future.

Author contributions

S.L. and X.F. conceived the topic and proposed the structure of this review. S.L. carried out the data curation, produced the figures, and wrote the manuscript in consultation with X.F. J.W. provided outstanding technical support for the production of the figures. X.P. participated in the discussion. X.F. supervised the project.

Acknowledgments

X.F. gratefully acknowledges the support from the National Natural Science Foundation of China (Grants Nos. 12032014 and 11921002). S.L. thanks Youfu Cui for sharing his interesting experience on medication.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The work was supported by the National Natural Science Foundation of China [12032014,11921002].