Diffusion Of Small Molecules Research Articles

Strong underwater adhesion of injectable hydrogels triggered by diffusion of small molecules.

It is challenging for injectable hydrogels to achieve high underwater adhesiveness. Based on this concern, we report a fully physically crosslinked injectable hydrogel composed of gelatin, tea polyphenols and urea, capable of realising smart adhesion to various materials, like glass and porcine skin, in diverse aqueous environments. The urea molecules are designed as crosslinking disruptors for interfering with the formation of hydrogen bonds in the hydrogel, therefore modulating its crosslinking density and mechanical properties such as tensile strength, toughness and adhesive strength. Triggered by physical diffusion of the urea molecules towards the surrounding liquid environment, the hydrogel can achieve efficient (∼10 s), self-strengthening and long-lasting (>2 weeks) underwater adhesion. Remarkably, for fresh porcine skin, the instantaneous underwater adhesive strength is 10.4 kPa whereas the peak strength is as high as 152.9 kPa with the aid of the self-strengthening effect. More interestingly, it can simultaneously form controllable underwater non-adhesive surfaces, regulated by changes in the diffusion-triggered local concentration of urea. Further, it is also biocompatible, antibacterial, biodegradable and 3D printable in water, which offers great convenience for various applications concerning smart interfacial adhesion, like biomedicine and flexible electronics. Likewise, the physical diffusion-mediated mechanism represents an innovative strategy for developing next-generation smart hydrogels.

Subcanalicular Nanochannel Volume Is Inversely Correlated With Calcium Content in Human Cortical Bone.

The spatial distribution of mineralization density is an important signature of bone growth and remodeling processes, and its alterations are often related to disease. The extracellular matrix of some vertebrate mineralized tissues is known to be perfused by a lacunocanalicular network (LCN), a fluid-filled unmineralized structure that harbors osteocytes and their fine processes and transports extracellular fluid and its constituents. The current report provides evidence for structural and compositional heterogeneity at an even smaller, subcanalicular scale. The work reveals an extensive unmineralized three-dimensional (3D) network of nanochannels (~30 nm in diameter) penetrating the mineralized extracellular matrix of human femoral cortical bone and encompassing a greater volume fraction and surface area than these same parameters of the canaliculi comprising the LCN. The present study combines high-resolution focused ion beam-scanning electron microscopy (FIB-SEM) to investigate bone ultrastructure in 3D with quantitative backscattered electron imaging (qBEI) to estimate local bone mineral content. The presence of nanochannels has been found to impact qBEI measurements fundamentally, such that volume percentage (vol%) of nanochannels correlates inversely with weight percentage (wt%) of calcium. This mathematical relationship between nanochannel vol% and calcium wt% suggests that the nanochannels could potentially provide space for ion and small molecule transport throughout the bone matrix. Collectively, these data propose a reinterpretation of qBEI measurements, accounting for nanochannel presence in human bone tissue in addition to collagen and mineral. Further, the results yield insight into bone mineralization processes at the nanometer scale and present the possibility for a potential role of the nanochannel system in permitting ion and small molecule diffusion throughout the extracellular matrix. Such a possible function could thereby lead to the sequestration or occlusion of the ions and small molecules within the extracellular matrix. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

PLGA Nanofiber/PDMS Microporous Composite Membrane-Sandwiched Microchip for Drug Testing.

Lung-on-a-chip devices could provide new strategies for a biomimetic lung cell microenvironment and construction of lung disease models in vitro, and are expected to greatly promote the development of drug evaluation, toxicological detection, and disease model building. In this study, we developed a novel poly (lactic-co-glycolic acid) (PLGA) nanofiber/polydimethylsiloxane (PDMS) microporous composite membrane-sandwiched lung-on-a-chip to perform anti-tumor drug testing. The composite membrane was characterized, and the results showed that it was permeable to molecules and thus could be used to study small-molecule drug diffusion. In addition, the microchip could apply perfusion fluids to simulate blood flow under extremely low fluid shear stress, and could also simulate the spherical-like shape of the alveoli by deformation of the composite membrane. Using this chip, we evaluated the anti-tumor drug efficacy of gefitinib in two kinds of non-small cell lung cancer cells, the lung adenocarcinoma NCI-H1650 cell line and the large cell lung cancer NCI-H460 cell line. We further probed the resistance of NCI-H460 cells to gefitinib under normoxic and hypoxic conditions. The established composite membrane-sandwiched lung chip can simulate more biochemical and biophysical factors in the lung physiological and pathological microenvironment, and it has important applications in the personalized treatment of lung tumors. It is expected to play a potential role in clinical diagnosis and drug screening.

