Adhesion Profile Research Articles

PERSPECTIVES OF CYCLOID TRANSMISSION

In modern mechanical engineering, transmissions with the use of an involute tooth profile are widespread. However, one of the main disadvantages of these transmissions is that they exposure to wear. In this study, research on the cycloid profile is conducted as an alternative option. Cycloid profiles are one of the profiles applied to the teeth in order to transmit motion. Although cycloid profiles are mainly used in instrumentation, satellites are made of cycloid profile in planetary gears. Cycloid profile teeth are less exposed to wear during operation. Practically, the shape of cycloidal teeth does not allow them to break, so there is no bending deformation in the teeth. In planetary gear transmission, the satellites are usually made of a cycloid profile. Cycloid profile teeth are exposed to less wear. Currently, planetary gear reducers are widely used mainly in the oil industry, drilling equipments, in the lifting mechanisms, gearboxes, on chain conveyors, rotary tables, in robotics, manufacturing, mechanical and chemical engineering fields and so on. The increased load capacity of the cycloid pinion gears is due to the multi-pair contact surface and it has a superior adhesion profile than the involute profile. The loading schemes of cycloidal and evolvent profile teeth shows that the normal force in contact Fn and its dangerous section on the tooth of the cycloidal profile is much less than in the case when the tooth has an involute profile. This is due to the fact that with cycloid profile transmission the number of teeth simultaneously transmitting the load is significantly greater than when implementing the same transmission with involute teeth. Cycloid profile gear reducers can be considered as a modern solution to current requirements such as high efficiency, smooth and quiet work, ability to accept short-term maximum loads, small overall size, minimum technical requirements etc. The simulation of the real load conditions and interference generated during the rotation of the shaft was developed in Solidworks in order to determine the contact stresses and the contact areas resulting from these stresses of the teeth of the gear and satellites of cycloid profile planetary gear reducers. This simulation determines the values of the teeth involved in the contact, the interference of those teeth, the contact areas and the contact stresses generated in these areas, depending on the angle of rotation of the shaft. The profile of the proposed teeth allows to achieve the minimum size with the maximum transmission ratio. Keywords: cycloid profile, cycloid transmission, planetary reducer, interference, simulation, contact area.

Tailoring Pyro- and Orthophosphate Species to Enhance Stem Cell Adhesion to Phosphate Glasses

Phosphate-based glasses (PBGs) offer significant therapeutic potential due to their bioactivity, controllable compositions, and degradation rates. Several PBGs have already demonstrated their ability to support direct cell growth and in vivo cytocompatibility for bone repair applications. This study investigated development of PBG formulations with pyro- and orthophosphate species within the glass system (40 − x)P2O5·(16 + x)CaO·20Na2O·24MgO (x = 0, 5, 10 mol%) and their effect on stem cell adhesion properties. Substitution of phosphate for calcium revealed a gradual transition within the glass structure from Q2 to Q0 phosphate species. Human mesenchymal stem cells were cultured directly onto discs made from three PBG compositions. Analysis of cells seeded onto the discs revealed that PBG with higher concentration of pyro- and orthophosphate content (61% Q1 and 39% Q0) supported a 4.3-fold increase in adhered cells compared to glasses with metaphosphate connectivity (49% Q2 and 51% Q1). This study highlights that tuning the composition of PBGs to possess pyro- and orthophosphate species only, enables the possibility to control cell adhesion performance. PBGs with superior cell adhesion profiles represent ideal candidates for biomedical applications, where cell recruitment and support for tissue ingrowth are of critical importance for orthopaedic interventions.

High expression of neutrophil and monocyte CD64 with simultaneous lack of upregulation of adhesion receptors CD11b, CD162, CD15, CD65 on neutrophils in severe COVID-19.

