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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 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]

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]

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]

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]

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]

To develop effective anti-cancer treatments, there is an urgent need for preclinical tumor models that accurately recapitulate essential tumor microenvironment (TME) hallmarks and reflect in vivo pharmacokinetics and pharmacodynamics in a reproducible manner. Incorporating tumor organoids in 3D bioprinting allows for the hierarchical assembly of heterogeneous TME components into tumor-sized anatomy. Further integration of tumor-on-a-chip and 3D bioprinting enables the reproduction of vascular perfusion and microcirculation systems. The design of 3D bioprinting tumor models involves essential considerations regarding assembly strategy, selection of cellular building blocks, and replication of complicated characteristics, such as tumor vasculature abnormalities, immune surveillance, and interorgan interactions. Bioprinting shows excellent potential for preclinical tumor modeling, with significant advantages over 2D cell cultures in replicating the tumor microenvironment (TME). Recently, the use of tumor organoids in bioprinting models has emerged as a groundbreaking approach to simulate volumetric tumor tissues. This synergetic fabrication method leverages the advantages of the spatial and geometric control of bioprinting to assemble heterogeneous TME components, while tumor organoids maintain collective cell behaviors. In this review, we provide a landscape of the latest progress on the convergence of 3D bioprinting and tumor organoids. Furthermore, we discuss the potential to incorporate organ-on-a-chip with bioprinting tumor organoids to improve the biomimicry and predictability of therapeutic performance. Lastly, we address the challenges to personalized medicine and predictive clinical integration. [ABSTRACT FROM AUTHOR]

Glioblastoma, an aggressive primary brain tumor, poses a significant challenge owing to its dynamic and intricate tumor microenvironment. This review investigates the innovative integration of biosensor-enhanced organ-on-a-chip (OOC) models as a novel strategy for an in-depth exploration of glioblastoma tumor microenvironment dynamics. In recent years, the transformative approach of incorporating biosensors into OOC platforms has enabled real-time monitoring and analysis of cellular behaviors within a controlled microenvironment. Conventional in vitro and in vivo models exhibit inherent limitations in accurately replicating the complex nature of glioblastoma progression. This review addresses the existing research gap by pioneering the integration of biosensor-enhanced OOC models, providing a comprehensive platform for investigating glioblastoma tumor microenvironment dynamics. The applications of this combined approach in studying glioblastoma dynamics are critically scrutinized, emphasizing its potential to bridge the gap between simplistic models and the intricate in vivo conditions. Furthermore, the article discusses the implications of biosensor-enhanced OOC models in elucidating the dynamic features of the tumor microenvironment, encompassing cell migration, proliferation, and interactions. By furnishing real-time insights, these models significantly contribute to unraveling the complex biology of glioblastoma, thereby influencing the development of more accurate diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

This review outlines the evolutionary journey from traditional two-dimensional (2D) cell culture to the revolutionary field of organ-on-a-chip technology. Organ-on-a-chip technology integrates microfluidic systems to mimic the complex physiological environments of human organs, surpassing the limitations of conventional 2D cultures. This evolution has opened new possibilities for understanding cell–cell interactions, cellular responses, drug screening, and disease modeling. However, the design and manufacture of microchips significantly influence their functionality, reliability, and applicability to different biomedical applications. Therefore, it is important to carefully consider design parameters, including the number of channels (single, double, or multi-channels), the channel shape, and the biological context. Simultaneously, the selection of appropriate materials compatible with the cells and fabrication methods optimize the chips' capabilities for specific applications, mitigating some disadvantages associated with these systems. Furthermore, the success of organ-on-a-chip platforms greatly depends on the careful selection and utilization of cell resources. Advances in stem cell technology and tissue engineering have contributed to the availability of diverse cell sources, facilitating the development of more accurate and reliable organ-on-a-chip models. In conclusion, a holistic perspective of in vitro cellular modeling is provided, highlighting the integration of microfluidic technology and meticulous chip design, which play a pivotal role in replicating organ-specific microenvironments. At the same time, the sensible use of cell resources ensures the fidelity and applicability of these innovative platforms in several biomedical applications. [ABSTRACT FROM AUTHOR]

