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Caffeine absorption in vivo in anesthetized rodents measured by transdermal microdialysis. Concentration-time profiles of caffeine skin penetration in mouse (A) and rat (C) abdominal skin surface. Area under the concentration-time curves (AUC) in mice (B) and in rats (D). 0 TS: native skin, without tape-stripping; 10 TS: sensitized skin, with 10 tape-strippings. N = 5, ***: p < 0.005 in twosample student t-test.
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To develop proper drug formulations and to optimize the delivery of their active ingredients through the dermal barrier, the Franz diffusion cell system is the most widely used in vitro/ex vivo technique. However, different providers and manufacturers make various types of this equipment (horizontal, vertical, static, flow-through, smaller and larg...
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... absorption was also compared in vivo in mice and rats with and without skin sensitization (Figure 7). The free levels of caffeine in the dermis showed a peak in both species at 60 min after the placement of caffeine cream containing patches on the skin. ...
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... The capillaries present the highest cross-sectional surface for fluid perfusion in the body. The currently available organ-on-a-chip or skin-on-a-chip systems apply different perfusion flow rates depending on the microchannel design and the placement and integration of cells or ex vivo tissues in the devices [5][6][7][8][9]. To achieve physiologically relevant conditions, the shear stress on the channel wall and cells and the tissue preparations should be considered. ...
... The skin permeability tests were performed in (1) a single-channel microfluidic diffusion chamber (sMDC, described earlier in detail by Lukács et al., 2019 [5] and Varga-Medveczky et al., 2021 [14]), (2) a multichannel microfluidic chamber, and 3) the LiveBox2 IVTech system (Figure 1). The technical details of the different devices are summarized in Table 2. ...
Organ-on-a-chip technologies show exponential growth driven by the need to reduce the number of experimental animals and develop physiologically relevant human models for testing drugs. In vitro, microfluidic devices should be carefully designed and fabricated to provide reliable tools for modeling physiological or pathological conditions and assessing, for example, drug delivery through biological barriers. The aim of the current study was to optimize the utilization of three existing skin-on-a-chip microfluidic diffusion chambers with various designs. For this, different perfusion flow rates were compared using cellulose acetate membrane, polyester membrane, excised rat skin, and acellular alginate scaffold in the chips. These diffusion platforms were integrated into a single-channel microfluidic diffusion chamber, a multi-channel chamber, and the LiveBox2 system. The experimental results revealed that the 40 µL/min flow rate resulted in the highest diffusion of the hydrophilic model formulation (2% caffeine cream) in each system. The single-channel setup was used for further analysis by computational fluid dynamics simulation. The visualization of shear stress and fluid velocity within the microchannel and the presentation of caffeine progression with the perfusion fluid were consistent with the measured data. These findings contribute to the development and effective application of microfluidic systems for penetration testing.
... SoC devices are microfluidic systems that mimic the structure and function of the skin in a miniaturized and integrated format. They consist of a microchannel network that contains a porous membrane, where a layer of skin cells (e.g., keratinocytes, fibroblasts, melanocytes, endothelial cells) is cultured [138] or skin tissue [139] is placed and exposed to the drug formulation in the upper channel while a buffer solution flows in the lower channel. The drug concentration in the lower channel can be measured by an online detector or a sampling port. ...
Skin is the largest organ and a multifunctional interface between the body and its environment. It acts as a barrier against cold, heat, injuries, infections, chemicals, radiations or other exogeneous factors, and it is also known as the mirror of the soul. The skin is involved in body temperature regulation by the storage of fat and water. It is an interesting tissue in regard to the local and transdermal application of active ingredients for prevention or treatment of pathological conditions. Topical and transdermal delivery is an emerging route of drug and cosmetic administration. It is beneficial for avoiding side effects and rapid metabolism. Many pharmaceutical, technological and cosmetic innovations have been described and patented recently in the field. In this review, the main features of skin morphology and physiology are presented and are being followed by the description of classical and novel nanoparticulate dermal and transdermal drug formulations. The biophysical aspects of the penetration of drugs and cosmetics into or across the dermal barrier and their investigation in diffusion chambers, skin-on-a-chip devices, high-throughput measuring systems or with advanced analytical techniques are also shown. The current knowledge about mathematical modeling of skin penetration and the future perspectives are briefly discussed in the end, all also involving nanoparticulated systems.
... Similarly, to the Franz diffusion cells, it contains two compartments, and the membrane or skin sample is placed between them. The major advantage of this technique is the reduction of volumes and required components, membranes, and skins, as discussed in details in our previous papers [38,39]. The diffusion surface was 0.5 cm 2 , which was separating the cream containing donor chamber and the PPF filled receptor chamber. ...
