Advancements in Skin‐Mediated Drug Delivery: Mechanisms, Techniques, and Applications

Abstract

Skin‐mediated drug delivery methods currently are receiving significant attention as a promising approach for the enhanced delivery of drugs through the skin. Skin‐mediated drug delivery offers the potential to overcome the limitations of traditional drug delivery methods, including oral administration and intravenous injection. The challenges associated with drug permeation through layers of skin, which act as a major barrier, are explored, and strategies to overcome these limitations are discussed in detail. This review categorizes skin‐mediated drug delivery methods based on the means of increasing drug permeation, and it provides a comprehensive overview of the mechanisms and techniques associated with these methods. In addition, recent advancements in the application of skin‐mediated drug delivery are presented. The review also outlines the limitations of ongoing research and suggests future perspectives of studies regarding the skin‐mediated delivery of drugs.

A comprehensive review of the underlying mechanisms and techniques of chemically‐enhanced, physically‐enhanced, and stimuli‐enhanced skin‐mediated drug delivery methods are presented along with the structures of skin and delivery routes of drugs through the skin layers. Various applications of each methods are discussed in this review with prospects on future directions of skin‐mediated drug delivery.

1. Introduction

Skin‐mediated drug delivery has emerged as an innovative and promising strategy for the effective, user‐friendly administration of drugs. With the ability to deliver drugs in a non‐invasive and painless manner, it offers a promising alternative to conventional methods, such as oral administration and intravenous injection.^{[ 1} , ² , ³ , ⁴ , ^{5 ]}

Oral administration is the most common and convenient route because it allows for the easy intake of drugs without causing discomfort to patients. However, it often is accompanied by a relatively slow onset of action and by challenges related to the degradation of drugs in the digestive system. When drugs are ingested, they must navigate the gastrointestinal tract where they may encounter various challenges, including acidic degradation and enzymatic breakdown. This can result in delaying the absorption of drugs and reduced efficacy. In addition, the first‐pass metabolism effect is another concern with the oral administration of drugs. The liver initially processes drugs absorbed through the gastrointestinal tract before reaching the systemic circulation. This hepatic metabolism can lead to significant drug metabolism and reduced bioavailability, requiring larger doses of drugs to achieve the desired therapeutic effect. In addition, oral administration may be less suitable for drugs with poor solubility or stability in the gastrointestinal environment.^{[ 6} , ⁷ , ^{8 ]} However, intravenous injection can achieve significant bioavailability and targeted delivery of drugs to specific regions of the body. However, intravenous injection has several drawbacks, for example, the risk of infection at the injection site, potential damage to veins and the injection site, the possibility of air embolism, and the formation of blood clots. Infections can occur if proper sterile procedures are not followed, and damaging the veins may lead to infiltration or phlebitis. Air bubbles that enter the veins can cause severe health concerns, and intravenous therapy can increase the risk of forming dangerous blood clots. These complications pose risks to the patient's health and they also restrict the patient's ability to self‐administer the medication.^{[ 9} , ¹⁰ , ^{11 ]}

In contrast, skin‐mediated drug delivery offers distinct advantages over the traditional methods. Human skin covers an approximate surface area of 2 m², and it is highly vascularized with a significant network of blood vessels.^{[ 12} , ¹³ , ^{14 ]} These characteristics contribute to the skin's extensive and easily accessible surface area, which makes it a favorable route for the absorption of drugs. By bypassing digestion and the acidic degradation process, skin‐mediated drug delivery enhances the bioavailability of drugs and allows lower dosages of drugs compared to oral administration. In addition, skin‐mediated drug delivery enables the selective delivery of drugs to specific tissues or organs which provides targeted therapy without the risk of infection. In addition, drugs can be released in a sustained and controlled manner which reduces the need for frequent dosing.

Despite its potential, skin‐mediated drug delivery faces challenges posed by the complex structure of human skin.^{[ 15} , ^{16 ]} Particularly, the stratum corneum layer, which acts as a major barrier to drug permeation, restricts the passage of large molecules (> 600 Da), and this limits the types of drugs that can be used.^{[ 17 ]} The complex characteristics of human skin, including its lipophilic stratum corneum and hydrophilic underlying layers, can influence the permeation of both lipophilic and hydrophilic drug molecules.^{[ 18} , ^{19 ]} To overcome these barriers, extensive research has focused on developing strategies to enhance drug permeation through the layers of skin. These strategies involve the design of skin‐mediated drug delivery systems, including the selection of suitable materials, optimization of the structures of the devices, and the utilization of specific operation mechanisms.^{[ 20} , ^{21 ]} These approaches aim to modify the properties of the stratum corneum or apply external energy sources to facilitate the absorption of drugs.

This review provides a comprehensive overview of the various methods used in the skin‐mediated delivery of drugs. First, the structures and functions of the skin layers, including the epidermis, dermis, and hypodermis, which have crucial roles in the delivery of drugs, are described in detail. The review also explores the wide range of applications where skin‐mediated drug delivery can be helpful. Subsequently, to enable these applications, the mechanisms and techniques of chemically‐enhanced, physically‐enhanced, and stimuli‐enhanced methods are presented. Moreover, representative examples of each method, including commercially available products suitable for clinical use, are introduced to showcase their practical applications. The review also addresses the current limitations of ongoing research, such as the stability of various formulations and regulatory considerations, and the review proposes future prospects for the advancement of skin‐mediated drug delivery techniques.

2. Skin

Human skin, which is the outermost layer of the human body, protects the body from external stimuli. It is ≈1.5 to 2.0 m² in area and comprises ≈15% of the total mass of a human. The skin consists of three layers, that is, the epidermis, dermis, and hypodermis (Figure 1a). The thickness of each layer may differ between people and also between different parts of the body.^{[ 12 ]}

Figure 1.

Structure of skin layers and applications of skin‐mediated drug delivery. a) Schematic illustration of the skin anatomy. b) Schematic illustration of structures of the epidermis layer. c) Potential applications of skin‐mediated drug delivery.

The epidermis layer is the most superficial layer of the skin, and it has an average thickness of ≈50 to 1500 µm.^{[ 22 ]} The epidermis acts as the actual protective layer from the external environment. As shown in Figure 1b, the epidermis layer is composed of five different layers, that is, i) the stratum corneum, ii) the stratum lucidum, iii) the stratum granulosum, iv) the stratum spinosum, and v) the stratum basale. The stratum corneum is the outermost layer of the five layers, and it typically is comprised of 10 to 30 corneocyte cells with an average thickness of 10 to 30 µm. However, the thickness of this layer varies over a wide range depending on the different regions of the body. The corneocyte cells are terminally differentiated keratinocytes, and they result in desquamation about 14 weeks after formation. This layer acts as a physical and chemical barrier that hinders the delivery of drugs across layers of the skin.^{[ 23} , ²⁴ , ²⁵ , ^{26 ]} The thin and clear stratum lucidum layer is right beneath the stratum corneum layer, and it has an average thickness of 5 to 10 µm. This layer exists only on the palms and soles of the human body, and it only has 2 to 3 keratinocyte cells.^{[ 27 ]} The subsequent layer is the stratum granulosum layer, which lies below the stratum lucidum layer or directly beneath the stratum corneum layer. It consists of 1 to 3 layers of flattened cells, and its thickness ranges from 1 to 3 µm. These cells undergo a process that is known as granular synthesis, and they produce and release lipids that are important in the formation of the protective barrier of the stratum corneum layer.^{[ 18 ]} The stratum spinosum layer lies beneath the stratum granulosum layer, and it typically has an average thickness in the range of 10 to 20 µm. This layer consists of several layers of polygonal cells connected by desmosomes, and it provides structural integrity and supports cellular communication. The stratum spinosum layer participates in cell proliferation, immune response, and the synthesis of keratin, a fibrous protein essential for the strong and resilient characteristics of the epidermis layer.^{[ 19} , ²⁸ , ^{29 ]} The basal layer is the stratum basale or the stratum germinativum layer, and it has an average thickness of 10 to 25 µm. This layer is made up of a single layer of cells that are constantly dividing to renew the skin. In this layer, there are cells called melanocytes, and they produce melanin, the pigment responsible for skin color.^{[ 30 ]}

The second layer of the skin is the dermis layer, which provides the skin with structural support and flexibility. This layer of skin is thicker than the epidermis layer, that is, its average thickness ranges from 0.5 to 3 mm. The dermis layer is comprised primarily of collagen and elastin fibers, and it contributes to the skin's strength, elasticity, and overall resilience.^{[ 31 ]} Various structures exist in this layer, for example, blood vessels, nerve endings, sweat glands, sebaceous glands, and hair follicles.^{[ 13 ]} The dermis layer contains blood vessels that widen or narrow to release or conserve heat, and it plays an essential role in regulating the temperature of the body. The dermis layer also is responsible for providing nutrients and oxygen to the epidermis layer, thereby supporting the growth and maintenance of the outermost epidermis layer of the skin.

