Folliculotropic Mycosis Fungoides In A Child: A Rare Case.

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides characterized by infiltration of hair follicle epithelium by neoplastic lymphoid cells. Generally, it is usually typified by indurated plaques and tumours mainly on the head and neck. However, a wide range of clinical signs have been noted. The clinical presentation of FMF may include prurigo-like lesions, acneiform lesions, cysts, nodules, areas of scarring alopecia, and hypopigmented plaques or papules with follicular prominences. The average age of diagnosis is 60 years while it is rare in childhood and adolescence. We discuss the case of a 12-year-old male patient who had an asymptomatic, erythematous, infiltrating plaque across his left nasolabial fold for three months prior to presentation. Histological assessment of lesion showed characteristic findings of follicular mucinosis with predominance of CD4+ lymphocytes and immunohistochemical studies were positive for CD3+ stains. An increased CD4:CD8 ratio and negative CD20 was also shown. Both findings were consistent with diagnosis of FMF.

The potential role of hsa_circ_0001079 in androgenetic alopecia via sponging hsa-miR-136-5p.

BACKGROUND: Androgenetic alopecia (AGA) is an androgen-dependent polygenic hereditary disease. METHODS: Diseased hair follicles from 5 AGA patients and normal hair follicles from 5 healthy individuals were selected as specimens to carry out whole transcriptome sequencing. Multiple high-expression circular RNAs (circRNAs) were screened from the diseased group. We further verified the presence of the circRNAs in the clinical specimens by real-time fluorescence quantitative PCR (qRT-PCR). RESULTS: In total, 100 circRNAs were significantly upregulated, and 184 circRNAs were significantly downregulated. The top 10 upregulated circRNAs were hsa_circ_0101041, hsa_circ_0001578, hsa_circ_0135062, hsa_circ_0002980, hsa_circ_0005062, hsa_circ_0072688, hsa_circ_0133954, hsa_circ_0001079, hsa_circ_0005974, hsa_circ_0000489. The top 10 downregulated circRNAs were hsa_circ_0001278, hsa_circ_0031482, hsa_circ_0008285, hsa_circ_0003784, hsa_circ_0077096, hsa_circ_0001148, hsa_circ_0006886, hsa_circ_0000638, hsa_circ_0084521, and hsa_circ_0101074. Among top 10 upregulated circRNAs, hsa_circ_0001079 showed significantly high expression via large-sample verification and clinical application potential. Based on a database comparison and base pairing analysis, we found that has-miR-136-5p bound to hsa_circ_0001079 and that hsa-miR-136-5p had potential binding sites with Wnt5A. CONCLUSION: In summary, through high-throughput sequencing and bioinformatic analysis, a potential diagnostic marker for alopecia and a key circRNA that might adsorb microRNA (miRNA) through a sponging mechanism, thus mediating alopecia, were discovered in this study.

Localisation and regulation of cholesterol transporters in the human hair follicle: mapping changes across the hair cycle.

Cholesterol has long been suspected of influencing hair biology, with dysregulated homeostasis implicated in several disorders of hair growth and cycling. Cholesterol transport proteins play a vital role in the control of cellular cholesterol levels and compartmentalisation. This research aimed to determine the cellular localisation, transport capability and regulatory control of cholesterol transport proteins across the hair cycle. Immunofluorescence microscopy in human hair follicle sections revealed differential expression of ATP-binding cassette (ABC) transporters across the hair cycle. Cholesterol transporter expression (ABCA1, ABCG1, ABCA5 and SCARB1) reduced as hair follicles transitioned from growth to regression. Staining for free cholesterol (filipin) revealed prominent cholesterol striations within the basement membrane of the hair bulb. Liver X receptor agonism demonstrated active regulation of ABCA1 and ABCG1, but not ABCA5 or SCARB1 in human hair follicles and primary keratinocytes. These results demonstrate the capacity of human hair follicles for cholesterol transport and trafficking. Future studies examining the role of cholesterol transport across the hair cycle may shed light on the role of lipid homeostasis in human hair disorders.

Acneiform Presentations of Folliculotropic Mycosis Fungoides.

