Recent developments in in vitro skin-on-a-chip technology: a narrative review

Recent developments in in vitro skin-on-a-chip technology

Article information

J Korean Med Assoc. 2025;68(10):662-672

Publication date (electronic) : 2025 October 10

doi : https://doi.org/10.5124/jkma.25.0081

Jae Jung Kim, PhD ¹

, Chong Won Choi, MD, PhD ²

, Jong Hwan Sung, PhD^,¹

¹Department of Chemical Engineering, Hongik University, Seoul, Korea

²Department of Dermatology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

Corresponding author: Jong Hwan Sung E-mail: jhsung22@hongik.ac.kr

Received 2025 June 5; Accepted 2025 July 7.

Abstract

Purpose

This review outlines recent advances in skin-on-a-chip (SoC) and skin-integrated multi-organ-on-a-chip (MOC) technologies, emphasizing their potential to enhance dermatological research and drug testing by mimicking human physiology.

Current Concepts

SoCs integrate skin models into microfluidic systems with dynamic perfusion, thereby enabling more physiologically relevant skin responses. MOC platforms link skin models with organ models such as the liver or gut, allowing the study of systemic interactions, including drug metabolism, immune responses, and inflammation.

Discussion and Conclusion

These microphysiological systems reproduce human physiology more closely than traditional models. Although technical challenges remain, ongoing development may significantly improve drug screening, disease modeling, and personalized dermatological applications.

Keywords: Skin; Organ-on-a-chip; Skin-on-a-chip; Multi-organ-on-a-chip

Introduction

1. Background

The skin serves as a physical barrier that protects the body from the external environment, preventing the entry of ultraviolet radiation, pathogens, and toxic substances. Beyond this barrier function, it carries out diverse physiological roles, including sensory perception, thermoregulation, and metabolic activity, through the organized assembly of distinct cell types within a characteristic 3-dimensional (3D) architecture.

Skin disorders are highly prevalent worldwide and impose substantial physical, psychological, and economic burdens on both individuals and society [1]. Conditions such as psoriasis, atopic dermatitis, and skin cancer can markedly impair patients’ quality of life [2]. Developing effective therapeutics for these diseases requires not only a structural and physiological understanding of the skin but also sophisticated experimental models. The skin is also a critical portal for drug delivery, and transdermal systems—being noninvasive and user-friendly—have attracted increasing attention [3]. These applications demand a detailed understanding of cutaneous structure, physiology, and absorption properties, along with advanced in vitro models capable of accurately predicting percutaneous drug permeation and biological responses.

Conventional 2-dimensional (2D) cell culture systems fail to replicate the skin’s structural and functional complexity, limiting their physiological relevance [4]. Although animal models enable observation of systemic responses, significant anatomical and physiological differences from humans, combined with ethical concerns, restrict their usefulness [5]. Policies aimed at reducing animal testing, especially in Europe, have further reinforced these limitations. Recent advances in hydrogels and microfluidic technologies have driven the development of organ-on-a-chip (OoC) platforms for skin modeling [6,7]. These platforms recreate tissue microenvironments, permitting precise control of nutrient supply, mechanical stimulation, and intercellular communication. Providing superior physiological fidelity compared to conventional approaches, OoC technology has also been extended to multi-organ-on-a-chip (MOC) systems that simulate inter-organ crosstalk [8,9].

2. Objectives

This article reviews the architecture and applications of state-of-the-art skin-on-a-chip (SoC) models derived from these technologies and explores the potential of multiorgan systems that incorporate skin components.

Structure and Physiology of the Skin

1. Skin architecture

The skin undergoes constant desquamation and renewal and is organized into 3 principal layers: the epidermis, dermis, and hypodermis. The epidermis, about 0.1 mm thick, is composed mainly of keratinocytes that originate in the basal layer, differentiate, and migrate to the stratum corneum, where terminal keratinization occurs. Other specialized cells in this layer include melanocytes, Langerhans cells, and Merkel cells. The low water content of the stratum corneum significantly influences drug permeation [10].

The dermis, which ranges from 1 to 3 mm in thickness, connects to the epidermis and is divided into papillary and reticular layers. It contains fibroblasts, immune cells, nerves, blood vessels, hair follicles, and sweat glands, providing elasticity, tensile strength, and nutritional support. With a water content of roughly 70%, the dermis is well suited for the diffusion of hydrophilic drugs. The hypodermis consists mainly of adipocytes, contributing insulation, mechanical protection, and pathways for neurovascular networks; in regions of thin skin, it may be absent [10]. Non-pathogenic resident microbiota at the skin surface are essential for immune development, reflecting the skin’s constant exposure to the environment [11].