The deepest layer of the skin is the hypodermis layer, also known as the subcutaneous tissue or the superficial fascia. It is composed primarily of adipose (fat) cells, connective tissue, and blood vessels.^{[ 14 ]} The hypodermis acts as an insulating layer, and it helps regulate the temperature of the body by providing thermal insulation.^{[ 32 ]} It also serves as a shock‐absorbing layer, and it protects the underlying structures, that is, muscles, bones, and organs. The hypodermis layer also plays a role in the storage of energy, that is, it stores excess calories in the form of fat for later use. The hypodermis also contains nerve endings and blood vessels that supply the skin and facilitate sensory perception and nutrient exchange.

Skin‐mediated drug delivery involves delivering a drug through the skin, from reaching the dermal layer close to the stratum corneum to deeper layers and eventually reaching the bloodstream or target tissue. Its potential is vast, and it encompasses various fields of medicine and cosmeceuticals (Figure 1c). Dermatological applications are prominent, including the treatment of skin conditions, such as melanoma, wounds, and tumors.^{[ 33} , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ^{38 ]} The ability to deliver drugs directly to the affected area allows for targeted therapy and improved treatment outcomes. Cosmeceuticals also benefit significantly from skin‐mediated drug delivery. The ability to deliver drugs directly to the skin allows for targeted facial healthcare, such as treating acne, improving skin texture, and reducing the signs of aging.^{[ 39} , ^{40 ]}

Beyond dermatology, skin‐mediated drug delivery has the potential to treat chronic or metabolic diseases. For instance, it can be utilized for localized pain management, offering a non‐invasive and effective option for patients suffering from chronic pain.^{[ 41} , ^{42 ]} In addition, the transdermal delivery of insulin holds promise for the treatment of diabetes, which would provide an alternative to traditional injections and improve patients’ compliance.^{[ 43 ]}

The range of applications also extends to other fields, such as the treatment of allergies and the delivery of hormones and nutrition. The skin can act as a convenient route for delivering allergy medications or hormones, offering a non‐invasive approach and potentially reducing the side effects associated with other methods of administration.^{[ 44} , ^{45 ]} Moreover, skin‐mediated drug delivery can facilitate the controlled release of essential nutrients for various purposes, such as athletic performance or wound healing. Furthermore, skin‐mediated drug delivery can be used to stimulate the production of sweat, which may have applications in monitoring fitness and managing certain health conditions.^{[ 46} , ⁴⁷ , ⁴⁸ , ⁴⁹ , ^{50 ]} To enable the diverse range of applications mentioned above, a comprehensive understanding of the precise drug delivery route through the skin and the utilization of various technologies are imperative.

3. Mechanisms of Skin‐Mediated Drug Delivery

3.1. Drug Delivery Routes

The drug absorption routes of skin‐mediated drug delivery methods can be categorized largely into three different routes by which drugs can pass through the stratum corneum layer, that is, the intercellular route, the transcellular route, and the appendageal route (Figure 2a). The intercellular route is the most common route. In this route, the drug molecules permeate through the intercellular spaces between the corneocytes of the stratum corneum layer.^{[ 51 ]} Drug molecules that move through this route may be relatively large, and hydrophilic molecules can be delivered.^{[ 52 ]} In the transcellular route, the drug molecules are delivered through the stratum corneum layer by directly passing the lipid bilayers of the cell membranes.^{[ 53 ]} Subsequently, the drug molecules diffuse through the epidermis layer, reach the dermis layer, and enter the systemic circulation. Since the molecules have to penetrate the lipid matrix of the cell membranes, only drugs that are lipophilic and relatively small can be delivered through the transcellular route.^{[ 54 ]} In the appendageal route, drugs are delivered through the hair follicles, sweat glands, and sebaceous glands in the skin.^{[ 55 ]} Drug molecules can penetrate deeper into the dermis layer when delivered with this route since these structures exist in relatively deeper regions than the stratum corneum layer. Drugs delivered through these routes have advantages in that polar or ionizable molecules as well as larger drug molecules can be delivered.^{[ 56} , ^{57 ]} However, since these structures cover only a small portion (≈0.1%) of the entire skin area, skin‐mediated drug delivery methods using these pathways are limited.^{[ 58 ]}

Figure 2.

An overview of operation mechanisms of skin‐mediated drug delivery methods. a) Schematic illustration of three different absorption routes of drugs for skin‐mediated drug delivery methods. b) Schematic illustration of chemically‐enhanced drug delivery methods, that is, semisolid (left), film (middle), and patch (right). c–e) Schematic illustrations of physically‐enhanced drug delivery methods. c) Two different types of ablation methods, that is, tape‐stripping (left), and microdermabrasion (right). d) Microneedle. e) Stretch‐triggered method. f–i) Schematic illustration of stimuli‐enhanced drug delivery methods. f) Thermal actuation. g) Electroporation. h) Iontophoresis. i) Sonophoresis.

3.2. Operation Mechanisms of Skin‐Mediated Drug Delivery Methods

When drugs are applied to the skin, the absorption of the drugs is limited due to the stratum corneum. Therefore, various methods to enable the delivery of drugs into the dermis layer have been developed by enhancing the permeability of drugs through the stratum corneum layer. In this review, we will focus mainly on such methods in terms of materials and devices that are used for these methods, which can be categorized into three different methods, that is, chemically‐enhanced methods, physically‐enhanced methods, and stimuli‐enhanced methods.

3.2.1. Chemically‐Enhanced Methods

Chemically‐enhanced skin‐mediated drug delivery is a diffusion‐based method in which drugs are not injected into the skin; rather, the drugs penetrate the skin by modifying the structure of the stratum corneum layer.^{[ 59 ]} This approach uses chemical enhancers to increase the permeability of drugs. Absorption enhancers increase skin permeability by lowering the barrier function of the skin.^{[ 60} , ⁶¹ , ^{62 ]} One common class of absorption enhancers includes water‐soluble organic solvents, such as ethanol and propylene glycol. These solvents increase the solubility of lipophilic molecules and promote their absorption into the skin.^{[ 63} , ^{64 ]} In addition, agents such as hyaluronic acid, urea derivatives, and salicylic acid are used mainly to decompose keratin and promote the absorption of drug molecules by moisturizing and softening the stratum corneum layer.^{[ 5} , ⁶⁵ , ^{66 ]} Surfactants, including higher alcohols, fatty acids, esters, glycerin, and lecithin act on the lipids to loosen the hard stratum corneum layer.^{[ 67 ]} Several formulation methods are used to apply these chemical molecules to the skin. In this paper, we have focused mainly on the formulations rather than chemical enhancer substances, which can be classified essentially into three types, that is, semisolids, films, and patches (Figure 2b).

Semisolids, such as creams or ointments, are the most basic drug delivery method.^{[ 68 ]} When applied to the skin, these formulations passively diffuse through the stratum corneum layer. Drug particles penetrate mainly through hair follicles of the skin to such an extent that they penetrate the epidermis to reach the dermis.^{[ 69 ]} This semisolid‐type drug delivery method usually includes a chemical enhancer to increase the skin permeability of drugs, but the size of the molecular mass must be low (< 400 Da).^{[ 67 ]} Semisolid medications can be applied to a wide area, but there is a risk of their being removed by external disruptions, such as one's clothing or movements. Although the drug is delivered directly to the site of action, there are limitations in the systemic delivery of the drug due to various factors, such as the skin barrier and external losses.^{[ 70 ]}

Film formulations are applied directly to the skin by an applicator or a metered pump dispenser spray. Then these formulations adhere to the skin as the solvent evaporates.^{[ 71 ]} The concentration of the drug in the residual film increases as the solvent of the formulation volatilizes, which leads to the level of supersaturation on the surface of the skin, increasing the thermodynamic activity of the formulation to reduce side effects or irritation.^{[ 72 ]} According to Fick's law of diffusion, the rate of drug permeation increases proportionally as the concentration of the drug increases.^{[ 73 ]} Without being washed away by external substances, it forms an invisible drug reservoir in the stratum corneum layer, and the drug is absorbed slowly into the systemic circulation.^{[ 74} , ^{75 ]} However, it takes some time for the coated, thin film to evaporate and form a film, so it is difficult to apply the drug uniformly using this approach.