Background and Aims:The pronounced neutrophilia observed in patients with coronavirus disease 2019 (COVID-19) infections suggests a role for these leukocytes in the pathology of the disease. Monocyte and neutrophil expression of CD64 and CD11b have been reported as early biomarkers to detect infections. The aim of this study was to study the expression of receptors for IgG (CD64) and adhesion molecules (CD11b, CD15s, CD65, CD162, CD66b) on neutrophils and monocytes in patients with severe COVID-19 after admission to an intensive care unit (ICU).Methods:The expression of receptors was analyzed using flow cytometry. EDTA blood from 23 patients with confirmed COVID-19 infection was sampled within 48 h of admission to the ICU. Leukocytes were labeled with antibodies to CD11b, CD15s, CD65s, CD162, CD64, and CD66b. Expression of receptors was reported as mean fluorescence intensity (MFI) or the percentage of cells expressing receptors.Results:Results are presented as comparison of COVID-19 patients with the healthy group and the receptor expression as MFI. Neutrophil receptors CD64 (2.5 versus 0.5) and CD66b (44.5 versus 34) were increased and CD15 decreased (21.6 versus 28.3) when CD65 (6.6 versus 4.4), CD162 (21.3 versus 21.1) and CD11b (10.5 versus 12) were in the same range. Monocytes receptors CD64 (30.5 versus 16.6), CD11b (18.7 versus 9.8), and CD162 (38.6 versus 36.5) were increased and CD15 decreased (10.3 versus 17.9); CD65 were in the same range (2.3 versus 1.96).Conclusion:Monocytes and neutrophils are activated during severe COVID-19 infection as shown by strong upregulation of CD64. High monocyte and neutrophil CD64 can be an indicator of a severe form of COVID19. The adhesion molecules (CD11b, CD162, CD65, and CD15) are not upregulated on otherwise activated neutrophils, which might lead to relative impairment of tissue migration. Low adhesion profile of neutrophils suggests immune dysfunction of neutrophils. Monocytes maintain upregulation of some adhesion molecules (CD11b, CD162) suggesting the persistence of an increased ability to migrate into tissues, even during a severe stage of COVID-19. Future research should focus on CD64 and CD11b kinetics in the context of prognosis.

α4β7 integrin-dependent adhesion of T cells to MAdCAM-1 is blocked by vedolizumab in patients with chronic refractory pouchitis

Background:The anti-α4β7 integrin antibody vedolizumab is an established therapeutic option for the treatment of inflammatory bowel disease (IBD). It has also been successfully used in patients with chronic antibiotic-refractory pouchitis following proctocolectomey with ileal pouch-anal anastomosis. However, the expression and function of gut-homing markers as well as strategies to predict the response to vedolizumab in pouchitis are understudied so far.Methods:We used flow cytometry and dynamic adhesion assays to study the expression and function of gut-homing integrins on T cells from patients with pouchitis and controls as well as longitudinally during therapy of pouchitis with vedolizumab. Moreover, we describe clinical effects of vedolizumab in a cohort of patients with pouchitis.Results:T cells from patients with pouchitis express a specific profile of gut-homing integrins. Integrin α4β7 on T cells from patients with pouchitis mediates adhesion to mucosal addressin cell adhesion molecule (MAdCAM)-1, which can be blocked by vedolizumab in vitro. Vedolizumab efficiently treats pouchitis in a portion of patients and response correlates with dynamic adhesion profiles to MAdCAM-1.Conclusion:Our data suggest that T cell trafficking seems to be important for the pathogenesis of pouchitis and support the therapeutic use of vedolizumab. Integrin function might serve as a biomarker to predict response to vedolizumab.

The Impact of Electrode Aging on the Structural and Mechanical Properties of Carbon Felt Electrodes for Vanadium Redox Flow Batteries

