Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Department of Pharmaceutics and Biopharmaceutics, Philipps-Universität Marburg, Marburg, Germany.
Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Eur J Pharm Biopharm. 2021 Jan;158:266-272. doi: 10.1016/j.ejpb.2020.11.018. Epub 2020 Nov 29.
The human hair follicle (HF) represents a promising drug delivery target as an anatomical entity by itself, but also as a gateway enabling dermal or systemic bioavailability of active cosmetic and pharmaceutical ingredients. Due to its morphological characteristics, the HF provides a mechanically driven transport process of nanoparticles (NPs) when external forces are applied. This mechanism was presented as the so-called ratchet effect within the framework of an in silico study published recently. To investigate the influence of massage frequency on the penetration depth of NPs, and, by this, to validate the results obtained in silico, we implemented a corresponding application protocol on an ex vivo porcine skin model. In this connection, we compared three different skin massage frequencies (4.2 Hz, 50 Hz, 100 Hz) for the topical application of cyanine 5-labeled silica NPs (Cy5-SNPs). To elucidate the interplay of frequency and particle size, we furthermore applied Cy5-SNPs of three different diameters (300 nm, 676 nm, 1000 nm). Confocal laser scanning microscopy was utilized to investigate the follicular penetration depth of Cy5-SNPs on cryohistological slices. By this, we could demonstrate that the massage frequency and the follicular penetration depth exhibit an inverse relation pattern. Thus, the highest follicular penetration depth was observed within the 4.2 Hz group, while the lowest follicular penetration depth was found within the 100 Hz group for each Cy5-SNP size category. Additionally, we found that 676 nm Cy5-SNPs penetrated significantly deeper into HFs than 300 nm Cy5-SNPs and 1000 nm Cy5-SNPs, respectively. Summarizing, our results show that a low massage frequency including a dominant radial direction component leads to deeper follicular penetration depths of NPs than automated 3D-oscillation massage at 50 Hz or 100 Hz. Thus, our findings are in line with recent in silico results. Regarding translational purposes, our results are of high interest, since a massage executed at 250BPM (4.2 Hz) is within a realizable range for manual application, e.g. for the implementation into clinical routines or the domestic use of drugs or cosmetics. Furthermore, the application of different massage frequencies offers the opportunity of patho-specific targeting as different anatomical parts of the HF can be reached.
人类毛囊（HF）作为一个解剖实体本身就是一个很有前途的药物输送靶点，但它也是一个使活性化妆品和药物成分能够经皮或全身生物利用的门户。由于其形态特征，当施加外力时，HF 提供了纳米颗粒（NP）的机械驱动输送过程。这个机制是在最近发表的一项计算机模拟研究中提出的所谓的棘轮效应。为了研究按摩频率对 NP 渗透深度的影响，并通过这种方式验证计算机模拟的结果，我们在离体猪皮模型上实施了相应的应用方案。在这方面，我们比较了三种不同的皮肤按摩频率（4.2 Hz、50 Hz、100 Hz）对花菁 5 标记二氧化硅 NPs（Cy5-SNPs）的局部应用。为了阐明频率和粒径的相互作用，我们还应用了三种不同粒径（300nm、676nm、1000nm）的 Cy5-SNPs。共聚焦激光扫描显微镜用于研究 Cy5-SNPs 在冷冻组织切片上的毛囊渗透深度。由此，我们可以证明按摩频率和毛囊渗透深度呈反比关系。因此，在每个 Cy5-SNP 尺寸类别中，观察到 4.2 Hz 组的毛囊渗透深度最高，而 100 Hz 组的毛囊渗透深度最低。此外，我们发现 676nm Cy5-SNPs 比 300nm Cy5-SNPs 和 1000nm Cy5-SNPs 分别更深地渗透到 HF 中。综上所述，我们的结果表明，包括主导径向分量的低按摩频率会导致 NP 的毛囊渗透深度比 50 Hz 或 100 Hz 的自动 3D 振动按摩更深。因此，我们的发现与最近的计算机模拟结果一致。就转化目的而言，我们的研究结果非常有趣，因为 250BPM（4.2 Hz）的按摩处于手动应用的可实现范围内，例如在临床常规中实施或在家庭中使用药物或化妆品。此外，应用不同的按摩频率为针对特定疾病的靶向治疗提供了机会，因为 HF 的不同解剖部位可以被触及。