Healthy adult skin hosts a diverse microbiome, with microorganisms that secrete factors inhibiting competing species, thereby stabilizing microbial communities. This microbiota regulates both innate and adaptive immunity, and its dysregulation has been linked to disorders such as acne, atopic dermatitis, and rosacea [12]. Microbial composition varies with age and hydration, creating opportunities for tailored therapeutics and cosmeceuticals [13]. The cutaneous extracellular matrix (ECM), composed primarily of fibrous proteins and proteoglycans, determines mechanical properties such as elasticity and tensile strength. Keratin, collagens IV/VII, and laminins dominate the epidermis, while collagens I, III, IV–VII, XIII, and XIV, elastin, and diverse glycoproteins characterize the dermis. The Young’s modulus of skin ranges from 5 kPa to 140 MPa, depending on ECM organization [14].

In vitro skin models generally focus on recreating the epidermal and dermal layers, although some also include the hypodermis [15]. Because the epidermis serves as the primary interface with external stimuli, it is particularly critical in drug delivery and disease modeling studies.

2. In vitro models reflecting physiological and pathological traits of skin

Skin diseases are highly prevalent worldwide and ranked fourth among non-fatal disease burdens in both 2010 and 2013, underscoring their socioeconomic impact [16]. Cutaneous homeostasis is sustained by intricate interactions among diverse cell types, ECM components, and immune networks, yet it is easily disrupted by factors such as age, genetics, ultraviolet radiation, and environmental insults [17].

Robust in vitro models that reproduce pathological states are indispensable for dermatologic research. Wound healing, for example, is most active during the proliferative phase—approximately 3 days to 2 weeks after injury [18]—and involves keratinocyte proliferation and migration, angiogenesis, and the formation of granulation tissue through fibroblast-mediated ECM deposition [19]. These processes are now examined using cell-based in vitro platforms ranging from simple 2D monocultures to complex 3D co-culture systems [20,21].

Systemic sclerosis is an autoimmune disorder characterized by excessive ECM accumulation and dermal fibrosis [22]. Conventional 2D models typically expose cells to fibrogenic stimuli such as transforming growth factor-β, but they fail to replicate the biomechanical and biochemical cues of the tissue microenvironment [23]. 3D in vitro models that capture these features are therefore regarded as promising alternatives [24].

Barrier function is another major focus of skin research. Multicellular 3D co-culture platforms have been designed to model the stratum corneum, which is generated when basal keratinocytes proliferate, migrate to the granular layer, synthesize structural proteins and lipids, and ultimately transform into corneocytes [25,26]. To mimic this process, epidermal keratinocytes are cultured atop supportive dermal constructs, often under an air–liquid interface, to promote stratified squamous epithelium formation. This allows subsequent analyses of corneocyte proteins and lipids [25,27]. Recent advances now permit targeted gene manipulation in keratinocytes using small interfering RNA before SoC fabrication, enabling detailed investigations of barrier regulation [25,28]. Such models are expected to become indispensable tools for evaluating novel barrier-enhancing agents and clarifying their underlying mechanisms.

3. Cutaneous drug metabolism

Once absorbed, drugs undergo enzymatic biotransformation that generally yields inactive metabolites, although prodrugs may be converted into active forms. While the liver remains the principal metabolic organ, the intestine and skin also contribute to drug metabolism [29,30]. Cutaneous metabolism, though less studied, can significantly influence the efficacy of transdermal agents.

Phase I metabolism includes oxidative, reductive, and hydrolytic reactions mediated by enzymes such as cytochrome P450 (CYPs), aldehyde oxidase (AO), aldehyde dehydrogenase (ALDH), aldo-keto reductase (AKR), alcohol dehydrogenase (ADH), esterases, flavin-containing monooxygenase (FMO), and cyclooxygenase (COX) [31]. Phase II metabolism involves conjugation reactions catalyzed by GST (glutathione S-transferase), UGT (UDP-glucuronosyltransferase), SULT (Sulfotransferase), NAT (N-Acetyltransferase), and MT (Methyltransferase) [32]. Kazem et al. [33] compared messenger RNA expression, protein levels, and enzymatic activities across different skin models [34]. Although CYP1A1 and CYP3A4 transcripts were detected in ex vivo skin, reconstructed human epidermis (RHE), and reconstructed human skin, corresponding enzymatic activities were limited [35]. AO activity was confined to ex vivo skin [36], while ALDH and AKR activities were observed in RHE [37,38]. ADH and esterases were present in several models but exhibited low activity, and FMO and COX showed inconsistent activity despite detectable expression [39–42]. Among Phase II enzymes, GST-P is strongly expressed in differentiated keratinocytes [43]. UGT activity in ex vivo and 3D models approached hepatic levels [44], while SULT and NAT showed activity in selected models [45]. Importantly, RHE demonstrated robust metabolic activity correlated with the differentiation status of keratinocytes.