Mathematical models of epidermal and dermal transport are essential for optimization and development of products for percutaneous delivery both for local and systemic indication and for evaluation of dermal exposure to chemicals for assessing their toxicity. These models often help directly by providing information on the rate of drug penetration through the skin and thus on the dermal or systemic concentration of drugs which is the base of their pharmacological effect. The simulations are also helpful in analyzing experimental data, reducing the number of experiments and translating the in vitro investigations to an in-vivo setting. In this study skin penetration of topically administered caffeine cream was investigated in a skin-on-a-chip microfluidic diffusion chamber at room temperature and at 32°C. Also the transdermal penetration of caffeine in healthy and diseased conditions was compared in mouse skins from intact, psoriatic and allergic animals. In the last experimental setup dexamethasone, indomethacin, piroxicam and diclofenac were examined as a cream formulation for absorption across the dermal barrier. All the measured data were used for making mathematical simulation in a three-compartmental model. The calculated and measured results showed a good match, which findings indicate that our mathematical model might be applied for prediction of drug delivery through the skin under different circumstances and for various drugs in the novel, miniaturized diffusion chamber.
... The first-generation devices were designed by Lukács et al. where the skin sample is stretched through a membrane holder [112]. The holder is merged with a donor cell, creating a funnel-like the bottom is separated from the peripheral perfusion fluid. ...
Novel formulations are developed for dermatological applications to address a wide range of patient needs and therapeutic challenges. By pushing the limits of pharmaceutical technology, these formulations strive to provide safer, more effective, and patient-friendly solutions for dermatological concerns, ultimately improving the overall quality of dermatological care. The article explores the different types of novel dermatological formulations, including nanocarriers, transdermal patches, microsponges, and microneedles, and the techniques involved in the cutaneous pharmacokinetics of these innovative formulations. Furthermore, the significance of knowing cutaneous pharmacokinetics and the difficulties faced during pharmacokinetic assessment have been emphasized. The article examines all the methods employed for the pharmacokinetic evaluation of novel dermatological formulations. In addition to a concise overview of earlier techniques, discussions on novel methodologies, including tape stripping, in vitro permeation testing, cutaneous microdialysis, confocal Raman microscopy, and matrix-assisted laser desorption/ionization mass spectrometry have been conducted. Emerging technologies like the use of microfluidic devices for skin absorption studies and computational models for predicting drug pharmacokinetics have also been discussed. This article serves as a valuable resource for researchers, scientists, and pharmaceutical professionals determined to enhance the development and understanding of novel dermatological drug products and the complex dynamics of cutaneous pharmacokinetics.
... The size of the standard Franz chamber requires large and mechanically robust samples that are difficult to achieve with cell culture-based approaches [12,13]. In order to overcome the limitations mentioned above, various microfluidic Franz chambers have been proposed that allow both automated sample collection and the utilization of substantially smaller samples [14][15][16][17][18][19][20]. The requirement of a continuous microfluidic flow, however, must be provided with a non-standard tissue culture infrastructure and also makes high throughput parallel measurements challenging to achieve. ...
... While both transwell inserts and Franz chambers are devices used to study biological barriers, their size, culture conditions, and mechanical requirements for the sample studied segregated their usage into distinct fields within pharmacology. Here, we demonstrated that, with proper sampling and mathematical corrections, regular transwell cell cultures can provide the information usually extracted from Franz chamber measurements [14][15][16][17][18][19][20][34][35][36]. Our estimate that 95% of the basal volume is removed during the automated sampling procedure (q b = 5.3%, Table 2) indicates that the basolateral compartment can be considered well-mixed on a time scale exceeding the length of the sampling period. ...
... One potential source of this discrepancy is the significant amount of test compound accumulating within the barrier layer, N. While the diffusion model (Figure 5a) provides an estimate in Equation (24), the sampling model presented does not consider it in Equations (16) and (17). Future work can develop a fitting procedure that handles both the diffusive model of the barrier layer and the adsorption effects of the sampling process. ...
