Organ-on-chip devices have provided the pharmaceutical and tissue engineering worlds much hope since they arrived and began to grow in sophistication. However, limitations for their applicability were soon realized as they lacked real-time monitoring and sensing capabilities. The users of these devices relied solely on endpoint analysis for the results of their tests, which created a chasm in the understanding of life between the lab the natural world. However, this gap is being bridged with sensors that are integrated into organ-on-chip devices. This review goes in-depth on different sensing methods, giving examples for various research on mechanical, electrical resistance, and bead-based sensors, and the prospects of each. Furthermore, the review covers works conducted that use specific sensors for oxygen, and various metabolites to characterize cellular behavior and response in real-time. Together, the outline of these works gives a thorough analysis of the design methodology and sophistication of the current sensor integrated organ-on-chips.

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To understand the transport of pharmaceutical agents and their effects on developing fetus, we have created a placental microsystem that mimics structural phenotypes and physiological characteristic of a placental barrier. We have shown the formation of a continuous network of epithelial adherens junctions and endothelial cell–cell junctions confirming the integrity of the placental barrier. More importantly, the formation of elongated microvilli under dynamic flow condition is demonstrated. Fluid shear stress acts as a mechanical cue triggering the microvilli formation. Pharmaceutical agents were administered to the maternal channel, and the concentration of pharmaceutical agents in fetal channel for coculture and control models were evaluated. In fetal channel, the coculture model exhibited about 2.5 and 2.2% of the maternal initial concentration for naltrexone and 6β-naltrexol, respectively. In acellular model, fetal channel showed about 10.5 and 10.3% of the maternal initial concentration for naltrexone and 6β-naltrexol, respectively. Gene expressions of epithelial cells after direct administration of naltrexone and 6β-naltrexol to the maternal channel and endothelial cells after exposure due to transport through placental barrier are also reported.

Mimicking microvascular tissue microenvironment in vitro calls for a cytocompatible technique of manufacturing biocompatible hollow microfibers suitable for cell‐encapsulation/seeding in and around them. The techniques reported to date either have a limit on the microfiber dimensions or undergo a complex manufacturing process. Here, a microfluidic‐based method for cell seeding inside alginate hollow microfibers is designed whereby mouse astrocytes (C8‐D1A) are passively seeded on the inner surface of these hollow microfibers. Collagen I and poly‐d‐lysine, as cell attachment additives, are tested to assess cell adhesion and viability; the results are compared with nonadditive‐based hollow microfibers (BARE). The BARE furnishes better cell attachment and higher cell viability immediately after manufacturing, and an increasing trend in the cell viability is observed between Day 0 and Day 2. Swelling analysis using percentage initial weight and width is performed on BARE microfibers furnishing a maximum of 124.1% and 106.1%, respectively. Degradation analysis using weight observed a 62% loss after 3 days, with 46% occurring in the first 12 h. In the frequency sweep test performed, the storage modulus (G′) remains comparatively higher than the loss modulus (G″) in the frequency range 0–20 Hz, indicating high elastic behavior of the hollow microfibers.

While 3D cell cultures continue to grow in complexity and physiological relevance, more work must be done to reach the full potential of a real-time cell sensing system that is able to match the macro-and microenvironments of target tissues. 1D and 2D real-time sensors have been reliably created utilizing micro-and nano-electrodes, or planar electrodes, respectively. [1] This work furthers the cause by using biocompatible, graphene-laden microfibers as cellular constructs, which can be used in conjunction with 3D micro-electrode arrays for a highly complex real-time sensing system to analyze electrical cellto-cell communication that occurs within the brain. Additionally, this study works toward the important task of identifying genetic changes caused by manufacturing, and contrasting this against the effects of long-term encapsulation in four genes that are important to neural health, such as, tyrosine hydroxylase (TH), tubulin beta 3 class 3 (TUBB-3), interleukin 1 beta (IL-1β), and tumor necrosis factor alfa (TNF-α). Identifying the effects of manufacturing has been neglected in previous works, [2] and thus the current work provides a crucial understanding of the implications of using 3D cell cultures for tissue modeling.Hydrogels, with their high water content and the ease of diffusion across their borders, are ideal candidates for applications wherein the spatiotemporal properties of the cells must be controlled for long-term observation. [3] In particular, microfibers are well-suited for this purpose, as their higher surface-to-volume ratio expedites the diffusion of nutrients and waste across the cell border, while allowing for highly complex and specific scaffold geometries. [4,2,3b,3e,5] Cell-laden microfibers can be created in a number of different ways, including wetspinning/extrusion; [6] however, microfluidics provides unmatched control over the size, shape, and degredation rates of the resulting microfibers, while still allowing for all potential cell-safe gelation methods. [4,3h,7] In this way, a cell suspension might be mixed with a prepolymer solution before polymerization or gelation, thereby resulting in Engineering conductive 3D cell scaffoldings offer advantages toward the creation of physiologically relevant platforms with integrated real-time sensing capabilities. Dopaminergic neural cells are encapsulated into graphene-laden alginate microfibers using a microfluidic approach, which is unmatched for creating highly-tunable microfibers. Incorporating graphene increases the conductivity of the alginate microfibers by 148%, creating a similar conductivity to native brain tissue. The cell encapsulation procedure has an efficiency of 50%, and of those cells, ≈30% remain for the entire 6-day observation period. To understand how the microfluidic encapsulation affects cell genetics, tyrosine hydroxylase, tubulin beta 3 class 3, interleukin 1 beta, and tumor necrosis factor alfa are analyzed primarily with real-time reverse transcription-quantitative polymerase chain reaction and secondarily wi...

