The human brain relies on highly organized neuronal networks to generate perception, memory, and behavior. When these networks are disrupted by stroke, trauma, or neurodegenerative disease, neurons are irreversibly lost and the adult central nervous system shows very limited regenerative capacity. As a result, millions of patients live with permanent neurological deficits for which no curative therapies exist.
Stem cell–based approaches, particularly human cortical brain organoids derived from pluripotent stem cells, offer a promising strategy for brain repair. These three-dimensional tissues generate diverse neuronal populations and partially recapitulate cortical architecture. After transplantation into rodent brains, organoids can survive, mature, and form connections with host tissue. However, current strategies rely largely on spontaneous graft–host integration, lacking spatial and temporal control. This can lead to inefficient integration, aberrant connectivity, and uncontrolled growth. Moreover, the injured brain presents an inhibitory environment that limits axonal regeneration, making structural guidance essential for effective circuit reconstruction.
COnNect addresses this limitation by introducing a bioengineering strategy to actively guide neuronal integration in vivo. The project combines human cortical organoids with light-responsive biomaterials that mimic key extracellular matrix properties while allowing precise spatial and temporal control through light-based fabrication. The central hypothesis is that transplanted organoid-derived neurons can reconstruct specific pathways when supported by a programmable, dynamic scaffold.
To test this, COnNect pursues four objectives: (1) develop human-specific, light-responsive hydrogels compatible with brain mechanics and supportive of survival and axonal growth; (2) establish advanced 3D bioprinting strategies enabling fabrication and selective removal of hydrogel structures in vitro and in vivo to create axon-guiding microchannels; (3) translate these tools to a cortical lesion model with spatially controlled integration; and (4) assess whether guided structural integration promotes functional network restoration.
By integrating stem cell biology, biomaterials engineering, and intravital light-based fabrication, COnNect moves beyond passive transplantation toward programmable neural integration. This approach establishes a conceptual and technological framework for controlled brain repair and may contribute to the long-term development of targeted regenerative strategies for focal brain lesions.