Microfluidic platforms have revolutionized research in biomedical engineering, enabling efficient and controlled experimentation. Here, we present a novel microfluidic device, the double‐microtube, which offers parallel flow of different fluids. The device is fabricated by transforming a flat structure on a substrate using pneumatic balloon actuator arrays. The inner and outer tubes of the device can be independently controlled, allowing for individual opening and closing of each tubular structure. The inner and outer tubes have diameters of 1 mm and 3 mm, respectively. The device has been successfully tested for cell culture, showcasing its potential application for tubular organ‐on‐a‐chip studies, such as blood vessels and the small intestine. The presented double‐microtube structure promises a new level of control for microfluidic studies, offering exciting opportunities for researchers in the field of biomedical engineering. © 2024 Institute of Electrical Engineer of Japan and Wiley Periodicals LLC. [ABSTRACT FROM AUTHOR]

Cellular phenotypes and functional responses are modulated by the signals present in their microenvironment, including extracellular matrix (ECM) proteins, tissue mechanical properties, soluble signals and nutrients, and cell–cell interactions. To better recapitulate and analyze these complex signals within the framework of more physiologically relevant culture models, high throughput culture platforms can be transformative. High throughput methodologies enable scientists to extract increasingly robust and broad datasets from individual experiments, screen large numbers of conditions for potential hits, better qualify and predict responses for preclinical applications, and reduce reliance on animal studies. High throughput cell culture systems require uniformity, assay miniaturization, specific target identification, and process simplification. In this review, we detail the various techniques that researchers have used to face these challenges and explore cellular responses in a high throughput manner. We highlight several common approaches including two‐dimensional multiwell microplates, microarrays, and microfluidic cell culture systems as well as unencapsulated and encapsulated three‐dimensional high throughput cell culture systems, featuring multiwell microplates, micromolds, microwells, microarrays, granular hydrogels, and cell‐encapsulated microgels. We also discuss current applications of these high throughput technologies, namely stem cell sourcing, drug discovery and predictive toxicology, and personalized medicine, along with emerging opportunities and future impact areas. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia (AML) management remains a significant challenge in oncology due to its low survival rates and high post-treatment relapse rates, mainly attributed to treatment-resistant leukaemic stem cells (LSCs) residing in bone marrow (BM) niches. This review offers an in-depth analysis of AML progression, highlighting the pivotal role of extracellular vesicles (EVs) in the dynamic remodelling of BM niche intercellular communication. We explore recent advancements elucidating the mechanisms through which EVs facilitate complex crosstalk, effectively promoting AML hallmarks and drug resistance. Adopting a temporal view, we chart the evolving landscape of EV-mediated interactions within the AML niche, underscoring the transformative potential of these insights for therapeutic intervention. Furthermore, the review discusses the emerging understanding of endothelial cell subsets' impact across BM niches in shaping AML disease progression, adding another layer of complexity to the disease progression and treatment resistance. We highlight the potential of cutting-edge methodologies, such as organ-on-chip (OoC) and single-EV analysis technologies, to provide unprecedented insights into AML–niche interactions in a human setting. Leveraging accumulated insights into AML EV signalling to reconfigure BM niches and pioneer novel approaches to decipher the EV signalling networks that fuel AML within the human context could revolutionise the development of niche-targeted therapy for leukaemia eradication. [ABSTRACT FROM AUTHOR]

Conventional dogma suggests that decompression sickness (DCS) is caused by nitrogen bubble nucleation in the blood vessels and/or tissues; however, the abundance of bubbles does not correlate with DCS severity. Since immune cells respond to chemical and environmental cues, we hypothesized that the elevated partial pressures of dissolved gases drive aberrant immune cell phenotypes in the alveolar vasculature. To test this hypothesis, we measured immune responses within human lung‐on‐a‐chip devices established with primary alveolar cells and microvascular cells. Devices were pressurized to 1.0 or 3.5 atm and surrounded by normal alveolar air or oxygen‐reduced air. Phenotyping of neutrophils, monocytes, and dendritic cells as well as multiplexed ELISA revealed that immune responses occur within 1 h and that normal alveolar air (i.e., hyperbaric oxygen and nitrogen) confer greater immune activation. This work strongly suggests innate immune cell reactions initiated at elevated partial pressures contribute to the etiology of DCS. [ABSTRACT FROM AUTHOR]

