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1. Mechanisms and Implications of Bacterial Invasion across the Human Skin Barrier

   https://doi.org/10.1128/spectrum.02744-21  

   Lipsky, Zachary W.; Patsy, Marisa; Marques, Cláudia N.; German, Guy K. (June 2022, Microbiology Spectrum)

   Claesen, Jan (Ed.)

   ABSTRACT Atopic dermatitis (AD) is associated with a deficiency of skin lipids, increased populations of Staphylococcus aureus in the microbiome, and structural defects in the stratum corneum (SC), the outermost layer of human skin. However, the pathogenesis of AD is ambiguous, as it is unclear whether observed changes are the result of AD or contribute to the pathogenesis of the disease. Previous studies have shown that S. aureus is capable of permeating across isolated human SC tissue when lipids are depleted to levels consistent with AD conditions. In this study, we expand upon this discovery to determine the mechanisms and implications of bacterial penetration into the SC barrier. Specifically, we establish if bacteria are permeating intercellularly or employing a combination of both inter- and intracellular travel. The mechanical implications of bacterial invasion, lipid depletion, and media immersion are also evaluated using a newly developed, physiologically relevant, temperature-controlled drip chamber. Results reveal for the first time that S. aureus can be internalized by corneocytes, indicating transcellular movement through the tissue during permeation, consistent with previous theoretical models. S. aureus also degrades the mechanical integrity of human SC, particularly when the tissue is partially depleted of lipids. These observed mechanical changes are likely the cause of broken or ruptured tissue seen as exudative lesions in AD flares. This work further highlights the necessity of lipids in skin microbial barrier function. IMPORTANCE Millions of people suffer from the chronic inflammatory skin disease atopic dermatitis (AD), whose symptoms are associated with a deficiency of skin lipids that exhibit antimicrobial functions and increased populations of the opportunistic pathogen Staphylococcus aureus . However, the pathogenesis of AD is ambiguous, and it remains unclear if these observed changes are merely the result of AD or contribute to the pathogenesis of the disease. In this article, we demonstrate the necessity of skin lipids in preventing S. aureus from penetrating the outermost barrier of human skin, thereby causing a degradation in tissue integrity. This bacterial permeation into the viable epidermis could act as an inflammatory trigger of the disease. When coupled with delipidated AD tissue conditions, bacterial permeation can also explain increased tissue fragility, potentially causing lesion formation in AD patients that results in further enhancing bacterial permeability across the stratum corneum and the development of chronic conditions. 

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2. Lipid depletion enables permeation of Staphylococcus aureus bacteria through human stratum corneum

   https://doi.org/10.1080/21688370.2020.1754706  

   Lipsky, Zachary W.; Marques, Cláudia N.; German, Guy K. (April 2020, Tissue Barriers)

   Atopic dermatitis (AD) is a chronic inflammatory disease that affects approximately 2-5% of adults worldwide. The pathogenesis of AD continues to be a well-debated point of conjecture, with numerous hypotheses having been proposed. AD conditions are associated with increased populations of Staphylococcus aureus and reduced skin lipids. In this study, we evaluate the ability of S. aureus to permeate across human stratum corneum (SC) exhibiting both normal and depleted lipid conditions consistent with AD. This permeation would enable bacteria to interact with underlying viable epidermal cells, which could serve as a trigger for inflammation and disease onset. Our results indicate that permeation of S. aureus through SC exhibiting normal lipid conditions is not statistically significant. However, bacteria can readily permeate through lipid depleted tissue over a 9-d period. These findings suggest that S. aureus may potentially act as the mechanistic cause, rather than merely the result of AD. 