Vanadium Redox Flow Batteries (VRFBs) represents a promising approach to large-scale energy storage of intermittently available renewable energy. However, this technology still faces major problems in terms of lifetime, efficiency, and costs. One limitation is the degradation of the electrode during operation, which influences the (electro)chemical and mechanical stability of the electrode.1,2 Performance deteriorations during cycling are frequently reported and the harsh environment of the sulfuric acid itself leads to electroless oxidation of the carbon-based electrodes.3 Previously, we have already presented the effect of thermal treatment and accelerated stress tests on the electrochemical and compositional properties of commercial carbon felt electrodes and their affinity towards side reactions like hydrogen evolution and carbon corrosion.4,5 These studies focused on the chemical aging at high temperature in sulfuric acid and the electrochemical aging in V(V) electrolyte to imitate the conditions of a charged, positive VRFB half-cell. To deepen the knowledge about (electro)chemical aging of carbon electrodes, we present a study on the impact of degradation on the structural and mechanical properties of carbon electrodes.Corresponding to our previous studies, different treatments were applied to mimic the effect of thermal activation, chemical, and electrochemical aging on the structure of carbon fiber electrodes. Thereby, the electrode material was either thermally treated at 400°C in air atmosphere, and immersed in sulfuric acid, or vanadium electrolyte under potential control. Structural changes were observed by scanning electron microscopy (SEM) and confirmed by topography images from atomic force microscopy (AFM) on single fibers. Furthermore, physisorption measurements were conducted to quantify the changes in porosity, surface area, and pore size distribution after each of the aforementioned treatments. Adhesion profiles were measured by AFM to analyze the wettability of the respective samples and to determine the modulus of elasticity.The characterization methods presented in this study are beneficial to investigate the mechanical degradation of carbon felt electrodes during operation. The extracted values like pore size distribution, fiber thickness, or modulus of elasticity are important for theoretical simulations on compression or flow behavior. Also, accelerated stress test procedures are helpful to evaluate the stability of new materials or modified carbon electrodes since electrode stability is an important aspect to consider for the long-term operation of VRFBs. References O. Nibel et al., J. Electrochem. Soc., 164, A1608–A1615 (2017) https://iopscience.iop.org/article/10.1149/2.1081707jes.I. Derr et al., J. Power Sources, 325, 351–359 (2016) http://dx.doi.org/10.1016/j.jpowsour.2016.06.040.I. Derr et al., Electrochim. Acta, 246, 783–793 (2017) http://dx.doi.org/10.1016/j.electacta.2017.06.050.L. Eifert, R. Banerjee, Z. Jusys, and R. Zeis, J. Electrochem. Soc., 165, A2577–A2586 (2018) https://iopscience.iop.org/article/10.1149/2.0531811jes.L. Eifert, Z. Jusys, R. J. Behm, and R. Zeis, Carbon N. Y., 158, 580–587 (2020) https://doi.org/10.1016/j.carbon.2019.11.029. Figure 1

Chitosan Hydrogel Doped with PEG-PLA Nanoparticles for the Local Delivery of miRNA-146a to Treat Allergic Rhinitis.

To prepare a binary formulation delivering miRNA-146 and evaluate a nucleic acid nasal delivery system by investigating its pharmacodynamic effects in allergic rhinitis. The gel/NPs/miR-146a thermosensitive in situ chitosan hydrogel carrying a nucleic acid was prepared and evaluated for its characteristics, including temperature sensitivity, gel strength, mucosal adhesion and drug release profile. After nasal administration of the formulation to ovalbumin-sensitized rats, the treatment of allergic rhinitis was verified by assessing nasal symptoms, hematology, hematoxylin-eosin (HE) staining and immunohistochemistry. Western Blot(WB) was used to analyze nasal inflammatory factors as well as miRNA-146-related factors, and the miR146 expression level was measured by PCR. Subsequently, the effects of the gel/NPs/miR-146a binary formulation were evaluated for the nasal delivery of nucleic acids in rhinitis therapy. The prepared binary formulation quickly formed a gel in the nasal cavity at a temperature of 34 °C with good mucosal adhesion, which delivered nucleic acids into the nasal mucosa stably and continuously. Gel/NPs/miR-146a was able to sustain the delivery of miRNA into the mucosa after nasal administration. When compared with the monolithic formulations, the gel/NPs/miR-146a binary formulation performed better regarding its nucleic acid delivery ability and pharmacodynamic effects. The gel/NPs/miR-146a binary preparation has a suitable nasal mucosal drug delivery ability and has a positive pharmacodynamic effect for the treatment of ovalbumin-induced rhinitis in rats. It can serve as a potential nucleic acid delivery platform for the treatment of allergic rhinitis.