Ex vivo skin is often subjected to freeze–thaw cycles that diminish enzymatic activity, and high concentrations of cryoprotectants markedly reduce tissue viability [46]. Freeze–thawing has been reported to increase caffeine permeability four- to five-fold and to disrupt tissue architecture [47]. Therefore, minimizing freeze–thaw exposure or strictly standardizing conditions is essential for reproducible results in skin-model experiments.

Skin-on-a-Chip Models

Ex vivo skin provides the highest physiological fidelity but is constrained by donor availability, procedural discomfort, and regulatory restrictions. Consequently, cell-based alternatives have been developed. Conventional 2D monocultures are easy to handle but fail to replicate intercellular interactions or physiological gradients [48].

To overcome these limitations, 3D collagen-based skin constructs have been introduced. In these systems, fibroblast-laden collagen hydrogels form the dermal compartment, while keratinocytes seeded on top generate the epidermis. However, the absence of vasculature restricts nutrient delivery, immune responses, and drug distribution [49,50].

OoC technology, which integrates microfluidics with tissue engineering, has gained significant momentum. SoC platforms provide continuous perfusion, precise control of shear stress, and reduced medium consumption, thereby supporting more physiological conditions, extended culture periods, and efficient drug testing [51,52]. Previous reviews have classified SoC models based on fabrication materials, cellular composition, and applications [53,54]. The present review categorizes SoCs according to integrated skin architecture and function and highlights technological advances, including vascularized SoCs and novel microfluidic designs.

1. Comparative analysis of SOC skin model types

Early SoC systems consisted of single-cell cultures maintained within microfluidic channels. For example, O'Neill et al. [55] cultured human keratinocytes on collagen patches under continuous perfusion, which enhanced cell viability. However, such simple configurations could not reproduce the skin’s complex 3D structure and intercellular interactions, prompting the development of more advanced models.

A common strategy involves injecting fibroblast-embedded hydrogels into SoC chambers to recreate the dermis, followed by seeding keratinocytes to establish the epidermis [7,56]. These constructs, fabricated via 3D printing or in-channel gelation, offer improved physiological realism. Lee et al. [7] introduced a gravity-driven perfusion SoC fabricated from PDMS that sustained skin models for 3 weeks in the absence of vasculature, although epidermal thickness remained heterogeneous.

Building upon this, Kim et al. [57] engineered a tripartite SoC that also incorporated the hypodermis. Using gelatin-based bioinks, distinct cell types were spatially patterned, and vascular channels were introduced to mimic hierarchical skin architecture. The platform demonstrated precise layer-specific marker distribution and lipid organization, supporting its applicability for drug-permeation and disease pathology studies.

Other investigations have transplanted ex vivo biopsy samples or commercial 3D constructs (e.g., EpiDermFT) into SoC devices [58,59]. While this approach preserves native tissue architecture, it requires strict sterility and approval from institutional review boards. For example, Tárnoki-Zách et al. [60] placed human abdominal skin or RHE into a 3D-printed SoC to study caffeine permeation, and Kim et al. [58] mounted microbiopsy tissue to monitor immune-cell migration and infection responses.

Finally, multilayered 2D membrane-based SoCs have been created by positioning distinct cell populations on separate layers to examine interlayer interactions and quantify responses to specific stimuli [61,62]. While these systems offer precise control over architecture and cue delivery, they are technically complex, and maintaining physiological fidelity remains a major challenge (Figure 1) [58,61].

Figure 1.

Examples of skin-on-a-chip models. (A) Skin-on-a-chip model using transferred skin. Reproduced from Kim JJ et al. Lab Chip 2019;19:3094–3103, with permission from the Royal Society of Chemistry [58]. (B) Multilayered skin-on-a-chip model. Reproduced from Wufuer M et al. Sci Rep 2016;6:37471, according to the Creative Commons license [61].

