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Cardiovascular organ-on-a-chip (OoC) devices are composed of engineered or native functional tissues that are cultured under controlled microenvironments inside microchips. These systems employ microfabrication and tissue engineering techniques to recapitulate human physiology. This review focuses on human OoC systems to model cardiovascular diseases, to perform drug screening, and to advance personalized medicine. We also address the challenges in the generation of organ chips that can revolutionize the large-scale application of these systems for drug development and personalized therapy.

Insulin is an essential regulator of blood glucose homeostasis that is produced exclusively byβcells within the pancreatic islets of healthy individuals. In those affected by diabetes, immune inflammation, damage, and destruction of isletβcells leads to insulin deficiency and hyperglycemia. Current efforts to understand the mechanisms underlyingβcell damage in diabetes rely onin vitro-cultured cadaveric islets. However, isolation of these islets involves removal of crucial matrix and vasculature that supports islets in the intact pancreas. Unsurprisingly, these islets demonstrate reduced functionality over time in standard culture conditions, thereby limiting their value for understanding native islet biology. Leveraging a novel, vascularized micro-organ (VMO) approach, we have recapitulated elements of the native pancreas by incorporating isolated human islets within a three-dimensional matrix nourished by living, perfusable blood vessels. Importantly, these islets show long-term viability and maintain robust glucose-stimulated insulin responses. Furthermore, vessel-mediated delivery of immune cells to these tissues provides a model to assess islet-immune cell interactions and subsequent islet killing-key steps in type 1 diabetes pathogenesis. Together, these results establish the islet-VMO as a novel,ex vivoplatform for studying human islet biology in both health and disease.

BackgroundVagal afferent neurons represent the key neurosensory branch of the gut-brain axis, which describes the bidirectional communication between the gastrointestinal system and the brain. These neurons are important for detecting and relaying sensory information from the periphery to the central nervous system to modulate feeding behavior, metabolism, and inflammation. Confounding variables complicate the process of isolating the role of the vagal afferents in mediating these physiological processes. Therefore, we developed a microfluidic model of the sensory branch of the gut-brain axis. We show that this microfluidic model successfully compartmentalizes the cell body and neurite terminals of the neurons, thereby simulates the anatomical layout of these neurons to more accurately study physiologically-relevant processes.MethodsWe implemented a primary rat vagal afferent neuron culture into a microfluidic platform consisting of two concentric chambers interconnected with radial microchannels. The microfluidic platform separated cell bodies from neurite terminals of vagal afferent neurons. We then introduced physiologically-relevant gastrointestinal effector molecules at the nerve terminals and assessed their retrograde transport along the neurite or capacity to elicit an electrophysiological response using live cell calcium imaging.ResultsThe angle of microchannel outlets dictated the probability of neurites growing into a chamber versus tracking along chamber walls. When the neurite terminals were exposed to fluorescently-labeled cholera toxin subunit B, the proteins were taken up and retrogradely transported along the neurites over the course of 24 h. Additionally, mechanical perturbation (e.g., rinsing) of the neurite terminals significantly increased intracellular calcium concentration in the distal soma. Finally, membrane-displayed receptor for capsaicin was expressed and trafficked along newly projected neurites, as revealed by confocal microscopy.ConclusionsIn this work, we developed a microfluidic device that can recapitulate the anatomical layout of vagal afferent neurons in vitro. We demonstrated two physiologically-relevant applications of the platforms: retrograde transport and electrophysiological response. We expect this tool to enable controlled studies on the role of vagal afferent neurons in the gut-brain axis.

Recent advancements in 3D tissue engineering and organ‐on‐a‐chip systems have revolutionized biomedical research by providing sophisticated platforms that mimic complex physiological environments. This review explores various techniques in 3D printing, including bioprinting materials, laser‐induced forward transfer, ink‐jet systems, and microextrusion methods, highlighting their roles in fabricating intricate tissue constructs. Physical and biochemical characterization methods for assessing these engineered tissues on microchips are discussed in detail, emphasizing their importance in accurately replicating physiological conditions. The review further delves into the development of multiple organ and single organ‐on‐a‐chip systems. It covers two‐organ, three‐organ, and four‐organ platforms, as well as individual systems such as pancreas‐on‐a‐chip, kidney‐on‐a‐chip, liver‐on‐a‐chip, lung‐on‐a‐chip, blood–brain barrier‐on‐a‐chip, heart‐on‐a‐chip, breast cancer‐on‐a‐chip, gut‐on‐a‐chip, and blood vessels‐on‐a‐chip. Each section addresses the unique challenges and advancements associated with these models, providing insights into their potential applications in drug testing, disease modelling, and personalized medicine. In conclusion, the article discusses current challenges and offers perspectives on future directions in 3D tissue engineering and organ‐on‐a‐chip technology, highlighting the transformative impact of these systems on biomedical research and healthcare. [ABSTRACT FROM AUTHOR]

The gut is a vital organ that is central to the absorption and metabolic processing of orally administered drugs. While there have been many models developed with the goal of studying the absorption of drugs in the gut, these models fail to adequately recapitulate the diverse, complex gastrointestinal microenvironment. The recent emergence of microfluidic organ-on-a-chip technologies has provided a novel means of modeling the gut, yielding radical new insights into the structure of the gut and the mechanisms through which it shapes disease, with key implications for biomedical developmental efforts. Such organ-on-a-chip technologies have been demonstrated to exhibit greater cost-effectiveness, fewer ethical concerns, and a better ability to address inter-species differences in traditional animal models in the context of drug development. The present review offers an overview of recent developments in the reconstruction of gut structure and function in vitro using microfluidic gut-on-a-chip (GOC) systems, together with a discussion of the potential applications of these platforms in the context of drug development and the challenges and future prospects associated with this technology. This paper outlines the characteristics of the different cell types most frequently used to construct microfluidic gut-on-a-chip models and the microfluidic devices employed for the study of drug absorption. And the applications of gut-related multichip coupling and disease modelling in the context of drug development is systematically reviewed. With the detailed summarization of microfluidic chip-based gut models and discussion of the prospective directions for practical application, this review will provide insights to the innovative design and application of microfluidic gut-on-a-chip for drug development. [Display omitted] [ABSTRACT FROM AUTHOR]

The human mammary gland represents a highly organized and dynamic tissue, uniquely characterized by postnatal developmental cycles. During pregnancy and lactation, it undergoes extensive hormone-stimulated architectural remodeling, culminating in the formation of specialized structures for milk production to nourish offspring. Moreover, it carries significant health implications, due to the high prevalence of breast cancer. Therefore, gaining insight into the unique biology of the mammary gland can have implications for managing breast cancer and promoting the well-being of both women and infants. Tissue engineering techniques hold promise to narrow the translational gap between existing breast models and clinical outcomes. Here, we provide an overview of the current landscape of breast tissue engineering, outline key requirements, and the challenges to overcome for achieving more predictive human breast models. We propose methods to validate breast function and highlight preclinical applications for improved understanding and targeting of breast cancer. Beyond mammary gland physiology, representative human breast models can offer new insight into stem cell biology and developmental processes that could extend to other organs and clinical contexts. [ABSTRACT FROM AUTHOR]