Barrier functionality of the blood–brain barrier (BBB) is provided by the tight junctions formed by a monolayer of the human brain endothelial cells (HBECs) internally around the blood capillaries. To mimic such barrier functionality in vitro, replicating the hollow tubular structure of the BBB along with the HBECs monolayer on its inner surface is crucial. Here, we developed a microfluidic manufacturing technique to pattern the HBECs on the surface of alginate‐based microstructures. The HBECs were seeded on the inner surface of these hollow microfibers using a custom‐built microfluidic device. The seeded HBECs were monitored for 9 days after manufacturing and cultured to form a monolayer on the inner surface of the alginate hollow microfibers in the maintenance media. A higher cell seeding density of 217 cells/mm length of the hollow microfiber was obtained using our microfluidic technique. Moreover, high accuracy of around 96% was obtained in seeding cells on the inner surface of alginate hollow microfibers. The microfluidic method illustrated in this study could be extrapolated to obtain a monolayer of different cell types on the inner surface of alginate hollow microfibers with cell‐compatible ECM matrix proteins. Furthermore, it will enable us to manufacture a range of microvascular systems in vitro by closely replicating the structural attributes of the native structure.

Barrier functionality of the blood-brain barrier (BBB) is provided by the tight junctions formed by a monolayer of the human brain endothelial cells (HBECs) internally around the blood capillaries. To mimic such barrier functionality in vitro, replicating the hollow tubular structure of the BBB along with the HBECs monolayer on its inner surface is crucial. Here, we developed an invasive microfluidic technique to obtain the HBECs monolayer on the inner surface of alginate-based hollow microfibers. The HBECs were seeded on the inner surface of these microfibers using a custom-built microfluidic device. The seeded HBECs were monitored for 9 days after manufacturing and cultured to form a monolayer on the inner surface of the alginate hollow microfibers in the maintenance media. A higher cell seeding density of 217 cells/mm length of the hollow microfiber was obtained using our microfluidic technique. Moreover, high accuracy of around 96 % was obtained in seeding cells on the inner surface of alginate hollow microfibers. The microfluidic method illustrated in this study could be extrapolated to obtain a monolayer of different cell types on the inner surface of alginate hollow microfibers with cell-compatible ECM matrix proteins. Furthermore, it will enable us to mimic a range of microvascular systems in vitro by closely replicating the structural attributes of the native structure.

The manufacturing of 3D cell scaffoldings provides advantages for modeling diseases and injuries by physiologically relevant platforms. A triple-flow microfluidic device was developed to rapidly fabricate alginate/graphene hollowalginate/graphene hollow microfibers based on the gelation of alginate induced with CaCl2. This five-channel pattern actualized continuous mild fabrication of hollow fibers under an optimized flowing rate ratio of 300: 200: 100 μL.min-1. The polymer solution was 2.5% alginate in 0.1% graphene, and a 30% polyethylene glycol solution was used as the sheath and core solutions. The morphology and physical properties of microstructures were investigated by scanning electron microscopy, electrochemical, and surface area analyzers. Subsequently, these conductive microfibers biocompatibility was studied by encapsulating mouse astrocyte cells within these scaffolds. The cells could successfully survive both the manufacturing process and prolonged encapsulation for up to 8 days. These unique 3D hollow scaffolds could significantly enhance the available surface area for nutrient transport to the cells. In addition, these conductive hollow scaffolds illustrated unique advantages such as 0.728 cm3.gr-1 porosity and twice more electrical conductivity in comparison to alginate scaffolds. The results confirm the potential of these scaffolds as a microenvironment that supports cell growth.