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The devastating effects and incurable nature of hereditary and sporadic retinal diseases such as Stargardt disease, age-related macular degeneration or retinitis pigmentosa urgently require the development of new therapeutic strategies. Additionally, a high prevalence of retinal toxicities is becoming more and more an issue of novel targeted therapeutic agents. Ophthalmologic drug development, to date, largely relies on animal models, which often do not provide results that are translatable to human patients. Hence, the establishment of sophisticated human tissue-based in vitro models is of upmost importance. The discovery of self-forming retinal organoids (ROs) derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) is a promising approach to model the complex stratified retinal tissue. Yet, ROs lack vascularization and cannot recapitulate the important physiological interactions of matured photoreceptors and the retinal pigment epithelium (RPE). In this study, we present the retina-on-a-chip (RoC), a novel microphysiological model of the human retina integrating more than seven different essential retinal cell types derived from hiPSCs. It provides vasculature-like perfusion and enables, for the first time, the recapitulation of the interaction of mature photoreceptor segments with RPE in vitro. We show that this interaction enhances the formation of outer segment-like structures and the establishment of in vivo-like physiological processes such as outer segment phagocytosis and calcium dynamics. In addition, we demonstrate the applicability of the RoC for drug testing, by reproducing the retinopathic side-effects of the anti-malaria drug chloroquine and the antibiotic gentamicin. The developed hiPSC-based RoC has the potential to promote drug development and provide new insights into the underlying pathology of retinal diseases.

Disorders of the synovial joint, such as osteoarthritis (OA) and rheumatoid arthritis (RA), afflict a substantial proportion of the global population. However, current clinical management has not been focused on fully restoring the native function of joints. Organ-on-chip (OoC), also called a microphysiological system, which typically accommodates multiple human cell-derived tissues/organs under physiological culture conditions, is an emerging platform that potentially overcomes the limitations of current models in developing therapeutics. Herein, we review major steps in the generation of OoCs for studying arthritis, discuss the challenges faced when these novel platforms enter the next phase of development and application, and present the potential for OoC technology to investigate the pathogenesis of joint diseases and the development of efficacious therapies. A recently developed human stem cell-derived, joint-mimicking organ-on-chip (OoC) comprising four 3D tissues demonstrated its ability to model joint inflammation and test potential disease-modifying drugs.Joint OoCs developed thus far fall into four broad categories: those modeling inflammation, simulating mechanical stimuli, recapitulating immune response, and studying genetic disposition.Accumulating evidence reveals the active, bidirectional crosstalk between different joint elements, highlighting the importance of incorporating multiple tissue components in joint OoCs.Recent advances in induced pluripotent stem cell-based tissue engineering pave the way for building personalized joint OoC to address patient heterogeneity.

Bone marrow(BM) is the primary site of hematopoiesis, supporting the self-renewal and differentiation of hematopoietic stem cells (HSCs). Its function depends on a highly complex microenvironment composed of stromal cells, vascular networks, extracellular matrix components, and dynamic biophysical signals. Traditional two-dimensional culture systems and animal models fail to adequately recapitulate the spatial architecture and dynamic regulatory processes of the human bone marrow niche, thereby limiting in-depth investigations into hematopoietic regulatory mechanisms, disease pathogenesis, and drug-induced bone marrow toxicity. In recent years, advances in microphysiological systems (MPS) have provided novel engineering approaches for the in vitro reconstruction of the bone marrow microenvironment. This review systematically summarizes current construction strategies for bone marrow MPS, including three-dimensional self-organized bone marrow organoids and microfluidic bone marrow-on-a-chip platforms. Particular attention is given to the roles of key cellular components, biomaterial scaffolds, vascularized architectures, and dynamic perfusion systems in biomimetic bone marrow engineering. In addition, we discuss strategies for constructing more complex models, such as vascular niches, vascularized bone tissue constructs, and bone metastasis models. Bone marrow MPS more faithfully recapitulate the hematopoietic microenvironment and provide a physiologically relevant in vitro platform for hematopoietic research, disease modeling, and drug evaluation, thereby supporting future advances in precision and regenerative medicine.