In the tumor microenvironment (TME), the interaction between cancer cells and the microvascular network plays a crucial role in cancer progression. It is also well known that an extremely low oxygen concentration is generated in the TME. However, the effects of oxygen concentration on the interaction between cancer cells and the microvascular network remain poorly understood. In the present study, we developed a microfluidic device with three gel channels and used this device to co-culture cancer cells and a microvascular network. We then investigated the cellular dynamics at different oxygen concentrations. Cancer cells and cells forming a microvascular network (endothelial cells and fibroblasts) were separately mixed with fibrin gels and placed in separate gel channels that flanked a middle gel channel lacking cells. During a seven-day co-culture, the dynamics of cancer cells and formation of a three-dimensional microvascular structure were observed. Cell culture was conducted at three different oxygen concentrations: atmospheric oxygen (21% O2), physiological normoxia (5% O2), and physiological hypoxia (1% O2, resembling the TME). Inspection revealed that cancer cells migrated toward the microvascular network under the co-culture conditions, a property that was potentiated at lower oxygen levels. Under physiological normoxia, endothelial cells formed a thick, dense microvascular network rather than migrating towards the cancer cells. In contrast, under physiological hypoxia, endothelial cells did not exhibit angiogenesis toward cancer cells. These results suggest that the microfluidic device described here will be useful for investigating the interactions between cancer cells and microvascular network under various oxygen conditions. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) affects millions of people worldwide, but there are limited drugs available to treat it, so acquiring a more comprehensive comprehension of the underlying reasons and mechanisms behind inflammation is crucial, as well as developing novel therapeutic approaches to manage it and mitigate or forestall associated harm. It is evident that current in vitro models cannot faithfully replicate all aspects of joint diseases, which makes them ineffective as tools for disease research and drug testing. Organ-on-a-chip (OoC) technology is an innovative platform that can mimic the microenvironment and physiological state of living tissues more realistically than traditional methods by simulating the spatial arrangement of cells and interorgan communication. This technology allows for the precise control of fluid flow, nutrient exchange, and the transmission of physicochemical signals, such as bioelectrical, mechanical stimulation and shear force. In addition, the integration of cutting-edge technologies like sensors, 3D printing, and artificial intelligence enhances the capabilities of these models. Here, we delve into OoC models with a particular focus on Synovial Joints-on-a-Chip, where we outline their structure and function, highlighting the potential of the model to advance our understanding of RA. We integrate the actual evidence regarding various OoC models and their possible integration for multisystem disease study in RA research for the first time and introduce the prospects and opportunities of the chip in RA etiology and pathological mechanism research, drug research, disease prevention and human precision medicine. Although many challenges remain, OoC holds great promise as an in vitro model that approaches physiology and dynamics. [ABSTRACT FROM AUTHOR]

The existing in vitro and in vivo models for studying osteoarthritis have significant limitations in replicating the complexity of joint tissues. This research aims to validate a Tissue-On-a-Chip system for osteoarthritis research. Osteochondral tissues obtained from knee replacement surgeries of patients with osteoarthritis were cultured in an Organ-On-a-Chip system. This system was designed to supply oxygen and glucose to the cartilage from the bone. The distribution of oxygen and glucose was evaluated by fluorescence using Image-iT Green Hypoxia and 2-NBDG, respectively. Cytotoxicity was measured using lactate dehydrogenase (LDH) levels in chip cultures compared to plate cultures (12 tissues per method). Glycosaminoglycans (GAGs), alkaline phosphatase (ALP), Coll2-1, and procollagen type II N-terminal propeptide (PIINP) were measured in the perfused medium of the Tissue-On-a-Chip over a period of 70 days. Fluorescence of Image-iT Green Hypoxia was observed only in the cartilage area, while 2-NBDG was distributed throughout the tissue. An increase in LDH levels was noted in the plate cultures on day 24 and in the Tissue-On-a-Chip cultures on day 63. Compared to the start of the culture, GAG content increased on day 52, while ALP showed variations. A notable increase in GAG, ALP, and Coll2-1 levels was observed on day 59. PIINP levels remained stable throughout the experiment. The validated osteochondral Tissue-On-a-Chip system can replicate the joint microenvironment, with hypoxic conditions in cartilage and normoxic conditions in bone. Tissue survival and component stability were maintained for approximately two months. This platform is a useful tool for evaluating new drugs and represents a viable alternative to animal models. [ABSTRACT FROM AUTHOR]

The incorporation of engineered muscle‐tendon junction (MTJ) with organ‐on‐a‐chip technology provides promising in vitro models for the understanding of cell‐cell interaction at the interface between muscle and tendon tissues. However, developing engineered MTJ tissue with biomimetic anatomical interface structure remains challenging, and the precise co‐culture of engineered interface tissue is further regarded as a remarkable obstacle. Herein, an interwoven waving approach is presented to develop engineered MTJ tissue with a biomimetic "M‐type" interface structure, and further integrated into a precise co‐culture microfluidic device for functional MTJ‐on‐a‐chip fabrication. These multiscale MTJ scaffolds based on electrospun nanofiber yarns enabled 3D cellular alignment and differentiation, and the "M‐type" structure led to cellular organization and interaction at the interface zone. Crucially, a compartmentalized co‐culture system is integrated into an MTJ‐on‐a‐chip device for the precise co‐culture of muscle and tendon zones using their medium at the same time. Such an MTJ‐on‐a‐chip device is further served for drug‐associated MTJ toxic or protective efficacy investigations. These results highlight that these interwoven nanofibrous scaffolds with biomimetic "M‐type" interface are beneficial for engineered MTJ tissue development, and MTJ‐on‐a‐chip with precise co‐culture system indicated their promising potential as in vitro musculoskeletal models for drug development and biological mechanism studies. [ABSTRACT FROM AUTHOR]

Infectious diseases caused by bacteria, viruses, fungi, and parasites pose a significant societal challenge. In response, scientists are developing advanced technology to enhance the prevention, diagnosis, and treatment of such diseases. One such promising technology is microfluidic systems, which are utilized in organ‐on‐a‐chip systems to replicate the microenvironments of organs. These systems have potential applications in drug screening, disease modeling, and personalized medicine. This review provides an overview of recent advances in organ‐on‐a‐chip platforms and their potential for preventing and diagnosing various infections. After discussing traditional techniques employed in studying infectious diseases, the role of microfluidic platforms in detecting infections is delved in. It is expound on advanced microfluidic‐based strategies for infection diagnosis, such as the polymerase chain reaction‐based microfluidic devices, enzyme linked immunosorbent assay‐based microfluidic devices, hierarchical nanofluidic molecular enrichment systemand µWestern blotting‐based microfluidic devices, and smartphone‐based microfluidic devices. Additionally, future research challenges and perspectives are discussed on microfluidic systems in biomedical and regenerative medicine applications. Consequently, microfluidic platforms have the potential to serve as fundamental frameworks for understanding infectious diseases, thereby leading to personalized regenerative medicine. hierarchical nanofluidic molecular enrichment system [ABSTRACT FROM AUTHOR]