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3. A Needle-free Transdermal Patch for Sampling Interstitial Fluid

   https://doi.org/10.1109/TBME.2023.3253811  

   O'Brien, Daniel J.; Mills, Darrian; Farina, Joseph; Paranjape, Makarand (January 2023, IEEE Transactions on Biomedical Engineering)

   Modern diagnostics is pivoting towards less invasive health monitoring in dermal interstitial fluid, rather than blood or urine. However, the skin’s outermost layer, the stratum corneum, makes accessing the fluid more difficult without invasive, needle-based technology. Simple, minimally invasive means for surpassing this hurdle are needed. Methods: To address this problem, a flexible, Band-Aid-like patch for sampling interstitial fluid was developed and tested. This patch uses simple resistive heating elements to thermally porate the stratum corneum, allowing the fluid to exude from the deeper skin tissue without applying external pressure. Fluid is then transported to an on-patch reservoir through selfdriving hydrophilic microfluidic channels. Results: Testing with living, ex-vivo human skin models demonstrated the device’s ability to rapidly collect sufficient interstitial fluid for biomarker quantification. Further, finite-element modeling showed that the patch can porate the stratum corneum without raising the skin’s temperature to paininducing levels in the nerve-laden dermis. Conclusion: Relying only on simple, commercially scalable fabrication methods, this patch outperforms the collection rate of various microneedle-based patches, painlessly sampling a human bodily fluid without entering the body. Significance: The technology holds potential as a clinical device for an array of biomedical applications, especially with the integration of on-patch testing. 

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4. 3D Printing of Biodegradable Polymeric Microneedles for Transdermal Drug Delivery Applications

   https://doi.org/10.3390/pharmaceutics16020237  

   Aldawood, Faisal Khaled; Parupelli, Santosh Kumar; Andar, Abhay; Desai, Salil (February 2024, Pharmaceutics)

   Microneedle (MN) technology is an optimal choice for the delivery of drugs via the transdermal route, with a minimally invasive procedure. MN applications are varied from drug delivery, cosmetics, tissue engineering, vaccine delivery, and disease diagnostics. The MN is a biomedical device that offers many advantages including but not limited to a painless experience, being time-effective, and real-time sensing. This research implements additive manufacturing (AM) technology to fabricate MN arrays for advanced therapeutic applications. Stereolithography (SLA) was used to fabricate six MN designs with three aspect ratios. The MN array included conical-shaped 100 needles (10 × 10 needle) in each array. The microneedles were characterized using optical and scanning electron microscopy to evaluate the dimensional accuracy. Further, mechanical and insertion tests were performed to analyze the mechanical strength and skin penetration capabilities of the polymeric MN. MNs with higher aspect ratios had higher deformation characteristics suitable for penetration to deeper levels beyond the stratum corneum. MNs with both 0.3 mm and 0.4 mm base diameters displayed consistent force–displacement behavior during a skin-equivalent penetration test. This research establishes guidelines for fabricating polymeric MN for high-accuracy and low-cost 3D printing. 

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5. A Pseudo‐Surfactant Chemical Permeation Enhancer to Treat Otitis Media via Sustained Transtympanic Delivery of Antibiotics

   https://doi.org/10.1002/adhm.202400457  

   Liu, Sophie_S; White, Joanna_M; Chao, Zhongmou; Li, Ruye; Wen, Shuxian; Garza, Ally; Tang, Wenjing; Ma, Xiaojing; Chen, Pengyu; Daniel, Susan; et al (May 2024, Advanced Healthcare Materials)

   Abstract Chemical permeation enhancers (CPEs) represent a prevalent and safe strategy to enable noninvasive drug delivery across skin‐like biological barriers such as the tympanic membrane (TM). While most existing CPEs interact strongly with the lipid bilayers in the stratum corneum to create defects as diffusion paths, their interactions with the delivery system, such as polymers forming a hydrogel, can compromise gelation, formulation stability, and drug diffusion. To overcome this challenge, differing interactions between CPEs and the hydrogel system are explored, especially those with sodium dodecyl sulfate (SDS), an ionic surfactant and a common CPE, and those with methyl laurate (ML), a nonionic counterpart with a similar length alkyl chain. Notably, the use of ML effectively decouples permeation enhancement from gelation, enabling sustained delivery across TMs to treat acute otitis media (AOM), which is not possible with the use of SDS. Ciprofloxacin and ML are shown to form a pseudo‐surfactant that significantly boosts transtympanic permeation. The middle ear ciprofloxacin concentration is increased by 70‐fold in vivo in a chinchilla AOM model, yielding superior efficacy and biocompatibility than the previous highest‐performing formulation. Beyond improved efficacy and biocompatibility, this single‐CPE formulation significantly accelerates its progression toward clinical deployment. 

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