BACKGROUND: Folliculotropic mycosis fungoides (FMF) is a variant of cutaneous T-cell lymphoma that has clinical overlap with a variety of inflammatory follicular unit disorders. However, we describe distinctive presentations of FMF with acneiform features that can be diagnostically challenging, leading to diagnostic delay. OBJECTIVE: To highlight the importance of histopathologic and immunohistochemical evaluation for diagnostic confirmation of presumed inflammatory follicular unit-based disorders that are unusual in presentation or unresponsive to standard therapies. METHODS: A cross-sectional retrospective study of 5 consecutive patients with a histopathologic diagnosis of FMF was conducted. The clinical, histopathologic, immunophenotypic, and molecular genetic features of cases are presented. RESULTS: We describe 5 patients with clinical and histopathologic presentations of FMF masquerading as hidradenitis suppurativa, furunculosis, or acne vulgaris (age range 34-66 years, 4:1 female to male). Clinical morphologies included open and closed comedones, inflammatory pustules, papules and nodules, follicular papules with keratotic plugging, cysts, and scarring involving the face, trunk, and intertriginous areas. All patients failed to respond to standard therapies, including topical and oral antibiotics, topical and oral retinoids, or topical corticosteroids, before receiving the diagnosis of FMF. Lesional skin biopsies showed a perifollicular CD4-positive T-lymphocytic infiltrate with pilotropism, intrafollicular mucin deposition, foreign-body granulomatous inflammation, acute inflammation, and follicular epithelial necrosis. None had concurrent systemic mycosis fungoides. LIMITATIONS: Small retrospective cohort study. CONCLUSION: We present these cases to expand the clinical and histopathologic spectrum of FMF that may strikingly resemble acneiform disorders and to highlight the importance of diagnostic reconsideration with histopathologic evaluation.

Analysis of Cytokines and ATP in Plucked Hair Follicles.

The concentrations of ATP, IL-6, and IL-10 were measured in extracts of plucked hair follicles from healthy volunteers (normal values) and patients with androgenetic alopecia and then, ATP, IL-6, and IL-10 content was calculated for each follicle. The resulting values were directly proportional to hair follicle length, except for IL-6. The concentration of extracted ATP correlated with lactate dehydrogenase activity indicating cell damage. In patients with androgenetic alopecia, IL-10 content exceeded the normal values in follicles with a length <1 mm and ATP content surpassed the normal in follicles >2 mm long. The content of IL-6 and IL-10 measured by ELISA was comparable with results of mRNA expression assayed by RT-PCR, which attested to moderate level of gene expression. The content of ATP and IL- 10, but not IL-6 depended on the length of plucked hair follicle and on pathogenetic factors affecting hair growth.

Skin transcriptome reveals the periodic changes in genes underlying cashmere (ground hair) follicle transition in cashmere goats.

BACKGROUND: Cashmere goats make an outstanding contribution to the livestock textile industry and their cashmere is famous for its slenderness and softness and has been extensively studied. However, there are few reports on the molecular regulatory mechanisms of the secondary hair follicle growth cycle in cashmere goats. In order to explore the regular transition through the follicle cycle and the role of key genes in this cycle, we used a transcriptome sequencing technique to sequence the skin of Inner Mongolian cashmere goats during different months. We analyzed the variation and difference in genes throughout the whole hair follicle cycle. We then verified the regulatory mechanism of the cashmere goat secondary hair follicle growth cycle using fluorescence quantitative PCR. RESULTS: The growth cycle of cashmere hair could be divided into three distinct periods: a growth period (March-September), a regression period (September-December), and a resting period (December-March). The results of differential gene analyses showed that March was the most significant month. Cluster analysis of gene expression throughout the whole growth cycle further supported the key nodes of the three periods of cashmere growth, and the differential gene expression of keratin corresponding to the ground haircashmere growth cycle further supported the results from tissue slices. Quantitative fluorescence analysis showed that KAP3-1, KRTAP 8-1, and KRTAP 24-1 genes had close positive correlation with the cashmere growth cycle, and their regulation was consistent with the growth cycle of cashmere. CONCLUSION: The growth cycle of cashmere cashmere could be divided into three distinct periods: a growth period (March-September), a regression period (September-December) and a resting period (December-March). March was considered to be the beginning of the cycle. KAP and KRTAP showed close positive correlation with the growth cycle of secondary hair follicle cashmere growth, and their regulation was consistent with the cashmere growth cycle. But hair follicle development-related genes are expressed earlier than cashmere growth, indicating that cycle regulation could alter the temporal growth of cashmere. This study laid a theoretical foundation for the study of the cashmere development cycle and provided evidence for key genes during transition through the cashmere cycle. Our study provides a theoretical basis for cashmere goat breeding.

