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The structure of one-well of a 96-well plate of a parallel artificial membrane permeability assay (PAMPA) system.
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During the last decades, several technologies were developed for testing drug delivery through the dermal barrier. Investigation of drug penetration across the skin can be important in topical pharmaceutical formulations and also in cosmeto-science. The state-of- the-art in the field of skin diffusion measurements, different devices, and diffusion...
Citations
... 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.
... 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.
... OoCs have been proven to be capable of building higher-level physiological functions of tissues such as the brain, eye, lung, liver, kidney, intestine, and placenta and have allowed researchers to study the pathological condition arising from a disrupted homeostatic state such as tumor (Kang et al, 2021). Recent advancements have expanded the scope of SoC, integrating it within skin disease modeling and platforms for rapid screening of therapeutic agents (Varga-Medveczky et al, 2021;Zhang et al, 2018). Its potential in dermatological research is expected to have a major impact on drug development and elucidation of the multifaceted nature of disease pathogenesis. ...
... Ligands 5, 3 & 4 were predicted to have better total drug clearance comparable to others, indicating none renal toxicity. Although, compounds displayed good physicochemical properties, however, they are likely to cause skin sensitization as they can penetrate through skin and this could interference against P-glycoprotein substrate enzyme (44). ...
Introduction: The human tau protein is a key protein involved in various neurodegenerative disease (NDs) including Parkinson’s disease (PD). The protein has high tendency to aggregate into oligomers, subsequently generating insoluble mass in the brain. Symptoms of PD include tremor, bradykinesia, rigidity, and postural instability. Currently drugs for PD treatment are only symptom-targeted while effective therapeutic treatment remains a challenge. The objective of this study is to identify novel promising anti-PD drugs using computational techniques. Method: ligand-based (LB) receptor modelling was conducted using LigandScout, validated and subjected to Glide XP docking, virtual screening, ADMET, and molecular dynamics predictions. Results: The adopted LB modelling generated pharmacophoric features of 5 hydrogen bond donors, 1 aromatic rings, and 7 hydrogen bond acceptors. The validation result indicated GH score of 0.73 and EF of 36.30 as validation protocols, probing it to be an ideal model. Using 3D query of the modelling a total of 192 compounds were retrieved from interbioscreen database containing 70,436 natural compounds. Interestingly, ligands 1, 2, 3, 4 and 5 orderly indicated higher binding affinities to the receptor with Glide XP docking of -7.451, -7.368, -7.101, -6.878, and -6.789 compared to a clinical drug Anle138b with -4.552 kcal/mol respectively. Furthermore, molecular dynamics and pkCSM pharmacokinetics demonstrated ligands 1, 2, & 4 having better stability and low toxicity profiles compared to the reference. Conclusion: In summary, the study pave way for discovery of small molecules that could be recommended as adjuvant /single candidate as ant-PD candidates upon further translational study.
... Thus, when designing skin OoCs, the reproduction of multiple layers of skin is crucial (i.e., epidermis, dermis, and hypodermis). However, because of its complexity, it is challenging to develop a suitable substitute that can simulate all the skin's properties [156]. In this context, the most common skin OoCs has been those generated by introducing directly the tissue inside the model, which continues to be regarded as the gold standard method for simulating physiological situations in a realistic setting [157,158]. ...
Drug evaluation has always been an important area of research in the pharmaceutical industry. However, animal welfare protection and other shortcomings of traditional drug development models pose obstacles and challenges to drug evaluation. Organ-on-a-chip (OoC) technology, which simulates human organs on a chip of the physiological environment and functionality, and with high fidelity reproduction organ-level of physiology or pathophysiology, exhibits great promise for innovating the drug development pipeline. Meanwhile, the advancement in artificial intelligence (AI) provides more improvements for the design and data processing of OoCs. Here, we review the current progress that has been made to generate OoC platforms, and how human single and multi-OoCs have been used in applications, including drug testing, disease modeling, and personalized medicine. Moreover, we discuss issues facing the field, such as large data processing and reproducibility, and point to the integration of OoCs and AI in data analysis and automation, which is of great benefit in future drug evaluation. Finally, we look forward to the opportunities and challenges faced by the coupling of OoCs and AI. In summary, advancements in OoCs development, and future combinations with AI, will eventually break the current state of drug evaluation.
... This "administration route" may also have special importance in those cases when the drug candidate shows instability in the plasma or the target tissue is the skin itself. To the best of our knowledge, skin penetration of α-aminophosphonates has not been investigated yet in diffusion chambers, neither ex vivo nor in vitro [25][26][27]. There are only data available from in silico studies on the gastrointestinal tract, blood-brain barrier and skin models [18,28]. ...
... 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.
... In particular, the advantages of the spatiotemporal control allow researchers to closely recapitulate in vivo functions (both normal and disease states) by integrating several well-understood components into a single in vitro chip. However, reliable skin-nerve interactions and communication in the anatomically innervated epidermis have not yet taken advantage of microfluidics because they are based on the structure of vertically stacked systems, such as transwell insert cultures 16,19,33,34 . ...
Reconstruction of skin equivalents with physiologically relevant cellular and matrix architecture is indispensable for basic research and industrial applications. As skin-nerve crosstalk is increasingly recognized as a major element of skin physiological pathology, the development of reliable in vitro models to evaluate the selective communication between epidermal keratinocytes and sensory neurons is being demanded. In this study, we present a three-dimensional innervated epidermal keratinocyte layer as a sensory neuron-epidermal keratinocyte co-culture model on a microfluidic chip using the slope-based air-liquid interfacing culture and spatial compartmentalization. Our co-culture model recapitulates a more organized basal-suprabasal stratification, enhanced barrier function, and physiologically relevant anatomical innervation and demonstrated the feasibility of in situ imaging and functional analysis in a cell-type-specific manner, thereby improving the structural and functional limitations of previous coculture models. This system has the potential as an improved surrogate model and platform for biomedical and pharmaceutical research.
