Brain Organoids on a Chip: Modeling Prenatal Nicotine Exposure
"A revolutionary approach using human brain organoids on a chip offers new insights into the effects of prenatal nicotine exposure on neurological development."
Advances in three-dimensional (3D) neural culture models, derived from human stem cells, are revolutionizing neuroscience research. These 3D models more faithfully replicate the pivotal functions and cytoarchitectures of in-vivo neural tissues, surpassing conventional two-dimensional (2D) culture models and animal models. This shift promises more relevant insights into human brain development and related disorders.
To establish these 3D neural models, brain organoids and brain-on-a-chip systems represent two typical approaches grounded in developmental biology and bioengineering, respectively. Brain organoids are formed through sequential in vitro neural development steps, including generating embryoid bodies (EBs) from stem cells, inducing neuroectoderm, expanding neuroepithelium in Matrigel, and differentiating organoids in suspension.
In contrast, brain-on-a-chip systems enhance the capacity to reconstitute in-vivo neural microenvironments, including intercellular interactions, extracellular matrix (ECM), and hemodynamics, in a deterministic manner. By combining the advantages of both organ-on-a-chip and organoid technologies, the organoid-on-a-chip platform has emerged as a new model to recapitulate the essential structural and physiological features of the in vivo tissue and the corresponding 3D tissue microenvironment.
From Animal Models to Human Organoids
Brain organoids provide a way to study the human brain and model neurological disease despite the inaccessibility of human brain samples and the limited similarity of animal models. They can be generated through various protocols to mimic the whole brain or specific brain regions. A 2018 human brain organoid-on-a-chip system used human induced pluripotent stem cells, embryoid-body culture, neural differentiation, 3D Matrigel, and fluid flow to model prenatal nicotine exposure.
How Brain Organoids on a Chip are Revolutionizing Research
Nicotine is recognized as a neurotoxin that can trigger various neural dysfunctions and long-lasting deficits when the fetal brain is exposed. Maternal smoking during pregnancy is associated with offspring intelligence, anxiety behaviors, cognitive ability, and neurodegenerative diseases later in adulthood. Understanding the effects of prenatal nicotine exposure (PNE) on human neurological development remains a challenge due to the differences between human and animal physiology.
- Enhanced Realism: Mimics in-vivo brain conditions more accurately than traditional 2D models.
- Controlled Environment: Offers precise control over biochemical and mechanical cues.
- Versatile Applications: Suitable for studying various neurodevelopmental disorders beyond nicotine exposure.
- Ethical Alternative: Reduces the need for animal models and human clinical trials.
- Real-Time Monitoring: Transparent microfluidic devices enable in situ real-time imaging of brain development processes.
Expanding Toxicity and Disease Models
Recent reviews describe brain organoid cultures as increasingly complex 3D models that can recapitulate electrical activity in utero and support research on psychosis, mood disorders, and environmentally induced disorders. Cerebral organoids derived from induced pluripotent stem cells have also been used to study neurodevelopment, neurodevelopmental disorders, prenatal toxin exposure, and gene-environment interactions. In neural-toxicity research, nicotine exposure was reported to induce premature neuronal differentiation and damage cortical development, while similar brain organoid-on-a-chip systems have been used to investigate impaired neurogenesis after cadmium and alcohol exposure.
Model Limitations and Translational Gaps
The commentary on human brain organoid-on-a-chip modeling states that the relevant existing approaches each have their own limitations. At the same time, preclinical models of developmental nicotine exposure have provided valuable insight into nicotine's effects on the developing brain. Those models have reported lasting effects on brain structure and neurotransmitter signaling, while prenatal tobacco-product use is associated with increased risk for neurodevelopmental disorders in offspring.
Future Directions and Implications
Understanding the early stages of human embryonic development is crucial for thoroughly investigating the effects of PNE on human brain development. The brain organoid-on-a-chip system utilized in the current work could serve as an alternative human-relevant neurodevelopmental model, eliminating ethical concerns regarding human clinical trials involving smoking pregnant women. For basic and translational neuroscience research, generating standardized and homogenous brain organoids is critical but remains an unsolved issue in this system. Nevertheless, the brain organoid-on-a-chip system opens a new avenue for modeling human prenatal neurodevelopmental disorders.
Toward Perfused Human Brain Models
Human midbrain organoid microphysiological systems have been engineered to model prenatal exposure to per- and polyfluoroalkyl substances, including PFOS. The reported system combines a human midbrain organoid with a perfusable device layer and uses a microelectrode-array plate for measurement. This example illustrates how organoid-on-a-chip platforms can extend prenatal neurodevelopment research beyond nicotine to other environmental exposures.
Evidence Beyond the Chip
A 2025 review examined brain magnetic resonance imaging studies of the effects of maternal prenatal tobacco exposure on the structure and function of offspring brains. The review highlights concern about lasting effects on fetal neurological development in the context of increasing global prevalence of maternal smoking during pregnancy. These imaging studies provide a broader human context for interpreting mechanistic findings from prenatal-exposure models.