Ulrike Blume-Peytavi

Hair follicles - a long-term reservoir for drug delivery.

Nanoparticles represent an important drug carrier system. Recently, we have reported on the penetration and storage behavior of particular and non-particular substances revealing the superiority of particular substances in the range of 300–400 nm. In this regard, it was assumed that the rigid hair shaft acts as a geared pump, moving the particles deeper into the hair follicle. In the present investigation, the storage reservoir capacity of the stratum corneum and the hair follicle infundibulum and canal are compared. Interestingly, we could demonstrate a 10 times longer storage within the hair follicles. These results underscore the importance of the hair follicle for drug delivery purposes, mainly highlighting new possibilities for the future concerning retarded delivery, application frequency, and galenic design.

Follicular transport route--research progress and future perspectives.

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.

Nanoparticles in dermatology

Recent advances in the field of nanotechnology have allowed the manufacturing of elaborated nanometer-sized particles for various biomedical applications. A broad spectrum of particles, extending from various lipid nanostructures such as liposomes and solid lipid nanoparticles, to metal, nanocrystalline and polymer particles have already been tested as drug delivery systems in different animal models with remarkable results, promising an extensive commercialization in the coming years. Controlled drug release to skin and skin appendages, targeting of hair follicle-specific cell populations, transcutaneous vaccination and transdermal gene therapy are only a few of these new applications. Carrier systems of the new generation take advantage of improved skin penetration properties, depot effect with sustained drug release and of surface functionalization (e.g., the binding to specific ligands) allowing specific cellular and subcellular targeting. Drug delivery to skin by means of microparticles and nanocarriers could revolutionize the treatment of several skin disorders. However, the toxicological and environmental safety of micro- and nanoparticles has to be evaluated using specific toxicological studies prior to a wider implementation of the new technology. This review aims to give an overview of the most investigated applications of transcutaneously applied particle-based formulations in the fields of cosmetics and dermatology.

Skin Penetration and Cellular Uptake of Amorphous Silica Nanoparticles with Variable Size, Surface Functionalization, and Colloidal Stability

In this study, the skin penetration and cellular uptake of amorphous silica particles with positive and negative surface charge and sizes ranging from 291 ± 9 to 42 ± 3 nm were investigated. Dynamic light scattering measurements and statistical analyses of transmission electron microscopy images were used to estimate the degree of particle aggregation, which was a key aspect to understanding the results of the in vitro cellular uptake experiments. Despite partial particle aggregation occurring after transfer in physiological media, particles were taken up by skin cells in a size-dependent manner. Functionalization of the particle surface with positively charged groups enhanced the in vitro cellular uptake. However, this positive effect was contrasted by the tendency of particles to form aggregates, leading to lower internalization ratios especially by primary skin cells. After topical application of nanoparticles on human skin explants with partially disrupted stratum corneum, only the 42 ± 3 nm particles were found to be associated with epidermal cells and especially dendritic cells, independent of their surface functionalization. Considering the wide use of nanomaterials in industries and the increasing interest for applications in pharmaceutics and cosmetics versus the large number of individuals with local or spread impairment of the skin barrier, e.g., patients with atopic dermatitis and chronic eczema, a careful dissection of nanoparticle-skin surface interactions is of high relevance to assess possible risks and potentials of intended and unintended particle exposure.

Hair Follicles – An Efficient Storage and Penetration Pathway for Topically Applied Substances

In the past, it was assumed that the intercellular route was the only relevant penetration pathway for topically applied substances. Recent results on follicular penetration obtained at the Center for Experimental and Applied Cutaneous Physiology, Charité – Universitätsmedizin Berlin, Germany, emphasize that the hair follicles represent a highly relevant and efficient penetration pathway and reservoir for topically applied substances.

Stratum Corneum Maturation

The importance of the stratum corneum and its barrier function for infants, especially for newborns, is clinically evident. Research regarding the maturation of the stratum corneum in neonates, i.e. when full barrier function is obtained, has produced varying results. Based on transepidermal water loss and percutaneous absorption studies, term infants seem to possess stratum corneum with adult barrier properties. Additionally, postnatal life is thought to accelerate stratum corneum maturation, so that even preterm infants have barrier function similar to term infants at 2–3 weeks of gestational age. However, a look at other parameters, such as skin thickness, skin pH and stratum corneum hydration, shows that neonatal skin is always adjusting to the extrauterine environment in contrast to the steady state of adult skin. This suggests that barrier stabilization may be dependent on achieving a balance between different parameters. However, it is still in question, which parameters, what balance and what timing. This paper provides an up-to-date overview on the neonatal skin barrier based on the review of current literature.

Nanoparticle-Based Targeting of Vaccine Compounds to Skin Antigen-Presenting Cells By Hair Follicles and their Transport in Mice

Particle-based drug delivery systems target active compounds to the hair follicle and may result in a better penetration and higher efficiency of compound uptake by skin resident cells. As previously proposed, such delivery systems could be important tools for vaccine delivery. In this study, we investigated the penetration of solid fluorescent 40 or 200 nm polystyrene nanoparticles (NPs) as well as virus particles in murine skin to further investigate the efficacy of transcutaneously (TC) applied particulate vaccine delivery route. We demonstrated that 40 and 200 nm NPs and modified vaccinia Ankara (MVA) expressing the green-fluorescent protein penetrated deeply into hair follicles and were internalized by perifollicular antigen-presenting cells (APCs). Fibered-based confocal microscopy analyses allowed visualizing in vivo particle penetration along the follicular duct, diffusion into the surrounding tissue, uptake by APCs and transport to the draining lymph nodes. The application of small particles, such as ovalbumin coding DNA or MVA, induced both humoral and cellular immune responses. Furthermore, TC applied MVA induced protection against vaccinia virus challenge. Our results strengthen the concept of TC targeting of cutaneous APCs by hair follicles and will contribute to the development of advanced vaccination protocols using NPs or viral vectors.

Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men

Androgenetic alopecia is the most common hair loss disorder, affecting both men and women. Initial signs of androgenetic alopecia usually develop during teenage years leading to progressive hair loss with a pattern distribution. Moreover, its frequency increases with age and affects up to 80 % Caucasian men and 42 % of women.

Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist

Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).

Basal cell carcinoma possibly originates from the outer root sheath and/or the bulge region of the vellus hair follicle

Abstract In the present study, the immunophenotype of basal cell carcinoma was analysed in comparison with human vellus hair follicular keratinocytes. We also established the lectin binding profile of basal cell carcinoma and human vellus hair follicles (VHF), using several lectins with different sugar specificities. Our findings showed an almost identical immunohistochemical profile for basal cell carcinoma and the suprabulbar region of the outer root sheath of VHF, whereas other follicular compartments such as the bulbar, the isthmus or the supraseboglandular regions did not correlate. In particular, homogeneous and constant expression of the basal differentiation markers CK 5 and CK 14 were found in both specimen, with no expression of the simple epithelium type keratin CK 8 and the suprabasal differentiation markers CK 1 and CK 10. CK 19 showed variable expression in basal cell carcinoma, with constant expression in the outer root sheath and the follicular bulge regions, but was always absent in interfollicular epidermal keratinocytes. In addition, the lectin binding profiles of basal cell carcinoma and the outer root sheath in the suprabulbar region of human VHF were comparable, with the presence of binding sites for PNA, Con A and WGA. These findings provide evidence for a histochemical relationship between basal cell carcinoma and the follicular epithelium of VHF which is closer than that with the epidermis, and suggest its possible origin from or possibly its differentiation pattern towards the cells of the outer root sheath and/or the follicular bulge region of the VHF.