... This miniaturized chip based on microfluidics is a platform to mimic the skin and its equivalents in a simple manner. Figure 13 depicts a solution for designing the skin-on-a-chip for testing drug penetration through the skin [119]. Sutterby et al. [74] reported that the skin-on-a-chip circumvented the drawbacks of traditional cell models by imparting control in the microenvironment and inducing related mechanical information. ...
... Figure 13. The experimental setup consists of two simultaneous skins-on-a-chip [119]. This setup contains a flow-through dynamic microfluidic device and a programmable syringe pump. ...
... 13, x FOR PEER REVIEW 18 of 25 a solution for designing the skin-on-a-chip for testing drug penetration through the skin[119]. ...
Organs-on-chips (OoCs) are miniature microfluidic systems that have arguably become a class of advanced in vitro models. Deep learning, as an emerging topic in machine learning, has the ability to extract a hidden statistical relationship from the input data. Recently, these two areas have become integrated to achieve synergy for accelerating drug screening. This review provides a brief description of the basic concepts of deep learning used in OoCs and exemplifies the successful use cases for different types of OoCs. These microfluidic chips are of potential to be assembled as highly potent human-on-chips with complex physiological or pathological functions. Finally, we discuss the future supply with perspectives and potential challenges in terms of combining OoCs and deep learning for image processing and automation designs.
... Drug diffusion and heat transfer in the dermal layers of the skin can be predicted using mathematical modeling and computational fluid dynamics [231]. In general, this device consists of three main parts: a set of polymer-based microfluidic channels, a frame that surrounds the microfluidic channel system, and a sample holder that holds and inserts the membrane or skin sample into the membrane chamber [232]. Additionally, the skin-on-a-chip microfluidic platform enables cost-effective and reliable drug screening as the delivery setup is miniaturised [232]. ...
... In general, this device consists of three main parts: a set of polymer-based microfluidic channels, a frame that surrounds the microfluidic channel system, and a sample holder that holds and inserts the membrane or skin sample into the membrane chamber [232]. Additionally, the skin-on-a-chip microfluidic platform enables cost-effective and reliable drug screening as the delivery setup is miniaturised [232]. Currently, a technology involving the connection of skin-on-a-chip devices to robotic systems for mid-throughput drug screening in the pharmaceutical industry is being validated and optimised [231]. ...
Skin delivery is an exciting and challenging field. It is a promising approach for effective drug delivery due to its ease of administration, ease of handling, high flexibility, controlled release, prolonged therapeutic effect, adaptability, and many other advantages. The main associated challenge, however, is low skin permeability. The skin is a healthy barrier that serves as the body's primary defence mechanism against foreign particles. New advances in skin delivery (both topical and transdermal) depend on overcoming the challenges associated with drug molecule permeation and skin irritation. These limitations can be overcome by employing new approaches such as lipid nanosystems. Due to their advantages (such as easy scaling, low cost, and remarkable stability) these systems have attracted interest from the scientific community. However, for a successful formulation, several factors including particle size, surface charge, components, etc. have to be understood and controlled. This review provided a brief overview of the structure of the skin as well as the different pathways of nanoparticle penetration. In addition, the main factors influencing the penetration of nanoparticles have been highlighted. Applications of lipid nanosystems for dermal and transdermal delivery, as well as regulatory aspects, were critically discussed.
... The diffusion of drugs and heat transfer into dermal layers of skin can be predicted using mathematical modeling and computational fluid dynamics (CFD) [52]. In general, this device design contains three main parts: a microfluidic channel assembly based on polymer, a frame surrounding the microfluidic channel system, and a sample holder which holds and inserts the membrane/skin sample into the microfluidic diffusion chamber [53]. The skin-on-a-chip microfluidic platform further provides an economical and reliable drug screening as the optimal approach is to miniaturize the diffusion setup [54]. ...
Upon exhaustive research, the transdermal drug delivery system (TDDS) has appeared as a potential, well-accepted, and popular approach to a novel drug delivery system. Ease of administration, easy handling, minimum systemic exposure, least discomfort, broad flexibility and tunability, controlled release, prolonged therapeutic effect, and many more perks make it a promising approach for effective drug delivery. Although, the primary challenge associated is poor skin permeability. Skin is an intact barrier that serves as a primary defense mechanism to preclude any foreign particle's entry into the body. Owing to the unique anatomical framework, i.e., compact packing of stratum corneum with tight junction and fast anti-inflammatory responses, etc., emerged as a critical physiological barrier for TDDS. Fusion with other novel approaches like nanocarriers, specially designed transdermal delivery devices, permeation enhancers, etc., can overcome the limitations. Utilizing such strategies, some of the products are under clinical trials, and many are under investigation. This review explores all dimensions that overcome poor permeability and allows the drug to attain maximum potential. The article initially compiles fundamental features, components, and design of TDDS, followed by critical aspects and various methods, including in vitro, ex vivo, and in vivo methods of assessing skin permeability. The work primarily aimed to highlight the recent advancement in novel strategies for effective transdermal drug delivery utilizing active methods like iontophoresis, electroporation, sonophoresis, microneedle, needleless jet injection, etc., and passive methods such as the use of liposomes, SLN, NLC, micro/nanoemulsions, dendrimers, transferosomes, and many more nanocarriers. In all, this compilation will provide a recent insight on the novel updates along with basic concepts, the current status of clinical development, and challenges for the clinical translation of TDDS.