Influence of Laser-Designed Microstructure Density on Interface Characteristics and on Preliminary Responses of Epithelial Cells

Current trends in designing medical and tissue engineering systems rely on the incorporation of micro- and nano-topographies for inducing a specific cellular response within the context of an aimed application. As such, dedicated studies have recently focused on understanding the possible effects of high and low density packed topographies on the behavior of epithelial cells, especially when considering their long-term viability and functionality. We proposed to use stair-like designed topographies with three different degrees of distribution, all created in polydimethylsiloxane (PDMS) as active means to monitor cell behavior. Our model cellular system was human bronchial epithelial cells (BEAS-2B), a reference line in the quality control of mesenchymal stem cells (MSCs). PDMS microtextured substrates of 4 µm square unit topographies were created using a mold design implemented by a KrF Excimer laser. Varying the spacing between surface features and their multiscale level distribution led to irregular stairs/lines in low, medium and high densities, respectively. Profilometry, scanning electron and atomic force microscopy, contact angle and surface energy measurements were performed to evaluate the topographical and interface characteristics of the designed surfaces, while density-induced cellular effects were investigated using traditional cell-based assays. Our analysis showed that microstructure topographical distribution influences the adhesion profiles of epithelial cells. Our analysis hint that epithelial organoid formation might be initiated by the restriction of cell spreading and migration when using user-designed, controlled micro-topographies on engineered surfaces.

Peridynamic modeling of adhesively bonded beams with modulus graded adhesives using refined zigzag theory

The present study provides a nonlocal beam model for the stress analysis of beams bonded with modulus adhesives using Peridynamic Least Square Minimization (PDLSM) and Refined Zigzag Theory (RZT). RZT is highly useful for the efficient and accurate stress analysis of thin and thick load-bearing structures. RZT avoids the use of shear correction factors to estimate the transverse shear stresses. PDLSM introduces the local derivatives in terms of their nonlocal forms. The PDLSM is applicable for the approximation of any order derivatives. In this study, the PDLSM was employed for the solution of the equilibrium equations of RZT. The robustness of the present approach was demonstrated by considering dissimilar bonded aluminum (Al)-carbon fiber-reinforced polymer composite (CFRP) beam. Modulus graded adhesives have been successfully implemented to minimize the stress concentrations occur in the bonded structures. In order to investigate the effects of the modulus graded adhesive layers on the stress minimization at the critical locations of the bonded beam, various adhesive models were investigated in detail. Each adhesive profile experienced different deformation and stress states. The peak stress levels near the adherend-adhesive interfaces were observed to be alleviated with the use of a modulus graded adhesive layer.

Small changes in PDMMLA structure influence the adsorption behavior of ECM proteins and syndecan-4 on PDMMLA derivative surfaces: Experimental validation by tensiometric surface force measurements

Cardiovascular diseases are the leading cause of death around the world according to the World Health Organization. In-stent restenosis is an inflammatory response of the immune system to endovascular stent implantation in atherosclerotic patients. Biocompatible and biodegradable polymers are of great interest in this field in order to limit the side effects of stent treatments. Poly([R,S]-3,3-dimethylmalic acid) (PDMMLA) is a new biodegradable statistical polyester which presents promising properties as a stent coating. In this work, we studied by dynamic tensiometry, the adhesion of extracellular matrix proteins (bovine serum albumin, fibronectin, fibrinogen, and vitronectin) and plasma membrane proteoglycan (syndecan-4) on three PDMMLA derivatives with different hydrophilicity levels. The results show that proteins have different adhesion profiles and affinity on these surfaces. They show similar behavior on the most hydrophilic surface, making hydrophilic, ionic and hydrogen type bonds. Then we compared each protein’s individual profile to that of a mixture of all studied proteins. The comparison shows that vitronectin and syndecan-4 are the quantitatively dominating proteins adsorbed by specific interactions. Based on the results from previous studies, this work allowed us to identify the most important PDMMLA surface as a promising biomaterial for bioactive stent-coating.

Extracellular Matrix Derived from High Metastatic Human Breast Cancer Triggers Epithelial-Mesenchymal Transition in Epithelial Breast Cancer Cells through αvβ3 Integrin.

