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Organoids: generation strategies, applications, and future challenges.
Organoids are microscopic 3D structures that resemble real organs, assembled in vitro from stem cells. Since the Dutch team of Hans Clevers successfully cultured intestinal stem cells to generate intestinal structures in 2009, organoid technology has developed rapidly, and culture protocols covering various organs such as the brain, liver, intestine, kidney, and bone have been established. These micro-organ models retain the cellular heterogeneity, tissue-specific structure, and genetic background of the original tissue. Compared to traditional two-dimensional culture, they provide a more physiologically relevant research platform. This article reviews organoid generation strategies, mainly dividing them into scaffold-free and scaffolded methods, and details specific generation protocols for brain, liver, intestine, kidney, and bone organoids. Furthermore, this article emphasizes innovations in bioengineering, such as organ-on-a-chip systems and 3D bioprinting technology. These technologies can enhance the maturity, vascularization, and reproducibility of organoids. The article also extensively discusses the biomedical applications of organoids, including in vitro disease models, infectious diseases, cancer, drug screening and toxicity testing, tissue engineering, and age-related diseases. Despite the significant potential of organoids, some challenges remain. Issues such as standardization, limited vascularization, ethical considerations, and scalability for industrial and clinical translation remain. Looking ahead, interdisciplinary efforts integrating stem cell biology, bioengineering, and computational methods promise to drive the development of organoid technology. This will make it a more robust and physiologically consistent model. Organoids hold the potential to become a cornerstone tool in biomedical research, bridging the gap between in vitro research and the clinical application of personalized medicine, drug development, and regenerative therapies.
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Potential Use of Organoids in Regenerative Medicine.
BACKGROUND: In vitro cell culture is crucial for studying human diseases and development. Compared to traditional monolayer cultures, 3D culturing with organoids offers significant advantages by more accurately replicating natural tissues' structural and functional features. This advancement enhances disease modeling, drug testing, and regenerative medicine applications. Organoids, derived from stem cells, mimic tissue physiology in a more relevant manner. Despite their promise, the clinical use of regenerative medicine currently needs to be improved by reproducibility, scalability, and maturation issues. METHODS: This article overviews recent organoid research, focusing on their types, sources, 3D culturing methods, and applications in regenerative medicine. A literature review of "organoid" and "regenerative medicine" in PubMed/MEDLINE highlighted relevant studies published over the past decade, emphasizing human-sourced organoids and their regenerative benefits, as well as the availability of free full-text articles. The review uses descriptive data, including tables and text, to illustrate the challenges and potential of organoids in regenerative medicine. RESULTS: The transition from 2D to 3D models, particularly organoids, has significantly advanced in vitro research. This review covers a decade of progress in various organoid types-such as liver, cholangiocyte, intestinal, pancreatic, cardiac, brain, thymus, and mammary organoids-and their 3D culture methods and applications. It addresses critical issues of maturity, scalability, and reproducibility and underscores the need for standardization and improved production techniques to facilitate broader clinical applications in regenerative medicine. CONCLUSIONS: Successful therapy requires increased scalability and standardization. Organoids have enormous potential in biological research, notwithstanding obstacles.
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Spontaneous Glioblastoma Spheroid Infiltration of Early-Stage Cerebral Organoids Models Brain Tumor Invasion.
Organoid methodology provides a platform for the ex vivo investigation of the cellular and molecular mechanisms underlying brain development and disease. The high-grade brain tumor glioblastoma multiforme (GBM) is considered a cancer of unmet clinical need, in part due to GBM cell infiltration into healthy brain parenchyma, making complete surgical resection improbable. Modeling the process of GBM invasion in real time is challenging as it requires both tumor and neural tissue compartments. Here, we demonstrate that human GBM spheroids possess the ability to spontaneously infiltrate early-stage cerebral organoids (eCOs). The resulting formation of hybrid organoids demonstrated an invasive tumor phenotype that was distinct from noncancerous adult neural progenitor (NP) spheroid incorporation into eCOs. These findings provide a basis for the modeling and quantification of the GBM infiltration process using a stem-cell-based organoid approach, and may be used for the identification of anti-GBM invasion strategies.
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Organoid modeling of Zika and herpes simplex virus 1 infections reveals virus-specific responses leading to microcephaly.