In the preclinical phase of drug development, it is necessary to determine how the active compound can pass through the biological barriers surrounding the target tissue. In vitro barrier models provide a reliable, low-cost, high-throughput solution for screening substances early in the drug candidate development process, thus reducing more complex and costly animal studies. In this pilot study, the transport properties of TB501, an antimycobacterial drug candidate, were characterized using an in vitro barrier model of VERO E6 kidney cells. The compound was delivered into the apical chamber of the transwell insert, and its concentration passing through the barrier layer was measured through the automated sampling of the basolateral compartment, where media were replaced every 30 min for 6 h, and the collected samples were stored for further spectroscopic analysis. The kinetics of TB501 concentration obtained from VERO E6 transwell cultures and transwell membranes saturated with serum proteins reveal the extent to which the cell layer functions as a diffusion barrier. The large number of samples collected allows us to fit a detailed mathematical model of the passive diffusive currents to the measured concentration profiles. This approach enables the determination of the diffusive permeability, the diffusivity of the compound in the cell layer, the affinity of the compound binding to the cell membrane as well as the rate by which the cells metabolize the compound. The proposed approach goes beyond the determination of the permeability coefficient and offers a more detailed pharmacokinetic characterization of the transwell barrier model. We expect the presented method to be fruitful in evaluating other compounds with different chemical features on simple in vitro barrier models. The proposed mathematical model can also be extended to include various forms of active transport.
... Moreover, constructing artificial 3D membranes is often cheaper and more representative of the physiology or structure of human skin in modeling skin wounds, taking the place of animal models in demonstrating the pharmacological effects of a drug [159,160]. Lukács et al. [161] developed microfluidics for artificial 3D membranes, a "skin-on-a-chip model", which was integrated with microfabricated sensors and aimed to develop proper drug formulations and optimize the delivery of their active ingredients via the dermal barrier. ...
For decades, tissue regeneration has been a challenging issue in scientific modeling and human practices. Although many conventional therapies are already used to treat burns, muscle injuries, bone defects, and hair follicle injuries, there remains an urgent need for better healing effects in skin, bone, and other unique tissues. Recent advances in three-dimensional (3D) printing and real-time monitoring technologies have enabled the creation of tissue-like membranes and the provision of an appropriate microenvironment. Using tissue engineering methods incorporating 3D printing technologies and biomaterials for the extracellular matrix (ECM) containing scaffolds can be used to construct a precisely distributed artificial membrane. Moreover, advances in smart sensors have facilitated the development of tissue regeneration. Various smart sensors may monitor the recovery of the wound process in different aspects, and some may spontaneously give feedback to the wound sites by releasing biological factors. The combination of the detection of smart sensors and individualized membrane design in the healing process shows enormous potential for wound dressings. Here, we provide an overview of the advantages of 3D printing and conventional therapies in tissue engineering. We also shed light on different types of 3D printing technology, biomaterials, and sensors to describe effective methods for use in skin and other tissue regeneration, highlighting their strengths and limitations. Finally, we highlight the value of 3D bioengineered membranes in various fields, including the modeling of disease, organ-on-a-chip, and drug development.
... In a full-thickness skin-on-a-chip model, a fibrin-based dermal matrix was used to construct a dermal scaffold and fill the upper surface and interior with keratin-forming cells and fibroblasts, respectively, resulting in a simple full-skin equivalent, which was also shown to be well structured by tissue staining [122] (Figure 3E). Biopsied skin tissue has also been used to replace monolayers of keratin-forming cells [123,124], to establish better models of full-thickness skin-on-a-chip. Other researchers have applied periodic mechanical stimulation to the skin based on a full-thickness skin-on-a-chip model to simulate circadian rhythms, resulting in an aging skin model that can be used for drug development and disease modelling in aging skin [125]. ...
... Researchers established an OC model containing mouse brain tissue sections and infused the microarray with different doses of STS-simulating chemotherapy drugs, ranging from 10 nM to 6 µM. Tissue staining revealed that the number of apoptotic cells increased with increasing STS concentrations [123]. This suggests that OCs have the potential to test precise drug dosing; however, many factors not included in the microarray model, such as the ratio of drug uptake and metabolism, need to be considered in the process of clinical translation. ...
Drugs may undergo costly preclinical studies but still fail to demonstrate their efficacy in clinical trials, which makes it challenging to discover new drugs. Both in vitro and in vivo models are essential for disease research and therapeutic development. However, these models cannot simulate the physiological and pathological environment in the human body, resulting in limited drug detection and inaccurate disease modelling, failing to provide valid guidance for clinical application. Organs-on-chips (OCs) are devices that serve as a micro-physiological system or a tissue-on-a-chip; they provide accurate insights into certain functions and the pathophysiology of organs to precisely predict the safety and efficiency of drugs in the body. OCs are faster, more economical, and more precise. Thus, they are projected to become a crucial addition to, and a long-term replacement for, traditional preclinical cell cultures, animal studies, and even human clinical trials. This paper first outlines the nature of OCs and their significance, and then details their manufacturing-related materials and methodology. It also discusses applications of OCs in drug screening and disease modelling and treatment, and presents the future perspective of OCs.