Chi-miR-30b-5p inhibits dermal papilla cells proliferation by targeting CaMKIIδ gene in cashmere goat.

BACKGROUND: During goat embryonic morphogenesis and postnatal initiation of hair follicle (HF) regeneration, dermal papilla (DP) cells play a vital role in hair formation. Growing evidence shows that microRNAs (miRNAs) participate in HF development and DP cell proliferation. However, the molecular mechanisms have not been thoroughly investigated. RESULT: In this study, we utilized miRNA sequencing (miRNA-Seq) to identify differentially expressed miRNAs at different HF cycling stages (anagen and telogen). MiRNA-Seq has identified 411 annotated miRNAs and 130 novel miRNAs in which 29 miRNAs were up-regulated and 32 miRNAs were down-regulated in the anagen phase compared to the telogen phase. Target gene prediction and functional enrichment analysis indicated some major biological pathways related to hair cycling, such as Wnt signaling pathways, ECM-receptor interaction, VEGF signaling pathway, biosynthesis of amino acids, metabolic pathways, ribosome and oxidative phosphorylation. Also, we explored the function of chi-miR-30b-5p in regulating hair growth cycle. Similar to the HF cycling, DP cells were isolated from skin and used to investigate miRNA functions. The MTT and EdU assays showed that the viability and proliferation of DP cells were inhibited or promoted after the transfection of chi-miR-30b-5p mimic or inhibitor, respectively. Bioinformatics analysis revealed CaMKIIδ as a candidate target gene of chi-miR-30b-5p, and the dual-luciferase and western blot assay demonstrated that chi-miR-30b-5p bound to the 3'UTR of CaMKIIδ and further inhibited its translation. CONCLUSION: Chi-miR-30b-5p was found to be highly expressed in the telogen than that in the anagen phase and could inhibit the proliferation of DP cells by targeting CaMKIIδ. Our study provides new information on the regulatory functions of miRNAs during HF development.

Enhanced Follicular Delivery of Finasteride to Human Scalp Skin Using Heat and Chemical Penetration Enhancers.

PURPOSE: The aim of this work was to evaluate whether improved topical delivery of finasteride, focussed to the hair follicles of human scalp skin could be achieved with application of short durations of heat and use of specific chemical penetration enhancers. METHODS: Franz cell experiments with human scalp skin were performed with a range of chemical penetration enhancers at 32°C and 45°C to simulate normal and heated conditions. Selected chemical penetration enhancers were taken forward for finite dose Franz cell studies which examined the effect of heat produced by a prototype external heating system that supplied either 20 or 30 min of additional heat over both a 24 h and a 1 h time period. RESULTS: Short durations of externally applied heat significantly increased finasteride penetration into human scalp skin after 24 h. Analysis of drug distribution in the skin after 1 h and 24 h indicated that both heat and chemical penetration enhancer selection influenced drug delivery to the hair follicles. CONCLUSION: The use of short durations of heat in combination with specific chemical penetration enhancers was able to increase the delivery of finasteride to human scalp skin and provide focussed drug delivery to the hair follicles.

Expression analysis of proteasome maturation protein (POMP) gene in Liaoning Cashmere goat.