Traditional in vitro models have inevitable limitations and there are significant differences in assessing drug efficacy and side effects as compared to human trials. Organ-on-a-chip technology simulates human organs in a physiological environment and functional chip with a high fidelity physiological or pathophysiological level, offering great innovative prospects for drug development. This paper mainly introduces the research progress and application of organ chip from the perspective of various systems in vivo. At the same time, the limitations of the current development process of organ chip and the future development direction are proposed. [ABSTRACT FROM AUTHOR]

The choroid plexus (CP), a highly vascularized endothelial–epithelial convolute, is placed in the ventricular system of the brain and produces a large part of the cerebrospinal fluid (CSF). Additionally, the CP is the location of a blood–CSF barrier (BCSFB) that separates the CSF from the blood stream in the CP endothelium. In vitro models of the CP and the BCSFB are of high importance to investigate the biological functions of the CP and the BCSFB. Since the CP is involved in several serious diseases, these in vitro models promise help in researching the processes contributing to the diseases and during the development of treatment options. In this review, we provide an overview on the available models and the advances that have been made toward more sophisticated and "in vivo near" systems as organoids and microfluidic lab-on-a-chip approaches. We go into the applications and research objectives for which the various modeling systems can be used and discuss the possible future prospects and perspectives. [ABSTRACT FROM AUTHOR]

Traditional drug development is a long and expensive process with high rates of failure. This has prompted the pharmaceutical industry to seek more efficient drug development frameworks, driving the emergence of organ-on-a-chip (OOC) based on microfluidic technologies. Unlike traditional animal experiments, OOC systems provide a more accurate simulation of human organ microenvironments and physiological responses, therefore offering a cost-effective and efficient platform for biomedical research, particularly in the development of new medicines. Additionally, OOC systems enable quick and real-time analysis, high-throughput experimentation, and automation. These advantages have shown significant promise in enhancing the drug development process. The success of an OOC system hinges on the integration of specific designs, manufacturing techniques, and biosensors to meet the need for integrated multiparameter datasets. This review focuses on the manufacturing, design, sensing systems, and applications of OOC systems, highlighting their design and sensing capabilities, as well as the technical challenges they currently face. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDDs) affect more than 50 million people worldwide, posing a significant global health challenge as well as a high socioeconomic burden. With aging constituting one of the main risk factors for some NDDs such as Alzheimer's disease (AD) and Parkinson's disease (PD), this societal toll is expected to rise considering the predicted increase in the aging population as well as the limited progress in the development of effective therapeutics. To address the high failure rates in clinical trials, legislative changes permitting the use of alternatives to traditional pre‐clinical in vivo models are implemented. In this regard, microphysiological systems (MPS) such as organ‐on‐a‐chip (OoC) platforms constitute a promising tool, due to their ability to mimic complex and human‐specific tissue niches in vitro. This review summarizes the current progress in modeling NDDs using OoC technology and discusses five critical aspects still insufficiently addressed in OoC models to date. Taking these aspects into consideration in the future MPS will advance the modeling of NDDs in vitro and increase their translational value in the clinical setting. [ABSTRACT FROM AUTHOR]

Recent advancements in organoid technology have heralded a transformative era in biomedical research, characterized by the emergence of gut organoids that replicate the structural and functional complexity of the human intestines. These stem cell-derived structures provide a dynamic platform for investigating intestinal physiology, disease pathogenesis, and therapeutic interventions. This model outperforms traditional two-dimensional cell cultures in replicating cell interactions and tissue dynamics. Gut organoids represent a significant leap towards personalized medicine. They provide a predictive model for human drug responses, thereby minimizing reliance on animal models and paving the path for more ethical and relevant research approaches. However, the transition from basic organoid models to more sophisticated, biomimetic systems that encapsulate the gut's multifaceted environment--including its interactions with microbial communities, immune cells, and neural networks--presents significant scientific challenges. This review concentrates on recent technological strides in overcoming these barriers, emphasizing innovative engineering approaches for integrating diverse cell types to replicate the gut's immune and neural components. It also explores the application of advanced fabrication techniques, such as 3D bioprinting and microfluidics, to construct organoids that more accurately replicate human tissue architecture. They provide insights into the intricate workings of the human gut, fostering the development of targeted, effective treatments. These advancements hold promise in revolutionizing disease modeling and drug discovery. Future research directions aim at refining these models further, making them more accessible and scalable for wider applications in scientific inquiry and clinical practice, thus heralding a new era of personalized and predictive medicine. [ABSTRACT FROM AUTHOR]

Increased protein-bound uremic toxins (PBUTs) in patients with chronic kidney disease (CKD) are associated with cardiovascular diseases (CVDs); however, whether retention of PBUTs causes CVD remains unclear. Previous studies assessing the impacts of PBUTs on the vasculature have relied on 2D cell cultures lacking in vivo microenvironments. Here, we investigated the impact of various PBUTs (p-cresol (PC), indoxyl sulfate (IS), and p-cresyl sulfate (PCS)) on microvascular function using an organ-on-a-chip (OOC). Human umbilical vein endothelial cells were used to develop 3D vessels. Chronic exposure to PC resulted in significant vascular leakage compared with controls, whereas IS or PCS treatment did not alter the permeability of 3D vessels. Increased permeability induced by PC was correlated with derangement of cell adherens junction complex, vascular endothelial (VE)-cadherin and filamentous (F)-actin. Additionally, PC decreased endothelial viability in a concentration-dependent manner with a lower IC50 in 3D vessels than in 2D cultures. IS slightly decreased cell viability, while PCS did not affect viability. PC induced inflammatory responses by increasing monocyte adhesion to endothelial surfaces of 3D vessels and IL-6 production. In conclusion, this study leveraged an OOC to determine the diverse effects of PBUTs, demonstrating that PC accumulation is detrimental to ECs during kidney insufficiency. [ABSTRACT FROM AUTHOR]

In recent years, research on organ-on-a-chip technology has been flourishing, particularly for drug screening and disease model development. Fibroblasts and vascular endothelial cells engage in crosstalk through paracrine signaling and direct cell–cell contact, which is essential for the normal development and function of the heart. Therefore, to faithfully recapitulate cardiac function, it is imperative to incorporate fibroblasts and vascular endothelial cells into a heart-on-a-chip model. Here, we report the development of a human heart-on-a-chip composed of induced pluripotent stem cell (iPSC)-derived cardiomyocytes, fibroblasts, and vascular endothelial cells. Vascular endothelial cells cultured on microfluidic channels responded to the flow of culture medium mimicking blood flow by orienting themselves parallel to the flow direction, akin to in vivo vascular alignment in response to blood flow. Furthermore, the flow of culture medium promoted integrity among vascular endothelial cells, as evidenced by CD31 staining and lower apparent permeability. The tri-culture condition of iPSC-derived cardiomyocytes, fibroblasts, and vascular endothelial cells resulted in higher expression of the ventricular cardiomyocyte marker IRX4 and increased contractility compared to the bi-culture condition with iPSC-derived cardiomyocytes and fibroblasts alone. Such tri-culture-derived cardiac tissues exhibited cardiac responses similar to in vivo hearts, including an increase in heart rate upon noradrenaline administration. In summary, we have achieved the development of a heart-on-a-chip composed of cardiomyocytes, fibroblasts, and vascular endothelial cells that mimics in vivo cardiac behavior. [ABSTRACT FROM AUTHOR]

