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Nanoparticles can be applied to the hair follicles, which can serve as reservoirs for triggered drug release. A valid measurement method for the determination of the pH within the hair follicle in vivo has not been shown yet. Here, melamine formaldehyde particles up to 9 µm in size were applied on 40 freshly plucked scalp hairs of eight individuals to determine the pH along the hair shaft down to the root area of the hair. For fluorescent pH indicators, pyranine and Nile blue were incorporated into the particles. Measurements were conducted using confocal laser scanning microscopy. A pH decay gradient could be found from the hair sheath towards the external hair shaft (p = 0.012) with pH values at the hair sheath of 6.63 ± 0.09, at the hair sheath end at 6.33 ± 0.11, and at the external hair shaft at 6.17 ± 0.09 (mean ± SE). The pH difference between the hair sheath end and the external hair shaft was found to be significant (p = 0.036). The results might be comparable with the pH within the hair follicle in vivo indicating a pH increase towards the hair root.

The motion of a single rigid nanoparticle inside a hair follicle is investigated by means of Brownian dynamics simulations. The cuticular hair structure is modeled as a periodic asymmetric ratchet-shaped surface. Induced by oscillating radial hair motion we find directed nanoparticle transport into the hair follicle with maximal velocity at a specific optimal frequency and an optimal particle size. We observe flow reversal when switching from radial to axial oscillatory hair motion. We also study the diffusion behavior and find strongly enhanced diffusion for axial motion with a diffusivity significantly larger than for free diffusion.

Hair follicle research is currently focused on the development of drug-loaded nanocarriers for the targeting of follicular structures in the treatment of skin and hair follicle-related disorders. In the present study, a dual-label nanocarrier system was implemented in which FITC-labeled BSA hydrogel nanocarriers loaded with the model drug and dye TRITC-dextran were applied topically to porcine ear skin. Follicular penetration and the distribution of both dyes corresponding to the nanocarriers and the model drug in the follicular ducts subsequent to administration to the skin were investigated using confocal laser scanning microscopy. The release of TRITC-dextran from the particles was induced by washing of the nanocarriers, which were kept in a buffer containing TRITC-labeled dextran to balance out the diffusion of the dextran during storage, thereby changing the concentration gradient. The results showed a slightly but statistically significantly deeper follicular penetration of fluorescent signals corresponding to TRITC-dextran as opposed to fluorescence corresponding to the FITC-labeled particles. The different localizations of the dyes in the cross-sections of the skin samples evidenced the release of the model drug from the labeled nanoparticles.

The aim of the present study was to solve the water insolubility limitation of the medically and cosmetically interesting substance Garcinia mangostana Linn (GML) extract by encapsulation, and to evaluate and investigate the penetration efficacy of free and encapsulated GML in two different vehicles (water and cream) in porcine ear skin. The follicular penetration depth was determined in 50 hair follicles for each of the four formulations by means of fluorescence microscopy. Tape stripping was used to compare the distribution properties of GML with all formulations on the stratum corneum. The results showed that encapsulated and free GML in the cream base penetrated deeper into hair follicles than if applied in an aqueous base. In addition, encapsulated GML could be distributed more homogeneously on the stratum corneum than the free GML. In conclusion, it was found that encapsulated GML in a cream base had the most effective penetration level in porcine ear skin.

More and more investigations confirm that nanoparticles are incapable of overcoming the intact skin barrier in vivo. Do nanoparticles still have a future in dermal drug delivery? Unlike many other topically applied substances, nanoparticles have not been reported to utilize the intercellular penetration pathway and preferentially make use of the follicular penetration pathway. Deep penetration into the follicular ducts has been described for a variety of particles and appears to be strongly influenced by particle size. For targeted drug delivery, smart nanoparticles are required which are able to release their loaded drugs subsequent to internal or external trigger stimuli, and thereby enable the translocation of the active agents into the viable epidermis. In the recent manuscript, three nanoparticles systems are summarized and compared which release their model drugs upon different trigger mechanisms. The BSA hydrogel nanoparticles release their model drug TRITC-dextran by passive diffusion due to a concentration gradient via a porous surface. The protease-triggered controlled release BSA nanoparticles release their model drug if they are applied simultaneously with protease nanoparticles, resulting in an enzymatic degradation of the particles and a release of the model drug FITC. Finally, the IR-triggered controlled release AuNP-doped BSA nanoparticles release their model drug FITC after photoactivation with wIRA. For all three nanoparticle systems, the release of their model drugs could be observed. For the first nanoparticle system, only low follicular penetration depths were found which might by due do an agglomeration effect. For the last two nanoparticle systems, deep follicular penetration and even an uptake by the sebaceous glands were verified. In conclusion, it could be demonstrated that nanoparticles do have a future in dermal drug delivery if smart nanoparticle systems are utilized which are able to release their drug at specific times and locations within the hair follicle.