Alterations in the composition and architecture of the extracellular matrix (ECM) can influence cancer growth and dissemination. During epithelial-mesenchymal transition (EMT), epithelial cells assume a mesenchymal cell phenotype, changing their adhesion profiles from cell-cell contacts to cell-matrix interactions, contributing to metastasis. Breast cancer cells present at different stages of differentiation, producing distinct ECMs in the same tumor mass. However, the contribution of ECM derived from metastatic tumor cells to EMT is unclear. Here, we showed the mechanisms involved in the interaction of MCF-7, a low-metastatic, epithelial breast cancer cell line, with the ECM produced by a high metastatic breast tumor cell, MDA-MB-231 (MDA-ECM). MDA-ECM induced morphological changes in MCF-7 cells, decreased the levels of E-cadherin, up-regulated mesenchymal markers, and augmented cell migration. These changes were accompanied by the activation of integrin-associated signaling, with increased phosphorylation of FAK, ERK, and AKT and activation canonical TGF-β receptor signaling, enhancing phosphorylation of SMAD2 and SMAD4 nuclear translocation in MCF-7 cells. Treatment with Kistrin (Kr), a specific ligand of integrin αvβ3 EMT induced by MDA-ECM, inhibited TGF-β receptor signaling in treated MCF-7 cells. Our results revealed that after interaction with the ECM produced by a high metastatic breast cancer cell, MCF-7 cells lost their characteristic epithelial phenotype undergoing EMT, an effect modulated by integrin signaling in crosstalk with TGF-β receptor signaling pathway. The data evidenced novel potential targets for antimetastatic breast cancer therapies.

Quantifying abrasive-blasted surface roughness profiles using scanning electron microscopy

Rough surface profiles are specified for metal surfaces so that corrosion preventative coatings adhere well and provide long-term protection. Simple stylus scans and replica tape are widely used in industry to characterize surfaces and control the quality of surface preparation. Unfortunately, a scientific, quantitative connection between adhesion and surface profile parameters remains unclear. Stereo-pair images from scanning electron microscopy, SEM, were used to digitally reconstruct and then characterize 3D surfaces, which is a technique that seems previously unreported in coatings applications. SEM results were consistent with those from a stylus profilometer, but the data from a surface scan are much more numerous than from a line scan, and SEM can provide very high magnifications. 3D surfaces at high magnification gave larger values for the increase in area developed by the abrasive blasting than were determined at lower magnifications and by the stylus profilometer. Nevertheless, both techniques showed that the surface roughness height and ramification was far less than might be expected from illustrations in the existing literature on coatings’ adhesion. Quantified characterization, with details shown at high magnification, may provide scientific insight into how the various features of a roughened surface enhance the adhesion of protective coatings.

The Endosperm-Derived Embryo Sheath Is an Anti-adhesive Structure that Facilitates Cotyledon Emergence during Germination in Arabidopsis.

Germination sensu stricto in Arabidopsis involvesseed-coat and endosperm rupture by the emerging seedling root. Subsequently, the cotyledons emerge rapidly from the extra-embryonic tissues of the seed, allowing autotrophic seedling establishment [1, 2]. Seedling survival depends upon the presence of an intact seedling cuticle that prevents dehydration, which has hitherto been assumed to form the interface between the newly germinated seedling and its environment [3-5]. Here, we show that in Arabidopsis, this is not the case. The primary interface between the emerging seedling and its environment is formed by an extra-cuticular endosperm-derived glycoprotein-rich structure called the sheath, which is maintainedas a continuous layer at seedling surfaces during germination and becomes fragmented as cotyledons expand. Mutants lacking an endosperm-specific cysteine-rich peptide (KERBEROS [KRS]) show a complete loss of sheath production [6]. Although krs mutants have no defects in germinationsensu stricto, they show delayed cotyledonemergence, a defect not observed in seedlingswith defects in cuticle biosynthesis. Biophysical analyses reveal that the surfaces of wild-type cotyledons show minimal adhesion to silicabeads in an aqueous environment at cotyledon emergence but that adhesion increases as cotyledons expand. In contrast, krs mutant cotyledons show enhanced adhesion at germination. Mutantswith defects in cuticle biosynthesis, but no sheath defects, show a similar adhesion profile to wild-type seedlings at germination. We propose that the sheath reduces the adhesiveness of thecotyledon surface under the humid conditions necessary for seed germination and thus promotesseed-coat shedding and rapid seedling establishment.

Three-Dimensional Observations of an Aperiodic Oscillatory Gliding Behavior in Myxococcus xanthus Using Confocal Interference Reflection Microscopy.

