Pore Dilation Research Articles

Soft interface instability and gas flow channeling in low-permeability deformable media

Understanding gas percolation through a clay layer or a shale formation is of great importance for the development of a geologic repository for nuclear waste disposal, a subsurface system for gas storage, and an engineering approach for hydrocarbon extraction from unconventional reservoirs. Gas injection experiments have revealed complex dynamic behaviours of gas percolation through water saturated compacted bentonite, characterized by a high breakthrough pressure, rapid breakthrough, a pressure/stress decay after the breakthrough, a relatively high migration rate, high-frequency periodic/nonperiodic variations in flow rate, stepwise rate reductions during relaxation, and low gas saturation over the whole process, all indicating channelling nature of the processes. Using linear stability analyses, we show that this channelling can autonomously emerge from the instability of the deformable interface between the injected gas and the compacted bentonite matrix driven by local stress concentration, pore dilation, and hydrologic gradient. Channel patterns formed would possess a fractal geometry. We further show that, once a percolating channel is established, the gas injected would percolate through the channel in a chain of gas bubbles, also due to the interface instability, resulting in periodic/chaotic variations in gas flow rate. Our work provides a unified explanation for key features observed for gas percolation in low-permeability deformable media. The work also suggests a possibility of designing an engineered barrier system for a nuclear waste repository that can have controllable gas release while limit water transport.

Activation mechanisms of dimeric mechanosensitive OSCA/TMEM63 channels

OSCA/TMEM63 channels, which have transporter-like architectures, are bona fide mechanosensitive (MS) ion channels that sense high-threshold mechanical forces in eukaryotic cells. The activation mechanism of these transporter-like channels is not fully understood. Here we report cryo-EM structures of a dimeric OSCA/TMEM63 pore mutant OSCA1.1-F516A with a sequentially extracellular dilated pore in a detergent environment. These structures suggest that the extracellular pore sequential dilation resembles a flower blooming and couples to a sequential contraction of each monomer subunit towards the dimer interface and subsequent extrusion of the dimer interface lipids. Interestingly, while OSCA1.1-F516A remains non-conducting in the native lipid environment, it can be directly activated by lyso-phosphatidylcholine (Lyso-PC) with reduced single-channel conductance. Structural analysis of OSCA1.1-F516A in lyso-PC-free and lyso-PC-containing lipid nanodiscs indicates that lyso-PC induces intracellular pore dilation by attracting the M6b to upward movement away from the intracellular side thus extending the intracellular pore. Further functional studies indicate that full activation of MS OSCA/TMEM63 dimeric channels by high-threshold mechanical force also involves the opening of both intercellular and extracellular pores. Our results provide the fundamental activation paradigm of the unique transporter-like MS OSCA/TMEM63 channels, which is likely applicable to functional branches of the TMEM63/TMEM16/TMC superfamilies.

Research on Closed Loop Control of Pulse Power Discharge Frequency

Abstract During the process of improving unconventional oil and gas reservoirs using electric pulse stimulation, to achieve optimal effects in terms of rock matrix pore dilation and fracturing, it is required that the electric pulse frequency is close to the inherent frequency of the reservoir. In the context of research focused on open-loop control for the discharge frequency of a high-pressure pulse device, the topological structure and mathematical model of the high-pressure pulse discharge device have been established. The analysis of current variations during the discharge process has been conducted. A closed-loop control strategy based on the super-helix sliding mode control has been proposed, along with the introduction of a nonlinear extended state observer. This strategy aims to achieve closed-loop control of the discharge frequency, and its effectiveness and control performance have been verified through simulation.

Progressive internal erosion during triaxial shearing: an X-ray micro-computed tomography study

Fines removal during internal erosion results in the permeability increase and strength reduction of granular soils. This study examines internal erosion during shearing of granular soils under triaxial loading conditions using a specially designed apparatus and X-ray computed tomography scans. Two gap-graded soil samples with different fines content are tested and scanned multiple times to characterise sample- and pore-scale volume change and fines content using image-processing techniques. Results show that internal erosion increases gradually with axial strain and has a complex impact on permeability increase due to the spatial variation of fines content. Triaxial shearing induces both pore contraction and dilation, destabilises the clogging of fine particles and promotes internal erosion. Also, the erosion of force-supporting fine particles at a high fines content facilitates pore contraction. The progressive internal erosion due to mechanical disturbance leads to the formation of a flow channel from the upstream loading platen throughout the sample, resulting in a dramatic increase in permeability. Overall, this study provides novel insights regarding the interplay between the hydro-mechanical processes during shearing under constant seepage.

