Engineering 3D neural models of neurodegeneration: the Neural Microenvironment Design Code (NMDC), design principles, and emerging new approach methodologies.

Neurodegenerative diseases are characterized by progressive neuronal loss driven not only by intrinsic cellular dysfunction but also by complex interactions within the neural microenvironment, including extracellular matrix (ECM) composition, neuroimmune signaling, and neurovascular dynamics. Conventional two-dimensional systems and animal models fail to recapitulate this complexity, limiting their predictive value. Recent advances in three-dimensional (3D) neural platforms, particularly 3D bioprinting and organoid technologies, have enabled the development of more physiologically relevant models that better reproduce brain architecture and multicellular organization. These systems enable the investigation of key pathological processes, including neuroinflammation, protein aggregation, and synaptic dysfunction, while aligning with emerging New Approach Methodologies (NAMs) aimed at improving human-relevant disease modeling. However, current platforms remain constrained by limited maturation, insufficient vascularization, incomplete immune integration, and experimental variability. A central premise of this review is that effective disease modeling requires not only biological complexity but also precise engineering of the neural microenvironment. To organize this engineering effort, we introduce the Neural Microenvironment Design Code (NMDC), a framework encompassing mechanical, biochemical, electrophysiological, and immune-barrier design codes that collectively define the neural microenvironment. Using the NMDC as an organizing framework, we synthesize recent advances across major neurodegenerative diseases and identify key design principles governing biomaterial selection, spatial organization, cellular integration, and biofabrication. Collectively, these approaches position 3D neural models as programmable, human-relevant systems for predictive drug screening and personalized therapeutic development.