The deltaproteobacterium Myxococcus xanthus is a model for bacterial motility and has provided unprecedented insights into bacterial swarming behaviors. Fluorescence microscopy techniques have been invaluable in defining the mechanisms that are involved in gliding motility, but these have almost entirely been limited to two-dimensional (2D) studies, and there is currently no understanding of gliding motility in a three-dimensional (3D) context. We present here the first use of confocal interference reflection microscopy (IRM) to study gliding bacteria, revealing aperiodic oscillatory behavior with changes in the position of the basal membrane relative to the substrate on the order of 90 nm in vitro First, we use a model planoconvex lens specimen to show how topological information can be obtained from the wavelength-dependent interference pattern in IRM. We then use IRM to observe gliding M. xanthus bacteria and show that cells undergo previously unobserved changes in their adhesion profile as they glide. We compare the wild type with mutants that have reduced motility, which also exhibit the same changes in the adhesion profile during gliding. We find that the general gliding behavior is independent of the proton motive force-generating complex AglRQS and suggest that the novel behavior that we present here may be a result of recoil and force transmission along the length of the cell body following firing of the type IV pili.IMPORTANCE 3D imaging of live bacteria with optical microscopy techniques is a challenge due to the small size of bacterial cells, meaning that previous studies have been limited to observing motility behavior in 2D. We introduce the application of confocal multiwavelength interference reflection microscopy to bacteria, which enables visualization of 3D motility behaviors in a single 2D image. Using the model organism Myxococcus xanthus, we identified novel motility behaviors that are not explained by current motility models, where gliding bacteria exhibit aperiodic changes in their adhesion to an underlying solid surface. We concluded that the 3D behavior was not linked to canonical motility mechanisms and that IRM could be applied to study a range of microbiological specimens with minimal adaptation to a commercial microscope.

A virtual-droplet system for sensing MMP9 activity of single suspended and adhered cancer cells

Cancer cells’ MMP9 activity plays vital roles in tumor development. Tumor cells are in an adhesion profile during cell-cell and cell-matrix interaction. However, it is challenging for current platforms (e.g., typical droplet systems) to measure MMP9 secreted by single cells in an adhesion profile and retrieve the cells of interest for downstream analysis. Herein, we report a single-cell protease sensor (SCPS) based on ‘virtual droplet’ that can fulfill the above two requirements. SCPS can form 648 virtual droplets within one minute as a one-cell-per-droplet profile, which offers an isolated space with a substrate to support cells’ adhesion and enables MMP9 measurement for hundreds of single adhered cells within two hours. In addition to high cellular heterogeneity of cancer cells in MMP9 production, we also found that adhered MDA-MB-231 cells produced relatively more MMP9 than that done by suspended cells. Furthermore, the cells producing high MMP9 and low MMP9 were retrieved and mRNA-sequence was performed on them. The results demonstrated that some KEGG pathways associated with cell migration and invasion were enriched and a few related genes (e.g., FYN, MAPK3, RAF) were upregulated in high-MMP9 cells. This SCPS system provides a promising strategy for measuring single-cell’s protease activity.

Human iPSC-derived Down syndrome astrocytes display genome-wide perturbations in gene expression, an altered adhesion profile, and increased cellular dynamics.

Down syndrome (DS), caused by the triplication of human chromosome 21, leads to significant alterations in brain development and is a major genetic cause of intellectual disability. While much is known about changes to neurons in DS, the effects of trisomy 21 on non-neuronal cells such as astrocytes are poorly understood. Astrocytes are critical for brain development and function, and their alteration may contribute to DS pathophysiology. To better understand the impact of trisomy 21 on astrocytes, we performed RNA-sequencing on astrocytes from newly produced DS human induced pluripotent stem cells (hiPSCs). While chromosome 21 genes were upregulated in DS astrocytes, we found consistent up- and down-regulation of genes across the genome with a strong dysregulation of neurodevelopmental, cell adhesion and extracellular matrix molecules. ATAC (assay for transposase-accessible chromatin)-seq also revealed a global alteration in chromatin state in DS astrocytes, showing modified chromatin accessibility at promoters of cell adhesion and extracellular matrix genes. Along with these transcriptomic and epigenomic changes, DS astrocytes displayed perturbations in cell size and cell spreading as well as modifications to cell-cell and cell-substrate recognition/adhesion, and increases in cellular motility and dynamics. Thus, triplication of chromosome 21 is associated with genome-wide transcriptional, epigenomic and functional alterations in astrocytes that may contribute to altered brain development and function in DS.