Patch forms are designed to store and deliver the drug so that it can be used for a longer period of time than the two methods explained above.^{[ 76} , ^{77 ]} A long‐lasting patch provides constant drug release, and the drug can be absorbed through the skin into the bloodstream for several days.^{[ 78 ]} The main components of a transdermal patch are organized layer by layer. An impermeable backing membrane is the outermost layer of the patch that protects the formulation. According to the type of patch, the drug may be contained within the membrane or in the adhesive. A semi‐permeable membrane may serve as a rate‐limiting barrier, and an adhesive layer contacts the skin. The release liner attached to the adhesive protects the adhesive during storage, and it is removed before application. Transdermal patches typically are designed in four ways, depending on how the drug is stored. First, a matrix system consists of a drug layer of a semisolid matrix containing a solution of the drug. Second, a reservoir type has a separate drug reservoir which is encapsulated by the membrane or an adhesive. Third, a drug‐in‐adhesive patch reduces the layer of the patch by putting the drug inside the adhesive.^{[ 79 ]} Last, a multi‐laminate structure with stacked drug‐in‐adhesive layers delivers two drugs at different release times. Patches have several advantages in that they are painless, non‐invasive, and easy to use. They make it convenient for patients who need repeated applications of the medication. However, the class of drugs suitable for this approach is largely limited to low molecular weight (< 600 Da) drugs due to the physiological barrier of the epidermis.^{[ 17 ]}

The chemically enhanced method, which is the most basic method of skin‐mediated drug delivery, is simple and has a low risk of side effects and skin irritation.^{[ 80 ]} This diffusion‐based method depends on the properties of the drug molecules. Drugs should be lipophilic, small, and limited to small doses and dosing frequency. Small molecules are delivered predominantly through the intercellular pathway, although other delivery routes also can be used. Therefore, a more active drug delivery method is required to use various types of drugs and routes.^{[ 1 ]}

3.2.2. Physically‐Enhanced Methods

Physically‐enhanced skin‐mediated drug delivery methods involve techniques that remove or penetrate the stratum corneum layer to enhance the skin permeability of drugs as well as methods that involve a triggering system. The stratum corneum has prompted the explorations of techniques to eliminate this layer for delivering drugs or directly delivering drugs to the inner layer by passing this layer. Moreover, drug delivery methods including a triggering system capable of releasing drugs when necessary have been developed as physically‐enhanced methods.

The ablation method, including the tape‐stripping method, and microdermabrasion, which directly eliminates the stratum corneum layer, is the most primitive method to enhance drug permeability (Figure 2c). The tape‐stripping method comes along with the placement and removal of adhesive tape on the skin to remove the stratum corneum layer.^{[ 81} , ⁸² , ^{83 ]} By repeating these processes several times, the stratum corneum layer is completely exfoliated.^{[ 84} , ^{85 ]} Another method to directly eliminate the stratum corneum layer is the microdermabrasion method, in which abrasive particles, such as aluminum oxide particles or sodium chloride, are ejected with high velocity to ablate the stratum corneum layer, while the abraded skin cells are drawn back to the device simultaneously.^{[ 86} , ⁸⁷ , ⁸⁸ , ^{89 ]} Although these ablation methods are simple and inexpensive, the poor reproducibility and inconvenience for routine use to patients limit the usage for regular applications. Moreover, these methods result in skin redness or irritation immediately after the ablation procedure, which may lead to infections, limiting the application to patients who do not have sensitive or compromised skin.^{[ 90 ]}

Microneedles can overcome the disadvantage of the ablation method, which is the possibility of damaging the skin. Microneedles are used to apply drugs directly to the dermis layer by creating direct pathways through the stratum corneum layer, thereby allowing drugs to penetrate directly into the underlying layers of the skin (Figure 2d).^{[ 91} , ⁹² , ⁹³ , ^{94 ]} They are made of various materials, such as metals, polymers, or silicon, and their heights range from 25 to 1500 µm, so that they can penetrate the stratum corneum layer which has a thickness of 10 to 20 µm but does not reach the pain receptors that are located in the dermis layer.^{[ 95 ]} Microneedles have various advantages, including ease of use, minimal pain or discomfort, and the potential for self‐administration by patients. Also, they can be fabricated in different forms including patches, arrays, or individual needles.^{[ 96} , ⁹⁷ , ⁹⁸ , ^{99 ]} However, some limitations that need to be improved are sterility issues and maintaining the stability of drugs and the ability of drugs to keep the chemical, physical, and biopharmaceutical properties during the delivery process.^{[ 95 ]}

Stretch‐triggered methods are a novel approach in physically enhanced skin‐mediated drug delivery that involves the release of drugs when an external trigger is applied (Figure 2e).^{[ 43} , ¹⁰⁰ , ^{101 ]} This mechanism offers precise control over drug release, allowing for on‐demand delivery and targeted administration. Such stretch‐triggered methods utilize specialized drug delivery systems that can be stretched or deformed to activate the process of releasing the drugs. When the equipment is stretched, it causes a change in the structure or composition of the device, leading to the release of drugs. However, additional research is needed to optimize the design and performance of these systems to ensure a reliable and controlled drug release while maintaining patients’ comfort and safety.

3.2.3. Stimuli‐Enhanced Methods

Stimuli‐enhanced skin‐mediated drug delivery methods utilize external stimuli to enhance the penetration of drugs through the skin. These methods harness various forms of stimuli, such as thermal stimulus, electric stimulus, and ultrasound, to facilitate the delivery of drugs across the stratum corneum and into the underlying layers of the skin.

The thermal actuation method, which is stimuli‐enhanced technology, can be divided into three different methods, that is, 1) the diffusion method, 2) the thermoporation method, and 3) the combined method (Figure 2f). The first method is an accelerated diffusion method in which heat is applied to the skin through a thermal actuator such as a laser or heater, which raises the temperature of the skin. The kinetic energy of the drug molecules is increased, thus enhancing the diffusion of drug molecules into the layers of the skin.^{[ 102} , ^{103 ]} The second method is the thermoporation method, a technique that involves applying heat to the skin to create pathways across the stratum corneum layer for the enhancement of drug delivery.^{[ 104} , ¹⁰⁵ , ^{106 ]} When local heat is applied to the skin, temporary pores are created through the stratum corneum layer since heat loosens keratin and induces lipid disruption. This allows the delivery of drug molecules into deeper layers of the skin. During the thermoporation process, thermal exposure can be applied in two different ways depending on the temperature of the applied heat. One way is applying a moderate temperature (lower than 100 °C) for a long time (longer than 1 s), and the other way is applying a high temperature (higher than 100 °C) for a short time (shorter than 1 s) so that no damage is caused to the deeper layers of skin. The combined method utilizes heat applied to the skin to physically eliminate the stratum corneum layer and to enhance the permeability of drugs by increasing the diffusion of the molecules of the drug.^{[ 107} , ^{108 ]} After the stratum corneum layer is removed, drugs are applied and the remaining heat after creating pathways in the stratum corneum layer enhances the diffusion of the drugs. The thermal actuation method has an advantage in that a variety of methods, such as laser and radiofrequency, can be used to generate heat.

Electroporation for skin‐mediated drug delivery is a method in which high‐voltage pulses are applied to permeate drugs from small molecules to macromolecules (Figure 2g).^{[ 109} , ^{110 ]} A voltage gradient across the skin layer of 30 to 100 V induces rearrangement of the lipid bilayer membrane by temporarily disturbing the structure, which results in the formation of pores and aqueous pathways that allow high‐molecular drugs to permeate through.^{[ 111} , ^{112 ]} During pulsing, pores with sizes of as small as 10 nm, and with a short lifetime between a few microseconds to a few seconds scale are formed and skin resistance decreases, which is partially reversible. It is influenced by various factors such as the electrical pulse conditions and the physicochemical properties of the drug.^{[ 38} , ¹¹³ , ^{114 ]} The delivery of drugs through the skin layer is enhanced with increased pulse voltage or pulse duration. For further explanations, an electrical pulse with medium voltage (> 30 V) and long pulse duration(≈100 ms) is more effective in enhancing the delivery of drug molecules than a pulse with high voltage (≈100 V) and short pulse duration (≈1 ms) under the same electrical charge since the longer pulse allows the transport of drugs with higher molecular weight.^{[ 115 ]} In addition to the pulse conditions, the design of electrodes used for applying electrical pulses also affects the performance of drug delivery. Since parallel plate electrodes are used to stimulate nerves and muscles under the skin, serpentine electrodes are introduced so that the electric field is mostly confined within the superficial layers of the skin. The transport rate increases by up to four times compared to passive diffusion when using the serpentine‐shaped electrodes.^{[ 116} , ¹¹⁷ , ^{118 ]}