Human kidney organoids and tubuloids are emerging models with the promise to overcome the limitations of conventional in vitro research models and to better recapitulate human kidney (dys)function. Recent developments have shown that organoids and tubuloids can be applied in various applications which depends on their ability to mimic kidney specific (dys)function. To date, segment specific drug transport, response to extracellular microenvironment, endocrine functions, and functional electrolyte and water transport have been described. Novel technological tools including multiomics, machine learning, automated high-throughput culture systems, and organ-on-a-chip can further advance kidney organoids and tubuloids to better understand these models and improve maturation for future applications of personalized disease modeling and reliable preclinical research models. The rising prevalence of kidney diseases urges the need for novel therapies. Kidney organoids and tubuloids are advanced in vitro models and have recently been described as promising tools to study kidney (patho)physiology. Recent developments have shown their application in disease modeling, drug screening, and nephrotoxicity. These applications rely on their ability to mimic (dys)function in vitro including endocrine activity and drug, electrolyte, and water transport. This review provides an overview of these emerging kidney models and focuses on the most recent developments that utilize their functional capabilities. In addition, we cover current limitations and provide future perspectives for this rapidly evolving field, including what these functional properties mean for translational and personalized medicine now and in the future. [ABSTRACT FROM AUTHOR]

Preclinical human‐relevant modeling of organ‐specific vasculature offers a unique opportunity to recreate pathophysiological intercellular, tissue‐tissue, and cell‐matrix interactions for a broad range of applications. Here, this work presents a reliable, and simply reproducible process for constructing user‐controlled long rounded extracellular matrix (ECM) embedded vascular microlumens on‐chip for endothelization and co‐culture with stromal cells obtained from human lung. This work demonstrates the critical impact of microchannel cross‐sectional geometry and length on uniform distribution and magnitude of vascular wall shear stress, which is key when emulating in vivo observed blood flow biomechanics in health and disease. In addition, this study provides an optimization protocol for multicellular culture and functional validation of the system. Moreover, this study shows the ability to finely tune rheology of the three‐dimensional natural matrix surrounding the vascular microchannel to match pathophysiological stiffness. In summary, this work provides the scientific community with a matrix‐embedded microvasculature on‐chip populated with all‐primary human‐derived pulmonary endothelial cells and fibroblasts to recapitulate and interrogate lung parenchymal biology, physiological responses, vascular biomechanics, and disease biogenesis in vitro. Such a mix‐and‐match synthetic platform can be feasibly adapted to study blood vessels, matrix, and ECM‐embedded cells in other organs and be cellularized with additional stromal cells. [ABSTRACT FROM AUTHOR]

Simple Summary: New treatments have made a big difference in helping people with multiple myeloma (MM) live longer. In fact, survival rates have almost doubled compared with treatments before 2000, thanks to these new and effective medications. This means more people with MM are surviving for more than 10 years after being diagnosed. However, because people are living longer, some unusual situations are arising, like cancer coming back in places outside the bone marrow, such as organs, lymph nodes, and even the central nervous system. To better understand and treat these new challenges, scientists are using advanced 3D models, especially looking at the bone marrow and other places where cancer may show up. This review identifies the best ways to use these 3D models, discusses the difficulties in recreating the complexity of the disease, and emphasizes how these advanced models can help fight MM. Recent therapeutic advancements have markedly increased the survival rates of individuals with multiple myeloma (MM), doubling survival compared to pre-2000 estimates. This progress, driven by highly effective novel agents, suggests a growing population of MM survivors exceeding the 10-year mark post-diagnosis. However, contemporary clinical observations indicate potential trends toward more aggressive relapse phenotypes, characterized by extramedullary disease and dominant proliferative clones, despite these highly effective treatments. To build upon these advances, it is crucial to develop models of MM evolution, particularly focusing on understanding the biological mechanisms behind its development outside the bone marrow. This comprehensive understanding is essential to devising innovative treatment strategies. This review emphasizes the role of 3D models, specifically addressing the bone marrow microenvironment and development of extramedullary sites. It explores the current state-of-the-art in MM modelling, highlighting challenges in replicating the disease's complexity. Recognizing the unique demand for accurate models, the discussion underscores the potential impact of these advanced 3D models on understanding and combating this heterogeneous and still incurable disease. [ABSTRACT FROM AUTHOR]

Organ-on-a-chip technology is considered a next-generation platform in pharmacology and toxicology. Nevertheless, this novel technology still faces several challenges concerning the respective materials which are used for these microfluidic devices. Currently available organ-chips are most often based on polydimethylsiloxane (PDMS). However, this material has strong limitations regarding compound binding. The current study investigated options to reduce compound absorption of the highly toxic nerve agent VX (1000 µmol/L) in a commercially available organ-chip. In addition, surface effects on degradation products of VX were investigated. The alternative polymer cyclic olefin copolymers (CoC) showed significantly less compound absorption compared to PDMS. Furthermore, a coating of PDMS- and CoC-based chips was investigated. The biocompatible polymer polyethyleneimine (PEI) successfully modified PDMS and CoC surfaces and further reduced compound absorption. A previously examined VX concentration after 72 h of 141 ± 10 µmol/L VX could be increased to 442 ± 54 µmol/L. Finally, the respective concentrations of VX and degradation products accounted for > 90% of the initial concentration of 1000 µmol/L VX. The currently described surface modification might be a first step towards the optimization of organ-on-a-chip surfaces, facilitating a better comparability of different studies and results. • An organ-on-a-chip model facilitating low compound absorption was investigated. • The highly toxic nerve agent VX was studied. • Surface effects and a novel polymer showed less compound absorption than traditional PDMS-based models. [ABSTRACT FROM AUTHOR]