Inverse Rheological Methods for the Determination of Polymer Structures, Diffusion of Small Molecules and Nanofiber Lengths

This paper presents so-called inverse rheology methods to determine various parameters that are essential to go further in terms of modelling and/or simulation in the field of polymer processing. The following systems from our previous works are presented: i) Determination of the molecular structure of a poly(∊-caprolactone) polymerized in-situ by ring-opening; ii) Measurement of the mutual diffusion coefficient: two cases are considered, namely the diffusion of a plasticizer and the diffusion of an organic peroxide in a polymer melt and iii) Determination of the average length of polymer nanofibers in suspension and study of the universal behavior of nanofibers of different natures in dilute and semi-dilute suspensions. The application of these different studies in the field of reactive extrusion, blending and multi-scale structuring are presented and discussed.

Understanding the impact of crystal lamellae organization on small molecule diffusion using a Monte Carlo approach

AbstractMany physicochemical processes depend on the diffusion of small molecules through solid materials. While crystallinity in polymers is advantageous with respect to structure performance, diffusion in such materials is difficult to predict. Here, we investigate the impact of crystal morphology and organization on the diffusion of small molecules using a lattice Monte Carlo approach. Interestingly, diffusion determined with this model does not depend on the internal morphology of the semi-crystalline regions. The obtained insight is highly valuable for developing predictive models for all processes in semi-crystalline polymers involving mass transport, like polymer degradation or drug release, and provide design criteria for the time-dependent functional behavior of multifunctional polymer systems.

Inverse Rheological Methods for the Determination of Polymer Structures, Diffusion of Small Molecules and Nanofiber Lengths

Abstract This paper presents so-called inverse rheology methods to determine various parameters that are essential to go further in terms of modelling and/or simulation in the field of polymer processing. The following systems from our previous works are presented: i) Determination of the molecular structure of a poly(e-caprolactone) polymerized in-situ by ring-opening; ii) Measurement of the mutual diffusion coefficient: two cases are considered, namely the diffusion of a plasticizer and the diffusion of an organic peroxide in a polymer melt and iii) Determination of the average length of polymer nanofibers in suspension and study of the universal behavior of nanofibers of different natures in dilute and semi-dilute suspensions. The application of these different studies in the field of reactive extrusion, blending and multi-scale structuring are presented and discussed.

Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells.

Simple SummaryThe gap junction protein connexin 43 (Cx43) facilitates direct intercellular communication and displays a complex dichotomous role in cancer. Here, we used breast cancer cell lines and CRISPR/Cas9 technology to dissect some of the poorly understood multimodal functions of Cx43 in this setting. Our data show that Cx43 directly modulates the formation of pro-tumorigenic tunneling nanotubes (TNTs), which are cellular protrusions that connect non-adjacent cells to facilitate cellular communication, including the direct cell–cell transfer of organelles. We identify several important cancer signaling pathways that affect TNT formation and show that this effect is strongly influenced by the presence or absence of Cx43. Finally, we demonstrate that Cx43 can affect TNT formation by modulating the cellular secretome. This work provides important insight into the pro-tumorigenic role of Cx43 and its interconnections with TNTs.Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and thin membrane projections that connect cells, facilitating the exchange of not only small molecules, but also larger proteins, organelles, bacteria, and viruses. Typically, TNTs exhibit increased formation under conditions of cellular stress and are more prominent in cancer cells, where they are generally thought to be pro-metastatic and to provide growth and survival advantages. Cx43 has been described in TNTs, where it is thought to regulate small molecule diffusion through gap junctions. Here, we developed a high-fidelity CRISPR/Cas9 system to knockout (KO) Cx43. We found that the loss of Cx43 expression was associated with significantly reduced TNT length and number in breast cancer cell lines. Notably, secreted factors present in conditioned medium stimulated TNTs more potently when derived from Cx43-expressing cells than from KO cells. Moreover, TNT formation was significantly induced by the inhibition of several key cancer signaling pathways that both regulate Cx43 and are regulated by Cx43, including RhoA kinase (ROCK), protein kinase A (PKA), focal adhesion kinase (FAK), and p38. Intriguingly, the drug-induced stimulation of TNTs was more potent in Cx43 KO cells than in wild-type (WT) cells. In conclusion, this work describes a novel non-canonical role for Cx43 in regulating TNTs, identifies key cancer signaling pathways that regulate TNTs in this setting, and provides mechanistic insight into a pro-tumorigenic role of Cx43 in cancer.