Iontophoresis is a stimuli‐enhanced method that increases the skin permeation of drugs using a voltage gradient across the skin with two electrodes (Figure 2h).^{[ 46} , ¹¹⁹ , ^{120 ]} This involves two mechanisms: electrorepulsion and electroosmosis. Electroosmotic flow is a bulk flow that occurs when a voltage difference is applied across a charged membrane. Because human skin is negatively charged above pH 4, the counter ion is a positive ion and electroosmotic flow occurs from anode to cathode.^{[ 121} , ^{122 ]} Conversely, the principle of electrorepulsion is as follows. An anode (positively charged) repels cationic drugs (positively charged) directly underneath, while a cathode (negatively charged) repels anionic drugs (negatively charged) into the skin. Electrical current is used to enhance and control the penetration of charged drugs through the skin barriers and into the tissues.^{[ 42} , ⁴⁸ , ⁴⁹ , ⁵⁰ , ^{120 ]} Drug doses can be easily controlled by changing the magnitude and duration of the stimulating current.^{[ 123} , ^{124 ]} A low electric current is applied at a low voltage to a small area of skin to prevent pain, irritation, or skin burns. Iontophoresis is widely utilized since electric fields increase the rate of drug delivery compared to passive diffusion‐based methods.^{[ 125} , ^{126 ]}

Magnetophoresis utilizes a magnetic field to enhance the drug delivery rate across the skin, and the basic mechanism includes both magnetorepulsion and magnetohydrokinesis.^{[ 127 ]} When a certain level of the magnetic field is applied to diamagnetic drug molecules, magnetic repulsive force is applied, which results in an improvement in the penetration depth of drug molecules through the skin. At the same time, when water molecules are exposed to an external magnetic field, magnetohydrokinetic flow occurs, which results in the enhancement in the delivery depth of drug molecules.

Sonophoresis is a stimuli‐enhanced method that uses ultrasound waves to enhance the delivery of drugs through the skin (Figure 2i).^{[ 128} , ¹²⁹ , ^{130 ]} The main mechanism of sonophoresis is the cavitation effect, which refers to the creation of cavities followed by the expansion, contraction, and distortion of cavitation bubbles. This creates temporary pores and disruptions in the skin's barrier, allowing drugs to penetrate deeper into the tissues.^{[ 131} , ¹³² , ^{133 ]} One of the key advantages of sonophoresis is the versatility of drugs it offers, controlled dosing, making it suitable for delivering a wide range of drugs, including both small molecules and larger substances, such as proteins. The intensity, frequency, and duration of the ultrasound waves can be adjusted to optimize the delivery of the drug. Low‐frequency ultrasound waves often are used in sonophoresis because they allow deeper penetration into the skin.^{[ 134} , ^{135 ]}

Although the aforementioned stimuli‐enhanced methods are the most advanced methods for skin‐mediated drug delivery which can enable the delivery of large molecules, there are several limitations. First, these methods involve complicated and time‐consuming processes and require the set‐up of complex equipment, thereby requiring greater expense than other methods. Moreover, most of these methods require people who have been trained on how to perform the procedure, so these methods are not suitable for routine use. There are some safety‐related issues, such as skin irritation and cell damage, that may occur due to external energy sources.

4. Applications

In this section, we introduce actual applications of the mechanisms that have been explained above. The devices that were used to conduct the experiments and the in vitro or in vivo experimental results of the enhanced drug delivery ability will be described. Furthermore, some commercialized products that are used for each skin‐mediated drug delivery method are introduced.

4.1. Chemically‐Enhanced Methods

4.1.1. Semisolids

In the semisolids method that relies on passive diffusion, chemical enhancers, and vesicles are used to enhance diffusion through skin absorption. Examples of chemical enhancers include hyaluronic acids, alcohols, fatty acids, and glycerin, which are included in most commercially available semisolid cosmetic products. Vesicles include liposomes, ethosomes, and transfersomes, and material and structural studies are being conducted to improve skin penetration and delivery efficiency.^{[ 61} , ⁶² , ^{139 ]} For example, framework nucleic acids (FNAs), a DNA nanostructure vesicle, show more than twice as much tumor suppression through doxorubicin delivery in a mouse melanoma model than liposomes (Figure 3a, left).^{[ 136 ]} By formulating semisolids, such as cream, ointment, lotion, gel, and spray, it can be applied easily to the skin along with drugs, according to the therapeutic purpose. Depending on the ratio of water and oil, it is divided into ointments with 80% oil, cream with half ratio, lotion with little oil, and oil‐free gel, which can be applied depending on the patient's preferences. For example, FNA can be incorporated into cream formulations for easy self‐application (Figure 3a, right), and there is nicoboxil/nonivamide ointment, Finalgon (Zentiva Pharma GmbH), for the treatment of acute non‐specific low back pain.^{[ 140} , ^{141 ]} Furthermore, Mentholatum lotion (Mentholatum Co.) with menthol and menthyl salicylate is a Food and Drug Administration (FDA) approved product for the relief of bruises, muscle pain, and joint pain. In addition, Finjuve (Almirall, S.A.) was commercialized as a finasteride spray for the treatment of hair loss.^{[ 142 ]}

Figure 3.

Applications of chemically‐enhanced drug delivery methods. a) Schematic illustration of semisolid formulations that target skin tumors (left) and photographs of cream formulations for facile daily application (right). Reproduced under the terms of the CC‐BY license.^{[ 136 ]} Copyright 2019, Springer Nature. b) Schematic illustration of the film‐forming process (left), a photograph of a film attached to the skin for wound healing (upper right), and a photograph of the peeling process of a film after drying (lower right). Reproduced under the terms of the CC BY‐NC‐ND license.^{[ 137 ]} Copyright 2017, Elsevier B.V. c) Schematic illustration of the structure of a patch used for delivering fentanyl for the purpose of pain treatment. d) Schematic illustration of nutrient patches applied to the skin for supplying nutrition. Reproduced under the terms of the CC‐BY license.^{[ 138 ]} Copyright 2021, Wiley‐VCH GmbH.

4.1.2. Films

Films are applied as a drug solution or delivered through a specific medium, such as spray and hydrogel. Examples of film‐forming solutions include liquid solutions for testosterone delivery and polymeric solutions of ketorolac for rapid pain relief.^{[ 143} , ^{144 ]} When the solutions flow down along the curved skin, it is difficult to form a film, so a spray is used for such cases.^{[ 80 ]} As the transdermal film‐forming spray, there are Axiron (Lilly USA, LLC), which contains testosterone to treat the absence of endogenous testosterone, and Evamist (Padagis LLC) which contains estrogen to treat hot flashes and symptoms caused by menopause. However, it is difficult to accurately deliver the drug by spraying, so hydrogels often are used for applying drugs to the desired area. Hydrogel formulations initially exist in semisolid phases within the medium, but upon application to the skin, they form a film, which ensures sustained release of the drug.^{[ 145} , ¹⁴⁶ , ¹⁴⁷ , ^{148 ]} For example, hydrogels are suitable for the systemic administration of tolterodine for the treatment of an overactive bladder. In addition, films can be peeled off at the end of treatment or whenever termination is desired. (Figure 3b, right).^{[ 137 ]}

4.1.3. Patches

Currently, skin‐mediated drug delivery is achieved predominantly by using patches. There are four types of drug patches that have been developed structurally, that is, matrix, reservoir, drug‐in‐adhesive, and multi‐laminate structures. One of the earliest structures is a matrix that contains drugs.^{[ 149} , ^{150 ]} For example, Habitrol (Dr. Reddy's Laboratories, Inc.), is well‐known as a nicotine patch, and it is used for smoking cessation. Next, it developed into a reservoir structure that can control the drug delivery rate through a membrane enclosing the drug layer. There are many examples of reservoir/membrane structures such as Scopolamine (Padagis, LLC) for the treatment of motion sickness, Catapress‐TTS (Boehringer Ingelheim Pharmaceuticals, Inc.) containing clonidine to treat hypertension, and Vivelle‐Dot (Novartis AG) containing estradiol for hormone treatment. However, as the risk and side effects increased, another developed structure of drug‐in‐adhesive became a well‐established product in the market. For example, Duragesic (Janssen Pharmaceuticals, Inc.) contains fentanyl to treat chronic pain (Figure 3c), Emsam (Somerset Pharmaceuticals, Inc.) contains selegiline to treat depression disorder, and Daytrana (Noven Pharmaceuticals, Inc.) contains methylphenidate for treating Attention‐Deficit Hyperactivity Disorder (ADHD). Recently, a multi‐laminate structure that delivers various drugs by stacking drug‐in‐adhesive layers has been studied. A representative example is the multivitamin patch (PatchAid, Inc.) which is applicable for healthcare (Figure 3d).^{[ 138 ]} Also, Cannabidiol patches made up of multiple layers of polymeric materials show good durability to treat chronic pain, anxiety, inflammation, and insomnia. The dosage of these patches can be adjusted to suit the therapeutic purpose.