Background In humans, topically applied nanocarriers penetrate effectively into the hair follicles where they can be exploited for the localized and targeted treatment of skin disorders. Objective The objective of the present study was to examine the applicability of particle-based systems for follicular drug delivery in companion animals and livestock, which have a large follicular reservoir. Animals Skin samples from 10 beagle dogs, 14 Wistar rats and four ears from freshly slaughtered cross-bred pigs were used. Methods Fluoresceinamine labelled poly (L-lactide-co-glycolide) nanocarriers (256 or 430 nm) were applied on the different skin samples. After penetration, skin biopsies were removed and cryohistological cross sections prepared and investigated with regard to the follicular penetration depths (in μm ± standard deviation) of the nanocarriers using confocal laser scanning microscopy. Results In canine, rat and porcine hair follicles, the smaller nanoparticles were detected at mean follicular penetration depths of 630.16 ± 135.75 μm, 253.55 ± 47.36 μm and 653.40 ± 94.71 μm, respectively. The larger particles were observed at average follicular depths of 604.79 ± 132.42 μm; 262.87 ± 55.25 μm and 786.81 ± 121.73 μm, respectively, in canine, rat and porcine hair follicles. Statistically significant differences (P < 0.05) in the mean follicular penetration depths of the differently sized nanocarriers could be determined for the canine and porcine skin samples. Conclusion The mean follicular penetration depths of the differently sized nanocarriers were mostly significantly different between the different species, which might be due to different species-specific follicular dimensions. This issue needs to be addressed specifically in further studies.

The application of particles in dermatology and cosmetology represents an emerging field and is closely connected with the question of risk assessment as the potential for, and consequences of, penetration of such particles into the living tissue has not been determined conclusively. In the medical sector, extensive research activities are in progress to develop particles, which can be used as efficient carriers for drug delivery through the skin barrier. In contrast, in cosmetic products, particles are mostly required to remain on the skin surface to fulfill their beneficial effect. Whereas the intercellular penetration of particles seems to be unlikely, the hair follicle has been shown to be a relevant penetration pathway for particles as well as an important long-term reservoir. It has been demonstrated that the penetration depth of the particles can be influenced by their size resulting in the possibility of a differentiated targeting of specific follicular structures. In the present review, the follicular penetration mechanisms and storage properties of particles are discussed.

Hair follicles represent interesting target sites for topically applied substances such as topical vaccinations or agents used in the field of regenerative medicine. In recent years, it could be shown that particles penetrate very effectively into the hair follicles. In the present study, the influence of particle size on the follicular penetration depths was examined. The penetration depths of two different types of particles sized 122 to 1000 nm were determined in vitro on porcine skin. The results revealed that the particles of medium size (643 and 646 nm, respectively) penetrated deeper into the porcine hair follicles than smaller or larger particles. It was concluded that by varying the particle size, different sites within the porcine hair follicle can be targeted selectively. For the human terminal hair follicle, the situation can be expected to be similar due to a similar size ratio of the hair follicles.

The Organization for Economic Cooperation and Development (OECD) recommends caffeine as a reference substance for in vitro skin absorption tests using Franz diffusion cells (FDC). However, it has not been possible to investigate the follicular penetration pathway using this method until now. The aim of this study was to develop a technique to allow the examination of the follicular penetration pathway of a substance penetrating into the skin. The OECD standard method was therefore combined with the follicle closing technique (FCT), an established in vivo method. By using test skin of varying follicular densities, different penetration values were obtained for the test substance caffeine. The follicular penetration rate was determined by an indirect calculation after modifying the in vivo FCT for use in the in vitro FDC. This method is the first to allow the differentiation of penetration pathways by combining the OECD standard method (using the FDC) and the FCT. Caffeine showed a surprisingly high rate of penetration through the follicular shunts in vitro.