2. Key technological elements of SoC platforms

1) Vascularization

Oxygen diffusion in skin is limited to approximately 200 µm, making vascular networks essential for sustaining nutrient and oxygen delivery. Two principal strategies are used in SoCs. Pre-vascularization introduces endothelial cells (e.g., human umbilical vein endothelial cells [HUVECs]) into prefabricated channels to form perfusable vessels [63,64]. For example, Mori et al. [64] created channels within a collagen matrix using nylon threads, seeded them with HUVECs, and subsequently overlaid an epidermal compartment. Alternatively, angiogenic approaches rely on intrinsic sprouting induced by growth factors such as vascular endothelial growth factor [65,66].

2) Matrix selection

Collagen remains the most widely used hydrogel, but it undergoes substantial contraction during long-term culture. To overcome this limitation, several groups have adopted low-shrinkage fibrin as an alternative [56,65]. Sriram et al. [56] employed fibrin within a poly(methyl methacrylate) (PMMA)-based SoC, incorporating a lid that could be opened or closed to modulate flow while simultaneously assessing drug permeability and tissue responses.

3) Immune integration

Cutaneous immunity involves Langerhans cells, macrophages, dendritic cells, and dynamic leukocyte trafficking. Kim et al. [58] introduced neutrophils isolated from whole blood into an SoC to model infection-driven migration, while Ramadan and Ting [62] incorporated U937 monocyte-derived cells to analyze lipopolysaccharid-induced inflammation. More recently, Michielon et al. [67] designed an open microfluidic SoC compatible with commercial Transwells, where MUTZ-3 monocyte-derived cells were recirculated beneath endothelialized reconstructed human skin. Upregulation of CD83 and CD86 occurred only under flow, highlighting the importance of dynamic immune cues.

4) Disease modeling

Immune-competent SoCs have been adapted to study chronic inflammatory dermatoses such as atopic dermatitis and psoriasis [68]. Atopic dermatitis results from barrier defects that facilitate allergen penetration, triggering type 2 T-helper responses and perpetuating inflammation. In contrast, psoriasis is a type 17 T-helper–mediated disorder, initiated by immune recognition of self-antigens exposed after cutaneous trauma [69]. Traditional mouse models, such as Nc/Nga mice for atopic dermatitis and imiquimod-induced psoriasis, partially recapitulate disease pathology but are limited by interspecies immune differences [68,70]. SoCs treated with disease-relevant cytokine cocktails now provide human-relevant models of atopic dermatitis and psoriasis [68]. Notably, a psoriasis SoC incorporating patient-derived immune cells has demonstrated potential for replicating patient-specific responses [71].

5) Mechanical stimulation

Efforts have also been made to replicate the physical environment of skin by applying mechanical stimulation within SoC systems. Lim et al. [72] applied cyclic tensile strain (10% stretch, 0.01–0.05 Hz) using a magnet-based device to SoCs and used the model to investigate aging and wrinkle formation. This stimulation reduced collagen and keratin expression, demonstrating that SoCs can mimic responses associated with skin aging. Additionally, a mechanically stimulated malignant melanoma SoC system was developed to study the mechanisms through which plantar malignant melanoma invades adjacent tissue [73]. While melanoma most often occurs in sun-exposed areas, some cases arise on the plantar surface [73,74]. A recent epidemiological study comparing plantar melanoma incidence with pressure distribution from body weight suggested that weight-bearing pressure contributes to disease onset [74,75]. Using an SoC system capable of applying physical forces, researchers showed that external pressure promotes invasion into surrounding tissue via actin filaments in malignant melanoma [73].

Inter-Organ Interactions Involving the Skin

Beyond serving as a barrier, the skin actively interacts with other organs in systemic physiology and pathology. Cutaneous sensitization contributes to food allergies, leading to the conceptualization of a skin–immune–gut axis [76]. Chronic dermatoses, such as psoriasis, frequently coincide with intestinal inflammation, suggesting that such inter-organ connections play a critical role in disease progression [77]. These complex interactions are difficult to reproduce using single-tissue models or conventional animal studies.

In this context, MOC systems, which are also referred to as microphysiological systems, have emerged. MOCs culture multiple organs in individual microfluidic chambers and interconnect them through fluid flow, enabling integrated analyses of inter-organ communication and systemic biological responses. These platforms support in vitro evaluation of drug pharmacokinetics and pharmacodynamics [78] and are being developed as important alternatives to animal experimentation.

1. Hair follicle–epidermis integration

Ataç et al. [59] designed a pumpless chip integrating hair follicles with epidermis to examine follicle-driven modulation of epidermal proliferation and differentiation. Using epidermal markers (K10, K15), a proliferation indicator (Ki67), and apoptosis assays (TUNEL assay), they demonstrated that dynamic perfusion enhanced tissue maintenance.