Liaoning Cashmere goat is a precious genetic resource of China. To explore the relationship between POMP and cashmere growth, we analyzed the expression of POMP. POMP encodes a hudrophilic protein which is most closely related to bos. RT-PCR showed that POMP was expressed in skin, heart, liver, spleen, lung, and kidney tissues. Real-time PCR showed that the expression of POMP was more active in the secondary hair follicles than the primary hair follicles in anagen. In situ hybridization showed that POMP was obviously expressed in the Inner Root Sheath (IRS) but no expression in Outer Root. The treatment of fibroblasts with melatonin (MT), fibroblast growth factors 5 (FGF5) and insulin-like growth factors 1 (IGF-1) showed that MT/FGF5/IGF-1 much performance for inhibiting the expression of POMP; MT + FGF5 inhibited the expression of POMP; MT + IGF-1 promoted the expression of POMP. When Noggin expression is decreased by siRNA, the expression of POMP is inhibited. To sum up, POMP strongly expressed in the root sheath of hair follicles, related to the development of the primary and secondary hair follicle; In addition, by adding MT/FGF5/IGF-1 or interfering with the Noggin expression to regulate the expression of POMP, to control the growth of Liaoning Cashmere goat cashmere.

Effect of Rubbing on the Distribution of Topically Applied Drugs into the Hair Follicles.

Rubbing actions are often conducted to apply topical formulations onto the skin. Although rubbing was found to increase the skin permeation of drugs, few reports have revealed whether rubbing enhanced either drug permeation through the stratum corneum (SC) or hair follicles (HFs) pathways, or through both. In the present study, we investigated the effects of rubbing on caffeine (CAF) distribution in the SC and HFs. The effect of rubbing direction on the skin penetration of CAF was also investigated. The skin concentration of CAF and its cumulative permeation amount were increased clearly by rubbing. More than six times higher CAF concentrations in the viable epidermis and dermis were observed 5 min after rubbing application compared with no rubbing. On the other hand, slightly increased CAF concentrations were observed in the SC, suggesting that CAF was delivered through the HF pathway by rubbing. Rubbing against the natural hair direction provided the highest skin permeation as well as skin concentrations. Changes in the morphology of the HF opening area might be related to the enhancement effect. These results may provide useful information to understand the effect of rubbing on the skin permeation of applied drugs.

Determination of the pH Gradient in Hair Follicles of Human Volunteers Using pH-Sensitive Melamine Formaldehyde-Pyranine Nile Blue Microparticles.

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.

Heat Enhanced Follicular Delivery of Isotretinoin to the Skin.

PURPOSE: The aim of this work was to evaluate the use of short durations of externally applied heat with chemical penetration enhancers to improve delivery of isotretinoin to the skin and in particular via the follicular route. METHODS: A range of chemical penetration enhancers were screened for their ability to improve isotretinoin delivery into human skin with heat using infinite dose, Franz cell experiments conducted in a water bath at a higher temperature to simulate heated conditions. Following this a prototype external heating system was developed that provided short durations of heat and its ability to improve delivery of finite doses into the skin and hair follicles was assessed. RESULTS: The magnitude of the effect of heat on drug delivery was influenced by the choice of vehicle with changes in isotretinoin flux across skin ranging from not statistically significant to 25 fold increases with heat in the infinite dose studies. The prototype heating system provided significant increases in the total delivery of isotretinoin into the skin from an optimised vehicle. Drug distribution in the skin revealed significant increases in isotretinoin delivery to the hair follicles, and deeper skin layers, but not to the stratum corneum, providing strong evidence that the enhancement in delivery occurred mainly via the hair follicles. CONCLUSION: These data indicate that the use of short durations of heat combined with chemical penetration enhancers offers a valuable strategy for improving the delivery of drugs such as isotretinoin to the skin via the hair follicles. Graphical Abstract Schematic illustration of the sodium thiosulphate heating system on a Franz diffusion cell and the subsequent impact of a short burst of heat on the delivery of isotretinoin into human skin.

Keratin network modifications lead to the mechanical stiffening of the hair follicle fiber.

The complex mechanical properties of biomaterials such as hair, horn, skin, or bone are determined by the architecture of the underlying fibrous bionetworks. Although much is known about the influence of the cytoskeleton on the mechanics of isolated cells, this has been less studied in tridimensional tissues. We used the hair follicle as a model to link changes in the keratin network composition and architecture to the mechanical properties of the nascent hair. We show using atomic force microscopy that the soft keratinocyte matrix at the base of the follicle stiffens by a factor of ∼360, from 30 kPa to 11 MPa along the first millimeter of the follicle. The early mechanical stiffening is concomitant to an increase in diameter of the keratin macrofibrils, their continuous compaction, and increasingly parallel orientation. The related stiffening of the material follows a power law, typical of the mechanics of nonthermal bending-dominated fiber networks. In addition, we used X-ray diffraction to monitor changes in the (supra)molecular organization within the keratin fibers. At later keratinization stages, the inner mechanical properties of the macrofibrils dominate the stiffening due to the progressive setting up of the cystine network. Our findings corroborate existing models on the sequence of biological and structural events during hair keratinization.

