Topical drug delivery is a cornerstone of dermatological therapy, but translating preclinical findings from animal models to human application presents significant challenges. Mouse models remain widely used due to convenience, cost, and established protocols, yet they differ fundamentally from human skin in ways that can profoundly influence drug absorption and activity. Wong et al. (2011) highlight the anatomical and physiological differences between mouse and human skin that limit direct translation of wound healing, absorption and drug-response studies.
As the field moves toward more predictive and ethical testing strategies, understanding these differences—and integrating human-relevant models—is essential for successful product development. To that end, recent innovations are shaping the field. For example, Gross et al. (2025) describe advances in cutaneous drug delivery technologies such as iontophoresis, underlining the need for accurate preclinical skin models to evaluate innovative approaches.
Against this backdrop, we outline nine critical considerations when comparing topical drug absorption studies between mouse and human skin, with a particular emphasis on the growing importance of ex vivo human skin models like TenSkin™.
1. Skin Structure and Thickness
Mouse skin is significantly thinner than human skin, particularly in the stratum corneum—the primary barrier to drug penetration. This difference not only accelerates absorption but can also exaggerate local drug concentration and receptor occupancy, making a compound appear more potent in mice than it will be in humans.
2. Hair Follicle Density and Use of Hairless Mouse Models
One of the most striking differences between mouse and human skin is hair follicle density. Mice have significantly more hair follicles per unit area, which creates additional pathways for drug penetration. These follicular routes deliver higher drug loads to deeper layers, which can trigger downstream pharmacological effects—such as enzyme activation or immune cell recruitment—at levels rarely achieved in human skin.
To address this, hairless mouse models—such as the SKH1 strain—are frequently used in topical drug development. While these models eliminate the confounding effects of dense fur and facilitate easier application and imaging, they come with their own limitations, Bond & Barry (1988) showed that hydration damage and barrier fragility in hairless mouse skin limit its relevance to human absorption studies. Additionally, other remaining fur-related artifacts such as lipid profiles, vascularization, and immune signaling mean drug-response pathways (e.g., cytokine release, angiogenesis) can still diverge from human outcomes.
Despite their convenience, hairless mice can still overestimate percutaneous absorption and underpredict retention time or barrier recovery kinetics observed in humans. Therefore, while they may be suitable for initial screening or comparative mechanistic studies, data from hairless mice should be validated in more predictive human models, such as ex vivo human skin platforms like TenSkin™, for translational relevance.
3. Lipid Composition
The stratum corneum lipid profile in mice differs in both content and organization. Human skin, rich in ceramides and multilamellar lipid structures, presents a tougher barrier, particularly for lipophilic drugs.
4. Enzymatic Activity and Cutaneous Metabolism
Enzyme expression and activity—such as esterases and cytochrome P450 enzymes—differ by species meaning a pro-drug may be over- or under-converted to its active form in mice, while active drugs can also be metabolized or inactivated more rapidly than in human skin.
5. Immune Response Differences
Murine immune networks (e.g., dendritic cell subsets, cytokine cascades) differ substantially from humans. For anti-inflammatory or immunomodulatory topicals, this can yield false positives for efficacy or mask human-specific adverse reactions.
6. Vehicle and Formulation Behavior
Vehicles influence not just flux but local concentration–time profiles, which dictate receptor activation and gene expression. A gel that drives rapid mouse absorption might create a short, supratherapeutic pulse of drug activity that never occurs in human skin. Recent reviews of advanced delivery methods (Gross et al., 2025) reinforce that vehicle–skin interactions must be tested in models that accurately reflect human barrier properties.
7. Exposure Conditions and Application Realism
Controlled murine studies rarely simulate real-world application variables such as occlusion, sweating, hydration, and repeated dosing affect drug residence time and downstream signaling. Mouse experiments rarely replicate these conditions, so pharmacodynamic readouts—like sustained biomarker modulation—can be misleading.
8. Regulatory and Scientific Emphasis on Human-Relevant Models
Regulators increasingly expect data on both absorption and pharmacological effect from human-relevant systems. Ex vivo human skin models like TenSkin™ preserve native architecture, viable cell populations, and mechanical tension, enabling measurement of target engagement, cytokine release, and gene-expression changes alongside penetration profiles.
TenSkin™ is a physiologically relevant ex vivo human skin model that retains native architecture and mechanical tension—key features for accurate prediction of percutaneous absorption, metabolism, and local tissue responses. Unlike reconstructed models or static explants, TenSkin™ provides human-specific insights in a format that supports reproducible dosing, long-term viability, and compatibility with both molecular and histological endpoints. This makes it ideally suited for bridging preclinical and clinical development, especially when translating from murine data.
9. Bridging Data Through Multiple Model
Using a tiered approach—mouse studies for mechanistic insights, followed by ex vivo human skin for predictive validation—provides a stronger basis for regulatory approval and product success. TenSkin™ and similar models reduce reliance on animals while improving translational confidence. Recent TenSkin™ studies (Conneely et al., 2025) illustrate how tensioned human explants can quantify biomarker shifts following treatment of commercial chemexfoliation agents providing a more complete translational bridge to the clinic.
Conclusion
While mouse models have contributed greatly to dermatological research, their physiological and metabolic differences from human skin are too significant to ignore when evaluating both topical drug absorption and pharmacological activity. Incorporating human-relevant models like TenSkin™ strengthens scientific rigor and provides data on penetration, metabolism, and functional response—aligning with ethical mandates, regulatory expectations, and the demand for products that perform predictably in real patients.
As the future of dermatological science unfolds, it’s clear: the skin of the matter is increasingly human.
References
Wong VW, Sorkin M, Glotzbach JP, Longaker MT, Gurtner GC. Surgical approaches to create murine models of human wound healing. J Biomed Biotechnol. 2011;2011:969618. doi: 10.1155/2011/969618. Epub 2010 Dec 1. PMID: 21151647; PMCID: PMC2995912.
Bond JR, Barry BW. Limitations of hairless mouse skin as a model for in vitro permeation studies through human skin: hydration damage. J Invest Dermatol. 1988 Apr;90(4):486-9. doi: 10.1111/1523-1747.ep12460958. PMID: 3351333.
Gross IP, Lima AL, Sá-Barreto LL, Gelfuso GM, Cunha-Filho M. Recent advances in cutaneous drug delivery by iontophoresis. Expert Opin Drug Deliv. 2025 Jun;22(6):857-874. doi: 10.1080/17425247.2025.2490267. Epub 2025 Apr 13. PMID: 40199721.
Conneely MJ, Namkoong J, Allison F, Hirata Tsutsumi SK, Grussu D, Willis R, Henderson K, Campbell PA, Moy M, Lesniak E, Wu J, Hickerson RP. A Tensioned Human Skin Explant Model Used for Preliminary Assessment of Chemexfoliant-Stimulated Bioeffects. JID Innov. 2024 Aug 23;5(1):100305. doi: 10.1016/j.xjidi.2024.100305. PMID: 39403555; PMCID: PMC11472606.
Ten Bio Team September 2025