4.2. Physically‐Enhanced Methods

4.2.1. Ablation Methods

Ablation methods involve physically eliminating the stratum corneum layer, which acts as the major barrier to skin‐mediated drug delivery. As a result, no barrier disrupts the delivery of drug molecules into the deep tissue layers and the permeability of drugs is enhanced. Thus, a large variety of drugs can be delivered by applying drug formulation to the treated regions where the stratum corneum layer is exfoliated and a pathway for drugs is formed.

The most primitive method is the tape‐stripping method, in which the stratum corneum layer is physically eliminated with adhesive tape (Figure 4a).^{[ 84 ]} This method begins by applying an adhesive tape product used for the exfoliation of the stratum corneum layers, such as D‐100 – D‐Squame tape strips (Clinical & Derm) and Smart Sticker (DermTech).^{[ 82} , ¹⁵⁵ , ^{156 ]} Pressure is applied to the attached tape, using the D‐500‐D‐Squame Pressure Instrument (Clinical & Derm).^{[ 82 ]} Subsequently, the adhesive tape is removed, and the whole process is repeated several times. The number of times will vary depending on various factors, such as the type of drug, the skin type, and the desired depth of delivery.^{[ 157 ]} The circular region in the right image appears to be red, indicating that the stratum corneum layer was eliminated.

Figure 4.

Applications of physically‐enhanced drug delivery methods. a) Photographs of the tape‐stripping procedure (left), and a photograph of a red mark after the tape‐stripping procedure, indicating a complete removal of the stratum corneum layer (right). Reproduced under the terms of the CC BY license.^{[ 84 ]} Copyright 2021, Oxford University Press. b) Images of hematoxylin and eosin (H&E) stained skin layers before and after microdermabrasion (left), and fluorescent images showing the difference in the delivered depth of drugs before and after microdermabrasion (right). Reproduced with permission.^{[ 151 ]} Copyright 2009, Elsevier B.V. c) Photographs of a flexible microneedle array patch (left), and the patch attached to the skin of a human arm (right). Reproduced under the terms of the CC BY 4.0 license.^{[ 152 ]} Copyright 2016, PLOS ONE. d) A photograph of a hollow microneedle. Reproduced under the terms of the CC BY‐NC 2.0 license.^{[ 153 ]} Copyright 2010, Springer Nature. e) An optical microscope image of a coated microneedle array (left), and a zoomed image of a coated microneedle (right). Reproduced with permission.^{[ 44 ]} Copyright 2019, Elsevier B.V. f) A schematic illustration of a dissolvable microneedle patch (left), and fluorescent images of the skin after 0 (top right), and 60 days (bottom right) of insertion. Reproduced with permission.^{[ 45 ]} Copyright 2019, Springer Nature. g) Schematic illustration of the process of super swelling hydrogel‐forming microneedle arrays. Reproduced under the terms of the CC BY 4.0 license.^{[ 154 ]} Copyright 2014, PLOS ONE.

The microdermabrasion method is another ablation method that takes away the stratum corneum layer by ejecting abrasive particles with high velocity into the stratum corneum layer.^{[ 151} , ¹⁵⁸ , ^{159 ]} Skin layers were H&E stained before and after the microdermabrasion process, and the brightfield images were taken, showing the removal of the stratum corneum layer as indicated in the dotted rectangle (Figure 4b, left).^{[ 151 ]} An FDA‐approved microdermabrasion device, MegaPeel Gold Series (DermaMed International), was used for exfoliating the stratum corneum layer, in which aluminum oxide particles with sizes between 100 and 300 µm were used as the abrasive particles. Moreover, for the assessment of the enhancement in drug delivery ability, sodium fluorescein solution was applied topically to the treated and non‐treated skin of monkeys for 2 h. Fluorescent images showed that the fluorescent molecules only reached the stratum corneum layer when applied to the non‐treated subjects, while the molecules were delivered deeper into the dermis layer when applied to the microdermabraded subjects (Figure 4b, right).

Despite the advantage that the ablation methods require simple operation processes, since the processes of directly getting rid of the stratum corneum layers may irritate the skin and cause discomfort or even cause pain to the applied skin regions, these methods are not applicable to patients that suffer from skin diseases or people with sensitive skin.

4.2.2. Microneedles

Microneedles directly penetrate the stratum corneum layer to enhance the delivery of drugs into the skin. There are five different types of microneedles that can be categorized depending on the differences in structures, materials, and acting mechanisms. The simplest type is the solid microneedle, which is typically made of solid materials, such as metal or polymer, and applied to the skin to create pathways for the delivery of drugs (Figure 4c).^{[ 152} , ¹⁶⁰ , ¹⁶¹ , ¹⁶² , ¹⁶³ , ¹⁶⁴ , ^{165 ]} The microneedles are removed from the skin after creating pathways and a drug‐loaded patch is applied to the same area. Drugs are released from the patch and diffused directly into the dermis layer as the stratum corneum layer does not exist. This method can be simplified as the “poke and patch” method since the microneedles poke the skin and a transdermal patch is applied for drug delivery. Since an additional process of applying drug formation to the skin is needed when using solid microneedles, microneedles were developed with different structures so they could be utilized to generate pathways and directly apply drugs.

One of these types of microneedles is a hollow microneedle, which contains a hollow pathway that allows the direct delivery of drugs (Figure 4d).^{[ 153} , ¹⁶⁶ , ¹⁶⁷ , ¹⁶⁸ , ¹⁶⁹ , ^{170 ]} These microneedles are inserted into the skin, and the drug is delivered through hollow channels, which enables precise and targeted drug delivery, as the drug can be injected directly into the desired skin layer. It can be simplified as the “poke and flow” method, as microneedles are poked into the skin to penetrate the stratum corneum layer, and drugs flow into the hollow pathways.

Coated microneedles are solid microneedles that are coated with drugs, which have advantages in that the drugs are protected from degradation or inactivation, compared to drugs in hollow microneedles.^{[ 171} , ¹⁷² , ¹⁷³ , ¹⁷⁴ , ¹⁷⁵ , ¹⁷⁶ , ^{177 ]} In addition, the coating may reduce pain and discomfort when the microneedles are being inserted into the skin. After the microneedles are inserted, the coating dissolves over time and releases drugs into the surrounding tissues. This method also is called the “coat and poke” method, and it provides controlled and sustained drug release, enhancing the efficiency of skin‐mediated drug delivery. A microneedle array coated with peanut protein extract (PE) was developed to evaluate the desensitization ability of microneedles (Figure 4e).^{[ 44 ]} When peanut‐sensitized mice were treated using PE‐coated microneedles, they showed lower symptoms of allergic reactions, such as anaphylaxis, than the untreated mice.

Dissolving microneedles are composed of materials that can dissolve after being inserted into the skin. These microneedles are designed to gradually dissolve, releasing the encapsulated drug into the skin.^{[ 178} , ¹⁷⁹ , ¹⁸⁰ , ¹⁸¹ , ¹⁸² , ¹⁸³ , ^{184 ]} Dissolving microneedles overcomes the limitations of solid‐based microneedles of the need for needle removal and disposal process, leading to the convenience of self‐administration. A contraceptive hormone was integrated into a dissolvable microneedle patch, which was released as the microneedles dissolved when inserted into the skin (Figure 4f).^{[ 45 ]} The microneedles were made from biodegradable materials, such as polylactic acid and polylactic‐co‐glycolic acid so that the entire microneedle could be dissolved after a certain time of insertion (Figure 4f, right).

Hydrogel‐forming microneedles are microneedles that are made of hydrogel materials that swell and form a hydrogel matrix after being inserted into the skin by absorbing interstitial fluid. The hydrogel matrix contains drug formulation, which is released over time as the hydrogel gradually dissolves or is absorbed by the skin.^{[ 185} , ¹⁸⁶ , ¹⁸⁷ , ¹⁸⁸ , ¹⁸⁹ , ¹⁹⁰ , ¹⁹¹ , ^{192 ]} This type of microneedle usually comprises materials that have superior biocompatibility compared to materials that are used for fabricating other types of microneedles. Drugs were loaded into a drug reservoir layer in a microneedle array which was fabricated from “super swelling” polymers that could form hydrogels and swell by absorbing interstitial fluid when inserted into the skin (Figure 4g).^{[ 154 ]} In vitro experiments using porcine skin, and in vivo experiments with rats were conducted by utilizing ibuprofen sodium, a commonly used medicine for the relief of fever and pain with a small molecular weight of 230 Da, and ovalbumin, a model compound with a large molecular weight, that is, 44.3 kDa. As a result, a high dose of ≈44 mg of ibuprofen sodium and 1.24 mg of ovalbumin were delivered across porcine skin within 24 h. Moreover, the plasma concentrations of both molecules increased after patches were applied to rats, indicating that the drugs were delivered effectively across the skin layer.

