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Patient-derived tumor organoid predicts drugs response in glioblastoma: A step forward in personalized cancer therapy?
Despite significant medical advances, glioblastoma multiforme (GBM) remains a formidable therapeutic challenge. Advent of targeted capture sequencing and patients-derived organoid cultures may hold the key to scientifically sound individualized treatment approaches. We report on our initial experience of using the combination of these two technologies to create a tailored approach of systemic therapies for a patient with GBM, which challenges the conventional treatment paradigm, as well as specifically highlighting the complexities of such an approach and the potential for a more favorable treatment outcome.
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Organoid-based systems for biomedical innovation: advances in disease modeling, drug screening, and precision medicine.
Organoid technology integrates stem-cell biology, biomaterials, and engineered culture platforms to recreate human tissue architecture with greater physiological relevance than 2D cultures or animal models. Advances in stem-cell differentiation and matrix design have facilitated the formation of complex, organ-specific 3D structures. This review presents the latest strategies for generating PSC and ASC-derived organoids, the role of biomaterials and microengineered systems in supporting their growth, and major applications in disease modeling and drug screening. Key translational challenges are also addressed in this manuscript. Stem-cell sources, scaffold materials, and platforms such as air-liquid interface systems and organoid-on-a-chip devices contribute significantly to structural and functional maturation. Organ-specific models across the brain, lung, intestine, liver, pancreas, stomach, and prostate are highlighted, along with ongoing limitations including insufficient vascularization, variability, and limited stromal or immune elements. Organoids represent promising human-relevant systems for biomedical research and therapeutic evaluation. Continued progress in biomaterials, microfluidics, and biobanking is strengthening their reproducibility, scalability, and translational potential.
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Application of a Blood-Brain Barrier Organ-on-a-Chip Model for Assessment of Countermeasure Efficiency Against Eastern Equine Encephalitis Virus.
Infection by neurotropic alphaviruses such as the Eastern equine encephalitis virus (EEEV) causes extensive inflammation in the central nervous system and tissue damage, including disruption of the blood-brain barrier (BBB). Neuroinflammation and BBB disruption following infection are critical pathological considerations for the development of robust countermeasure strategies. Encephalitic disease resulting from EEEV infection currently lacks FDA-approved therapeutic intervention strategies, thus exposing a major capability gap in the ability to address the global health burden that could result from alphavirus infections. In this manuscript, we present a gravity-flow Neurovascular Unit (gNVU) model of the human BBB that may be used for modeling EEEV-induced neuropathology and evaluating countermeasures. The data generated using this model show that EEEV infection causes a time-dependent disruption of BBB integrity and increases the inflammatory load in a manner that correlates with an increase in the viral load. The data also show that the route of introduction of the pathogen has an impact on the pathology measured, with infection through the brain side eliciting a greater inflammatory outcome than infection through the vascular route. Overall, the included data support the utility of this organ-on-a-chip (OOC) platform of the human BBB in understanding encephalitic disease caused by neurotropic viruses and evaluation of therapeutic intervention strategies.
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A new microphysiological platform to study the permeation of neuroactive agents across intestinal and brain barriers.
To replicate key physiological barriersin vitro, we utilized the CELLBLOKS® modular microphysiological system. Specifically, human cerebral microvascular endothelial hCMEC/D3 cells, human retinal pigment epithelial cells, and rat small intestinal IEC-6 cells were grown in CELLBLOKS® to mimic the blood-brain (BBB), blood-cerebrospinal fluid (BCSFB), and intestinal (IB) barriers, respectively. Eugenol is an essential oil component known to permeate the central nervous system (CNS)in vivoafter intravenous (IVA) and oral (OA) administrations; it was therefore used to simulate IVA and OA into the CELLBLOKS® system, using also celiprolol as negative control compound, since it is known for its poor ability to permeate in the CNS from the bloodstream. In particular, the IVA (systemic) of the compounds was simulated by their direct addition to the bloodstream-like lower channel of CELLBLOKS® (basolateral side of both BCSFB and IB; apical side for BBB), whereas their OA was simulated by apical addition to IEC-6. Permeation measurements, via High-performance liquid chromatography, across physiological barriers cultured in CELLBLOKS® demonstrated that, following both simulated oral and systemic administration, eugenol crosses the mimicked BBB and the BCSFB indiscriminately; conversely, the permeation of celiprolol across these barriers results strongly limited in comparison to eugenol. To assess downstream neuroactivity, dopaminergic neuron-like PC12 cells were cultured on NANOSTACKS™ inserts and incorporated into the BBB and BCSFB blocks. After simulated IVA and OA, significant eugenol-induced dopamine release by PC12 cells was evidenced both in BBB- and BCSFB-delimited neuronal-like compartments. These results validate the CELLBLOKS® and NANOSTACKS™ platforms as robust tools characterized by low costs, high reproducibility and ease of manipulation forin vitrostudies of brain targeting of new drugs. This system requires two weeks culture period to be ready for the simulationin vitroof IB, BBB, BCFSB and neuronal tissues, appearing useful in limiting pre-clinical animal testing.