Gut Microbiota and Intestinal Trans-Epithelial Permeability.

Constant remodeling of tight junctions to regulate trans-epithelial permeability is essential in maintaining intestinal barrier functions and thus preventing diffusion of small molecules and bacteria to host systemic circulation. Gut microbiota dysbiosis and dysfunctional gut barrier have been correlated to a large number of diseases such as obesity, type 2 diabetes and inflammatory bowel disease. This led to the hypothesis that gut bacteria-epithelial cell interactions are key regulators of epithelial permeability through the modulation of tight junctions. Nevertheless, the molecular basis of host-pathogen interactions remains unclear mostly due to the inability of most in vitro models to recreate the differentiated tissue structure and components observed in the normal intestinal epithelium. Recent advances have led to the development of a novel cellular model derived from intestinal epithelial stem cells, the so-called organoids, encompassing all epithelial cell types and reproducing physiological properties of the intestinal tissue. We summarize herein knowledge on molecular aspects of intestinal barrier functions and the involvement of gut bacteria-epithelial cell interactions. This review also focuses on epithelial organoids as a promising model for epithelial barrier functions to study molecular aspects of gut microbiota-host interaction.

Membrane-cross-linked polymersomes with tumor pH-tunable selective permeability as intelligent nanoreactors and drug delivery vehicles

Stimuli-responsive polymersomes have attracted great attention not only as smart drug delivery vehicles but also as intelligent artificial nanoreactors. Herein, we develop a series of membrane-cross-linked (MCL) polymersomes with cross-linking density-mediated and tumor pH-tunable selective membrane permeability for stimuli-responsive drug delivery and controllable enzymatic reaction. The diblock copolymers consisting of poly(ethylene glycol) (PEG) and copolymerized with methacrylate monomers containing piperidine or coumarin moieties were synthesized and self-assembled into polymersomes that can encapsulate both small molecule doxorubicin hydrochloride (DOX) and large molecule glucose oxidase (GOD). After photo-cross-linking, the optimized cross-linking density and pH-responsive segments endow the polymersomes with superior stability and ultra pH-sensitive selective membranes permeability upon changing pH from 7.4 to 6.5. Drug release and enzymatic reaction are triggered by pH change via the enhanced membrane permeability of the polymersomes loading DOX and GOD. With diffusion of small molecules into or out of the polymersomes including DOX, glucose, and O2, the massively generated hydrogen peroxide (H2O2) under the catalysis of GOD and the released DOX can synergistically kill cancer cells. Thus, the polymersomes with the tumor pH-responsive and cross-linking density-mediated membrane permeability show promising applications as a unique platform for cancer therapy.

Biofluid‐Permeable Electronics: Electronic‐ECM: A Permeable Microporous Elastomer for an Advanced Bio‐Integrated Continuous Sensing Platform (Adv. Mater. Technol. 7/2020)

Inspired by the dermal extracellular matrix, a three-dimensional, ultrathin, and fibrous polydimethylsiloxane membrane is engineered for chronic, continuous monitoring applications by Ahyeon Koh and co-workers (article number 2000242). This platform exhibits biomimetic viscoelastic and nonliar mechanics, cytocompatibility, and a bio-fluid permeable interface for transdermal water, gas, and small molecule diffusion for stretchable bioelectronics.