Porous microneedles are microneedles that have porous surfaces or internal structures. This structure maximizes the surface area of microneedles, resulting in a larger quantity of drugs or bioactive substances, compared to other microneedles^{.[ 91} , ^{92 ]} Moreover, the porosity enables better control of the release rate of drug molecules. Recently, a porous microneedle patch was developed that can deliver drugs by inducing electroosmotic flow.^{[ 193 ]} The porous microneedle was loaded with ovalbumin solution, a typical drug molecule that activates the immune system. In vitro and in vivo experiments were conducted to validate the effective delivery of drugs using this porous microneedle when electroosmotic flow was induced. Although the diffusion rate of drugs without the electroosmotic flow was too slow, the rate was enhanced to a comparable level with the subcutaneous injection method, when electroosmotic flow was generated through the porous microneedle.

4.3. Stimuli‐Enhanced Methods

4.3.1. Thermal Actuation

As explained previously, the thermal actuation method can be categorized as the diffusion method, the thermoporation method, and the combined method. For the diffusion method, a thermal actuator controls the rate of drug diffusion by delivering thermal energy to the drug‐loaded device in a controlled manner. Devices powered by heat and light deliver sufficient heat energy to the skin to promote drug diffusion through the skin layers. For example, a programmable heater attached to a patch controls drug delivery through the skin (Figure 5a).^{[ 194 ]} As a drug delivery vehicle, mesoporous silica nanoparticles (MSNs) are used to increase the adsorption of the drug. The heat that is generated weakens the bond between MSN and the drug, causing the diffusion of drug through the skin layers.

Figure 5.

Applications of stimuli‐enhanced drug delivery methods. a) Schematic illustration of controlled drug delivery by thermal actuation (left), and cross‐sectional fluorescence images of the skin of a pig before (top right), and after (bottom right) the diffusion of Rhodamine B dyes at 40 °C. Reproduced with permission.^{[ 194 ]} Copyright 2014, Springer Nature. b) Cross‐sectional brightfield microscopy images of skin of humans before (left), and after (right) 100 ms exposure of 415 °C. Reproduced with permission.^{[ 105 ]} Copyright 2008, Elsevier B.V. c) Simulation results of the electroporation process with water molecules. Reproduced with permission.^{[ 195 ]} Copyright 2012, IEEE. d) Photographs of an electroporation patch attached to the skin of a mouse (left), and the simulated electrical field distribution of the electroporation patch (right). Reproduced under the terms of the CC‐BY license.^{[ 38 ]} Copyright 2015, Springer Nature. e) Schematic illustration of the delivery mechanism of a fentanyl iontophoretic transdermal system. f) Schematic illustration of a device with iontophoretic an anode and a cathode placed on the skin with chemical sensors for sensing interstitial fluid and sweat. Reproduced with permission.^{[ 47 ]} Copyright 2021, Springer Nature. g) Schematic illustration of the use of a stretchable electronic facial mask (top), and the underlying mechanism of sonophoresis by the stretchable electronic facial mask (bottom). Reproduced with permission.^{[ 39 ]} Copyright 2022, American Chemical Society. h) Schematic illustration of the setup (left), and the process (right) of double‐frequency sonophoresis. Reproduced with permission.^{[ 196 ]} Copyright 2012 Elsevier B.V.

The thermoporation method involves applying heat for a certain time to damage the stratum corneum layer, resulting in the enhancement of drug permeability. The effect of heat on skin‐mediated drug delivery was examined by applying heat to skin samples of porcine and humans. Calcein was used as a hydrophilic drug model to assess the effect of heat on the penetration depth of the drugs (Figure 5b).^{[ 105 ]} High temperatures of 100 to 315 °C were applied with three different time ranges, that is, 100 ms, 1 s, and 5 s. The results showed that the flux of hydrophilic molecules across the skin layer was enhanced by up to 760 times when the skin was heated to the highest temperature, that is, 315 °C.

The laser is a representative example of a thermal actuator that is used extensively for the combined method of thermal actuation. There are various types of lasers according to their wavelengths. A CO₂ laser with a long wavelength of 10 600 nm can be used to increase the thermal effect, since it is highly absorbed by water and the absorbed light energy is converted into heat, rapidly heating the skin tissue in a very short time.^{[ 197} , ^{198 ]} Also, a 15 J cm⁻² long‐pulsed neodymium‐doped yttrium‐aluminum‐garnet (Nd:YAG) laser with a wavelength of 1064 nm can be used to exfoliate and weaken corneocytes. Laser actuators are used to deliver drugs for the treatment of various diseases, such as acne vulgaris. Long‐wavelength infrared lasers treat active acne by triggering thermal coagulation of the sebaceous glands and associated hair follicles to reduce sebum production.^{[ 199 ]} Several infrared lasers have been studied and utilized for active acne, including the 1550 nm Erbium Glass, 1064 nm Nd:YAG, and 1320 nm Nd:YAG lasers.^{[ 200} , ^{201 ]}

4.3.2. Electroporation

By applying short pulses of high electric fields, electroporation further increases the diffusion‐dependent delivery of drugs with a small molecular weight of less than 600 Da.^{[ 111} , ^{202 ]} Unstable pores with a short lifetime normally can form, but exposure to an electric field leads to the formation of a larger number of stable pores per unit area and per unit time (Figure 5c).^{[ 117} , ^{195 ]} For example, there is nalbuphine with 357 Da to treat pain, domperidone with 426 Da to stimulate gastrointestinal motility, and buprenorphine with 504 Da to treat opioid addiction.^{[ 203} , ²⁰⁴ , ^{205 ]}

Electroporation also can deliver drugs with large molecular weights up to 40 kDa, which is impossible with other methods. Examples of macromolecules include cyclosporine A with 1.2 kDa to treat rheumatoid arthritis, salmon calcitonin with 3.6 kDa to treat osteoporosis, and dextran sulfate with 5 kDa to prevent cell aggregation.^{[ 206} , ²⁰⁷ , ^{208 ]} There is also heparin with 12 kDa and defibrase with 36 kDa to prevent blood coagulation, and Fluorescein isothiocyanate‐dextran, which is used as a molecular size marker for drug delivery studies, shows that its molecular weight can be up to about 40 kDa.^{[ 209} , ²¹⁰ , ^{211 ]} They rely on large electroporation equipment and have now evolved into skin‐adhesive patches. For example, there is an electroporated patch (ep‐Patch) consisting of a parylene film which provides intimate surface contact to skin and micromachined electrodes that generate a highly uniform electric field (Figure 5d).^{[ 38 ]} Under electroporation conditions of 5 electrical pulses, 70 V voltage, 20 ms pulse duration, and 2 s pulse interval, it was demonstrated for the first time that non‐invasive electroporation patches can achieve efficient siRNA and DNA transport into both healthy and tumor tissue in vivo.

The encouraging results of skin‐mediated electroporation drug delivery studies have convinced researchers to investigate the potential of electroporation‐based medical therapies.^{[ 116 ]} Several current studies have demonstrated that electroporation can be used to improve gene delivery, including DNA vaccines, and non‐invasive anti‐cancer drug delivery to solid tumor tissue.^{[ 212} , ²¹³ , ^{214 ]} More interestingly, recent studies have reported that electroporation alone, without therapeutically active molecules, resulted in tissue ablation by irreversibly destroying target cells within a limited area without affecting adjacent cells.^{[ 215 ]} However, there are negative effects, such as skin damage and muscle contraction, due to the high voltage of electroporation, so additional research is needed.

4.3.3. Iontophoresis

Iontophoresis uses a small electrical current of 0.5 to 20 mA to increase the penetration of charged drugs through the skin barrier into tissues.^{[ 216 ]} The dose can be controlled easily by changing the magnitude and duration of the applying current. Since this method has good safety, most in vivo experiments are possible and have been commercialized widely.

One of the various applications of this method is skin‐mediated drug delivery. Examples of therapeutic drug administration through iontophoresis include lidocaine for local anesthesia and acyclovir for herpes labialis treatment.^{[ 217} , ^{218 ]} Furthermore, the Fentanyl Iontophoretic Transdermal System IONSYS (Alza.) patch for acute pain management is FDA‐approved (Figure 5e).^{[ 41} , ^{42 ]} In this patch, the opioid agonist, fentanyl, is available for both passive diffusion‐based and active iontophoretic skin‐mediated delivery to enable rapid delivery of the drug. Also, there are iontophoresis‐based patches that have been approved by the FDA and commercialized, such as LidoSite (Vyteris, Inc.) that deliver lidocaine for short‐acting dermal anesthetic and Zecuity (NuPathe, Inc.) that deliver sumatriptan for anti‐migraine medication. In addition, a common example used for clinical purposes is tap water iontophoresis for the treatment of hyperhidrosis.^{[ 219} , ^{220 ]} It works by placing the hand or feet in a shallow container filled with tap water and sending a light electrical current through the water and the surface of the skin. Total (Dermadry, Inc.) is the equipment used in this method, which has been approved by the FDA. This method has been used extensively due to the possibility of long‐term operation with no serious side effects; however, it does require the direction of a medical professional.