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Multilayered Nanocarriers as a New Strategy for Delivering Drugs with Protective and Anti-inflammatory Potential: Studies in Hippocampal Organotypic Cultures Subjected to Experimental Ischemia.
Oxidative stress and neuroinflammation play a pivotal role in pathomechanisms of brain ischemia. Our research aimed to formulate a nanotheranostic system for delivering carnosic acid as a neuroprotective agent with anti-oxidative and anti-inflammatory properties to ischemic brain tissue, mimicked by organotypic hippocampal cultures (OHCs) exposed to oxygen-glucose deprivation (OGD). In the first part of this study, the nanocarriers were formulated by encapsulating two types of nanocores (nanoemulsion (AOT) and polymeric (PCL)) containing CA into multilayer shells using the sequential adsorption of charged nanoobjects method. The newly designed nanoparticles possessed favorable physicochemical characteristics as reflected by zeta potential and other parameters. Next, we demonstrated that the newly designed gadolinium-containing nanoparticles were not toxic to OHCs and did not affect the detrimental effects of OGD on the viability of the hippocampal cells. Importantly, they readily crossed the artificial blood-brain barrier based on the human cerebral microvascular endothelial (hCMEC/D3) cell line. Furthermore, the PCL-Gd carnosic acid-loaded nanoparticles displayed anti-inflammatory potential, expressed as decreased OGD-induced HIF-1α and IL-1β levels. Results of the molecular study revealed a complex mechanism of the nanoformulation on ischemia-related neuroinflammation in OHCs, including anti-inflammatory protein A20 stimulation and moderate attenuation of the NFκB signaling pathway. Summing up, this study points to acceptable biocompatibility of the newly designed CA-containing theranostic nanoformulation and emphasizes their interaction with inflammatory processes commonly associated with the ischemic brain.
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A 3D Microfluidic Blood-Brain Barrier Chip for Real-Time Assessment of Micro/Nanoplastics Permeability and Neuroinflammatory Injury.
The micro/nanoplastics (MNPs) have been evidenced to exert detrimental effects on the blood-brain barrier (BBB) and the central nervous system (CNS). However, there is still a lack of effective research models on the mechanism of nerve injury caused by microplastics particles. This study focuses on analyzing the particle size characteristics of MNPs precipitated from plastic water bottles under different conditions of storage and uses 3D BBB microfluidic chips to assess the permeability and dynamic neurotoxicity of MNPs. The results showed that there was a significant increase in the average diameter of MNPs in purified water stored in plastic bottles. Moreover, the cultivation of BBB cells or neuronal cells with two different particle sizes of MNPs showed a significant decrease in cell survival rates. When MNPs were infused into the peripheral unit of the biomimetic chip, they could penetrate from the endothelial cell unit to the neuronal unit and induce a dynamic injury process with neuroinflammation, accompanied by tight junction disruptions, increased ROS levels, decreased mitochondrial membrane potential, decreased lipid droplet levels, and increased inflammatory effects. The research results based on engineering 3D microfluidic chips lay the foundation for a deeper understanding of the inflammatory damage to nerve cells caused by MNPs crossing the BBB.
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Human Neural Organoids for Studying Brain Cancer and Neurodegenerative Diseases.
The lack of relevant in vitro neural models is an important obstacle on medical progress for neuropathologies. Establishment of relevant cellular models is crucial both to better understand the pathological mechanisms of these diseases and identify new therapeutic targets and strategies. To be pertinent, an in vitro model must reproduce the pathological features of a human disease. However, in the context of neurodegenerative disease, a relevant in vitro model should provide neural cell replacement as a valuable therapeutic opportunity. Such a model would not only allow screening of therapeutic molecules but also can be used to optimize neural protocol differentiation [for example, in the context of transplantation in Parkinson's disease (PD)]. This study describes two in vitro protocols of 1) human glioblastoma development within a human neural organoids (NO) and 2) neuron dopaminergic (DA) differentiation generating a three-dimensional (3D) organoid. For this purpose, a well-standardized protocol was established that allows the production of size-calibrated neurospheres derived from human embryonic stem cell (hESC) differentiation. The first model can be used to reveal molecular and cellular events occurring during in glioblastoma development within the neural organoid, while the DA organoid not only represents a suitable source of DA neurons for cell therapy in Parkinson's disease but also can be used for drug testing.