A Multiscale Approach for Estimating Permeability Properties of Polymers with Complex Aromatic Backbones: A Case Study on Diffusivity of Small Gas Molecules in Polyphenylene Ether

AbstractState‐of‐the‐art multiscale computational chemistry simulations is employed to predict diffusivity of small gaseous molecules in a generic polyphenylene ether (PPE). The diffusivities are obtained from trajectory analysis of gaseous molecules in molecular dynamics simulations using coarse‐grained dissipative particle dynamics (DPD) simulations to design the amorphous starting structure. Required intra‐ and intermolecular parameters of the DPD simulations are automatically generated using the automated fragmentation and parametrization protocol. A comparison of calculated diffusion coefficients with experimental data for five gaseous molecules in PPE shows adequate accuracy of computational‐chemistry‐based approaches in the prediction of diffusion coefficients. These estimates, validated against measurements reported in the literature, serve as proof of concept for applicability of these new multiscale modeling strategies for complex polymers with aromatic backbones.

Electronic‐ECM: A Permeable Microporous Elastomer for an Advanced Bio‐Integrated Continuous Sensing Platform

AbstractTissue interfaced electronics have become promising candidates for transcending beyond conventional diagnostic technology, enabling chronic, quantitative health monitoring possibilities; however, these systems have primarily relied on impenetrable materials that contribute to the mechanical and physical mismatch of bioelectronic interfaces. Inspired by the soft mechanics and physical architecture of the epidermal extracellular matrix, this study presents a 3D microporous, fibrous mesh of polydimethylsiloxane for epidermal electronics. The resulting elastic microfiber mat, exhibits a minimal mechanical footprint with analogous viscoelastic behavior, cytocompatibility, and biofluid‐permeable interface capable of small molecule, gas, and transdermal water diffusion. Electrocardiography electrodes heterogeneously integrate within the synthetic electronic‐extracellular matrix (e‐ECM) membrane and achieve chronic high resolution biopotential monitoring during typically debilitating environments (e.g., vigorous sweating) for conventional bioelectronics. The e‐ECM platform provides a substrate template for open‐mesh electronics, enabling advanced implementations in long‐term quantitative analysis monitoring for wearable and implantable devices.

Formation of hydrotropic drug/gemini surfactant based catanionic vesicles as efficient nano drug delivery vehicles

Strategic designing catanionic system that leads to vesicle formation is advantageous if one of the components is hydrotropic ‘drug’. Vesicles are size-selective filters that offer passive diffusion of small molecules including drugs and are the best alternatives to liposomes and niosomes. Drug molecules can be carried irrespective to their polarity in vesicles cage/bilayer, which makes them a convenient drug delivery vehicle. Herein we have investigated concentration/composition dependent catanionic vesicles through synergistic interactions between cationic gemini surfactants (GS) and hydrotropic drug, diclofenac sodium (DS). Variables studied to get shape and size-dependent catanionic vesicles includes: alkyl chain length of GS and concentration of DS. We used spectroscopic probes to study the microscopic interactions, dynamic light scattering (DLS) to determine the size and transmission electron microscopy (TEM) and small angle neutron scattering (SANS) to determine the exact shape and size of the vesicles. This work could be of interest in the field of drug delivery as the possible new age nano-carriers.

A 3D Printed Self-Sustainable Cell-Encapsulation Drug Delivery Device for Periocular Transplant-Based Treatment of Retinal Degenerative Diseases.