In addition, iontophoresis has been shown to be a promising approach for sweat stimulation.^{[ 48} , ⁴⁹ , ⁵⁰ , ²²¹ , ^{222 ]} Sweat contains a large amount of metabolic data, enabling health monitoring, such as alcohol, caffeine, and lactate levels.^{[ 50 ]} Also, chemical sensors that respond to substances in sweat can be applied to the diagnosis of diseases, such as diabetes through glucose level and cystic fibrosis through chloride ion concentration.^{[ 47} , ⁴⁸ , ⁴⁹ , ²²¹ , ²²³ , ^{224 ]} Chemical sensing begins with the application of an iontophoresis current that allows the delivery of the sweat‐stimulating molecule, pilocarpine nitrate (Figure 5f).^{[ 47 ]} Sweat is collected in a Macroduct Advanced Sweat Collection System (ELITech Group) and applied to a chemical sensor. At the same time, an electroosmotic flow of biomarkers, such as glucose, is induced from the interstitial fluid to the surface of the skin (a process called “reverse iontophoresis”), which can be detected stably without crosstalk between individual sensors, enabling simultaneous monitoring.^{[ 222} , ²²⁵ , ²²⁶ , ²²⁷ , ²²⁸ , ^{229 ]} Because electroosmotic flow occurs from anode to cathode, it can be applied to the delivery of cationic drugs such as buspirone and lidocaine.^{[ 230} , ^{231 ]}

4.3.4. Sonophoresis

Sonophoresis utilizes ultrasound waves to enhance the permeability of drugs through the skin. Unlike other stimuli‐enhanced methods, sonophoresis does not directly utilize heat or electrical energy, which can be dangerous to the human body. Thus, sonophoresis is relatively safer. Thus, this method is applicable to humans, and it has a large variety of applications such as pain management, dermatology, and cosmeceuticals.^{[ 39} , ⁴⁰ , ¹⁹⁶ , ^{232 ]} For example, a stretchable electronic facial mask (SEFM) with piezoelectric components was fabricated to be used for delivering ultrasound waves for facial healthcare purposes (Figure 5g).^{[ 39 ]} The SEFM was designed to form conformal contact with the entire surface of the complex structure of the human face to maximize the propagation efficiency of ultrasound waves. Also, since the application for facial healthcare lasts for tens of minutes, it was designed so that hands are free to use when using the SEFM. The skin moisture content was measured before and after hyaluronic acid was delivered using the SEFM, and the results showed that the skin moisture content of the ultrasound‐treated group was up to 20% higher than the control group. The sonophoresis method also can be used for bone growth therapy with commercialized products applicable to humans, including EXOGEN (Bioventus) and AccelStim (Orthofix Medical, Inc.), both of which are FDA‐approved. Furthermore, studies that utilize two different ultrasound frequencies were conducted for further enhancement of drug permeability. Both low‐frequency (20 kHz) and high‐frequency (1 MHz) ultrasound waves were applied simultaneously to enhance the permeability of drugs across the skin (Figure 5h).^{[ 196 ]} In vitro tests were conducted with porcine skin to validate the effect of the dual‐frequency sonophoresis method on the enhancement of drug delivery. Two different types of drugs were used, one with low molecular weight (glucose, 180 Da) and one with high molecular weight (insulin, 5 kDa). The results showed that the amounts of the low and high molecular‐weight drugs that were delivered were enhanced by 6.32 and 2.01 times, respectively, when dual‐frequency ultrasound waves were applied, compared to when solely low‐frequency ultrasound was applied.

4.4. Multimodal Methods

Several methods often are used sequentially to facilitate the effect of skin‐mediated drug delivery. Accordingly, studies that applied two or more of the aforementioned skin‐mediated drug delivery methods have been reported.^{[ 43} , ²³³ , ²³⁴ , ²³⁵ , ²³⁶ , ²³⁷ , ²³⁸ , ^{239 ]} These multimodal methods further enhanced the delivery of drugs through the skin by combining several methods to overcome the disadvantages of each method. Among these methods, since microneedles can be integrated easily with other methods into a single device, several studies have been presented that combined microneedles with other methods for skin‐mediated drug delivery.

For example, as shown in Figure 6a, microneedles can be organized with stretch‐triggered drug delivery devices.^{[ 43 ]} The device releases drugs when a tensile strain is applied, which can be induced by both natural body motions and intentional actions. Drugs were loaded into the fabricated reservoirs, and they were released into the body after the device was stretched. In vivo studies with a diabetic mouse model showed that insulin was efficiently delivered when the device was directly applied to the mouse skin. Microneedles can also be integrated with electrodes to deliver electrical energy for the purpose of iontophoresis. Devices could be fabricated into an iontophoresis‐microneedle array patch (IMAP) for delivering insulin (Figure 6b).^{[ 233 ]} In vitro studies showed that using both microneedle arrays and iontophoresis resulted in 1.88 and 4.41 times greater drug delivery ability compared to using each method alone. In an in vivo study on diabetic rats, the normoglycemic time, which is the time when the blood glucose level is in the normoglycemic state, was measured to evaluate the amount of drug delivered. The normoglycemic time could not be measured when only iontophoresis was used since a normal blood glucose level could not be reached, while combining microneedle arrays with iontophoresis resulted in 1.2 times longer normoglycemic time compared to microneedle arrays alone. Ion‐conductive porous microneedles, which could be used as iontophoresis electrodes were fabricated as another type of device (Figure 6c).^{[ 234 ]} The transdermal resistance was lowered due to the porous structure of the microneedle arrays, providing a stable and safe transdermal electroosmosis flow across the layer of skin. In addition, the porous structure allows drugs with larger molecules to be delivered. In vitro studies showed that drugs with a large range of molecular weight from 180 to 10000 Da could be delivered with the fabricated porous microneedle array patch. Microneedles integrated with a 3D‐printed microheater device were also introduced to regulate the drug delivery rate.^{[ 240 ]} The microheater enhanced the diffusion rate of the drug molecules, which was controlled by changing the temperature of the microheater device. This study raised the possibility of developing an on‐demand dose‐controllable drug delivery system. A further advanced type of device that utilizes microneedles with sonophoresis and iontophoresis together also was developed (Figure 6d).^{[ 235 ]} The microneedles were fabricated with hyaluronic acid solutions that can be fully dissolved when inserted into the skin‐like hydrogel. To assess the effect of iontophoresis and ultrasound, hyaluronic acid microneedles containing rhodamine B were used to conduct in vitro studies with a transparent gelatin hydrogel used as a tissue model. The efficiency of drug delivery increased significantly when both ultrasound and electrical current were applied, compared to when the drug was delivered passively. Moreover, an FDA‐approved commercialized device, Sylfirm X (BENEV Company Inc.), that combines microneedles with the electroporation method was developed that can be used for treating skin troubles, such as discoloration, rosacea, and melasma, by rejuvenating skin tissues.

Figure 6.

Applications of multimodal drug delivery methods. a) A photograph (top left) and an SEM image (top right) of the stretch‐triggered microneedle array, and photographs of the device applied on the skin of a mouse before stretching (bottom left), and after stretching (bottom right). Reproduced with permission.^{[ 43 ]} Copyright 2015, American Chemical Society. b) Schematic illustration of the iontophoresis‐microneedle array patch (left), and drug delivery mechanism of the device (right). Reproduced under the terms of the CC BY 4.0 license.^{[ 233 ]} Copyright 2020, Springer Nature. c) Schematic illustration of a microneedle array patch integrated with iontophoresis electrodes, and a photograph of the device attached to the skin (inset). Reproduced under the terms of the CC BY 4.0 license.^{[ 234 ]} Copyright 2021, Springer Nature. d) Schematic illustration of the simultaneous application of sonophoresis and iontophoresis integrated with microneedles. Reproduced under the terms of the CC BY 4.0 license.^{[ 235 ]} Copyright 2020, Springer Nature. e) Schematic illustration of the simultaneous application of sonophoresis and iontophoresis. Reproduced with permission.^{[ 236 ]} Copyright 2019, Springer Nature.

Devices that can conduct two or more methods of skin‐mediated drug delivery without utilizing microneedles also were developed. For example, Figure 6e shows a device that can conduct both iontophoresis and sonophoresis which can operate individually as well as simultaneously.^{[ 236 ]} The enhancement ratio, which is defined as the ratio peak area of the treated sample against the peak area of the control, was compared to evaluate the efficiency of the skin‐mediated drug delivery methods. The results indicated that the simultaneous application of sonophoresis and iontophoresis enhanced the delivery of glutamic acid through the skin compared to the individual application of each method. A similar commercialized device, Dermisonic (Silk'n Ltd), that combines iontophoresis and sonophoresis methods is used to enhance skincare treatments.