Tumor organoids, derived from tumor tissues, are three-dimensional structures created in vitro to mimic in vivo tumor growth. They possess comparable genetic lineage and pathological characteristics to the original tumor, making them a promising research platform for studying tumor biology. In recent years, significant advancements in techniques such as microfluidics, cell coculture and vascularization have greatly promoted the development of Organ-on-a-Chip (OoC) and expanded the applications of tumor organoid models in both basic and clinical translational research. These advancements include leveraging tumor organoid models to investigate drug resistance mechanisms, perform drug screening, and facilitate clinical trials of precisional therapy. However, current organoid models still face several limitations, including the instability of cell culture quality, low cost-effectiveness, and the inability to accurately replicate the complex tumor microenvironment and spatial structures. Further research is needed to overcome these technical bottlenecks and improve the application of organoid models in cancer research, thereby further enhancing the depth of tumor research. This review summarized the development history and latest progress of tumor organoids. In terms of the latest applications of tumor organoids, this article reviewed disease modeling, research and development of innovative tumor drugs, and their application in personalized treatment. It also summarized the recent clinical researches of organoids; In addition, this review provided a detailed introduction to the technological progress of tumor organoids, including the development of novel culture devices, simulation of tumor microenvironment, and induction of angiogenesis. In summary, this review explored the latest developments, defects and future directions in the research of tumor organoids, aiming to provide reference for the study of tumor organoids. [ABSTRACT FROM AUTHOR]

Simple Summary: The development and use of migrastatic drugs could help improve the outcomes for patients with high-grade non-muscle-invasive bladder cancer and muscle-invasive bladder cancer by inhibiting bladder cancer cell invasion and thereby decreasing the likelihood of disease progression and metastasis. A key barrier to this is the lack of suitable models to assess bladder cancer cell invasiveness. Here, we describe a bladder cancer-on-a-chip model. We demonstrate that our model supports the retention of the bladder cancer cell phenotype and can be used to reproducibly assess and quantify the invasiveness of live bladder cancer cells. Treatment with ATN-161, a well-known migrastatic drug, caused a dose-dependent decrease in bladder cancer cell invasiveness thereby validating the ability of our model to test migrastatic drugs. To our knowledge, a bladder cancer-on-a-chip model that can specifically assess bladder cancer invasiveness has not previously been described. We have developed a bladder cancer-on-a-chip model which supports the 3D growth of cells and can be used to assess and quantify bladder cancer cell invasiveness in a physiologically appropriate environment. Three bladder cancer cell lines (T24, J82, and RT4) were resuspended in 50% Matrigel® and grown within a multi-channel organ-on-a-chip system. The ability of live cells to invade across into an adjacent 50% Matrigel®-only channel was assessed over a 2-day period. Cell lines isolated from patients with high-grade bladder cancer (T24 and J82) invaded across into the Matrigel®-only channel at a much higher frequency compared to cells isolated from a patient with low-grade cancer (RT4) (p < 0.001). The T24 and J82 cells also invaded further distances into the Matrigel®-only channel compared to the RT4 cells (p < 0.001). The cell phenotype within the model was maintained as assessed by cell morphology and immunohistochemical analysis of E-cadherin. Treatment with ATN-161, an α5β1 integrin inhibitor and well-known migrastatic drug, caused a dose-dependent decrease in the invasiveness of the J82 cells (p < 0.01). The combined data demonstrate that our bladder cancer-on-a-chip model supports the retention of the bladder cancer cell phenotype and can be used to reproducibly assess and quantify the invasiveness of live bladder cancer cells. [ABSTRACT FROM AUTHOR]

Static well plates remain the gold standard to study viral infections in vitro, but they cannot accurately mimic dynamic viral infections as they occur in the human body. Therefore, we established a dynamic cell culture platform, based on centrifugal microfluidics, to study viral infections in perfusion. To do so, we used human primary periodontal dental ligament (PDL) cells and herpes simplex virus-1 (HSV-1) as a case study. By microscopy, we confirmed that the PDL cells efficiently attached and grew in the chip. Successful dynamic viral infection of perfused PDL cells was monitored using fluorescent imaging and RT-qPCR-based experiments. Remarkably, viral infection in flow resulted in a gradient of HSV-1-infected cells gradually decreasing from the cell culture chamber entrance towards its end. The perfusion of acyclovir in the chip prevented HSV-1 spreading, demonstrating the usefulness of such a platform for monitoring the effects of antiviral drugs. In addition, the innate antiviral response of PDL cells, measured by interferon gene expression, increased significantly over time in conventional static conditions compared to the perfusion model. These results provide evidence suggesting that dynamic viral infections differ from conventional static infections, which highlights the need for more physiologically relevant in vitro models to study viral infections. [ABSTRACT FROM AUTHOR]

Microfluidics have revolutionized cell culture by allowing for precise physical and chemical environmental control. Coupled with electrodes, microfluidic cell culture can be activated or have its changes sensed in real-time. We used our previously developed reliable and stable microfluidic device for cell growth and monitoring to design, fabricate, and characterize a whole-channel impedance-based sensor and used it to systematically assess the electrical and electrochemical influences of microfluidic channel boundaries coupled with varying electrode sizes, distances, coatings, and cell coverage. Our investigation includes both theoretical and experimental approaches to investigate how design parameters and insulating boundary conditions change impedance characteristics. We examined the system with various solutions using a frequency range of 0.5 Hz to 1 MHz and a modulation voltage of 50 mV. The results show that impedance is directly proportional to electrode distance and inversely proportional to electrode coating, area, and channel size. We also demonstrate that electrode spacing is a dominant factor contributing to impedance. In the end, we summarize all the relationships found and comment on the appropriateness of using this system to investigate barrier cells in blood vessel models and organ-on-a-chip devices. This fundamental study can help in the careful design of microfluidic culture constructs and models that require channel geometries and impedance-based biosensing. [ABSTRACT FROM AUTHOR]

Insulin is an essential regulator of blood glucose homeostasis that is produced exclusively byβcells within the pancreatic islets of healthy individuals. In those affected by diabetes, immune inflammation, damage, and destruction of isletβcells leads to insulin deficiency and hyperglycemia. Current efforts to understand the mechanisms underlyingβcell damage in diabetes rely onin vitro-cultured cadaveric islets. However, isolation of these islets involves removal of crucial matrix and vasculature that supports islets in the intact pancreas. Unsurprisingly, these islets demonstrate reduced functionality over time in standard culture conditions, thereby limiting their value for understanding native islet biology. Leveraging a novel, vascularized micro-organ (VMO) approach, we have recapitulated elements of the native pancreas by incorporating isolated human islets within a three-dimensional matrix nourished by living, perfusable blood vessels. Importantly, these islets show long-term viability and maintain robust glucose-stimulated insulin responses. Furthermore, vessel-mediated delivery of immune cells to these tissues provides a model to assess islet-immune cell interactions and subsequent islet killing-key steps in type 1 diabetes pathogenesis. Together, these results establish the islet-VMO as a novel,ex vivoplatform for studying human islet biology in both health and disease.

