cell interactions and an overall more physiologically relevant microenvironment. While cerebral organoids form the brain cytoarchitecture and composition, they generally lack oligodendrocytes, the cells responsible for myelination in the central nervous system. The myelinoid protocol pioneered by Madhavan et al. in 2018, and subsequently modified by others, offer a reproducible method for generating organoids with robust OPC and oligodendrocytes populations that track the endogenous neurons forming functional neuronal networks ensheathed with myelin. Finally, the ability to generate myelinoids from patient derived hPSCs (induced-PSCs) offer major advantages and opportunities to explore patient-specific pathogenesis over the developmental and maturation stages of oligodendrocytes. This allows for the development of personalized therapeutic approaches. Limitations As is the case with every model system, myelinoids have their limitations. Due to the methods involved with generating the organoids, there can be a large degree of experimental variability. Additionally, due to the long duration over which myelination occurs, optimizing the dosage of molecules and treatments involved in myelin development can be difficult. The advantage of drug screening in this model comes with its own limitations. It can be difficult to scale myelinoid experiment to an appropriate scale for high throughput screening due to the long duration of protocols and limited efficiency. Myelinoids capture a large number of cell types found in vivo, however, they fail to capture all cell types. Microglia are absent in some myelinoids as was observed by James et al. in their 2021 protocol. Myelinoids also do not capture any behavioral abnormalities. Finally, a challenge with all organoid cultures is that they rely on diffusion for nutrients to reach cells. Therefore, many organoids will develop a necrotic center due to a lack of nutrients making their way to the innermost cells. Recently, vascularized organoids have been developed and may potentially alleviate this issue, however, myelinoids as described in current protocols are not vascularized. References