Comparison of a transdermal contraceptive patch with a newly sourced adhesive component versus EVRA patch: A double-blind, randomized, bioequivalence and adhesion study in healthy women

ObjectiveTo evaluate the bioequivalence of norelgestromin and ethinyl estradiol (NGMN-EE) and adhesion of a transdermal contraceptive patch containing a newly sourced adhesive component (test) compared with the marketed (reference) patch. Study designIn this randomized, double-blind, 2-way crossover study, healthy women received single 7-day application of both test and reference patches. Treatment phase included two treatment periods of 11 days each separated by a 21-day washout period starting from day of patch removal (day 8) of treatment period 1. Assessments included NGMN and EE pharmacokinetics (PK), adhesion using European Medicines Agency (EMA) 5-point scale, irritation potential and application-site reactions, and safety. Patches were bioequivalent if 90% CIs of ratios of means of test/reference for AUC168h, AUCinf, and Css fell within 80–125%. Patch adhesion was comparable if ratios of mean cumulative adhesion percentage values of test/reference were ≥90.0%. ResultsSeventy women were randomized; 57 completed both treatments with ≥80% adhesion (score 0–1). Bioequivalence of test and reference patches was demonstrated as 90% CI of ratio of geometric means for AUC168h, AUCinf, and Css for NGMN and EE fell within 80–125%. Both patches had similar adhesion properties (geometric mean ratio was 100.3% [90% CI, 93.2–107.9]). Similar rates of mild-to-moderate itching (11% vs 10%) and erythema events (79% vs 74%) were reported for test and reference patches, respectively, on day 8. ConclusionsThe test patch with the newly sourced adhesive component is bioequivalent to the currently marketed NGMN-EE transdermal patch and has similar adhesion and irritation potential. Implications statementThe norelgestromin and ethinyl estradiol transdermal patch containing a newly sourced adhesive component is bioequivalent to the currently marketed patch for both active moieties. Both patches had similar adhesion, irritation potential, and safety profiles.

Safe-by-design development of a topical patch for drug delivery

Few topical products have been developed specifically to treat acute and chronic arthritis and inflammation, using non-steroidal anti-inflammatory drugs (NSAIDs). The lack of dosing accuracy commonly found in locally applied semisolid products for cutaneous use is a critical issue that leads to treatment failure. The aim of the present work is to develop a differentiated and innovative topical patch based on a monolithic hydrogel for ibuprofen skin delivery, in order to provide a safer and accurate way of drug administration along with improved treatment compliance. Topical patches based on hydroxypropylmethylcellulose (HPMC) were optimized in composition, in terms of enhancer and adhesive, supported on a systematic assessment of in vitro release and permeation behavior and adhesion properties. Several mathematical models were used to scrutinize the release mechanisms from the patches. In vitro release kinetics was shown to be mainly driven by diffusion. However, other mechanisms seemed to be also present, supporting the feasibility of using patches for sustained drug delivery. PEG 200 provided the best permeation rate, with a permeation enhancement ratio of ca. 3 times higher, than the commercial reference. The addition of Eudragit L30D 55 to the formulation led to the best adhesion profile, thus achieving a successful development based on a safe-by-design concept.

Development of a New Vented Chest Seal Dressing for Treatment of Open Pneumothorax.

The most common life-threatening complications from both blunt and penetrating thoracic injury are hemothorax, pneumothorax, or a combination of both. New guidelines, set out by the Tactical Combat Casualty Care (TCCC), advises that vented chest seal dressings are used to manage open or sucking chest wounds. Designing out risk is a fundamental criterion for ensuring the optimal performance of a device is obtained that offers the casualty the greatest chance of survival. Two key areas of risk in the application of vented chest seal dressings are adhesion failure and vent failure. This study assesses a new design of vented chest seal dressing for both adhesion and vent profile. The development of this new design for a vented chest seal has been tested for adhesion and venting properties and shown to have performance criteria suitable for the treatment of open pneumothorax and design features that minimize the risk of product failure during use.