Traditional in vitro models have inevitable limitations and there are significant differences in assessing drug efficacy and side effects as compared to human trials. Organ-on-a-chip technology simulates human organs in a physiological environment and functional chip with a high fidelity physiological or pathophysiological level, offering great innovative prospects for drug development. This paper mainly introduces the research progress and application of organ chip from the perspective of various systems in vivo. At the same time, the limitations of the current development process of organ chip and the future development direction are proposed.

Spheroids and organoids have attracted significant attention as innovative models for disease modeling and drug screening. By employing diverse types of spheroids or organoids, it is feasible to establish microphysiological systems that enhance the precision of disease modeling and offer more dependable and comprehensive drug screening. High-throughput microphysiological systems that support optional, parallel testing of multiple drugs have promising applications in personalized medical treatment and drug research. However, establishing such a system is highly challenging and requires a multidisciplinary approach. This study introduces a dynamic Microphysiological System Chip Platform (MSCP) with multiple functional microstructures that encompass the mentioned advantages. We developed a high-throughput lung cancer spheroids model and an intestine-liver-heart-lung cancer microphysiological system for conducting parallel testing on four anti-lung cancer drugs, demonstrating the feasibility of the MSCP. This microphysiological system combines microscale and macroscale biomimetics to enable a comprehensive assessment of drug efficacy and side effects. Moreover, the microphysiological system enables evaluation of the real pharmacological effect of drug molecules reaching the target lesion after absorption by normal organs through fluid-based physiological communication. The MSCP could serves as a valuable platform for microphysiological system research, making significant contributions to disease modeling, drug development, and personalized medical treatment.

Abstract The human mammary gland represents a highly organized and dynamic tissue, uniquely characterized by postnatal developmental cycles. During pregnancy and lactation, it undergoes extensive hormone-stimulated architectural remodeling, culminating in the formation of specialized structures for milk production to nourish offspring. Moreover, it carries significant health implications, due to the high prevalence of breast cancer. Therefore, gaining insight into the unique biology of the mammary gland can have implications for managing breast cancer and promoting the well-being of both women and infants. Tissue engineering techniques hold promise to narrow the translational gap between existing breast models and clinical outcomes. Here, we provide an overview of the current landscape of breast tissue engineering, outline key requirements, and the challenges to overcome for achieving more predictive human breast models. We propose methods to validate breast function and highlight preclinical applications for improved understanding and targeting of breast cancer. Beyond mammary gland physiology, representative human breast models can offer new insight into stem cell biology and developmental processes that could extend to other organs and clinical contexts.

Abstract In recent years, research on organ-on-a-chip technology has been flourishing, particularly for drug screening and disease model development. Fibroblasts and vascular endothelial cells engage in crosstalk through paracrine signaling and direct cell–cell contact, which is essential for the normal development and function of the heart. Therefore, to faithfully recapitulate cardiac function, it is imperative to incorporate fibroblasts and vascular endothelial cells into a heart-on-a-chip model. Here, we report the development of a human heart-on-a-chip composed of induced pluripotent stem cell (iPSC)-derived cardiomyocytes, fibroblasts, and vascular endothelial cells. Vascular endothelial cells cultured on microfluidic channels responded to the flow of culture medium mimicking blood flow by orienting themselves parallel to the flow direction, akin to in vivo vascular alignment in response to blood flow. Furthermore, the flow of culture medium promoted integrity among vascular endothelial cells, as evidenced by CD31 staining and lower apparent permeability. The tri-culture condition of iPSC-derived cardiomyocytes, fibroblasts, and vascular endothelial cells resulted in higher expression of the ventricular cardiomyocyte marker IRX4 and increased contractility compared to the bi-culture condition with iPSC-derived cardiomyocytes and fibroblasts alone. Such tri-culture-derived cardiac tissues exhibited cardiac responses similar to in vivo hearts, including an increase in heart rate upon noradrenaline administration. In summary, we have achieved the development of a heart-on-a-chip composed of cardiomyocytes, fibroblasts, and vascular endothelial cells that mimics in vivo cardiac behavior.

Abstract Increased protein-bound uremic toxins (PBUTs) in patients with chronic kidney disease (CKD) are associated with cardiovascular diseases (CVDs); however, whether retention of PBUTs causes CVD remains unclear. Previous studies assessing the impacts of PBUTs on the vasculature have relied on 2D cell cultures lacking in vivo microenvironments. Here, we investigated the impact of various PBUTs (p-cresol (PC), indoxyl sulfate (IS), and p-cresyl sulfate (PCS)) on microvascular function using an organ-on-a-chip (OOC). Human umbilical vein endothelial cells were used to develop 3D vessels. Chronic exposure to PC resulted in significant vascular leakage compared with controls, whereas IS or PCS treatment did not alter the permeability of 3D vessels. Increased permeability induced by PC was correlated with derangement of cell adherens junction complex, vascular endothelial (VE)-cadherin and filamentous (F)-actin. Additionally, PC decreased endothelial viability in a concentration-dependent manner with a lower IC50 in 3D vessels than in 2D cultures. IS slightly decreased cell viability, while PCS did not affect viability. PC induced inflammatory responses by increasing monocyte adhesion to endothelial surfaces of 3D vessels and IL-6 production. In conclusion, this study leveraged an OOC to determine the diverse effects of PBUTs, demonstrating that PC accumulation is detrimental to ECs during kidney insufficiency.

Following the global spread of COVID-19, scientists and engineers have adapted technologies and developed new tools to aid in the fight against COVID-19. This review discusses various approaches to engineering biomaterials, devices, and therapeutics, especially at micro and nano levels, for the prevention, diagnosis, and treatment of infectious diseases, such as COVID-19, serving as a resource for scientists to identify specific tools that can be applicable for infectious-disease-related research, technology development, and treatment. From the design and production of equipment critical to first responders and patients using three-dimensional (3D) printing technology to point-of-care devices for rapid diagnosis, these technologies and tools have been essential to address current global needs for the prevention and detection of diseases. Moreover, advancements in organ-on-a-chip platforms provide a valuable platform to not only study infections and disease development in humans but also allow for the screening of more effective therapeutics. In addition, vaccines, the repurposing of approved drugs, biomaterials, drug delivery, and cell therapy are promising approaches for the prevention and treatment of infectious diseases. Following a comprehensive review of all these topics, we discuss unsolved problems and future directions.

