Physiological Relevance of Engineered Brain Models

Engineered brain models, including brain organoids and brain-on-a-chip systems, are generally assessed in terms of their physiological relevance. Although this language is useful for emphasizing the need to better approximate human biology, it can also obscure important differences among context of use, required validation strategy and ethical considerations. In this Opinion, we argue that physiological relevance should not be treated as a universal measure of model quality. Instead, its meaning should be defined relative to its application domain, including animal-model comparison, interpretation of single-cell atlases, clinical translation, donor representation, and emerging functional applications such as synthetic biological intelligence. For some applications, particularly patient-specific disease modeling and therapeutic screening, greater human physiological relevance may be required. For others, including biohybrid computing, controllable neural interfaces, interpretability, and ethical considerations may be more important. Moving beyond simplistic terminology will help improve scientific interpretation, prevent overstating findings, and support more responsible development of engineered brain models.