Comparison of structural characteristics and molecular markers of rabbit skin, pig skin, and reconstructed human epidermis for an ex vivo human skin model

Uhm, Chanyang; Jeong, Haengdueng; Lee, Su Hyon; Hwang, Jae Sung; Lim, Kyung Min; Nam, Ki Taek

doi:10.1007/s43188-023-00185-1

Cited by 15 publications

(3 citation statements)

References 21 publications

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“…11,34 Porcine skin was chosen as a surrogate for human skin due to its similar histological and physiological markers, thickness, and anatomy. 95,96 The porcine dermal samples were collected posthumously and applied as a membrane between the two chambers of the Franz cell. A known amount of H2S-loaded Mg2(dobdc) was packed into the top donor chamber while HEPES buffer (pH 7.4) was added to the bottom acceptor chamber (SI Fig.…”

Section: Resultsmentioning

confidence: 99%

Transdermal hydrogen sulfide delivery enabled by open metal site metal-organic frameworks

Mandel,

Lotlikar,

Runcevski

et al. 2024

Preprint

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Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter involved in many physiological processes that are integral to proper cellular functioning, including chemical signaling, redox balancing, and modification of vital proteins. Due to its profound anti-inflammatory and antioxidant properties, H2S plays important roles in preventing inflammatory skin disorders and improving wound healing. Transdermal H2S delivery is a therapeutically viable option for the man-agement of such disorders. However, current small-molecule H2S donors are not optimally suited for transdermal deliv-ery and typically generate electrophilic byproducts that may lead to undesired toxicity. Here, we demonstrate that H2S release from metal-organic frameworks (MOFs) bearing coordinatively unsaturated metal centers is a promising alterna-tive for controlled transdermal delivery of gaseous H2S without the release of unwanted byproducts. In particular, exten-sive gas sorption measurements and powder X-ray diffraction (PXRD) studies of eleven MOFs support that the Mg-based framework Mg2(dobdc) (dobdc4− = 2,5-dioxidobenzene-1,4-dicarboxylate) is uniquely well-suited for transdermal H2S delivery due to its strong yet completely reversible binding of H2S, high capacity (14.7 mmol/g or 33.3 wt% at 1 bar and 25 °C), and lack of toxicity. In addition, Rietveld refinement of high-quality synchrotron PXRD data from a H2S-dosed mi-crocrystalline sample of Mg2(dobdc) supports that the high H2S capacity of this framework arises due to the presence of three distinct binding sites: at the Mg centers through a Mg⋅⋅⋅S interaction (primary site), through a short S⋅⋅⋅S interaction to the polarized H2S molecules at the primary sites (secondary site), and in the center of the pores (tertiary site). Last, we demonstrate that transdermal delivery of H2S from this framework is sustained over a 24 h period through porcine skin. Not only is this significantly longer than sodium sulfide (Na2S), but this represents the first example of controlled trans-dermal delivery of pure H2S gas. Overall, H2S-loaded Mg2(dobdc) is an easily accessible, solid-state source of H2S, ena-bling safe storage and transdermal delivery of this therapeutically relevant gas.

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Section: Resultsmentioning

confidence: 99%

Transdermal hydrogen sulfide delivery enabled by open metal site metal-organic frameworks

Mandel,

Lotlikar,

Runcevski

et al. 2024

Preprint

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show abstract

“…To this end, an ex vivo Franz cell model was used (Section S8). , Porcine skin was chosen as a surrogate for human skin due to its similar histological and physiological markers, thickness, and anatomy. , The porcine dermal samples were collected posthumously and applied as a membrane between the two chambers of the Franz cell. A known amount of H 2 S-loaded Mg 2 (dobdc) was packed into the top donor chamber, while HEPES buffer (pH 7.4) was added to the bottom acceptor chamber (Figure S127).…”

Section: Resultsmentioning

confidence: 99%

Transdermal Hydrogen Sulfide Delivery Enabled by Open-Metal-Site Metal–Organic Frameworks