Chronic white adipose tissue (WAT) inflammation has been recognized as a critical early event in the pathogenesis of obesity-related disorders. This process is characterized by the increased residency of proinflammatory M1 macrophages in WAT. However, the lack of an isogenic human macrophage-adipocyte model has limited biological studies and drug discovery efforts, highlighting the need for human stem cell-based approaches. Here, human induced pluripotent stem cell (iPSC) derived macrophages (iMACs) and adipocytes (iADIPOs) are cocultured in a microphysiological system (MPS). iMACs migrate toward and infiltrate into the 3D iADIPOs cluster to form crown-like structures (CLSs)-like morphology around damaged iADIPOs, recreating classic histological features of WAT inflammation seen in obesity. Significantly more CLS-like morphologies formed in aged and palmitic acid-treated iMAC-iADIPO-MPS, showing the ability to mimic inflammatory severity. Importantly, M1 (proinflammatory) but not M2 (tissue repair) iMACs induced insulin resistance and dysregulated lipolysis in iADIPOs. Both RNAseq and cytokines analyses revealed a reciprocal proinflammatory loop in the interactions of M1 iMACs and iADIPOs. This iMAC-iADIPO-MPS thus successfully recreates pathological conditions of chronically inflamed human WAT, opening a door to study the dynamic inflammatory progression and identify clinically relevant therapies.

Abstract The female reproductive system comprises the internal and external genitalia, which communicate through intricate endocrine pathways. Besides secreting hormones that maintain the female secondary sexual characteristics, it also produces follicles and offspring. However, the in vitro systems have been very limited in recapitulating the specific anatomy and pathophysiology of women. Organ-on-a-chip technology, based on microfluidics, can better simulate the cellular microenvironment in vivo, opening a new field for the basic and clinical research of female reproductive system diseases. This technology can not only reconstruct the organ structure but also emulate the organ function as much as possible. The precisely controlled fluidic microenvironment provided by microfluidics vividly mimics the complex endocrine hormone crosstalk among various organs of the female reproductive system, making it a powerful preclinical tool and the future of pathophysiological models of the female reproductive system. Here, we review the research on the application of organ-on-a-chip platforms in the female reproductive systems, focusing on the latest progress in developing models that reproduce the physiological functions or disease features of female reproductive organs and tissues, and highlighting the challenges and future directions in this field.

Natural bone is a material with a hierarchical porous structure; therefore, the pore size of bone tissue at the micro-scale is crucial for osteoblast function and osteogenesis. However, the physiological mechanisms behind pore size-regulated osteogenesis remain unclear. Trabecular separation is one of the main parameters of bone trabeculae structure, which is the gap between the trabeculae and can be understood as porosity. This study uses a bioinspired bone chip made from polydimethylsiloxane (PDMS) to mimic the multiscale microstructures of healthy and osteoporotic bone tissue based on data on trabecular separation from healthy and osteoporotic mice. Microchannels in the chip were made in the same topology and substrate but at different micro-scales. The result showed that osteoblasts seeded into the smaller microchannel (200 μm in diameter, mimicking healthy bone) demonstrate greater osteogenic capability and autophagy than in the larger one (350 μm in diameter, mimicking osteoporotic bone). In addition, changes in osteogenesis between each microchannel after using the autophagy inhibitor chloroquine (CQ) indicated that osteogenesis was accelerated by autophagy in the 200 μm microchannel. Finally, we found stronger osteogenesis in the 200 μm microchannel, which depends on the activation of Hippo/YAP signaling. This bioinspired bone chip, which mimics the cellular behavioral changes in the osteoporotic microenvironment at the tissue level during the transition from healthy to osteoporotic bone, is expected to be the ideal in vitro platform for studying osteoporosis (OP).

Abstract Clinical outcome after traumatic brain injury (TBI) is closely associated conditions of other organs, especially lungs as well as degree of brain injury. Even if there is no direct lung damage, severe brain injury can enhance sympathetic tones on blood vessels and vascular resistance, resulting in neurogenic pulmonary edema. Conversely, lung damage can worsen brain damage by dysregulating immunity. These findings suggest the importance of brain-lung axis interactions in TBI. However, little research has been conducted on the topic. An advanced disease model using stem cell technology may be an alternative for investigating the brain and lungs simultaneously but separately, as they can be potential candidates for improving the clinical outcomes of TBI. In this review, we describe the importance of brain-lung axis interactions in TBI by focusing on the concepts and reproducibility of brain and lung organoids in vitro. We also summarize recent research using pluripotent stem cell-derived brain organoids and their preclinical applications in various brain disease conditions and explore how they mimic the brain-lung axis. Reviewing the current status and discussing the limitations and potential perspectives in organoid research may offer a better understanding of pathophysiological interactions between the brain and lung after TBI.

In vitro models of kidneys have limited effectiveness owing to the complex structure and functions of the kidney when compared with other organs. Therefore many renal function evaluations are currently being carried out through animal experiments. In contrast, efforts are being made to apply biomimetic systems, such as organ-on-a-chip, which is based on microfluidic device technology, to serve as an in vitro model for the kidney. These systems aimed to recreate a physiological cultivation environment. This review has provided an overview of organ-on-a-chip research focused on glomeruli and tubules as in vitro models for the kidney and discusses future prospects.

Abstract Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitochondrial Transplant Convergent Working Group (CWG), to explore three key issues that limit clinical translation: (1) storage of mitochondria, (2) biomaterials to enhance mitochondrial uptake, and (3) dynamic models to mimic the complex recipient tissue environment. In this review, we present a summary of CWG conclusions related to these three issues and provide an overview of pre-clinical studies aimed at building a more robust toolkit for translational trials.

The female reproductive system comprises the internal and external genitalia, which communicate through intricate endocrine pathways. Besides secreting hormones that maintain the female secondary sexual characteristics, it also produces follicles and offspring. However, the in vitro systems have been very limited in recapitulating the specific anatomy and pathophysiology of women. Organ-on-a-chip technology, based on microfluidics, can better simulate the cellular microenvironment in vivo, opening a new field for the basic and clinical research of female reproductive system diseases. This technology can not only reconstruct the organ structure but also emulate the organ function as much as possible. The precisely controlled fluidic microenvironment provided by microfluidics vividly mimics the complex endocrine hormone crosstalk among various organs of the female reproductive system, making it a powerful preclinical tool and the future of pathophysiological models of the female reproductive system. Here, we review the research on the application of organ-on-a-chip platforms in the female reproductive systems, focusing on the latest progress in developing models that reproduce the physiological functions or disease features of female reproductive organs and tissues, and highlighting the challenges and future directions in this field. [ABSTRACT FROM AUTHOR]

