Organ on chip (OoC) technologies have the potential to improve the translation of promising therapies currently failing in clinical trials at great expense and time due to dissimilarities between animal and human biology. Successful OoC models integrate human cells within 3D tissues with surrounding biomolecular components, and have benefited from the use of inert 3D gels and scaffolds used as templates, prompting tissue formation. However, monitoring technologies used to assess tissue integrity and drug effects are ill adapted to 3D biology. Here, a tubular electroactive scaffold serves as a template for a 3D human intestine, and enables dynamic electrical monitoring of tissue formation over 1 month. Cell‐ and extracellular matrix component‐invoked changes in the properties of the scaffold alleviate the need for posthoc placement of invasive metallic electrodes or downstream analyses. Formation of in vivo‐like stratified and polarized intestinal tissue compete with lumen contrasts with other quasi‐3D models of the intestine using rigid porous membrane to separate cell types. These results provide unprecedented real‐time information on tissue formation with highly sensitive multimodal operation, thanks to dual electrode and transistor operation. This device and the methodology for tissue growth within it represents a paradigm shift for disease modeling and drug discovery.

Emerging viruses will continue to be a threat to human health and wellbeing into the foreseeable future. The COVID-19 pandemic revealed the necessity for rapid viral sensing and inhibitor screening in mitigating viral spread and impact. Here, we present a platform that uses a label-free electronic readout as well as a dual capability of optical (fluorescence) readout to sense the ability of a virus to bind and fuse with a host cell membrane, thereby sensing viral entry. This approach introduces a hitherto unseen level of specificity by distinguishing fusion-competent viruses from fusion-incompetent viruses. The ability to discern between competent and incompetent viruses means that this device could also be used for applications beyond detection, such as screening antiviral compounds for their ability to block virus entry mechanisms. Using optical means, we first demonstrate the ability to recapitulate the entry processes of influenza virus using a biomembrane containing the viral receptor that has been functionalized on a transparent organic bioelectronic device. Next, we detect virus membrane fusion, using the same, label-free devices. Using both reconstituted and native cell membranes as materials to functionalize organic bioelectronic devices, configured as electrodes and transistors, we measure changes in membrane properties when virus fusion is triggered by a pH drop, inducing hemagglutinin to undergo a conformational change that leads to membrane fusion.

3D cell models have made strides in the past decades in response to failures of 2D cultures to translate targets during the drug discovery process. Here, we report on a novel multiwell plate bioelectronic platform, namely, the e-transmembrane, capable of supporting and monitoring complex 3D cell architectures. Scaffolds made of PEDOT:PSS [poly(3,4-ethylenedioxythiophene):polystyrene sulfonate] are microengineered to function as separating membranes for compartmentalized cell cultures, as well as electronic components for real-time in situ recordings of cell growth and function. Owing to the high surface area–to–volume ratio, the e-transmembrane allows generation of deep, stratified tissues within the porous bulk and cell polarization at the apico-basal domains. Impedance spectroscopy measurements carried out throughout the tissue growth identified signatures from different cellular systems and allowed extraction of critical functional parameters. This platform has the potential to become a universal tool for biologists for the next generation of high-throughput drug screening assays.

In vitro models of the gut–microbiome axis are in high demand. Conventionally, intestinal monolayers grown on Transwell setups are used to test the effects of commensals/pathogens on the barrier integrity, both under homeostatic and pathophysiological conditions. While such models remain valuable for deepening the understanding of host–microbe interactions, often, they lack key biological components that mediate this intricate crosstalk. Here, a 3D in vitro model of the vertebrate intestinal epithelium, interfaced with immune cells surviving in culture for over 3 weeks, is developed and applied to proof‐of‐concept studies of host–microbe interactions. More specifically, the establishment of stable host–microbe cocultures is described and functional and morphological changes in the intestinal barrier induced by the presence of commensal bacteria are shown. Finally, evidence is provided that the 3D vertebrate gut models can be used as platforms to test host–microbe–parasite interactions. Exposure of gut–immune–bacteria cocultures to helminth “excretory/secretory products” induces in vivo‐like up‐/down‐regulation of certain cytokines. These findings support the robustness of the modular in vitro cell systems for investigating the dynamics of host–microbe crosstalk and pave the way toward new approaches for systems biology studies of pathogens that cannot be maintained in vitro, including parasitic helminths.

The blood-brain barrier (BBB) restricts paracellular and transcellular diffusion of compounds and is part of a dynamic multicellular structure known as the “neurovascular unit” (NVU), which strictly regulates the brain homeostasis and microenvironment. Several neuropathological conditions (e.g., Parkinson’s disease and Alzheimer’s disease), are associated with BBB impairment yet the exact underlying pathophysiological mechanisms remain unclear. In total, 90% of drugs that pass animal testing fail human clinical trials, in part due to inter-species discrepancies. Thus, in vitro human-based models of the NVU are essential to better understand BBB mechanisms; connecting its dysfunction to neuropathological conditions for more effective and improved therapeutic treatments. Herein, we developed a biomimetic tri-culture NVU in vitro model consisting of 3 human-derived cell lines: human cerebral micro-vascular endothelial cells (hCMEC/D3), human 1321N1 (astrocyte) cells, and human SH-SY5Y neuroblastoma cells. The cells were grown in Transwell hanging inserts in a variety of configurations and the optimal setup was found to be the comprehensive tri-culture model, where endothelial cells express typical markers of the BBB and contribute to enhancing neural cell viability and neurite outgrowth. The tri-culture configuration was found to exhibit the highest transendothelial electrical resistance (TEER), suggesting that the cross-talk between astrocytes and neurons provides an important contribution to barrier integrity. Lastly, the model was validated upon exposure to several soluble factors [e.g., Lipopolysaccharides (LPS), sodium butyrate (NaB), and retinoic acid (RA)] known to affect BBB permeability and integrity. This in vitro biological model can be considered as a highly biomimetic recapitulation of the human NVU aiming to unravel brain pathophysiology mechanisms as well as improve testing and delivery of therapeutics.

A one-pot route to ureasil core–shell nanoparticles that exhibit low polydispersity, high stability and low cytotoxicity is reported.

3D cell culture formats more closely resemble tissue architecture complexity than 2D systems, which are lacking most of the cell-cell and cell-microenvironment interactions of the in vivo milieu. Scaffold-based systems integrating natural biomaterials are extensively employed in tissue engineering to improve cell survival and outgrowth, by providing the chemical and physical cues of the natural extracellular matrix (ECM). Using the freeze-drying technique, porous 3D composite scaffolds consisting of poly(3,4-ethylene-dioxythiophene) doped with polystyrene sulfonate (PEDOT:PSS), containing ECM components (i.e., collagen, hyaluronic acid, and laminin) are engineered for hosting neuronal cells. The resulting scaffolds exhibit a highly porous microstructure and good conductivity, determined by scanning electron microscopy and electrochemical impedance spectroscopy, respectively. These supports boast excellent mechanical stability and water uptake capacity, making them ideal candidates for cell infiltration. SH-SY5Y human neuroblastoma cells show enhanced cell survival and proliferation in the presence of ECM compared to PEDOT:PSS alone. Whole-cell patch-clamp recordings acquired from differentiated SHSY5Y cells in the scaffolds demonstrate that ECM constituents promote neuronal differentiation in situ. These findings reinforce the usability of 3D conducting supports as engineered highly biomimetic and functional in vitro tissue-like platforms for drug or disease modeling.

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