Synergistic regulation of fusion pore opening and dilation by SNARE and synaptotagmin-1.

Fusion pore opening is a transient intermediate state of synaptic vesicle exocytosis, which is highly dynamic and precisely regulated by the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex and synaptotagmin-1 (Syt1). Yet, the regulatory mechanism is not fully understood. In this work, using single-channel membrane fusion electrophysiology, we determined that SNAREpins are important for driving fusion pore opening and dilation but incapable of regulating the dynamics. When Syt1 was added, the closing frequency of fusion pores significantly increased, while the radius of fusion pores mildly decreased. In response to Ca2+, SNARE/Syt1 greatly increased the radius of fusion pores and reduced their closing frequency. Moreover, the residue F349 in the C2B domain of Syt1, which mediates Syt1 oligomerization, was required for clamping fusion pore opening in the absence of Ca2+, probably by extending the distance between the two membranes. Finally, in Ca2+-triggered fusion, the primary interface between SNARE and Syt1 plays a critical role in stabilizing and dilating the fusion pore, while the polybasic region of Syt1 C2B domain has a mild effect on increasing the radius of the fusion pore. In summary, our results suggest that Syt1, SNARE, and the anionic membrane synergically orchestrate the dynamics of fusion pore opening in synaptic vesicle exocytosis.

Enhancing the Study of Quantal Exocytotic Events: Combining Diamond Multi-Electrode Arrays with Amperometric PEak Analysis (APE) an Automated Analysis Code.

MicroGraphited-Diamond-Multi Electrode Arrays (μG-D-MEAs) can be successfully used to reveal, in real time, quantal exocytotic events occurring from many individual neurosecretory cells and/or from many neurons within a network. As μG-D-MEAs arrays are patterned with up to 16 sensing microelectrodes, each of them recording large amounts of data revealing the exocytotic activity, the aim of this work was to support an adequate analysis code to speed up the signal detection. The cutting-edge technology of microGraphited-Diamond-Multi Electrode Arrays (μG-D-MEAs) has been implemented with an automated analysis code (APE, Amperometric Peak Analysis) developed using Matlab R2022a software to provide easy and accurate detection of amperometric spike parameters, including the analysis of the pre-spike foot that sometimes precedes the complete fusion pore dilatation. Data have been acquired from cultured PC12 cells, either collecting events during spontaneous exocytosis or after L-DOPA incubation. Validation of the APE code was performed by comparing the acquired spike parameters with those obtained using Quanta Analysis (Igor macro) by Mosharov et al.

The Anisotropic Behavior of a Clay Shale: Strength, Hydro‐Mechanical Couplings and Failure Processes

AbstractMany rocks exhibit a structural composition, which leads to an anisotropic behavior of different properties. A proper understanding of the directional dependency of these properties is required to analyze and predict the failure behavior of the rock mass upon stress changes during many geo‐engineering applications. This study investigates the selected host rock for nuclear waste disposal in Switzerland, Opalinus Clay, for its anisotropic unconfined compressive and tensile strength, poromechanical response, and effective shear strength in an extensive laboratory testing campaign. The results show the lowest unconfined compressive strength at angles of 30°–45° between the bedding plane and the compressive load direction, whereby the lowest tensile strength is found to be normal to the bedding orientation. Triaxial consolidated‐undrained compression tests reveal an anisotropic poromechanical behavior as well as peak and residual effective strength values, which are largely controlled by the orientation of the bedding plane with respect to the maximum principal stress. The magnitude of excess pore water pressures and dilation are both functions of loading configuration. The comparison of peak strength values for different loading angles indicates that the lowest effective shear strength can be expected at a loading configuration of approximately 45° between bedding orientation and the loading axis. The variation in the hydro‐mechanical response is associated with the microstructure controlling the poroelasticity and the failure processes. The results provide a deeper understanding of failure in anisotropic rocks contributing to the development of constitutive models for predicting the rock mass response.