Microfluidic 3D cell culture devices that enable the recapitulation of key aspects of organ structures and functions in vivo represent a promising preclinical platform to improve translational success during drug discovery. Essential to these engineered devices is the spatial patterning of cells from different tissue types within a confined microenvironment. Traditional fabrication strategies lack the scalability, cost‐effectiveness, and rapid prototyping capabilities required for industrial applications, especially for processes involving thermoplastic materials. Here, an approach to pattern fluid guides inside microchannels is introduced by establishing differential hydrophilicity using pressure‐sensitive adhesives as masks and a subsequent selective coating with a biocompatible polymer. Optimal coating conditions are identified using polyvinylpyrrolidone, which resulted in rapid and consistent hydrogel flow in both the open‐chip prototype and the fully bonded device containing additional features for medium perfusion. The suitability of the device for dynamic 3D cell culture is tested by growing human hepatocytes in the device under controlled fluid flow for a 14‐day period. Additionally, the study demonstrated the potential of using the device for pharmaceutical high‐throughput screening applications, such as predicting drug‐induced liver injury. The approach offers a facile strategy of rapid prototyping thermoplastic microfluidic organ chips with varying geometries, microstructures, and substrate materials. [ABSTRACT FROM AUTHOR]

Retinal diseases are leading causes of blindness globally. Developing new drugs is of great significance for preventing vision loss. Current drug discovery relies mainly on two-dimensional in vitro models and animal models, but translation to human efficacy and safety is biased. In recent years, the emergence of retinal organoid technology platforms, utilizing three-dimensional microenvironments to better mimic retinal structure and function, has provided new platforms for exploring pathogenic mechanisms and drug screening. This review summarizes the latest advances in retinal organoid technology, emphasizing its application advantages in high-throughput drug screening, efficacy and toxicity evaluation, and translational medicine research. The review also prospects the combination of emerging technologies such as organ-on-a-chip, 3D bioprinting, single cell sequencing, gene editing with retinal organoid technology, which is expected to further optimize retinal organoid models and advance the diagnosis and treatment of retinal diseases. [ABSTRACT FROM AUTHOR]

Fibrosis is a pathological condition that in the muscular context is linked to primary diseases such as dystrophies, laminopathies, neuromuscular disorders, and volumetric muscle loss following traumas, accidents, and surgeries. Although some basic mechanisms regarding the role of myofibroblasts in the progression of muscle fibrosis have been discovered, our knowledge of the complex cell–cell, and cell–matrix interactions occurring in the fibrotic microenvironment is still rudimentary. Recently, vascular dysfunction has been emerging as a key hallmark of fibrosis through a process called endothelial‐mesenchymal transition (EndoMT). Nevertheless, no effective therapeutic options are currently available for the treatment of muscle fibrosis. This lack is partially due to the absence of advanced in vitro models that can recapitulate the 3D architecture and functionality of a vascularized muscle microenvironment in a human context. These models could be employed for the identification of novel targets and for the screening of potential drugs blocking the progression of the disease. In this review, we explore the potential of 3D human muscle models in studying the role of endothelial cells and EndoMT in muscle fibrotic tissues and identify limitations and opportunities for optimizing the next generation of these microphysiological systems. Starting from the biology of muscle fibrosis and EndoMT, we highlight the synergistic links between different cell populations of the fibrotic microenvironment and how to recapitulate them through microphysiological systems. [ABSTRACT FROM AUTHOR]