Mandel,

Lotlikar,

Runčevski

et al. 2024

J. Am. Chem. Soc.

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Hydrogen sulfide (H 2 S) is an endogenously produced gasotransmitter involved in many physiological processes that are integral to proper cellular functioning. Due to its profound anti-inflammatory and antioxidant properties, H 2 S plays important roles in preventing inflammatory skin disorders and improving wound healing. Transdermal H 2 S delivery is a therapeutically viable option for the management of such disorders. However, current small-molecule H 2 S donors are not optimally suited for transdermal delivery and typically generate electrophilic byproducts that may lead to undesired toxicity. Here, we demonstrate that H 2 S release from metal−organic frameworks (MOFs) bearing coordinatively unsaturated metal centers is a promising alternative for controlled transdermal delivery of H 2 S. Gas sorption measurements and powder X-ray diffraction (PXRD) studies of 11 MOFs support that the Mg-based framework Mg 2 (dobdc) (dobdc 4− = 2,5-dioxidobenzene-1,4-dicarboxylate) is uniquely well-suited for transdermal H 2 S delivery due to its strong yet reversible binding of H 2 S, high capacity (14.7 mmol/g at 1 bar and 25 °C), and lack of toxicity. In addition, Rietveld refinement of synchrotron PXRD data from H 2 S-dosed Mg 2 (dobdc) supports that the high H 2 S capacity of this framework arises due to the presence of three distinct binding sites. Last, we demonstrate that transdermal delivery of H 2 S from Mg 2 (dobdc) is sustained over a 24 h period through porcine skin. Not only is this significantly longer than sodium sulfide but this represents the first example of controlled transdermal delivery of pure H 2 S gas. Overall, H 2 S-loaded Mg 2 (dobdc) is an easily accessible, solid-state source of H 2 S, enabling safe storage and transdermal delivery of this therapeutically relevant gas.

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“…One of the toxicological tests employed to assess the safety of a substance is acute dermal toxicity, which determines if a substance can cause irreversible damage to the skin and/or systemic toxicity after dermal application [ 17 ]. Commonly, rodents and rabbits are used for dermal toxicity studies; however, the use of minipigs has increased recently owing to similarities with humans in the anatomy and physiology of their skin [ 18 – 24 ]. Additionally, regulatory agencies such as the U.S. Food and Drug Administration (FDA) and Organization for Economic Co-operation and Development (OECD) have encouraged the use of minipigs in dermal toxicity studies [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Toxicity of a novel antifungal agent (ATB1651 gel) in Yucatan minipigs (Sus scrofa) following 4 weeks of daily dermal administration

Kim,

Kang,

Yang

et al. 2024

Toxicol Res.

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ATB1651 gel is an antifungal drug candidate that enhances antifungal activity through substitution of several aryl rings, alkyl chains, and methyl groups. To ensure safety of use of ATB1651 gel, assessment of its potentially toxic side effects is necessary. In this study, we examined the repeated-dose toxicity of ATB1651 gel to Yucatan minipigs (Sus scrofa) in accordance with the Good Laboratory Practice guidelines. Five doses of ATB1651 gel (0%, 0.2%, 0.5%, 1.0%, 3.0%) were administered dermally to the left and right flanks of 38 minipigs daily for 4 weeks. Mortality, clinical symptoms, dermal scores, body weights, and physiological, biochemical, pathological, and toxicokinetic analyses were performed after the treatment period. No systemic toxicological damage was observed in either male or female minipigs regardless of dose; however, dermal application of ATB1651 gel caused some skin alterations at the application sites. Specifically, erythema and eschar formation, edema, and scabs or raise spots were observed at the application site(s) in males in the 3.0% ATB1651 gel treatment group and in females at ATB1651 gel concentrations ≥ 1.0%, with dermal scores ranging from grade 1 to 2. Additionally, histopathological assay indicated infiltration of different types of inflammatory cells and the presence of pustule/crust at the application site(s) in both males and females at ATB1651 gel concentrations ≥ 0.5%. However, these changes were reversible after a 2-week recovery period and were considered a local irritation effect of ATB1651 gel. The no-observed-adverse-effect level of ATB1651 gel was 3.0% with regard to topical and systemic toxicity in both male and female minipigs. Collectively, our results imply that ATB1651 gel is a safe candidate for clinical development as an antifungal drug with a wide therapeutic window.

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Comparison of structural characteristics and molecular markers of rabbit skin, pig skin, and reconstructed human epidermis for an ex vivo human skin model

Cited by 15 publications

References 21 publications

Transdermal hydrogen sulfide delivery enabled by open metal site metal-organic frameworks

Transdermal hydrogen sulfide delivery enabled by open metal site metal-organic frameworks

Transdermal Hydrogen Sulfide Delivery Enabled by Open-Metal-Site Metal–Organic Frameworks

Toxicity of a novel antifungal agent (ATB1651 gel) in Yucatan minipigs (Sus scrofa) following 4 weeks of daily dermal administration

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