3D human tissue models/microphysiological systems (3D/MPS) can represent human physiology. Linking organ models can improve biological fidelity and predictive capability.3D/MPS may be infected with HIV, enabling studies of pathogenesis, host–virus interactions, inflammation, neuropathogenesis, and HIV reservoirs.Integrating immune cells or lymphoid tissues into 3D/MPS facilitates study of HIV immune responses, leukocyte depletion, immune ontogeny, immunotherapies, and vaccines.Application of 3D/MPS to therapeutic development facilitates sophisticated preclinical pharmacology, in silico modeling, predictions of human response and safety, and evaluation of potency of biologics.Tissue sources and/or modifications permit study of unique conditions, including TB co-infection, substance use, and special populations (e.g., medically fragile, pregnant or lactating people, and children). Three-dimensional (3D) human tissue models/microphysiological systems (e.g., organs-on-chips, organoids, and tissue explants) model HIV and related comorbidities and have potential to address critical questions, including characterization of viral reservoirs, insufficient innate and adaptive immune responses, biomarker discovery and evaluation, medical complexity with comorbidities (e.g., tuberculosis and SARS-CoV-2), and protection and transmission during pregnancy and birth. Composed of multiple primary or stem cell-derived cell types organized in a dedicated 3D space, these systems hold unique promise for better reproducing human physiology, advancing therapeutic development, and bridging the human–animal model translational gap. Here, we discuss the promises and achievements with 3D human tissue models in HIV and comorbidity research, along with remaining barriers with respect to cell biology, virology, immunology, and regulatory issues. Three-dimensional (3D) human tissue models/microphysiological systems (e.g., organs-on-chips, organoids, and tissue explants) model HIV and related comorbidities and have potential to address critical questions, including characterization of viral reservoirs, insufficient innate and adaptive immune responses, biomarker discovery and evaluation, medical complexity with comorbidities (e.g., tuberculosis and SARS-CoV-2), and protection and transmission during pregnancy and birth. Composed of multiple primary or stem cell-derived cell types organized in a dedicated 3D space, these systems hold unique promise for better reproducing human physiology, advancing therapeutic development, and bridging the human–animal model translational gap. Here, we discuss the promises and achievements with 3D human tissue models in HIV and comorbidity research, along with remaining barriers with respect to cell biology, virology, immunology, and regulatory issues.

In infectious disease such as sepsis and COVID‐19, blood vessel leakage treatment is critical to prevent fatal progression into multi‐organ failure and ultimately death, but the existing effective therapeutic modalities that improve vascular barrier function are limited. Here, this study reports that osmolarity modulation can significantly improve vascular barrier function, even in an inflammatory condition. 3D human vascular microphysiological systems and automated permeability quantification processes for high‐throughput analysis of vascular barrier function are utilized. Vascular barrier function is enhanced by >7‐folds with 24–48 h hyperosmotic exposure (time window of emergency care; >500 mOsm L−1) but is disrupted after hypo‐osmotic exposure (<200 mOsm L−1). By integrating genetic and protein level analysis, it is shown that hyperosmolarity upregulates vascular endothelial‐cadherin, cortical F‐actin, and cell–cell junction tension, indicating that hyperosmotic adaptation mechanically stabilizes the vascular barrier. Importantly, improved vascular barrier function following hyperosmotic exposure is maintained even after chronic exposure to proinflammatory cytokines and iso‐osmotic recovery via Yes‐associated protein signaling pathways. This study suggests that osmolarity modulation may be a unique therapeutic strategy to proactively prevent infectious disease progression into severe stages via vascular barrier function protection. This study reports that osmolarity modulation can significantly improve vascular barrier function, even in an inflammatory condition by using 3D human vascular microphysiological systems and automated permeability quantification processes.

The gut-liver axis maintains metabolic homeostasis and immune regulation through continuous bidirectional communication, and its dysregulation contributes to a range of metabolic, inflammatory, and immune-mediated diseases. Integrated gut-liver axis model systems offer unique tools for dissecting these complex interactions by isolating individual variables that are difficult to disentangle , while allowing flexible experimental controls over them. Here, we review advances in gut-liver axis models from static co-cultures to microfluidic systems and their applications in pharmacokinetic and mechanistic studies. We identify underexplored areas, including metabolite-mediated gut-liver crosstalk, immune-mediated interorgan communication, and disease-specific modeling, and outline technical challenges to achieving physiologically faithful and reliable integrated platforms. By addressing these challenges, gut-liver axis models will contribute to a mechanistic understanding of gut-liver pathobiology that is difficult to achieve through clinical studies, animal models, or individual organ systems alone.

Various systemic metabolic diseases arise from prolonged crosstalk across multiple organs, triggering serious impairments in various physiological systems. These diseases are intricate systemic pathologies characterized by complex mechanisms and an unclear etiology, making the treatment challenging. Efforts have been made to develop in vitro models to understand these diseases and devise new treatments. However, there are limitations in reconstructing the causal relationships between diseases and interorgan crosstalk, including the tissue‐specific microenvironment. Alternatively, multi‐organ microphysiological systems (MOMPS) present new possibilities for capturing the complexity of systemic metabolic diseases by replicating human microphysiology and simulating diverse interorgan crosstalk. Controlled interactions and scalable representations of biological complexity in MOMPS offer a more accurate portrayal of organ interactions, enabling the identification of novel relationships between organ crosstalk, metabolism, and immunity. This, in turn, can yield valuable insights into disease mechanisms and drug development research and enhance the efficiency of preclinical studies. In this review, the examples and technical capabilities of MOMPS pathological modeling for various diseases are discussed, leveraging state‐of‐the‐art biofabrication technology of MOMPS. It evaluates the current opportunities and challenges in this field. Multi‐organ microphysiological systems (MOMPS) replicate human microphysiology and interorgan crosstalk. The precise fabrication of MOMPS requires various elements, including biomaterials, cell sources, accurate organ crosstalk, biofabrication techniques, and humanized design. The MOMPS enhances the understanding of systemic metabolic disease mechanisms, improves drug development, and increases the efficiency of preclinical studies by capturing the complexity of organ interactions and tissue‐specific microenvironments..