Stem cell therapy holds immense potential as a viable treatment for a widespread range of intractable disorders. As the safety of stem cell transplantation having been demonstrated in numerous clinical trials, various kinds of stem cells are currently utilized in medical applications. Despite the achievements, the therapeutic benefits of stem cells for diseases are limited, and the data of clinical researches are unstable. To optimize tthe effectiveness of stem cells, engineering approaches have been developed to enhance their inherent abilities and impart them with new functionalities, paving the way for the next generation of stem cell therapies. This review offers a detailed analysis of engineered stem cells, including their clinical applications and potential for future development. We begin by briefly introducing the recent advances in the production of stem cells (induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs)). Furthermore, we present the latest developments of engineered strategies in stem cells, including engineered methods in molecular biology and biomaterial fields, and their application in biomedical research. Finally, we summarize the current obstacles and suggest future prospects for engineered stem cells in clinical translations and biomedical applications. [ABSTRACT FROM AUTHOR]

Bone metastases are a common cause of suffering in breast and prostate cancer patients, however, the interaction between bone cells and cancer cells is poorly understood. Using a series of co‐culture, conditioned media, human cancer spheroid, and organ‐on‐a‐chip experiments, this study reveals that osteocytes suppress cancer cell proliferation and increase migration via tumor necrosis factor alpha (TNF‐α) secretion. This action is regulated by osteocyte primary cilia and associated intraflagellar transport protein 88 (IFT88). Furthermore, it shows that cancer cells block this mechanism by secreting transforming growth factor beta (TGF‐β), which disrupts osteocyte cilia and IFT88 gene expression. This bi‐directional crosstalk signaling between osteocytes and cancer cells is common to both breast and prostate cancer. This study also proposes that osteocyte inhibition of cancer cell proliferation decreases as cancer cells increase, producing more TGF‐β. Hence, a positive feedback loop develops accelerating metastatic tumor growth. These findings demonstrate the importance of cancer cell‐osteocyte signaling in regulating breast and prostate bone metastases and support the development of therapies targeting this pathway. [ABSTRACT FROM AUTHOR]

Tumor tissue engineering holds great promise for replicating the physiological and behavioral characteristics of tumors in vitro. Advances in this field have led to new opportunities for studying the tumor microenvironment and exploring potential anti‐cancer therapeutics. However, the main obstacle to the widespread adoption of tumor models is the poor understanding and insufficient reconstruction of tumor heterogeneity. In this review, the current progress of engineering heterogeneous tumor models is discussed. First, the major components of tumor heterogeneity are summarized, which encompasses various signaling pathways, cell proliferations, and spatial configurations. Then, contemporary approaches are elucidated in tumor engineering that are guided by fundamental principles of tumor biology, and the potential of a bottom‐up approach in tumor engineering is highlighted. Additionally, the characterization approaches and biomedical applications of tumor models are discussed, emphasizing the significant role of engineered tumor models in scientific research and clinical trials. Lastly, the challenges of heterogeneous tumor models in promoting oncology research and tumor therapy are described and key directions for future research are provided. [ABSTRACT FROM AUTHOR]

Advances in stem cell (SC) technology allow the generation of cellular models that recapitulate the histological, molecular and physiological properties of humanized in vitro three dimensional (3D) models, as well as production of cell-derived therapeutics such as extracellular vesicles (EVs). Improvements in organ-on-chip platforms and human induced pluripotent stem cells (hiPSCs) derived neural/glial cells provide unprecedented systems for studying 3D personalized neural tissue modeling with easy setup and fast output. Here, we highlight the key points in differentiation procedures for neurons, astrocytes, oligodendrocytes and microglia from single origin hiPSCs. Additionally, we present a well-defined humanized neural tissue-on-chip model composed of differentiated cells with the same genetic backgrounds, as well as the therapeutic potential of bone marrow mesenchymal stem cells (BMSCs)-derived extracellular vesicles to propose a novel treatment for neuroinflammation derived diseases. Around 100 nm CD9 + EVs promote a more anti-inflammatory and pro-remodeling of cell–cell interaction cytokine responses on tumor necrosis factor-α (TNF-α) induced neuroinflammation in neural tissue-on-chip model which is ideal for modeling authentic neural-glial patho-physiology. [ABSTRACT FROM AUTHOR]

In recent decades, microphysiological constructs and systems (MPCs and MPSs) have undergone significant development, ranging from self‐organized organoids to high‐throughput organ‐on‐a‐chip platforms. Advances in biomaterials, bioinks, 3D bioprinting, micro/nanofabrication, and sensor technologies have contributed to diverse and innovative biofabrication tactics. MPCs and MPSs, particularly tissue chips relevant to absorption, distribution, metabolism, excretion, and toxicity, have demonstrated potential as precise, efficient, and economical alternatives to animal models for drug discovery and personalized medicine. However, current approaches mainly focus on the in vitro recapitulation of the human anatomical structure and physiological‐biochemical indices at a single or a few simple levels. This review highlights the recent remarkable progress in MPC and MPS models and their applications. The challenges that must be addressed to assess the reliability, quantify the techniques, and utilize the fidelity of the models are also discussed. [ABSTRACT FROM AUTHOR]