Viral infection in early pregnancy is a major cause of microcephaly. However, how distinct viruses impair human brain development remains poorly understood. Here we use human brain organoids to study the mechanisms underlying microcephaly caused by Zika virus (ZIKV) and herpes simplex virus (HSV-1). We find that both viruses efficiently replicate in brain organoids and attenuate their growth by causing cell death. However, transcriptional profiling reveals that ZIKV and HSV-1 elicit distinct cellular responses and that HSV-1 uniquely impairs neuroepithelial identity. Furthermore, we demonstrate that, although both viruses fail to potently induce the type I interferon system, the organoid defects caused by their infection can be rescued by distinct type I interferons. These phenotypes are not seen in 2D cultures, highlighting the superiority of brain organoids in modeling viral infections. These results uncover virus-specific mechanisms and complex cellular immune defenses associated with virus-induced microcephaly.
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Patient-derived complex organoids are a critical tool to understand and explore pediatric malignant brain tumors.
Pediatric malignant brain tumors (PMBTs) remain among the most common and challenging cancers in children and adolescents, with current therapies often failing to deliver satisfactory outcomes. A major obstacle is their intrinsic and extrinsic resistance mechanisms, underscoring the urgent need for innovative therapeutic strategies and accurate preclinical modeling. Recent advances in organoid-based technologies offer promising tools to mimic PMBTs more faithfully in vitro. These three-dimensional (3D) models can replicate key features of the tumor and its brain-like microenvironment, providing valuable platforms for studying resistant cancer cells and testing novel treatment approaches. This review discusses the relevance of cultured 3D systems, organoids and tumoroids, in pediatric neuro-oncology, emphasizing their role in precision medicine. These models have become essential for dissecting the complex biology and dynamic biological processes of all PMBTs, while bridging clinical challenges with experimental discoveries, ultimately enabling more effective and personalized treatments for young patients.
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Biofabrication of 3D bioprinted and organ-on-chip blood-brain barrier models using hCMEC/D3 for intranasal delivery of central nervous system therapeutics.
The BBB remains a major obstacle to effective treatment of CNS disorders by limiting the entry of most therapeutics into the brain. The hCMEC/D3 is widely used as anin vitromodel to study BBB structure, permeability, and drug transport. In parallel, intranasal administration has gained prominence as a non-invasive route to bypass the BBB and deliver therapeutics directly to the brain via olfactory and trigeminal pathways. This review critically explores how hCMEC/D3 models support the development of intranasal N2B drug delivery strategies. Advances in co-culture systems, 3D constructs, and microfluidic BBB-on-chip platforms have improved the physiological relevance of hCMEC/D3. Integration with nasal epithelial models, including ALI cultures and nasal-on-chip systems, enables simulation of the entire N2B transport route. Emerging delivery systems, including mucoadhesive nanoparticles, ligand-targeted carriers, and prodrugs, are evaluated for their performance in dual-barrierin vitromodels. While progress is evident, challenges remain in translatability and standardisation. Future efforts integrating omics, machine learning, and organ-on-chip technologies will enhance predictive modelling and accelerate CNS drug development.
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The endothelium, a key actor in organ development and hPSC-derived organoid vascularization.
Over the last 4 decades, cell culture techniques have evolved towards the creation of in vitro multicellular entities that incorporate the three-dimensional complexity of in vivo tissues and organs. As a result, stem cells and adult progenitor cells have been used to derive self-organized 3D cell aggregates that mimic the morphological and functional traits of organs in vitro. These so-called organoids were first generated from primary animal and human tissues, then human pluripotent stem cells (hPSCs) arose as a new tool for organoid generation. Due to their self-renewal capacity and differentiation potential, hPSCs are an unlimited source of cells used for organoids. Today, hPSC-derived small intestinal, kidney, brain, liver, and pancreas organoids, among others, have been produced and are promising in vitro human models for diverse applications, including fundamental research, drug development and regenerative medicine. However, achieving in vivo-like organ complexity and maturation in vitro remains a challenge. Current hPSC-derived organoids are often limited in size and developmental state, resembling embryonic or fetal organs rather than adult organs. The use of endothelial cells to vascularize hPSC-derived organoids may represent a key to ensuring oxygen and nutrient distribution in large organoids, thus contributing to the maturation of adult-like organoids through paracrine signaling.Here, we review the current state of the art regarding vascularized hPSC-derived organoids (vhPSC-Orgs). We analyze the progress achieved in the generation of organoids derived from the three primary germ layers (endoderm, mesoderm and ectoderm) exemplified by the pancreas, liver, kidneys and brain. Special attention will be given to the role of the endothelium in the organogenesis of the aforementioned organs, the sources of endothelial cells employed in vhPSC-Org protocols and the remaining challenges preventing the creation of ex vivo functional and vascularized organs.