AIMS Due to ethical reasons, in vivo penetration studies are not applicable at all stages of development of new substances. Therefore, the development of appropriate in vitro methods is essential, as well as the comparison of the obtained in vivo and in vitro data, in order to identify their transferability. The aim of the present study was to investigate the follicular penetration of caffeine in vitro and to compare the data with the in vivo results determined previously under similar conditions. METHODS The Follicular Closing Technique (FCT) represents a method to investigate the follicular penetration selectively. In the present study, FCT was combined with the Franz diffusion cell in order to differentiate between follicular and intercellular penetration of caffeine into the receptor medium in vitro. Subsequently, the results were compared with the data obtained in an earlier study investigating follicular and intercellular penetration of caffeine in vivo. RESULTS The comparison of the data revealed that the in vitro experiments were valuable for the investigation of the follicular penetration pathway, which contributed in vivo as well as in vitro to approximately 50% of the total penetration, whereas the kinetics of caffeine penetration were shown to be significantly different. CONCLUSIONS The combination of FCT with the Franz diffusion cell represents a valuable method to investigate follicular penetration in vitro. Nevertheless, in vivo experiments should not be abandoned as in vitro, structural changes of skin occur and blood flow and metabolism are absent, probably accounting for reduced penetration rates in vitro.

In recent years, hair follicles have attracted much attention in several fields of research. Representing complex and dynamic three-dimensional structures, which undergo highly specific growth cycles, the hair follicles are susceptible to several disturbances, for example, infectious diseases, various forms of hair loss, autoimmune diseases, androgen-associated diseases and skin tumors. Consequently, they are increasingly considered to be relevant drug targets and to represent drug delivery routes through the stratum corneum into deeper skin layers. The effectiveness of follicular or even transfollicular penetration depends on not only the penetrating substance or on its vehicle, but also on follicular density, size and reservoir, as well as on the activity status of the hair follicle. Follicular targeting, ideally topical delivery of substances to specific compartments and cell populations within the hair follicles, offers opportunities in the treatment of hair follicle-associated diseases, immunotherapy and even gene therapy, as the bulge region of the hair follicle represents a reservoir of stem cells. This present paper gives an overview of the recent developments in the fascinating field of hair follicles, their disorders and their opportunities.

The important role of hair follicles as penetration pathways and reservoir structures for topically applied compounds has been validated in numerous animal models as well as in humans. Follicular penetration rates are modulated by regional variations in size and proportions and the functional status. Advances have especially been made in the targeting of hair follicle-associated cell populations including antigen-presenting cells and stem cells. Improved investigative methods based on differential stripping, spectrophotometry and confocal laser scanning microscopy have led to the determination of the penetration profiles and kinetics for a multiplicity of drugs and drug delivery systems. The observation that particulate delivery systems aggregate and remain in hair follicle openings and their penetration along the follicular duct occurs in a size-dependent manner, which has led to advanced concepts of targeted drug delivery of bioactive compounds in the field of solid particles, as well as semi-solid particles, such as liposomes. This review summarizes the recent progress in this field, and underlines the necessity for pilot studies in human volunteers to further the development of clinical applications for follicular targeting.

For at least two decades, nanoparticles have been investigated for their capability to deliver topically applied substances through the skin barrier. Based on findings that nanoparticles are highly suitable for penetrating the blood–brain barrier, their use for drug delivery through the skin has become a topic of intense research. In spite of the research efforts by academia and industry, a commercial product permitting the nanoparticle-assisted delivery of topically applied drugs has not yet been developed. However, nanoparticles of approximately 600 nm in diameter have been shown to penetrate efficiently into the hair follicles, where they can be stored for several days. The successful loading of nanoparticles with drugs and their triggered release inside the hair follicle may present an ideal method for localized drug delivery. Depending on the particle size, such a method would permit targeting specific structures in the hair follicles such as stem cells or immune cells or blood vessels found in the vicinity of the hair follicles.

Hair follicles represent reservoirs for localized drug therapy and transport pathways for systemic drug delivery. This study describes an approach towards developing a novel procedure for quantifying topically applied substances located in the hair follicles of porcine ear skin, a model for human in vivo skin, using a fluorescent dye. Approximately 5% of the topically applied dye was recovered from the hair follicles, which is in accordance with a previous study.