2. Drug-toxicity platforms

A gut–liver–skin (and occasionally kidney) MOC supported repeated-dose testing for up to 28 days while maintaining organ viability; homeostasis was achieved within 2 to 4 days, though excretory functions remained limited [79]. Ganzerla et al. [80] used the HUMIMIC Chip 3plus (TissUse) to connect skin, gut, and liver, enabling comparison of systemic toxicity between dermal and oral exposure to bisphenol A and its analogue bisphenol S. The device maintained organ-specific functionality, allowing simultaneous assessment of absorption, metabolism, and gene-expression changes across the integrated organs.

These advances underscore the potential of integrated MOC platforms for studying cutaneous contributions to systemic disease and for replacing animal experimentation in safety evaluation (Figure 2) [79].

Figure 2.

Multi-organ-on-a-chip model recapitulating the intestine–liver–skin–kidney axis. 1~4: Locations for each organ module, intestine (1), liver (2), skin (3), and kidney (4) tissue, respectively. Reproduced from Maschmeyer I et al. Lab Chip 2015;15:2688–2699, according to the Creative Commons license [79].

Columbia University investigators have developed a four-organ chip integrating heart, liver, bone, and skin tissues derived from human induced pluripotent stem cells. Each tissue compartment remained independently viable, but all were interconnected through an endothelialized vascular network carrying circulating immune cells, thereby permitting inter-organ substance exchange and crosstalk [81]. Notably, exosomes released from the cardiac module migrated to other tissues and elicited distinct physiological responses.

At the University of Central Florida, researchers created a heart–liver–skin MOC to evaluate systemic toxicity following topical drug application. The platform demonstrated that systemic drug responses varied depending on the integrity of the cutaneous barrier, highlighting the skin’s role not merely as a passive shield but as an active regulator of whole-body pharmacokinetics [82].

Lee and Sung [83] established a gut–skin axis on an SoC and showed that exposing the intestinal module to pro-inflammatory stimuli upregulated antimicrobial peptides, such as human beta defensin-2, in the skin compartment. This provided an in vitro demonstration of inter-organ inflammatory signaling and a key proof-of-concept for integrating SoC and MOC technologies in the study of immune-mediated diseases.

The development of such skin-axis models is expected to advance understanding of comorbidities associated with cutaneous diseases. Severe, long-standing psoriasis, for instance, is linked to psoriatic arthritis, cardiovascular disease, and metabolic syndrome—a progression described as the psoriatic march [84]. Similarly, children with atopic dermatitis frequently develop food allergy, allergic rhinitis, and asthma—the so-called atopic march [84]. Because these comorbidities result from aberrant activation of skin-derived immune cells, integrating skin SoCs with other organ models in MOC platforms offers a promising strategy for elucidating disease pathogenesis.

Conclusion

Far from functioning merely as a barrier, the skin orchestrates a wide array of physiological and immunological processes, serving as a pivotal player in drug delivery and disease pathogenesis. In vitro skin models have advanced steadily, and SoC technology, integrating microfluidics with tissue engineering, now provides physiologically precise cutaneous platforms. While conventional 2D and simple 3D cultures lack structural and functional fidelity, SoCs allow controlled shear stress, continuous perfusion, and multicellular co-culture, supporting long-term maintenance and functional evaluation. Recent innovations incorporating vasculature, immune cells, and mechanical-stimulation modules have further refined these systems, enabling detailed investigation of inflammation, aging, and wound repair.

Beyond stand-alone applications, SoCs are increasingly integrated into MOC configurations that model skin–gut, skin–liver, and skin–heart axes. These platforms enable the evaluation of systemic effects following topical exposure and the simulation of inter-organ inflammatory signaling, offering both ethical and physiological advantages over animal models.

Key directions for future development include (1) establishing standardized fabrication and analytical protocols to improve reproducibility; (2) advancing miniaturization and automation to support high-throughput screening; (3) generating patient-specific SoCs for precision medicine and individualized drug-response prediction; and (4) integrating SoC data with artificial intelligence–based analytics to decode complex biological signals and enhance disease-prediction accuracy.

SoC technology thus has the potential to evolve from an advanced skin model into a central platform for precision therapeutics and drug development, with broad applications across medical and industrial sectors. Chronic dermatoses such as atopic dermatitis, psoriasis, and skin cancer have traditionally received less research attention than life-threatening diseases, in part due to the absence of suitable experimental models. SoC-based platforms can address this gap by enabling individualized response prediction, disease modeling, and the development of functional cosmetics and nutraceuticals. Accordingly, the future outlook for SoC applications is highly promising in both biomedical research and industry.

Notes

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Data Availability

Not applicable.

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