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Advances in gut-brain organ chips.
The brain and gut are sensory organs responsible for sensing, transmitting, integrating, and responding to signals from the internal and external environment. In-depth analysis of brain-gut axis interactions is important for human health and disease prevention. Current research on the brain-gut axis primarily relies on animal models. However, animal models make it difficult to study disease mechanisms due to inherent species differences, and the reproducibility of experiments is poor because of individual animal variations, which leads to a significant limitation of real-time sensory responses. Organ-on-a-chip platforms provide an innovative approach for disease treatment and personalized research by replicating brain and gut ecosystems in vitro. This enables a precise understanding of their biological functions and physiological responses. In this article, we examine the history and most current developments in brain, gut, and gut-brain chips. The importance of these systems for understanding pathophysiology and developing new drugs is emphasized throughout the review. This article also addresses future directions and present issues with the advancement and application of gut-brain-on-a-chip technologies.
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Rethinking Neuroregenerative Microenvironments: Synergy Between Bioengineering and Organoids.
Neurological injuries and neurodegenerative disorders, including spinal cord injury, traumatic brain injury, stroke, and Parkinson's disease remain largely incurable. In the central nervous system (CNS), a self-reinforcing cascade of neuroinflammation, oxidative stress, blood-brain barrier breakdown, and glial fibrotic scarring restricts long-distance axonal regrowth and graft survival. The peripheral nervous system (PNS) exhibits greater intrinsic regenerative potential, yet critical-length defects remain challenging and have driven the development of clinically relevant conduit designs. This review provides an overview of the microenvironment following CNS injury and summarizes the key design requirements for engineered repair matrices, while highlighting lessons from advanced peripheral nerve guidance conduits. Injectable extracellular matrix (ECM)-mimetic and smart hydrogels can conformally fill CNS cavities, modulate immune and redox cascades, restore vascular function, and provide permissive niches for neural stem/progenitor and endothelial cells. CNS-compatible bioinks and 3D bioprinting enable the fabrication of neurovascular architectures and multicellular constructs with controlled mechanics, topology, and circuit geometry. Advances in nerve guidance conduits inform translation of PNS principles to the brain and spinal cord. Organoid-based strategies, including vascularized organoids, biomaterial-supported grafts, and organoid-neuroelectronic interfaces, suggest routes toward modular biohybrid constructs. Integrating pathology-informed biomaterials, biofabrication, and organoid engineering offers a roadmap for neural circuit reconstruction.
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Building the blood-brain barrier: a scalable self-assembling 3D model of the brain microvasculature under unidirectional flow.
The blood vessels of the central nervous (CNS) system form a tight, protective blood-brain barrier (BBB). This barrier is essential for healthy CNS function but also poses a hurdle in the treatment of increasingly common neurological disorders. Additionally, BBB dysfunction is a hallmark of many neurological diseases, further emphasizing a need for a better understanding of BBB function in health and disease. We present a human self-assembling 3D model of the BBB in a microfluidic cell culture platform that allows culture of 48 models in parallel on one tissue culture plate. Human brain microvascular endothelial cells, pericytes, and astrocytes form highly reproducible BBB vascular networks under unidirectional perfusion and remain viable for a minimum of 14 days. Immunostaining reveals close cell-cell interactions with pericytes and astrocyte endfeet in direct contact with the brain microvasculature. Compared to endothelial monocultures, co-cultures with astrocytes or pericytes result in improved barrier function, lower vessel diameters, increased branching, and alignment of the vessels in the direction of fluid flow. These results were most pronounced in tri-cultures containing all three cell types. Unlike similar models previously reported, this brain microvasculature model allows for unidirectional perfusion without the need for pumps and syringes. Combined with its high-throughput nature, this feature renders the model suitable for studies of BBB function in health and disease, and assessment of potential BBB restorative therapies.