The liver is one of the most important organs, with a complex physiology. Current in-vitro approaches are not accurate for disease modeling and drug toxicity research. One of those features is liver zonation, where cells display different physiological states due to different levels of oxygen and nutrient supplements. Organ-on-a-chip technology employs microfluidic platforms that enable a controlled environment for in-vitro cell culture. In this study, we propose a microfluidic design embedding a gas channel (of ambient air), creating an oxygen gradient. We numerically simulate different flow rates and cell densities with the COMSOL Multiphysics package considering cell-specific consumption rates of oxygen and glucose. We establish the cell density and flow rate for optimum oxygen and glucose distribution in the cell culture chamber. Furthermore, we show that a physiologically relevant concentration of oxygen and glucose in the chip is reached after 24 h and 30 min, respectively. The proposed microfluidic design and optimal parameters we identify in this paper provide a tool for in-vitro liver zonation studies. However, the microfluidic design is not exclusively for liver cell experiments but is foreseen to be applicable in cell studies where different gas concentration gradients are critical, e.g., studying hypoxia or toxic gas impact. [ABSTRACT FROM AUTHOR]

Simple Summary: Because of the limitations of current in vivo and in vitro models, this review considers a human relevant approach: modeling colorectal radiotoxicity through human-derived organoids and microfluidics. This system can offer a closer representation of the microenvironment. Co-culturing bacteria and patient derived tumor organoids under a radiotherapy setup, can enable an understanding of the interplay between radiotherapy, the gut microbiota, patient outcomes and assess radioprotective agents of interest. However, challenges in model development highlight the necessity for refinement, questioning their potential to bridge the gap between preclinical research and clinical applications in CRC treatment. Radiotherapy is a commonly employed treatment for colorectal cancer, yet its radiotoxicity-related impact on healthy tissues raises significant health concerns. This highlights the need to use radioprotective agents to mitigate these side effects. This review presents the current landscape of human translational radiobiology, outlining the limitations of existing models and proposing engineering solutions. We delve into radiotherapy principles, encompassing mechanisms of radiation-induced cell death and its influence on normal and cancerous colorectal cells. Furthermore, we explore the engineering aspects of microphysiological systems to represent radiotherapy-induced gastrointestinal toxicity and how to include the gut microbiota to study its role in treatment failure and success. This review ultimately highlights the main challenges and future pathways in translational research for pelvic radiotherapy-induced toxicity. This is achieved by developing a humanized in vitro model that mimics radiotherapy treatment conditions. An in vitro model should provide in-depth analyses of host-gut microbiota interactions and a deeper understanding of the underlying biological mechanisms of radioprotective food supplements. Additionally, it would be of great value if these models could produce high-throughput data using patient-derived samples to address the lack of human representability to complete clinical trials and improve patients' quality of life. [ABSTRACT FROM AUTHOR]