Asymmetric gating of a human hetero-pentameric glycine receptor

Hetero-pentameric Cys-loop receptors constitute a major type of neurotransmitter receptors that enable signal transmission and processing in the nervous system. Despite intense investigations into their working mechanism and pharmaceutical potentials, how neurotransmitters activate these receptors remains unclear due to the lack of high-resolution structural information in the activated open state. Here we report near-atomic resolution structures resolved in digitonin consistent with all principle functional states of the human α1β GlyR, which is a major Cys-loop receptor that mediates inhibitory neurotransmission in the central nervous system of adults. Glycine binding induces cooperative and symmetric structural rearrangements in the neurotransmitter-binding extracellular domain but asymmetrical pore dilation in the transmembrane domain. Symmetric response in the extracellular domain is consistent with electrophysiological data showing cooperative glycine activation and contribution from both α1 and β subunits. A set of functionally essential but differentially charged amino acid residues in the transmembrane domain of the α1 and β subunits explains asymmetric activation. These findings provide a foundation for understanding how the gating of the Cys-loop receptor family members diverges to accommodate specific physiological environments.

A pentameric TRPV3 channel with a dilated pore.

Transient receptor potential (TRP) channels are a large, eukaryotic ion channel superfamily that control diverse physiological functions, and therefore are attractive drug targets1-5. More than 210 structures from more than 20 different TRP channels have been determined, and all are tetramers4. Despite this wealth of structures, many aspects concerning TRPV channels remain poorly understood, including the pore-dilation phenomenon, whereby prolonged activation leads to increased conductance, permeability to large ions and loss of rectification6,7. Here, we used high-speed atomic force microscopy (HS-AFM) to analyse membrane-embedded TRPV3 at the single-molecule level and discovered a pentameric state. HS-AFM dynamic imaging revealed transience and reversibility of the pentamer in dynamic equilibrium with the canonical tetramer through membrane diffusive protomer exchange. The pentamer population increased upon diphenylboronic anhydride (DPBA) addition, an agonist that has been shown to induce TRPV3 pore dilation. On the basis of these findings, we designed a protein production and data analysis pipeline that resulted in a cryogenic-electron microscopy structure of the TRPV3 pentamer, showing an enlarged pore compared to the tetramer. The slow kinetics to enter and exit the pentameric state, the increased pentamer formation upon DPBA addition and the enlarged pore indicate that the pentamer represents the structural correlate of pore dilation. We thus show membrane diffusive protomer exchange as an additional mechanism for structural changes and conformational variability. Overall, we provide structural evidence for a non-canonical pentameric TRP-channel assembly, laying the foundation for new directions in TRP channel research.

Three membrane fusion pore families determine the pathway to pore dilation

During exocytosis secretory vesicles fuse with a target membrane and release neurotransmitters, hormones, or other bioactive molecules through a membrane fusion pore. The initially small pore may subsequently dilate for full contents release, as commonly observed in amperometric traces. The size, shape, and evolution of the pore is critical to the course of contents release, but exact fusion pore solutions accounting for membrane tension and bending energy constraints have not been available. Here, we obtained exact solutions for fusion pores between two membranes. We find three families: a narrow pore, a wide pore, and an intermediate tether-like pore. For high tensions these are close to the catenoidal and tether solutions recently reported for freely hinged membrane boundaries. We suggest membrane fusion initially generates a stable narrow pore, and the dilation pathway is a transition to the stable wide pore family. The unstable intermediate pore is the transition state that sets the energy barrier for this dilation pathway. Pore dilation is mechanosensitive, as the energy barrier is lowered by increased membrane tension. Finally, we study fusion pores in nanodiscs, powerful systems for the study of individual pores. We show that nanodiscs stabilize fusion pores by locking them into the narrow pore family.

α-Synuclein is required for sperm exocytosis at a post-fusion stage.

The sperm acrosome is a large dense-core granule whose contents are secreted by regulated exocytosis at fertilization through the opening of numerous fusion pores between the acrosomal and plasma membranes. In other cells, the nascent pore generated when the membrane surrounding a secretory vesicle fuses with the plasma membrane may have different fates. In sperm, pore dilation leads to the vesiculation and release of these membranes, together with the granule contents. α-Synuclein is a small cytosolic protein claimed to exhibit different roles in exocytic pathways in neurons and neuroendocrine cells. Here, we scrutinized its function in human sperm. Western blot revealed the presence of α-synuclein and indirect immunofluorescence its localization to the acrosomal domain of human sperm. Despite its small size, the protein was retained following permeabilization of the plasma membrane with streptolysin O. α-Synuclein was required for acrosomal release, as demonstrated by the inability of an inducer to elicit exocytosis when permeabilized human sperm were loaded with inhibitory antibodies to human α-synuclein. The antibodies halted calcium-induced secretion when introduced after the acrosome docked to the cell membrane. Two functional assays, fluorescence and transmission electron microscopies revealed that the stabilization of open fusion pores was responsible for the secretion blockage. Interestingly, synaptobrevin was insensitive to neurotoxin cleavage at this point, an indication of its engagement in cis SNARE complexes. The very existence of such complexes during AE reflects a new paradigm. Recombinant α-synuclein rescued the inhibitory effects of the anti-α-synuclein antibodies and of a chimeric Rab3A-22A protein that also inhibits AE after fusion pore opening. We applied restrained molecular dynamics simulations to compare the energy cost of expanding a nascent fusion pore between two model membranes and found it higher in the absence than in the presence of α-synuclein. Hence, our results suggest that α-synuclein is essential for expanding fusion pores.