Self-sustainable release of brain-derived neurotrophic factor (BDNF) to the retina using minimally invasive cell-encapsulation devices is a promising approach to treat retinal degenerative diseases (RDD). Herein, we describe such a self-sustainable drug delivery device with human retinal pigment epithelial (ARPE-19) cells (cultured on collagen coated polystyrene (PS) sheets) enclosed inside a 3D printed semi-porous capsule. The capsule was 3D printed with two photo curable polymers: triethylene glycol dimethacrylate (TEGDM) and polyethylene glycol dimethylacrylate (PEGDM). The capsule’s semi-porous membrane (PEGDM) could serve three functions: protecting the cells from body’s immune system by limiting diffusion (5.97 ± 0.11%) of large molecules like immunoglobin G (IgG)(150 kDa); helping the cells to survive inside the capsule by allowing diffusion (43.20 ± 2.16%) of small molecules (40 kDa) like oxygen and necessary nutrients; and helping in the treatment of RDD by allowing diffusion of cell-secreted BDNF to the outside environment. In vitro results showed a continuous BDNF secretion from the device for at least 16 days, demonstrating future potential of the cell-encapsulation device for the treatment of RDD in a minimally invasive and self-sustainable way through a periocular transplant.

Directionality of Plasmodesmata-Mediated Transport in Arabidopsis Leaves Supports Auxin Channeling

The plant hormone auxin serves as central regulator of growth and development. Auxin transporters in the plasma membrane are assumed to define tissue-level patterns of auxin distribution [1, 2]. However, auxin is small enough to diffuse through the plasmodesmata that connect neighboring cells [3], presenting an alternative pathway, whose contribution to auxin transport remained largely unexplored [4]. Here, photoactivation microscopy [5, 6] was used to measure the capacity for small-molecule diffusion in the epidermis of Arabidopsis thaliana leaves. In the elongated epidermis cells covering the midrib and petiole, the plasmodesmata-mediated cell-wall permeability was found to be several times higher in the longitudinal than in the transverse direction. The physiological relevance of this asymmetry was tested through quantification of the shade-avoidance response, which depends on auxin transport from the leaf tip to the petiole in the abaxial side of the leaf [7], with the hypothesis that directionality of diffusion supplements transporter-mediated auxin movement [8]. Triggering the response by auxin application at the tip led to stronger leaf movement in wild-type plants than in gsl8 mutants [9], which lack the callose synthase necessary to establish directionality. The results match the predictions of a mathematical model of auxin transport based on the permeabilities measured in wild-type and mutant plants. It is concluded that plasmodesmata permeability can be selectively modulated within a plant cell and that the conferred directionality in diffusion can influence the tissue-specific distribution patterns of small molecules, like auxin. VIDEO ABSTRACT.

Connexin 43 Regulates Multiple Aspects of Chick Cranial Neural Crest Cell Development

Connexins are transmembrane proteins that cluster to form intercellular channels called gap junctions, which allow direct diffusion of small molecules and ions between adjacent cells. Connexin 43 (Cx43) is one of the predominant components of gap junctions and is expressed in multiple organisms and their tissues. To date, however, very little is known about the role of gap junctions, and specifically Cx43, in the neural crest. Our prior immunohistochemical analyses revealed that Cx43 is expressed in premigratory cranial neural crest cells both prior to and during their epithelial‐to‐mesenchymal transition (EMT), and in migratory neural crest cells. Given the robust expression of Cx43 in premigratory neural crest cells, we sought to elucidate the role of Cx43, and gap junctions in particular, during neural crest cell EMT. To this end, we evaluated the presence of gap junctions in the neural crest and performed perturbation experiments to alter the levels of Cx43 in both premigratory and migratory neural crest cells. Our fixed and live imaging results reveal that gap junction formation occurs within both the premigratory and migratory neural crest cell populations. Moreover, morpholino‐mediated reduction in Cx43 protein levels prevents neural crest cells from forming functional gap junctions, as assessed by live imaging of transfer of the gap junction‐specific dye Calcein in the embryo. Additionally, depletion of Cx43 from premigratory neural crest cells reduces the size of the premigratory neural crest cell domain and also delays the emergence of neural crest cells from the dorsal neural tube. This delayed neural tube exit phenotype can be rescued by introduction of full‐length rat Cx43 that is refractory to the morpholino. These data suggest that gap junctions, and Cx43 in particular, are involved in early neural crest cell specification and in the emergence of neural crest cells from the neural tube.Support or Funding InformationThe work was supported by an American Association for Anatomy Postdoctoral Fellowship to K.J. and grants to L.A.T. (NIH R01DE024217, American Cancer Society RSG‐15‐023‐01‐CSM).