Microfluidic systems have become integral for lab‐on‐a‐chip and organ‐on‐a‐chip applications across numerous disciplines. These systems, typically fabricated using polydimethylsiloxane (PDMS) chips on glass substrates, lack the bioactivity required for such applications. To overcome this, biomolecules are immobilized using either oxygen (O2) plasma treatment or chemical reagents like amino silanes. However, O2 plasma treatments are unstable and cannot covalently immobilize biomolecules, while wet‐chemistry approaches are toxic, time‐consuming, and expensive. A novel microfluidic platform that combines two plasma surface treatments: Plasma‐activated coating (PAC) and atmospheric pressure plasma jet (APPJ), to enable reagent‐free covalent immobilization of biomolecules is described here. These surface treatments, unlike O2 plasma, covalently immobilized fibronectin on PDMS and glass, and significantly improved endothelial cell attachment and proliferation. By combining PAC and APPJ, a hybrid microfluidic platform with equivalent bond strength to standard O2 plasma devices, but with significantly enhanced endothelial cell growth in and artery‐on‐a‐chip model, is developed. This platform is also amenable to high‐shear applications such as coronary shear, with endothelial cells aligning with flow, as seen in human arteries. By providing reagent‐free covalent immobilization of biomolecules within a microfluidic system, this technology has the potential to radically improve organ‐on‐a‐chip development as well as lab‐on‐a‐chip systems, point‐of‐care diagnostics, and sensors. [ABSTRACT FROM AUTHOR]

Numerous diseases, including age‐related macular degeneration (AMD), arise from the blood‐retinal barrier and blood vessel abnormalities in the eye; unfortunately, there is a lack of reliable in vitro models for their systematic study. This study describes a high‐throughput microphysiological system (MPS) designed to model the outer Blood‐Retinal Barrier (oBRB). The MPS platform is engineered to integrate seamlessly with high‐content screening technologies, utilizing a design with a single oBRB model incorporating RPE (retina pigment epithelial cells) and endothelial cell co‐culture to fit within a single 96‐well. Arranged in the standard 96‐well plate format, the platform allows high‐throughput assessment of barrier integrity through 3D confocal imaging (ZO‐1 staining), Trans Epithelial Electrical Resistance (TEER), and permeability measurements. The oBRB model enables the investigation of crosstalk among different cell types in co‐culture. This includes assessing changes in the barrier integrity of the Retinal Pigment Epithelium (RPE) monolayer and investigating neovascularization events resulting from endothelial cell remodeling. The platform is positioned for utility in drug discovery and development efforts targeting diseases involving oBRB damage and choroidal neovascularization, such as age‐related macular degeneration. [ABSTRACT FROM AUTHOR]

Polydimethylsiloxane (PDMS), commonly used in organ‐on‐a‐chip (OoC) systems, faces limitations in replicating complex geometries, hindering its effectiveness in creating 3D OoC models. In contrast, poly(ethylene glycol)diacrylate (PEGDA‐250), favored for its fabrication ease and resistance to small molecule absorption, is increasingly used for 3D printing microfluidic devices. However, applications in cell culture have been limited due to poor cell adhesion. Here, a nanoporous PEGDA ink (P‐PEGDA) is introduced to enhance cell adhesion. P‐PEGDA is formulated with a porogen, photopolymerized, followed by the porogen removal. Utilizing P‐PEGDA, complex microstructures, and membranes as thin as 27 µm are 3D‐printed. Porogen concentrations from 10 to 30% are tested yielding constructs with increasing porosity and oxygen permeability surpassing PDMS, without compromising printing resolution. Tests across four cell lines show >80% cell viability, with a notable 77‐fold increase in MDA‐MB‐231 cell coverage on the porous scaffolds. Finally, an OoC model comprising a gyroid scaffold with a central opening filled with a cancer spheroid is introduced. This setup, after a 14 days co‐culture, demonstrates significant endothelial sprouting and integration within the spheroid. The P‐PEGDA formulation is suitable for high‐resolution 3D printing of constructs for 3D cell culture and OoC owing to its printability, gas permeability, biocompatibility, and cell adhesion. [ABSTRACT FROM AUTHOR]

Adverse cardiac outcomes in COVID-19 patients, particularly those with preexisting cardiac disease, motivate the development of human cell-based organ-on-a-chip models to recapitulate cardiac injury and dysfunction and for screening of cardioprotective therapeutics. Here, we developed a heart-on-a-chip model to study the pathogenesis of SARS-CoV-2 in healthy myocardium established from human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and a cardiac dysfunction model, mimicking aspects of preexisting hypertensive disease induced by angiotensin II (Ang II). We recapitulated cytopathic features of SARS-CoV-2-induced cardiac damage, including progressively impaired contractile function and calcium handling, apoptosis, and sarcomere disarray. SARS-CoV-2 presence in Ang II-treated hearts-on-a-chip decreased contractile force with earlier onset of contractile dysfunction and profoundly enhanced inflammatory cytokines compared to SARS-CoV-2 alone. Toward the development of potential therapeutics, we evaluated the cardioprotective effects of extracellular vesicles (EVs) from human iPSC which alleviated the impairment of contractile force, decreased apoptosis, reduced the disruption of sarcomeric proteins, and enhanced beta-oxidation gene expression. Viral load was not affected by either Ang II or EV treatment. We identified MicroRNAs miR-20a-5p and miR-19a-3p as potential mediators of cardioprotective effects of these EVs. [ABSTRACT FROM AUTHOR]

The article explores the development and potential applications of "Oral Cavity-on-a-Chip" technology, which aims to replicate the oral cavity in a controlled miniature setting. This technology has the potential to revolutionize dental research, drug development, personalized medicine, and personalized dentistry. The article discusses the design of these microfluidic models, their applications in various scientific domains, and the different types of models tailored for specific research inquiries. It also highlights the potential applications of Oral Cavity-on-a-Chip in advancing dental and medical research, testing the efficacy and safety of oral medications, studying dental materials' interactions, and enabling personalized treatments. The article acknowledges the challenges of complexity, scalability, and reproducibility that need to be addressed for widespread adoption, but also emphasizes the promising future avenues of integrating multi-organ systems and improving imaging and sensing techniques. [Extracted from the article]

Microfluidics, a multidisciplinary field at the intersection of physics, engineering and biology is reshaping drug discovery. This review delves into its historical evolution, fundamental principles, components and manufacturing techniques. Microfluidics operates with precision, offering laminar flow, efficient mass transfer and scaling laws. Platforms like microscale cell culture systems, high-throughput screening techniques, lab-on-a-chip devices and organ-on-a-chip systems are driving advancements in disease modeling and pharmacokinetics. Despite challenges in device fabrication, regulation and costs, microfluidics promises an efficient, patient-centric future for drug discovery. Collaborative innovation can unlock its potential, making drug development faster, more precise and accessible. Microfluidics stands as a transformative force with the potential to revolutionize the drug development process. [ABSTRACT FROM AUTHOR]