Investigation on the Biological Safety and Activity of a Gluconolactone-Based Lotion for Dermocosmetic Application.

(1) Background: Cosmeceuticals are formulas enriched with active ingredients that exert efficacy on different skin molecular targets. (2) Methods: Cell viability and the absence of potential irritant risk were evaluated on keratinocytes (HaCaT), fibroblasts (NHDF), adipocytes (3T3-L1), sebocytes (PCi-SEB_CAU) and reconstructed human epidermis (RHE), respectively. Several treatments were performed to evaluate the ability of the lotion to stimulate the production of collagen and elastin, stimulate the differentiation of keratinocytes and reduce the number of senescent cells following UVB stimulation. In addition, the modulation of genes involved in the production, storage and accumulation of sebum were investigated. (3) Results: The results obtained demonstrated the biosafety of the formula in all cell lines tested. The 24-h treatment with non-cytotoxic concentrations determined an increase in the expression of the collagen (COL1A1), elastin (ELN) and involucrin (IVL) genes, while a reduction of peroxisome proliferator-activated receptor-gamma (PPARγ) gene expression and a reduction of SA-βgal-positive cells were found. Moreover, the treatment did not interfere with normal steroid 5-alpha reductase (5RDA3) gene expression levels. (4) Conclusions: Data collected demonstrated the biosafety of the lotion, the non-comedogenic property and a multi targets anti-aging effect. In particular, data collected on the booster lotion make it a valid way to counteract the pore dilatation aging related.

Serinc5 Restricts HIV Membrane Fusion by Altering Lipid Order and Heterogeneity in the Viral Membrane.

The host restriction factor, Serinc5, incorporates into budding HIV particles and inhibits their infection by an incompletely understood mechanism. We have previously reported that Serinc5 but not its paralogue, Serinc2, blocks HIV cell entry by membrane fusion, specifically by inhibiting fusion pore formation and dilation. A body of work suggests that Serinc5 may alter the conformation and clustering of the HIV fusion protein, Env. To contribute an additional perspective to the developing model of Serinc5 restriction, we assessed Serinc2 and Serinc5's effects on HIV pseudoviral membranes. By measuring pseudoviral membrane thickness via cryo-electron microscopy and order via the fluorescent dye, FLIPPER-TR, Serinc5 was found to increase membrane heterogeneity, skewing the distribution toward a larger fraction of the viral membrane in an ordered phase. We also directly observed for the first time the coexistence of membrane domains within individual viral membrane envelopes. Using a total internal reflection fluorescence-based single particle fusion assay, we found that treatment of HIV pseudoviral particles with phosphatidylethanolamine (PE) rescued HIV pseudovirus fusion from restriction by Serinc5, which was accompanied by decreased membrane heterogeneity and order. This effect was specific for PE and did not depend on acyl chain length or saturation. Together, these data suggest that Serinc5 alters multiple interrelated properties of the viral membrane─lipid chain order, rigidity, line tension, and lateral pressure─which decrease the accessibility of fusion intermediates and disfavor completion of fusion. These biophysical insights into Serinc5 restriction of HIV infectivity could contribute to the development of novel antivirals that exploit the same weaknesses.

Mechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel

The transmembrane voltage gradient is a general physico-chemical cue that regulates diverse biological function through voltage-gated ion channels. How voltage sensing mediates ion flows remains unknown at the molecular level. Here, we report six conformations of the human Eag2 (hEag2) ranging from closed, pre-open, open, and pore dilation but non-conducting states captured by cryo-electron microscopy (cryo-EM). These multiple states illuminate dynamics of the selectivity filter and ion permeation pathway with delayed rectifier properties and Cole-Moore effect at the atomic level. Mechanistically, a short S4-S5 linker is coupled with the constrict sites to mediate voltage transducing in a non-domain-swapped configuration, resulting transitions for constrict sites of F464 and Q472 from gating to open state stabilizing for voltage energy transduction. Meanwhile, an additional potassium ion occupied at positions S6 confers the delayed rectifier property and Cole-Moore effects. These results provide insight into voltage transducing and potassium current across membrane, and shed light on the long-sought Cole-Moore effects.