5. Conclusion and Prospects

This review article provides a comprehensive overview of skin‐mediated drug delivery systems and the various techniques and mechanisms used to enhance drug permeation through the skin. The skin, being a formidable barrier, presents significant challenges for drug delivery, but through innovative approaches, substantial progress has been made to overcome the barrier associated with the skin. One prominent strategy highlighted in this review is the chemical or physical modification of the stratum corneum, the outermost layer of the skin, which plays a pivotal role in drug permeation. By altering the properties of the stratum corneum, researchers have successfully improved the penetration of various drugs. These modifications can be achieved through techniques like the use of chemical enhancers, ablation, and penetration. Furthermore, the review acknowledges the potential of advanced stimuli‐enhanced approaches in enhancing skin‐mediated drug delivery. Various techniques, such as thermal actuation, electroporation, iontophoresis, and sonophoresis, have demonstrated the ability to generate a flow of drug molecules across the skin, leading to the improved efficiency of drug delivery. These stimuli‐enhanced methods offer alternative pathways for drug transport and hold promise for overcoming specific challenges associated with certain drug formulations or skin conditions. Importantly, the application of these techniques covered in this review extends from diseases associated with the skin to various chronic or metabolic diseases, showcasing the broad potential impact of skin‐mediated drug delivery. The ability to deliver drugs through the skin opens up new avenues for precise and targeted treatments, allowing for localized therapy while minimizing systemic side effects. Moreover, the implications of skin‐mediated drug delivery extend beyond therapeutic purposes. These approaches also hold promise for the development of cosmeceutical products, which combine cosmetic and pharmaceutical benefits. By delivering drugs through the skin, cosmeceutical products can improve the health and appearance of the skin and offer opportunities for skincare, anti‐aging, and other cosmetic applications. In addition, it also offers non‐invasive diagnostic tools by enabling the detection of biomarkers or therapeutic drug levels in the skin, providing valuable insights into disease progression and the efficacy of treatments.

However, it is essential to be aware of the safety concerns associated with skin‐mediated drug delivery systems. While these innovative approaches offer significant benefits, potential risks, and side effects must be evaluated thoroughly and addressed to ensure the safety of patients and the effectiveness of treatments. Optimizing drug formulations for skin‐mediated delivery is a critical area for future research. The development of safe, stable, and effective drug formulations that maximize drug permeation while minimizing side effects is paramount. Advancements in nanotechnology, biomaterials, and formulation design offer exciting prospects for improving the efficacy and safety of skin‐mediated drug delivery systems.

Another critical aspect to consider is the influence of various skin conditions on the effectiveness of skin‐mediated drug delivery methods. Factors such as temperature, humidity level, and pH levels of the skin have been shown to have an impact on the delivery rate of drugs. For instance, a high core temperature of the skin may hinder the enhancement of drug permeation in thermal actuation methods. Similarly, moist skin can lower the electrical resistance of skin layers, potentially leading to an overdose of drugs when applying electrical current for iontophoresis. Therefore, it is imperative to conduct further research to understand the fundamental conditions of the skin that may significantly impact the performance of skin‐mediated drug delivery systems.

In addition, it is essential to acknowledge that not all individuals, ranging from pediatrics to the elderly, may benefit equally from skin‐mediated drug delivery advancements. The demand for skin‐mediated drug delivery is particularly high in populations where traditional methods, such as oral administration or intravenous injections, pose challenges. However, the characteristics of skin layers vary significantly among these vulnerable populations, such as pediatric and elderly patients. For example, infants have more sensitive skin than adults and the thickness of each layer of skin changes with age. Consequently, the applicability of skin‐mediated drug delivery techniques may differ or require specific operating conditions for such individuals. Therefore, it is imperative to conduct further research to explore and understand the distinct characteristics of skin layers among different populations. This knowledge will help tailor skin‐mediated drug delivery methods to accommodate diverse individuals, considering their unique skin properties and requirements. By addressing these factors, we can expand the accessibility and effectiveness of skin‐mediated drug delivery across a broader range of individuals, including those with specific skin conditions or vulnerabilities.

Considering these factors and conducting comprehensive research, skin‐mediated drug delivery systems can be optimized to ensure their safety and efficacy for diverse populations of patients. Furthermore, ongoing efforts to refine these delivery systems, considering various skin conditions and age groups, will pave the way for personalized medicine and targeted treatments, enhancing patient outcomes and overall healthcare (Table 1 ).

Table 1.

Summary of skin‐mediated drug delivery methods.

	Mechanism	Penetration depth	Delivery time	Ease to use (need of professional)	Triggering system	Side effects	Application	Molecular weights of drugs	Reference(s)
Chemically‐enhanced	Semisolids	Low	Long (hours ∼ days)	Easy (X)	No	‐ Possibility of external loss	‐ Tumor ‐ Pain ‐ Hair loss	Low	[67, 70, 136, 140, 141, 142]
	Film	Low	Long (hours ∼ days)	Easy (X)	No	‐ Low uniformity	‐ Pain ‐ Menopause	Low	[74, 75, 137]
	Patch	Low	Long (hours ∼ days)	Easy (X)	No	‐ Limited molecular weight	‐ Smoke cessation ‐ Motion sickness ‐ Hypertension ‐ Pain ‐ Depression disorder ‐ ADHD ‐ Healthcare	Low	[17, 77, 138, 149, 150]
Physically‐enhanced	Ablation	Deep	Short (minutes ∼ hours	Difficult (O)	Yes	‐ Skin redness ‐ Infections		Low	[82, 84, 90, 151, 155, 156]
	Microneedle	Low to deep	Short (minutes ∼ hours)	Difficult (O)	Yes	‐ Sterility issues ‐ Discomfort ‐ Pain	‐ Allergy ‐ Contraception ‐ Pain	Low to high	[44, 45, 95, 152, 153, 154, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192]
Stimuli‐enhanced	Thermal actuation	Deep	Short (minutes ∼ hours)	Difficult (O)	Yes	‐ Skin irritation ‐ Thermal injury		Low to high	[104, 105, 107, 194, 197, 198, 199, 200, 201]
	Electroporation	Deep	Short (minutes ∼ hours)	Difficult (O)	Yes	‐ Skin irritation ‐ Discomfort	‐ Pain ‐ Opioid addiction ‐ Rheumatoid arthritis	Low to high	[38, 109, 111, 195, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215]
	Iontophoresis	Deep	Short (minutes ∼ hours)	Difficult (O)	Yes	‐ Skin irritation	‐ Anesthesia ‐ Herpes labialis ‐ Pain ‐ Hyperhidrosis ‐ Sweat stimulation	Low to high	[41, 42, 47, 48, 49, 50, 120, 121, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231]
	Sonophoresis	Deep	Short (few minutes)	Difficult (O)	Yes	‐ Skin irritation ‐ Heat sensation	‐ Facial healthcare	Low to high	[39, 40, 128, 130, 196, 232]

Conflict of Interest

The authors declare no conflict of interest.

Biographies

Dong Ha Lee received his B.S. degree in materials science and engineering at Yonsei University, South Korea. He is now on a Ph.D. course at the Department of Materials Science and Engineering in Yonsei University and Korea Institute of Science and Technology (KIST). His research interests focus on wearable devices and biomedical electronics.

Sunyoung Lim received her B.S. degree in mechanical and biomedical engineering at Ewha Women's University, South Korea. She is now on an M.S. course at the School of Biomedical Engineering in Korea University and Korea Institute of Science and Technology (KIST). Her research interests focus on wearable devices for biomedical applications.

Sung Soo Kwak received his Ph.D. degree from Sungkyunkwan University in 2018. After that, he served as a postdoctoral fellow at Sungkyunkwan University from 2018 to 2019 and Northwestern University from 2019 to 2021. He is now a senior researcher in the Center for Bionics at Korea Institute of Science and Technology (KIST). His current research is focused on wireless sensor platforms and energy systems.

Joohee Kim received her Ph.D. degree from UNIST in 2019. After that, she served as a postdoctoral fellow at Yonsei University from 2019 to 2020 and Northwestern University from 2020 to 2022. She is now a senior researcher in the Center for Bionics at Korea Institute of Science and Technology (KIST). Her current research is focused on physiological monitoring and drug delivery systems.

Lee D. H., Lim S., Kwak S. S., Kim J., Advancements in Skin‐Mediated Drug Delivery: Mechanisms, Techniques, and Applications. Adv. Healthcare Mater. 2024, 13, 2302375. 10.1002/adhm.202302375