Expression and distribution patterns of spermine, spermidine, and putrescine in rat hair follicle.

No expression and distribution patterns of polyamines (PAs), spermine, spermidine, and their precursor putrescine in mammalian hair follicle are available, although polyamines are known to correlate well with hair growth and epidermal tumor genesis. Immunohistochemistry (IHC) using our original two monoclonal antibodies (mAbs) ASPM-29 specific for spermine or spermidine, and APUT-32 specific for putrescine allowed us to detect immunoreactivity for polyamines in hair follicles from normal adult rats. A wide range of immunoreactivity for the total spermine and spermidine was observed in the compartments of hair follicle: The highest degree of immunoreactivity for polyamines was observed in the matrix, in the Huxley's layer, in the deeper Henle's layer, and in the cuticle of the inner root sheath/the hair cuticle, while moderate immunoreactivity existed in the lower-to-mid cortex and the companion layer, followed by lower immunoreactivity in the outer root sheath, including the bulge region and in the deeper medulla, in which the immunoreactivity was also evident in their nuclei. In addition, somewhat surprisingly, with IHC by APUT-32 mAb, we detected significant levels of putrescine in the compartments, in which the immunostaining pattern was the closely similar to that of the total spermine and spermidine. Thus, among these compartments, the cell types of the matrix, the Huxley's layer, the deeper Henle's layer, and the cuticle of the inner root sheath/the hair cuticle seem to have the biologically higher potential in compartments of anagen hair follicle, maybe suggesting that they are involved more critically in the biological event of hair growth. In addition, we noted sharp differences of immunostaining by IHCs between ASPM-29 mAb and APUT-32 mAb in the epidermis cells and fibroblast. ASPM-29 mAb resulted in strong staining in both the cell types, but APUT-32 mAb showed only very light staining in both types. Consequently, the use of the two IHCs could be extremely useful in further studies on hair cycle and epidermal tumor genesis experimentally or clinically.

Is Human Sebum the Source of Skin Follicular Ultraviolet-Induced Red Fluorescence? A Cellular to Histological Study.

BACKGROUND: The ultraviolet-induced red fluorescence (UVRF) from human skin follicles was suggested to be a result of Propionibacterium acnes and was used for the monitoring of acne. More recent studies suggested that the UVRF may be more related to sebum rather than to microorganisms. OBJECTIVE: To clarify whether human sebum or follicular microorganisms are the source of UVRF. METHODS: We examined the fluorescence of human-derived SZ95 sebocytes, human sebaceous glands, sebum extracted from the sebaceous glands, and bacteria isolated from human hair follicles under ultraviolet light. RESULTS: SZ95 sebocytes, human sebaceous glands, and sebum do not emit UVRF. Two types of UVRF peaking at about 635 nm and at about 620 nm were detected in P. acnes and Staphylococcus epidermidis, respectively. This is the first report that S. epidermidis emits UVRF when it is anaerobically cultured and then exposed to air. CONCLUSION: Human follicular UVRF is emitted by resident bacteria, not by sebum. Therefore, UVRF may be used to monitor certain species of skin microorganisms.

Gene Expression Profiling of the Intact Dermal Sheath Cup of Human Hair Follicles.

Cells that constitute the dermal papillae of hair follicles might be derived from the dermal sheath, the peribulbar component of which is the dermal sheath cup. The dermal sheath cup is thought to include the progenitor cells of the dermal papillae and possesses hair inductive potential; however, it has not yet been well characterized. This study investigated the gene expression profile of the intact dermal sheath cup, and identified dermal sheath cup signature genes, including extracellular matrix components and bone morphogenetic protein-binding molecules, as well as transforming frowth factor beta 1 as an upstream regulator. Among these, gremilin-2, a member of the bone morphogenetic protein antagonists, was found by in situ hybridization to be highly specific to the dermal sheath cup, implying that gremlin-2 is a key molecule contributing to maintenance of the properties of the dermal sheath cup.