Implementation and validation of pressure-dependent gas permeability model for bentonite in FEM code Thebes

In an Engineered Barrier System of a nuclear waste repository, gas migrates through: a) diffusion/advection of dissolved gases, b) two-phase continuum flow, c) dilatant pathway flow and d) single-phase gas flow through macro-fractures in the soil. The gas production rate and the corresponding gas pressure accumulation affect the clay material behaviour and its properties such as air entry value. For the safe design of the EBS system, computational models need to account for the identified transport mechanisms. This study presents an enhancement in the finite element code Thebes [1, 2] that replicates the observed increase in permeability at higher gas pressures, e.g. due to pore dilatancy and gas fracture as proposed by Xu et al. [3]. The formulation links permeability to gas pressure and threshold/critical pressure. For model validation, the study utilizes a gas injection experiment carried out in IfG (Institute for Rock Mechanics, Germany) on Opalinus Clay [4]. The results show a good fit against the measurements while giving insight into gas flow through clays.

Understanding Peat Soil Deformation and Mechanisms of Peat Collapse Across a Salinity Gradient in the Southwestern Everglades

AbstractSaltwater intrusion is a significant threat to the structure and ecology of inland and coastal freshwater wetlands, altering biogeochemical cycling and disrupting important ecosystem services. As sea level rises along the Florida coast, the saltwater interface progressively moves further inland reaching freshwater soils previously unexposed to saltwater. One result of this soil salinization is a phenomenon called peat collapse which is currently observable along the South Florida coastline. While previous studies have proposed conceptual models to explain peat collapse many uncertainties still exist regarding the physical mechanisms that trigger this phenomenon. In this study we use a unique combination of laboratory and field‐based measurements using geophysical methods, deformation rods, gas traps, time‐lapse photography, and hydraulic conductivity measurements to investigate the effects of salinization on the physical properties of peat soils across a salinity gradient in the southwestern Everglades. Our results show that freshwater peat soils have about three times greater degree of pore dilation when compared to peat soils previously exposed to saltwater conditions. Differences in soil surface deformation were also observed and related to differences in the soil matrix physical integrity across the salinity gradient. This work also uses electrical resistivity imaging surveys to image areas of peat collapse and demonstrates: (a) the role of salinity in the development of collapse features; and (b) the apparent lack of evidence to suggest subsurface lithological controls on the development of collapse features. A simplified conceptual framework for better understanding peat collapse and pock formation is presented.

Human LAMP1 accelerates Lassa virus fusion and potently promotes fusion pore dilation upon forcing viral fusion with non-endosomal membrane.

Lassa virus (LASV) cell entry is mediated by the interaction of the virus glycoprotein complex (GPC) with alpha-dystroglycan at the cell surface followed by binding to LAMP1 in late endosomes. However, LAMP1 is not absolutely required for LASV fusion, as this virus can infect LAMP1-deficient cells. Here, we used LASV GPC pseudoviruses, LASV virus-like particles and recombinant lymphocytic choriomeningitis virus expressing LASV GPC to investigate the role of human LAMP1 (hLAMP1) in LASV fusion with human and avian cells expressing a LAMP1 ortholog that does not support LASV entry. We employed a combination of single virus imaging and virus population-based fusion and infectivity assays to dissect the hLAMP1 requirement for initiation and completion of LASV fusion that culminates in the release of viral ribonucleoprotein into the cytoplasm. Unexpectedly, ectopic expression of hLAMP1 accelerated the kinetics of small fusion pore formation, but only modestly increased productive LASV fusion and infection of human and avian cells. To assess the effects of hLAMP1 in the absence of requisite endosomal host factors, we forced LASV fusion with the plasma membrane by applying low pH. Unlike the conventional LASV entry pathway, ectopic hLAMP1 expression dramatically promoted the initial and full dilation of pores formed through forced fusion at the plasma membrane. We further show that, while the soluble hLAMP1 ectodomain accelerates the kinetics of nascent pore formation, it fails to promote efficient pore dilation, suggesting the hLAMP1 transmembrane domain is involved in this late stage of LASV fusion. These findings reveal a previously unappreciated role of hLAMP1 in promoting dilation of LASV fusion pores, which is difficult to ascertain for endosomal fusion where several co-factors, such as bis(monoacylglycero)phosphate, likely regulate LASV entry.