... In recent years, there have been significant developments leading to the establishment of a range of skin-on-a-chip platforms, as summarized in Table 1. These are based on a wide variety of tissue models, from keratinocyte [148][149][150][151][152] or fibroblast [77,[153][154][155] cultures to HSEs [146,147,156] or ex vivo tissue [157][158][159][160][161]. They have been applied to study transdermal transport [146,157,[162][163][164] and wound healing [77,151,155] or to assess the response to shear stress [77,147,[152][153][154], chemical agents [146,[148][149][150]154,160,161,[165][166][167] or electrical stimuli [77,151]. ...
... In recent years, there have been significant developments leading to the establishment of a range of skin-on-a-chip platforms, as summarized in Table 1. These are based on a wide variety of tissue models, from keratinocyte [148][149][150][151][152] or fibroblast [77,[153][154][155] cultures to HSEs [146,147,156] or ex vivo tissue [157][158][159][160][161]. They have been applied to study transdermal transport [146,157,[162][163][164] and wound healing [77,151,155] or to assess the response to shear stress [77,147,[152][153][154], chemical agents [146,[148][149][150]154,160,161,[165][166][167] or electrical stimuli [77,151]. Furthermore, new microfluidic systems for skin disease emulation have also emerged [148,158,168,169]. ...
Skin is widely used as a drug delivery route due to its easy access and the possibility of using relatively painless methods for the administration of bioactive molecules. However, the barrier properties of the skin, along with its multilayer structure, impose severe restrictions on drug transport and bioavailability. Thus, bioengineered models aimed at emulating the skin have been developed not only for optimizing the transdermal transport of different drugs and testing the safety and toxicity of substances but also for understanding the biological processes behind skin wounds. Even though in vivo research is often preferred to study biological processes involving the skin, in vitro and ex vivo strategies have been gaining increasing relevance in recent years. Indeed, there is a noticeably increasing adoption of in vitro and ex vivo methods by internationally accepted guidelines. Furthermore, microfluidic organ-on-a-chip devices are nowadays emerging as valuable tools for functional and behavioural skin emulation. Challenges in miniaturization, automation and reliability still need to be addressed in order to create skin models that can predict skin behaviour in a robust, high-throughput manner, while being compliant with regulatory issues, standards and guidelines. In this review, skin models for transdermal transport, wound repair and cutaneous toxicity will be discussed with a focus on high-throughput strategies. Novel microfluidic strategies driven by advancements in microfabrication technologies will also be revised as a way to improve the efficiency of existing models, both in terms of complexity and throughput.
... Depending on the type of skin model on the chip, the function of the skin chip is also different. STFB [7,8,17] is generally used to construct multi-organ co-culture chips to establish a circulatory system to study drug metabolism. SMFC is more committed to a more accurate simulation of full-thickness skin. ...
... Similar to the Franz diffusion cells, it contains two compartments, and the membrane or skin is placed between them. The major advantage of this technique is the reduction in needed volumes and pieces in the required components, membranes and skins, as discussed in detail in our previous papers [25,35]. The diffusion surface is 0.5 cm 2 , which separates the aminophosphonate cream-containing donor chamber and the PPF-filled receptor chamber. ...
α-Aminophosphonates are organophosphorus compounds with an obvious similarity with α-amino acids. Owing to their biological and pharmacological characteristics, they have attracted the attention of many medicinal chemists. α-Aminophosphonates are known to exhibit antiviral, antitumor, antimicrobial, antioxidant and antibacterial activities, which can all be important in pathological dermatological conditions. However, their ADMET properties are not well studied. The aim of the current study was to provide preliminary information about the skin penetration of three preselected α-aminophosphonates when applying them as topical cream formulations in static and dynamic diffusion chambers. The results indicate that aminophosphonate 1a, without any substituent in the para position, shows the best release from the formulation and the highest absorption through the excised skin. However, based on our previous study, the in vitro pharmacological potency was higher in the case of para-substituted molecules 1b and 1c. The particle size and rheological studies revealed that the 2% cream of aminophosphonate 1a was the most homogenous formulation. In conclusion, the most promising molecule was 1a, but further experiments are proposed to uncover the possible transporter interactions in the skin, optimize the topical formulations and improve PK/PD profiles in case of transdermal delivery.