Inflammasome Activation Characterizes Lesional Skin of Folliculitis Decalvans.

Folliculitis decalvans (FD) is a chronic inflammatory disease leading to scarring alopecia with poorly defined pathogenesis. The aim of this study was to investigate the expression of markers associated with the activation of innate immune signals, such as inflammasome (NALP1 and NALP3), interleukin (IL)-1ß and IL-8 and type I interferon (MxA). A retrospective monocentric study was conducted and included 17 patients with FD with available biopsies. Disease activity (stable vs. active) was defined clinically and histologically. Immunostaining was performed using antibodies directed against NALP1, NALP3, IL-1ß, IL-8, and MxA on FD skin biopsies. Results were compared with normal controls and lichen planopilaris. Eleven patients had active disease and 6 had stable disease. NALP1, NALP3, and IL-1ß expression were significantly increased in hair follicles in FD compared with controls and lichen planopilaris. This study highlights the predominant immune signal associated with inflammasome activation in FD, suggesting the use of IL-1ß blockade in FD.

Ovine keratome: identification, localisation and genomic organisation of keratin and keratin-associated proteins.

Wool is composed primarily of proteins belonging to the keratin family. These include the keratins and keratin-associated proteins (KAPs) that are responsible for the structural and mechanical properties of wool fibre. Although all human keratin and KAP genes have been annotated, many of their ovine counterparts remain unknown and even less is known about their genomic organisation. The aim of this study was to use a combinatory approach including comprehensive cDNA and de novo genomic sequencing to identify ovine keratin and KAP genes and their genomic organisation and to validate the keratins and KAPs involved in wool production using ovine expressed sequence tag (EST) libraries and proteomics. The number of genes and their genomic organisation are generally conserved between sheep, cattle and human, despite some unique features in the sheep. Validation by protein mass spectrometry identified multiple keratins (types I and II), epithelial keratins and KAPs. However, 15 EST-derived genes, including one type II keratin and 14 KAPs, were identified in the sheep genome that were not present in the NCBI gene set, providing a significant increase in the number of keratin genes mapped on the sheep genome.

How to Discern Folliculotropic Mycosis Fungoides From Follicular Mucinosis Using a Pediatric Case.

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) with folliculotropic, atypical lymphocytes that may or may not have mucin deposition surrounding the hair follicle. Follicular mucinosis (FM) is a primary or secondary finding in FMF, lupus, or collagen vascular diseases that is only a histological process of mucin deposition surrounding the hair follicles. We present a case of a 6-year-old boy who had features of both FMF and primary follicular mucinosis (PFM). The case reveals key insights on FMF with concurrent FM in pediatric patients and how to differentiate between FMF and PFM.

Development of a Two-Dimensional Model for Predicting Transdermal Permeation with the Follicular Pathway: Demonstration with a Caffeine Study.

PURPOSE: The development of a new two-dimensional (2D) model to predict follicular permeation, with integration into a recently reported multi-scale model of transdermal permeation is presented. METHODS: The follicular pathway is modelled by diffusion in sebum. The mass transfer and partition properties of solutes in lipid, corneocytes, viable dermis, dermis and systemic circulation are calculated as reported previously [Pharm Res 33 (2016) 1602]. The mass transfer and partition properties in sebum are collected from existing literature. None of the model input parameters was fit to the clinical data with which the model prediction is compared. RESULTS: The integrated model has been applied to predict the published clinical data of transdermal permeation of caffeine. The relative importance of the follicular pathway is analysed. Good agreement of the model prediction with the clinical data has been obtained. The simulation confirms that for caffeine the follicular route is important; the maximum bioavailable concentration of caffeine in systemic circulation with open hair follicles is predicted to be 20% higher than that when hair follicles are blocked. CONCLUSIONS: The follicular pathway contributes to not only short time fast penetration, but also the overall systemic bioavailability. With such in silico model, useful information can be obtained for caffeine disposition and localised delivery in lipid, corneocytes, viable dermis, dermis and the hair follicle. Such detailed information is difficult to obtain experimentally.