In drug development, conventional preclinical and clinical testing stages rely on cell cultures and animal experiments, but these methods may fall short of fully representing human biology. To overcome this limitation, the emergence of organ-on-a-chip (OOC) technology has sparked interest as a transformative approach in drug testing research. By closely replicating human organ responses to external signals, OOC devices hold immense potential in revolutionizing drug efficacy and safety predictions. This review focuses on the advancements, applications, and prospects of OOC devices in drug testing. Based on the latest advances in the field of OOC systems and their clinical applications, this review reflects the effectiveness of OOC devices in replacing human volunteers in certain clinical studies. This review underscores the critical role of OOC technology in transforming drug testing methodologies. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has emerged as a promising approach in the treatment of diverse cancer types. However, the development of novel immunotherapeutic agents faces persistent challenges due to poor translation from preclinical to clinical stages. To address these challenges, the integration of microfluidic models in research efforts has recently gained traction, bridging the gap between in vitro and in vivo systems. This approach enables modeling of the complex human tumor microenvironment and interrogation of cancer-immune interactions. In this review, we analyze the current and potential applications of microfluidic tumor models in cancer immunotherapy development. We will first highlight current trends in the immunooncology landscape. Subsequently, we will discuss recent examples of microfluidic models applied to investigate mechanisms of immune-cancer interactions and for developing and screening cancer immunotherapies in vitro. First steps toward their validation for predicting human in vivo outcomes are discussed. Finally, promising opportunities that microfluidic tumor models offer are highlighted considering their advantages and current limitations, and we suggest possible next steps toward their implementation and integration into the immunooncology drug development process. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is currently a serious and growing public health problem. In tackling this challenge, organ‐on‐chip (OoC) technology, combined with cell culture and microfluidics, presents a powerful approach for constructing sophisticated tissue models in vitro that can simulate the physiological and pathological microenvironments of human organs. Nowadays, OoC technology has emerged as a pivotal tool in advancing our understanding of CVD pathogenesis, facilitating tissue regeneration studies, conducting efficient drug screening, and assessing therapeutic effects. Moreover, it offers a diverse array of study platforms for preclinical research, fostering innovative approaches towards combating CVD and improving patient outcomes. In this review, we first present the key advantages of OoC technology, including its highly relevant physiological microenvironment, incorporation of integrated functions, and the possibility of the construction of multiorgan‐on‐a‐chip through microfluidic linkage. Then, we summarized the role of OoC in the construction of disease pathological models, which provides a new channel for the exploration of disease pathological mechanisms. Moreover, we discuss the application of this technology in cardiac regeneration and drug screening. Finally, we discuss the challenges of tissue models constructed based on OoC technology and the prospects of this innovative approach. [ABSTRACT FROM AUTHOR]

The vasculature of the brain consists of specialized endothelial cells that form a blood-brain barrier (BBB). This barrier, in conjunction with supporting cell types, forms the neurovascular unit (NVU). The NVU restricts the passage of certain substances from the bloodstream while selectively permitting essential nutrients and molecules to enter the brain. This protective role is crucial for optimal brain function, but presents a significant obstacle in treating neurological conditions, necessitating chemical modifications or advanced drug delivery methods for most drugs to cross the NVU. A deeper understanding of NVU in health and disease will aid in the identification of new therapeutic targets and drug delivery strategies for improved treatment of neurological disorders. To achieve this goal, we need models that reflect the human BBB and NVU in health and disease. Although animal models of the brain's vasculature have proven valuable, they are often of limited translational relevance due to interspecies differences or inability to faithfully mimic human disease conditions. For this reason, human in vitro models are essential to improve our understanding of the brain's vasculature under healthy and diseased conditions. This review delves into the advancements in in vitro modeling of the BBB and NVU, with a particular focus on microfluidic models. After providing a historical overview of the field, we shift our focus to recent developments, offering insights into the latest achievements and their associated constraints. We briefly examine the importance of chip materials and methods to facilitate fluid flow, emphasizing their critical roles in achieving the necessary throughput for the integration of microfluidic models into routine experimentation. Subsequently, we highlight the recent strides made in enhancing the biological complexity of microfluidic NVU models and propose recommendations for elevating the biological relevance of future iterations. Importantly, the NVU is an intricate structure and it is improbable that any model will fully encompass all its aspects. Fit-for-purpose models offer a valuable compromise between physiological relevance and ease-of-use and hold the future of NVU modeling: as simple as possible, as complex as needed. [ABSTRACT FROM AUTHOR]

The human neurovascular system is a complex network of blood vessels and brain cells that is essential to the proper functioning of the brain. Researchers have become increasingly interested in the system for developing drugs to treat neuroinflammation. Currently, creating neurovascular models begins with animal models, followed by testing on humans in clinical trials. However, the high number of medication failures that pass through animal testing indicates that animal models do not always reflect the outcome of human clinical trials. To overcome the challenges of the issues with animal models, a neurovascular‐unit‐on‐a‐chip system is developed to accurately replicate the in vivo human neurovascular microenvironment. By replicating the human neurovascular unit, a more accurate representation of human physiology can be achieved compared to animal models. The ability to detect proinflammatory cytokines in situ and monitor physiological changes can provide an invaluable tool for evaluating the efficacy and safety of drugs. Using nanosized graphene oxide for in situ detection of inflammatory responses is an innovative approach that can advance the field of neuroinflammation research. Overall, the developed neuroinflammation‐on‐a‐chip system has the potential to provide a more efficient and effective method for developing drugs for treating neurodegenerative diseases and other central nervous system diseases. [ABSTRACT FROM AUTHOR]