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With the rapid development and commercial interest in the organ-on-a-chip (OoC) field, there is a need for materials addressing key experimental demands and enabling both prototyping and large-scale production. Here, we utilized the gas-permeable, thermoplastic material polymethylpentene (PMP). Three methods were tested to prototype transparent PMP films suitable for transmission light microscopy: hot-press molding, extrusion, and polishing of a commercial, hazy extruded film. The transparent films (thickness 20, 125, 133, 356, and 653 µm) were assembled as the cell-adhering layer in sealed culture chamber devices, to assess resulting oxygen concentration after 4 days of A549 cell culture (cancerous lung epithelial cells). Oxygen concentrations stabilized between 15.6% and 11.6%, where the thicker the film, the lower the oxygen concentration. Cell adherence, proliferation, and viability were comparable to glass for all PMP films (coated with poly-L-lysine), and transparency was adequate for transmission light microscopy of adherent cells. Hot-press molding was concluded as the preferred film prototyping method, due to excellent and reproducible film transparency, the possibility to easily vary film thickness, and the equipment being commonly available. The molecular orientation in the PMP films was characterized by IR dichroism. As expected, the extruded films showed clear orientation, but a novel result was that hot-press molding may also induce some orientation. It has been reported that orientation affects the permeability, but with the films in this study, we conclude that the orientation is not a critical factor. With the obtained results, we find it likely that OoC models with relevant in vivo oxygen concentrations may be facilitated by PMP. Combined with established large-scale production methods for thermoplastics, we foresee a useful role for PMP within the OoC field. [ABSTRACT FROM AUTHOR]

The evolution in the biomedical engineering field boosts innovative technologies, with microfluidic systems standing out as transformative tools in disease diagnosis, treatment, and monitoring. Numerical simulation has emerged as a tool of increasing importance for better understanding and predicting fluid-flow behavior in microscale devices. This review explores fabrication techniques and common materials of microfluidic devices, focusing on soft lithography and additive manufacturing. Microfluidic systems applications, including nucleic acid amplification and protein synthesis, as well as point-of-care diagnostics, DNA analysis, cell cultures, and organ-on-a-chip models (e.g., lung-, brain-, liver-, and tumor-on-a-chip), are discussed. Recent studies have applied computational tools such as ANSYS Fluent 2024 software to numerically simulate the flow behavior. Outside of the study cases, this work reports fundamental aspects of microfluidic simulations, including fluid flow, mass transport, mixing, and diffusion, and highlights the emergent field of organ-on-a-chip simulations. Additionally, it takes into account the application of geometries to improve the mixing of samples, as well as surface wettability modification. In conclusion, the present review summarizes the most relevant contributions of microfluidic systems and their numerical modeling to biomedical engineering. [ABSTRACT FROM AUTHOR]

Clinical outcome after traumatic brain injury (TBI) is closely associated conditions of other organs, especially lungs as well as degree of brain injury. Even if there is no direct lung damage, severe brain injury can enhance sympathetic tones on blood vessels and vascular resistance, resulting in neurogenic pulmonary edema. Conversely, lung damage can worsen brain damage by dysregulating immunity. These findings suggest the importance of brain-lung axis interactions in TBI. However, little research has been conducted on the topic. An advanced disease model using stem cell technology may be an alternative for investigating the brain and lungs simultaneously but separately, as they can be potential candidates for improving the clinical outcomes of TBI. In this review, we describe the importance of brain-lung axis interactions in TBI by focusing on the concepts and reproducibility of brain and lung organoids in vitro. We also summarize recent research using pluripotent stem cell-derived brain organoids and their preclinical applications in various brain disease conditions and explore how they mimic the brain-lung axis. Reviewing the current status and discussing the limitations and potential perspectives in organoid research may offer a better understanding of pathophysiological interactions between the brain and lung after TBI. [ABSTRACT FROM AUTHOR]

Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitochondrial Transplant Convergent Working Group (CWG), to explore three key issues that limit clinical translation: (1) storage of mitochondria, (2) biomaterials to enhance mitochondrial uptake, and (3) dynamic models to mimic the complex recipient tissue environment. In this review, we present a summary of CWG conclusions related to these three issues and provide an overview of pre-clinical studies aimed at building a more robust toolkit for translational trials. [ABSTRACT FROM AUTHOR]

While the human gut microbiota has a significant impact on gut health and disease, understanding of the roles of gut microbes, interactions, and collective impact of gut microbes on various aspects of human gut health is limited by the lack of suitable in vitro model system that can accurately replicate gut‐like environment and enable the close visualization on causal and mechanistic relationships between microbial constitutents and the gut. , In this study, we present a scalable Gut Microbiome‐on‐a‐Chip (GMoC) with great imaging capability and scalability, providing a physiologically relevant dynamic gut‐microbes interfaces. This chip features a reproducible 3D stratified gut epithelium derived from Caco‐2 cells (µGut), mimicking key intestinal architecture, functions, and cellular complexity, providing a physiolocially relevant gut environment for microbes residing in the gut. Incorporating tumorigenic bacteria, enterotoxigenic Bacteroides fragilis (ETBF), into the GMoC enable the observation of pathogenic behaviors of ETBF, leading to µGut disruption and pro‐tumorigenic signaling activations. Pre‐treating the µGut with a beneficial gut microbe Lactobacillus spp., effectively prevent ETBF‐mediated gut pathogenesis, preserving the healthy state of the µGut through competition‐mediated colonization resistance. The GMoC holds potential as a valuable tool for exploring unknown roles of gut microbes in microbe‐induced pathogenesis and microbe‐based therapeutic development. [ABSTRACT FROM AUTHOR]

Organ‐on‐a‐chip, also known as “tissue chip,” is an advanced platform based on microfluidic systems for constructing miniature organ models in vitro. They can replicate the complex physiological and pathological responses of human organs. In recent years, the development of bone and joint‐on‐chip platforms aims to simulate the complex physiological and pathological processes occurring in human bones and joints, including cell–cell interactions, the interplay of various biochemical factors, the effects of mechanical stimuli, and the intricate connections between multiple organs. In the future, bone and joint‐on‐chip platforms will integrate the advantages of multiple disciplines, bringing more possibilities for exploring disease mechanisms, drug screening, and personalized medicine. This review explores the construction and application of Organ‐on‐a‐chip technology in bone and joint disease research, proposes a modular construction concept, and discusses the new opportunities and future challenges in the construction and application of bone and joint‐on‐chip platforms. [ABSTRACT FROM AUTHOR]

Facile, durable and biocompatible integration of hybrid Lab‐on‐a‐Chip devices has remained an important challenge in microengineering. Here, the robust and seamless integration of off‐stoichiometry thiol‐ene‐epoxy (OSTE+) thermosets with a diverse range of thermoplastic and glass materials is demonstrated. While direct bonding offers sturdy proprieties for the majority of the material hybrids (up to 1.5 MPa), further surface priming enhances the bonding strength for those of lower surface energy (up to seven‐fold). Using microfluidic devices with a unique configuration of chambers and microchannels down to 100 µm, the impact of various bonding methods on their fluidic functionality is further shown. To investigate the utility of hybrid devices for pharmacological and toxicological studies, both pristine and primed devices are benchmarked against polydimethylsiloxane (PDMS) with regard to cell biocompatibility and drug absorption. While being on par with PDMS in terms of cell viability, pristine OSTE+ devices show an 11‐fold lower absorption of hydrophobic drug molecules. Although surface priming enhances the bonding strength, it compromises other criteria in device performance and biological applications. Combined, results demonstrate a novel integration approach for facile manufacturing of hybrid microfluidic devices using a material toolbox suitable for cell and pharmaceutical studies. [ABSTRACT FROM AUTHOR]