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The Emerging Role of Neuronal Organoid Models in Drug Discovery: Potential Applications and Hurdles to Implementation.
The high failure rate of drugs in the clinical pipeline is likely in part the result of inadequate preclinical models, particularly those for neurologic disorders and neurodegenerative disease. Such preclinical animal models often suffer from fundamental species differences and rarely recapitulate all facets of neurologic conditions, whereas conventional two-dimensional (2D) in vitro models fail to capture the three-dimensional spatial organization and cell-to-cell interactions of brain tissue that are presumed to be critical to the function of the central nervous system. Recent studies have suggested that stem cell-derived neuronal organoids are more physiologically relevant than 2D neuronal cultures because of their cytoarchitecture, electrophysiological properties, human origin, and gene expression. Hence there is interest in incorporating such physiologically relevant models into compound screening and lead optimization efforts within drug discovery. However, despite their perceived relevance, compared with previously used preclinical models, little is known regarding their predictive value. In fact, some have been wary to broadly adopt organoid technology for drug discovery because of the low-throughput and tedious generation protocols, inherent variability, and lack of compatible moderate-to-high-throughput screening assays. Consequently, microfluidic platforms, specialized bioreactors, and automated assays have been and are being developed to address these deficits. This mini review provides an overview of the gaps to broader implementation of neuronal organoids in a drug discovery setting as well as emerging technologies that may better enable their utilization. SIGNIFICANCE STATEMENT: Neuronal organoid models offer the potential for a more physiological system in which to study neurological diseases, and efforts are being made to employ them not only in mechanistic studies but also in profiling/screening purposes within drug discovery. In addition to exploring the utility of neuronal organoid models within this context, efforts in the field aim to standardize such models for consistency and adaptation to screening platforms for throughput evaluation. This review covers potential impact of and hurdles to implementation.
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Organotypic culture of human brain explants as a preclinical model for AI-driven antiviral studies.
Viral neuroinfections represent a major health burden for which the development of antivirals is needed. Antiviral compounds that target the consequences of a brain infection (symptomatic treatment) rather than the cause (direct-acting antivirals) constitute a promising mitigation strategy that requires to be investigated in relevant models. However, physiological surrogates mimicking an adult human cortex are lacking, limiting our understanding of the mechanisms associated with viro-induced neurological disorders. Here, we optimized the Organotypic culture of Post-mortem Adult human cortical Brain explants (OPAB) as a preclinical platform for Artificial Intelligence (AI)-driven antiviral studies. OPAB shows robust viability over weeks, well-preserved 3D cytoarchitecture, viral permissiveness, and spontaneous local field potential (LFP). Using LFP as a surrogate for neurohealth, we developed a machine learning framework to predict with high confidence the infection status of OPAB. As a proof-of-concept, we showed that antiviral-treated OPAB could partially restore LFP-based electrical activity of infected OPAB in a donor-dependent manner. Together, we propose OPAB as a physiologically relevant and versatile model to study neuroinfections and beyond, providing a platform for preclinical drug discovery.
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Three-dimensional model of glioblastoma by co-culturing tumor stem cells with human brain organoids.
Emerging three-dimensional (3D) cultures of glioblastoma are becoming powerful models to study glioblastoma stem cell behavior and the impact of cell-cell and cell-microenvironment interactions on tumor growth and invasion. Here we describe a method for culturing human glioblastoma stem cells (GSCs) in 3D by co-culturing them with pluripotent stem cell-derived brain organoids. This requires multiple coordinated steps, including the generation of cerebral organoids, and the growth and fluorescence tagging of GSCs. We highlight how to recognize optimal organoid generation and how to efficiently mark GSCs, before describing optimized co-culture conditions. We show that GSCs can efficiently integrate into brain organoids and maintain a significant degree of cell fate heterogeneity, paving the way for the analysis of GSC fate behavior and lineage progression. These results establish the 3D culture system as a viable and versatile GBM model for investigating tumor cell biology and GSC heterogeneity.This article has an associated First Person interview with the first author of the paper.