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The flexibility and tunability of metal organic frameworks (MOFs), crystalline porous materials composed of a network of metal ions coordinated by organic ligands, confer their variety of applications as drug delivery systems or as sensing and imaging agents. However, such properties also add to the difficulty in ensuring their safe implementation when interaction with biological systems is considered. In the current study, we used real-time sensorial strategies and cellular-based approaches to allow for fast and effective screening of two MOFs of prevalent use, namely, MIL-160 representative of a hydrophilic and ZIF-8 representative of a hydrophobic framework. The two MOFs were synthesized \"in house\" and exposed to human bronchial epithelial (BEAS-2B) cells, a pertinent toxicological screening model. Analysis allowed evaluation and differentiation of particle-induced cellular effects as well identification of different degrees and routes of toxicity, all in a high-throughput manner. Our results show the importance of performing screening toxicity assessments before introducing MOFs to biomedical applications. Our proposed screening assays could be extended to a wider variety of cell lines to allow for identification of any deleterious effects of MOFs, with the range of toxic mechanisms to be differentiated based on cell viability, morphology and cell-substrate interactions, respectively. Our analysis highlights the importance of considering the physicochemical properties of MOFs when recommending a MOF-based therapeutic option or MOFs implementation in biomedical applications.

Background Organomodified nanoclays (ONC), two-dimensional montmorillonite with organic coatings, are increasingly used to improve nanocomposite properties. However, little is known about pulmonary health risks along the nanoclay life cycle even with increased evidence of airborne particulate exposures in occupational environments. Recently, oropharyngeal aspiration exposure to pre- and post-incinerated ONC in mice caused low grade, persistent lung inflammation with a pro-fibrotic signaling response with unknown mode(s) of action. We hypothesized that the organic coating presence and incineration status of nanoclays determine the inflammatory cytokine secretary profile and cytotoxic response of macrophages. To test this hypothesis differentiated human macrophages (THP-1) were acutely exposed (0–20 µg/cm 2 ) to pristine, uncoated nanoclay (CloisNa), an ONC (Clois30B), their incinerated byproducts (I-CloisNa and I-Clois30B), and crystalline silica (CS) followed by cytotoxicity and inflammatory endpoints. Macrophages were co-exposed to lipopolysaccharide (LPS) or LPS-free medium to assess the role of priming the NF-κB pathway in macrophage response to nanoclay treatment. Data were compared to inflammatory responses in male C57Bl/6J mice following 30 and 300 µg/mouse aspiration exposure to the same particles. Results In LPS-free media, CloisNa exposure caused mitochondrial depolarization while Clois30B exposure caused reduced macrophage viability, greater cytotoxicity, and significant damage-associated molecular patterns (IL-1α and ATP) release compared to CloisNa and unexposed controls. LPS priming with low CloisNa doses caused elevated cathepsin B/Caspage-1/IL-1β release while higher doses resulted in apoptosis. Clois30B exposure caused dose-dependent THP-1 cell pyroptosis evidenced by Cathepsin B and IL-1β release and Gasdermin D cleavage. Incineration ablated the cytotoxic and inflammatory effects of Clois30B while I-CloisNa still retained some mild inflammatory potential. Comparative analyses suggested that in vitro macrophage cell viability, inflammasome endpoints, and pro-inflammatory cytokine profiles significantly correlated to mouse bronchioalveolar lavage inflammation metrics including inflammatory cell recruitment. Conclusions Presence of organic coating and incineration status influenced inflammatory and cytotoxic responses following exposure to human macrophages. Clois30B, with a quaternary ammonium tallow coating, induced a robust cell membrane damage and pyroptosis effect which was eliminated after incineration. Conversely, incinerated nanoclay exposure primarily caused elevated inflammatory cytokine release from THP-1 cells. Collectively, pre-incinerated nanoclay displayed interaction with macrophage membrane components (molecular initiating event), increased pro-inflammatory mediators, and increased inflammatory cell recruitment (two key events) in the lung fibrosis adverse outcome pathway.

Addition of nanoclays into a polymer matrix leads to nanocomposites with enhanced properties to be used in plastics for food packaging applications. Because of the plastics’ high stored energy value, such nanocomposites make good candidates for disposal via municipal solid waste plants. However, upon disposal, increased concerns related to nanocomposites’ byproducts potential toxicity arise, especially considering that such byproducts could escape disposal filters to cause inhalation hazards. Herein, we investigated the effects that byproducts of a polymer polylactic acid-based nanocomposite containing a functionalized montmorillonite nanoclay (Cloisite 30B) could pose to human lung epithelial cells, used as a model for inhalation exposure. Analysis showed that the byproducts induced toxic responses, including reductions in cellular viability, changes in cellular morphology, and cytoskeletal alterations, however only at high doses of exposure. The degree of dispersion of nanoclays in the polymer matrix appeared to influence the material characteristics, degradation, and ultimately toxicity. With toxicity of the byproduct occurring at high doses, safety protocols should be considered, along with deleterious effects investigations to thus help aid in safer, yet still effective products and disposal strategies.

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.

Nanoclays are layered mineral silicates that originate from the clay fraction of soil and carry a platelet thickness of about 1 nm and lengths and widths of up to several microns. Due to their nanoscale dimensions, they have been used for numerous applications ranging from media for oil well drilling to sorbents in treatment of waste-water. Additionally, upon functionalization with organic modifiers, nanoclays have been incorporated into polymers to form nanocomposites with increased mechanical strength, barrier properties, UV dispersion, and fire resistance to be implemented in food packaging or medical devices related applications. Such increased implementation into industrial and commercial products has brought scrutiny onto nanoclays and associated nanocomposites toxicity. Previous studies have shown for instance that nanoclays induce cytotoxic and genotoxic effects upon cellular or model animal exposure, however little investigations were performed to identify how nanoclay functionalization may influence such toxicological profiles. Moreover, most of the studies related to nanoclays and nanocomposites toxicity only refer to their consumption/usage exposure and fail to assess manufacturing or disposal exposures. Herein, we aimed to understand how the physical and chemical properties of nanoclay systems (i.e. pristine and organically modified, along with a nanoclay-enforced nanocomposite) in both their as-received (mimicking manufacturing) and thermally degraded (mimicking end of life cycle incineration) forms influence lung cells, used to model inhalation toxicity. Physical and chemical properties of the materials were investigated via microscopical and spectroscopical approaches, while toxicity profiles were assessed both in real-time or at disparate time points via in vitro cellular and molecular assays, cell imaging, and electric cell-substrate impedance sensing. Our analyses showed that nanoclays and nanocomposites properties (both physical and chemical) influence the materials’ degradation profile and ultimately their induced toxicity in model cellular systems. The toxic effects were displayed either by reductions in cell proliferation and viability, changes in cell morphology, and/or alterations in the cell cytoskeleton. Overall, our results provide unique insights into how materials properties, both physical and chemical dictate materials’ toxicological profiles throughout their life cycle (from manufacturing to disposal) with such information to be possibly aiding in safe-by-design strategies as well as safety protocols implementation in areas of exposure.