Towards improved understanding of the viscoelastic properties of functionalized lemon peel fibers in suspension based on microstructure, hydration value and swelling volume

Lemon peel fibers were obtained using different processing conditions (pH, addition of salts, mechanical processing and storage), they showed distinctly different viscoelastic properties when dispersed in an aqueous solution. In order to gain insight in the mechanism underlying their texturizing properties, the volume occupation in dispersion was determined through small molecule diffusion experiments and the swelling volume was measured by a conventional method. Based on the diffusion coefficient of glucose as a function of fiber concentration, the hydration value and volume occupancy of differently functionalized fibers were calculated. The diffusion based volume occupancy and the swelling volume were related with the fiber suspension microstructure and its rheological properties. High pressure homogenization (HPH) improved the viscoelastic properties, mainly due to an increase of the swelling volume. Salt addition and pH influenced the hydration value, the swelling volume and viscoelastic properties. These results show that the texturizing properties of lemon peel fibers induced by HPH, are mainly determined by the extent of swelling and network formation rather than an increased fiber hydration value.

Role of free volume in molecular mobility and performance of glassy polymers for corrosion-protective coatings

ABSTRACTGlassy polymer coatings on metal substrates rely on their mechanical, physical, and transport properties for corrosion protection. These properties are influenced by free volume between polymer chains that plays a critical role in coating performance. Free volume permits local segmental mobility that affects mechanical properties, such as yield and adhesion, and also permits diffusion of small molecules (water, ions, and oxygen) through the coating to the substrate. Fractional free volume is calculated from the specific volume and Bondi group contribution theory for the occupied volume. Free volume distribution (free volume element size and number) is measured by positron annihilation lifetime spectroscopy (PALS) using the ortho-positronium (oPs) probe, which detects free volume elements in glassy polymer coatings. The oPs probe is sensitive to phenomena that affect both the mechanical and barrier properties of coatings including physical ageing, water sorption, and plasticisation, making PALS a suitable allied testing method for corrosion-protective coatings.

All-polymer Planar Photonic Crystals as an Innovative Tool for the Analysis of Air

The possibility to evaluate the molecular diffusivity in polymer thin films used for packaging and device encapsulation directly in-situ would represent a paradigm changer in the assesment of barrier properties and of air quality. Indeed, employing the packaging itself as a smart sensor could lead to waste reduction and mitigate food poisoning effects. In this work, we demonstrate a new technique that exploits simple UV-Vis reflectance spectroscopy to identify the kinetic of diffusion of small molecules in the vapor phase through polymer thin films and polymer multilayered structures. The new method allows then to assess the presence of the analyte in air and its diffusion coefficient in agreement with gravimetric data reported in literature.

A Microfluidic Culture Platform to Assess Axon Degeneration.

The field of microfluidics allows for the precise spatial manipulation of small amounts of fluids. Within microstructures, laminar flow of fluids can be exploited to control the diffusion of small molecules, creating desired microenvironments for cells. Cellular neuroscience has benefited greatly from devices designed to fluidically isolate cell bodies and axons. Microfluidic devices specialized for neuron compartmentalization are made of polydimethylsiloxane (PDMS) which is gas permeable, is compatible with fluorescence microscopy, and has low cost. These devices are commonly used to study signals initiated exclusively on axons, somatodendritic compartments, or even single synapses. We have also found that microfluidic devices allow for rapid, reproducible interrogation of axon degeneration. Here, we describe the methodology for assessing axonal degeneration in microfluidic devices. We describe several use cases, including enucleation (removal of cell bodies) and trophic deprivation to investigate axon degeneration in pathological and developmental scenarios, respectively.