Capillary Pressure Behavior of CO2 - Shale System at Elevated Temperatures

In this study, changes in capillary entry pressure of shale when interacting with CO2, under different temperatures have been investigated. The combined impact of temperature and petrophysical properties of shale (water content, water activity, permeability and porosity) on capillary entry pressure was addressed. Pressure breakthrough measurements were used to evaluate the minimum entry pressure of CO2 through shale. A heavy-duty oven was used to vary the temperature in order to investigate the impact of temperature on CO2 capillary entry pressure through shale. Results showed that capillary entry pressure of shale when interacting with CO2 was highly affected by temperature. Higher temperatures decreased capillary entry pressure of shale. We believe that pore dilation, where pore throat size expands due to the application of heat, may have caused this decrease in capillary entry pressure. However, in some cases higher temperature activated clay swelling that may have caused an apparent decrease in pore throat radii of shale which translated into higher capillary entry pressure. Results also showed that there exists no distinct relationship between petrophysical properties of shale and its measured capillary entry pressure when interacting with CO2 at different temperatures. Heat could alter pore throat radii and cause pore dilation which may alter measured capillary entry pressure. Interfacial tension decreases with increasing temperature and that can be attributed to the weakening of intermolecular forces at the two immiscible fluids interface. Swelling of clay could be related to temperature-induced transition from passive to an active clay.

Enhanced Fluctuations in Facial Pore Size, Redness, and TEWL Caused by Mask Usage Are Normalized by the Application of a Moisturizer.

Mask wearing is described as one of the main public health measures against COVID-19. Mask wearing induces various types of subjective and objective facial skin damage, such as hair pore dilatation and redness. Facial pore size and redness show morning-to-evening intra-day fluctuations. It remains unknown whether mask usage affects fluctuations in pore size and redness. We measured facial skin hydration, transepidermal water loss (TEWL), pore size, and redness four times a day for 6 weeks in 20 healthy young women. After a 2-week no-mask-usage period (baseline period), all subjects wore unwoven masks for 2 weeks; then, for the following 2 weeks, they applied masks after the topical application of a moisturizer containing a Galactomyces ferment filtrate (GFF) skin care formula (Pitera™). We demonstrated that mask wearing significantly increased the intra-day fluctuations of pore size, redness, and TEWL. In addition, significant correlations were evident among these three parameters. Notably, these mask-induced skin changes were significantly improved, achieving a return to baseline levels, by the application of a GFF-containing moisturizer. In conclusion, mask wearing aggravates intra-day fluctuations in pore size and redness. Appropriate moisturization can minimize this mask-related skin damage, most likely by normalizing the elevated TEWL.

The Challenge in Combining Pelotherapy and Electrotherapy (Iontophoresis) in One Single Therapeutic Modality

Pelotherapy and electrotherapy are therapeutic methodologies with proven success in physical medicine and rehabilitation (PMR) and dermatology fields. The main purpose of these therapeutic modalities is to reduce pain, accelerate wound healing, alleviate muscle spasms, and improve mobility, and muscle tone. Their main challenge is in the passage of some ionic species through the skin barrier. The use of drugs, such as diclofenac, corticosteroids or steroids, has gained widespread efficacy recognition in physical therapy and the therapeutic action of these drugs is widely studied in experimental and clinical trials. Unlike pharmaceutical and cosmetic clays, peloids are not subject to any prior quality control or subject to any specific European regulation. The dermal absorption values are an integral part of the risk assessment process for peloids. This work explores the converging points between these two transdermal drug delivery systems (TDDS) and the presentation of methodologies to achieve peloid safety compliance, especially concerning the potential and degree of toxicity arising from ion exchange and trace elements. TDDS is applied to the pharmaceuticals industry and drug is the generic term for the active substances released into skin tissues. The transdermal delivery of drugs or clay components with therapeutic properties is limited due to the excellent barrier function of the stratum corneum. The transdermal drug delivery of pelotherapy is enhanced by temperature and electrically by iontophoresis. The low voltage of iontophoresis and sweat phenomena with pore dilation driven by pelotherapy allows the use of the same pathways: hair follicles and sweat pore. The therapeutic integration of iontophoresis and pelotherapy focused on patient benefits and low safety-related risk may contribute to the outstanding physiological performance of pelotherapy, specifically, in the way the essential elements and exchange cations pass through the skin barrier. The validation of an innovative iontophoretic systems applied to pelotherapy can also promote future challenges in the obtaining of the ideal therapeutic control of peloids and the clinical validation of results with physiological efficacy recognition.