Clostridioides difficile ( C. difficile ) is a leading cause of nosocomial diarrhea and colitis, including severe pseudomembranous colitis, particularly following antibiotic-induced dysbiosis. The pathogenesis of C. difficile infection (CDI) is primarily driven by the action of two large exotoxins, toxin A (TcdA) and toxin B (TcdB), which compromise intestinal epithelial integrity and trigger strong mucosal inflammation. These toxins lead to the disassembly of epithelial junctions, immune cell infiltration, and release of pro-inflammatory mediators. Despite extensive research, mechanistic insight into C. difficile -host interactions and correlates of protection remain limited, in part due to the physiological constraints of conventional two-dimensional (2D) in vitro models. Here, we present a three-dimensional (3D) microphysiological Intestine-on-Chip (IoC) model as a dynamic and immunocompetent in vitro platform to study toxin-mediated pathogenesis and therapeutic interventions in CDI. In contrast to traditional static cell culture systems composed solely of epithelial monolayers, the immunocompetent IoC (i-IoC) model integrates Caco-2 C2BBe1 epithelial cells, primary human umbilical vein endothelial cells (HUVECs), monocyte-derived macrophages, and circulating neutrophils (polymorphonuclear leukocytes, (PMN)) under continuous perfusion, thus more closely mimicking the tissue architecture and immune microenvironment of the human intestine. Upon stimulation with purified TcdA and TcdB, the i-IoC model exhibited toxin-specific disruption of epithelial junctional proteins, macrophage depletion, elevated cytokine secretion, and recruitment and transmigration of PMN, thereby replicating hallmark features of acute CDI. Notably, the model responded with higher sensitivity and biological complexity than static 2D cultures. Toxin-neutralizing antibody sera effectively attenuated these pathological responses, reducing both structural damage and inflammatory mediator release. Our findings demonstrate that the i-IoC model faithfully recapitulates key aspects of CDI pathophysiology, including epithelial damage, immune cell dynamics, and cytokine-driven inflammation. This platform offers a versatile and translationally relevant tool to study host–pathogen interactions and to evaluate preventive or therapeutic strategies aimed at mitigating C. difficile toxin (CDT)-mediated tissue injury.

This study focuses on the use of pulsed electric fields (PEF) in microfluidics for controlled cell studies. The commonly used material for soft lithography, polydimethylsiloxane (PDMS), does not fully ensure the necessary chemical and mechanical resistance in these systems. Integration of specific analytical measurement setups into microphysiological systems (MPS) are also challenging. We present an off-stoichiometry thiol-ene (OSTE)-based microchip, containing integrated electrodes for PEF and transepithelial electrical resistance (TEER) measurement and the equipment to monitor pH and oxygen concentration in situ. The effectiveness of the MPS was empirically demonstrated through PEF treatment of the C6 cells. The effects of PEF treatment on cell viability and permeability to the fluorescent dye DapI were tested in two modes: stop flow and continuous flow. The maximum permeability was achieved at 1.8 kV/cm with 16 pulses in stop flow mode and 64 pulses per cell in continuous flow mode, without compromising cell viability. Two integrated sensors detected changes in oxygen concentration before and after the PEF treatment, and the pH shifted towards alkalinity following PEF treatment. Therefore, our proof-of-concept technology serves as an MPS for PEF treatment of mammalian cells, enabling in situ physiological monitoring.

Animal studies have shown that early life exposure to general anesthetics may impair brain development. However, the implications of this phenomenon in human patients remain unclear. In this study, we use an induced pluripotent stem cell (iPSC)-derived human brain microphysiological system (bMPS) to investigate the effects of early sevoflurane (SEV) exposure on human brain development. Human iPSCs were cultured and differentiated into neural progenitor cells (NPCs) and then into bMPS. At week 8, bMPSs were exposed to 2.4% SEV for 4 h. Four weeks after exposure, immunofluorescence (IF), Western blotting (WB), and quantitative real-time polymerase chain reaction (qPCR) were conducted to evaluate the alteration of nerve cells in bMPS. After SEV exposure, the number of apoptotic cells increases, and the level of neural differentiation markers decreases. The ratios of mature neurons over NPCs and mature oligodendrocytes over oligodendrocyte progenitor cells (OPCs) are reduced, which leads to a reduction in myelination. SEV also impedes the development of astrocytes and synaptogenesis, especially the formation of excitatory synapses. Meanwhile, SEV increases the expression of molecules in the mammalian target of rapamycin (mTOR) signal pathway. In conclusion, early SEV exposure substantially disrupts the development of human brain tissue, and the mTOR signal pathway is likely to be involved in this alteration.