This study aims to develop an ex vivo organ‐on‐a‐chip model, intervertebral Disc‐on‐a‐ChipMF, to investigate integrated effects of mechanical loading and nutrition on disc health. The system consists of a detachable multilayer microfluidic chip, a Computer‐Arduino‐based control system, and a mechanical loading unit, which are optimized for accurate axial force measurement and the maintenance of a 21‐day ex vivo disc culture. To ensure accuracy of axial force, the axial mechanical loading regimen is optimized, using the Computer‐Arduino‐based system and low‐profile force sensors (LPFS) to control the mechanical loading unit, and the force distribution on the disc surface is modeled by computational simulation. A 21‐day ex vivo disc culture is demonstrated using the Disc‐on‐a‐ChipMF system, with optimized mechanical loading (0.02 MPa at 1Hz, 1.5 hr day−1) and flow rate (1 µL min−1). The structural integrity, collagen breakdown, catabolic enzyme activities, and disc cell and collagen alignment reveal that the on‐chip cultured discs exhibit a preferred disc health similar to that of native discs for up to 21 days, while discs in a static culture show degenerative changes. The mouse Disc‐on‐a‐ChipMF system mimics in vivo disc microenvironment and provides a valuable platform for studying the effects of various factors on disc health and degeneration and testing new therapies. [ABSTRACT FROM AUTHOR]

Three-dimensional cancer-on-a-chip tissue models aim to replicate the key hallmarks of the tumour microenvironment and allow for the study of dynamic interactions that occur during tumour progression. Recently, complex cancer-on-a-chip models incorporating multiple cell types and biomimetic extracellular matrices have been developed. These models have generated new research directions in engineering and medicine by allowing for the real-time observation of cancer-host cell interactions in a physiologically relevant microenvironment. However, these cancer-on-a-chip models have yet to overcome limitations including the complexity of device manufacturing, the selection of optimal materials for preclinical drug screening studies, long-term microfluidic cell culture as well as associated challenges, and the technical robustness or difficulty in the use of these microfluidic platforms. In this review, an overview of the tumour microenvironment, its unique characteristics, and the recent advances of cancer-on-a-chip models that recapitulate native features of the tumour microenvironment are presented. The current challenges that cancer-on-a-chip models face and the future directions of research that are expected to be seen are also discussed. Highlights: • Recent advanced cancer-on-a-chip models for studying the tumour microenvironment are reviewed. • Models examining interactions between tumours and multiple components of the tumour microenvironment are discussed. • Advanced cancer-on-a-chip models can provide a controlled environment for studying complex aspects of cancer biology. [ABSTRACT FROM AUTHOR]

The National Center for Advancing Translational Sciences (NCATS) Assay Guidance Manual (AGM) Workshop on 3D Tissue Models for Antiviral Drug Development, held virtually on 7–8 June 2022, provided comprehensive coverage of critical concepts intended to help scientists establish robust, reproducible, and scalable 3D tissue models to study viruses with pandemic potential. This workshop was organized by NCATS, the National Institute of Allergy and Infectious Diseases, and the Bill and Melinda Gates Foundation. During the workshop, scientific experts from academia, industry, and government provided an overview of 3D tissue models' utility and limitations, use of existing 3D tissue models for antiviral drug development, practical advice, best practices, and case studies about the application of available 3D tissue models to infectious disease modeling. This report includes a summary of each workshop session as well as a discussion of perspectives and challenges related to the use of 3D tissues in antiviral drug discovery. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDs) are characterized by uncontrolled loss of neuronal cells leading to a progressive deterioration of brain functions. The transition rate of numerous neuroprotective drugs against Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, leading to FDA approval, is only 8–14% in the last two decades. Thus, in spite of encouraging preclinical results, these drugs have failed in human clinical trials, demonstrating that traditional cell cultures and animal models cannot accurately replicate human pathophysiology. Hence, in vitro three-dimensional (3D) models have been developed to bridge the gap between human and animal studies. Such technological advancements in 3D culture systems, such as human-induced pluripotent stem cell (iPSC)-derived cells/organoids, organ-on-a-chip technique, and 3D bioprinting, have aided our understanding of the pathophysiology and underlying mechanisms of human NDs. Despite these recent advances, we still lack a 3D model that recapitulates all the key aspects of NDs, thus making it difficult to study the ND's etiology in-depth. Hence in this review, we propose developing a combinatorial approach that allows the integration of patient-derived iPSCs/organoids with 3D bioprinting and organ-on-a-chip technique as it would encompass the neuronal cells along with their niche. Such a 3D combinatorial approach would characterize pathological processes thoroughly, making them better suited for high-throughput drug screening and developing effective novel therapeutics targeting NDs. [ABSTRACT FROM AUTHOR]