Transcriptomic profiling of gamma ray induced mutants from the CGL1 human hybrid cell system reveals novel insights into the mechanisms of radiation-induced carcinogenesis

BackgroundSomatic cell hybrid systems generated by combining cancerous with non-cancerous cells provide useful model systems to study neoplastic transformation. Combined with recent advances in omics-based technologies, novel molecular signatures that drive radiation-induced carcinogenesis can be analyzed at an exceptional global level. MethodsHere, we present a complete whole-transcriptome analysis of gamma-induced mutants (GIM) and gamma irradiated control (CON) segregants isolated from the CGL1 (HeLa x normal fibroblast) human hybrid cell-system exposed to high doses of radiation.Using the Human Transcriptome Array 2.0 microarray technology and conservative discrimination parameters, we have elucidated 1067 differentially expressed genes (DEGs) between tumorigenic and non-tumorigenic cells. ResultsGene ontology enrichment analysis revealed that tumorigenic cells demonstrated shifts in extracellular matrix (ECM) and cellular adhesion profiles, dysregulation of cyclic AMP (cAMP) signaling, and alterations in nutrient transport and cellular energetics. Furthermore, putative upstream master regulator analysis demonstrated that loss of TGFβ1 signaling due to reduced SMAD3 expression is involved in radiation-induced carcinogenesis. ConclusionsTaken together, this study presents novel insights into specific gene expression and pathway level differences that contribute to radiation-induced carcinogenesis in a human cell-based model. This global transcriptomic analysis and our published tumor suppressor gene deletion loci analyses will allow us to identify and functionally test candidate nexus upstream tumor suppressor genes that are deleted or silenced after exposure to radiation.

Abstract 1908: Using hierarchical clustering of differential gene expression patterns to study the contribution of the extracellular matrix in breast cancer

Abstract Breast cancer is the most frequently invasive cancer type among women worldwide, accounting for over 2 million new cases annually and 25% of all cancers diagnosed in women. Considering significant advances in the diagnostics and treatment of breast cancer it remains a leading cause of cancer mortality worldwide. The extracellular matrix (ECM) is a meshwork of fibrous proteins and proteoglycans that is essential for providing a physical framework and facilitating biochemical cues to maintain tissue homeostasis. However, the ECM also has a well-established role in tumour development and progression. Increasing evidence suggests that the ECM may impede targeted therapies and novel approaches that target the composition of the ECM may improve drug delivery and efficacy. Using the xCELLigence real time analysis platform, we monitored the growth of several breast cancer cell lines on the major fibrous proteins of the ECM to elucidate the contribution of individual ECM components on cell behaviour. Coupling this with endpoint assays, we have identified diverse adhesion, proliferation and migration profiles for each cell line on each substrate. RNA was extracted from cells in 2-Dimensional culture on 1) collagen, 2) fibronectin, 3) laminin and 4) stimulated by various growth factors and from cells in 3-Dimensional culture. Using qRT-PCR, we examined the expression of 40 genes that code for proteins known to directly or indirectly regulate the composition of the ECM. We determined that there is significant differential gene expression amongst each cell line in response to individual ECM components. Using a hierarchical clustering analysis of our gene panel, we have identified a strong relationship amongst cell lines maintained on collagen and fibronectin. We used STRING[1] analysis to help us refine a gene signature and are currently examining our gene set in patient tissue samples. Our hypothesis is that the composition of the ECM regulates gene expression and this correlates with advanced cancer stage. This work has the potential to create a clinically relevant gene signature to be used in the prediction of invasive cancers. Understanding how the ECM influences these proteins may provide information on the design of novel ECM targeted therapies in breast cancer. 1. Szklarczyk, D., et al., The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic acids research, 2017. 45(D1):p. D362-D368. Citation Format: Joanne Nolan, Amira F. Mahdi, Aoife J. Lowery, Colum P. Dunne, Patrick A. Kiely. Using hierarchical clustering of differential gene expression patterns to study the contribution of the extracellular matrix in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1908.