Integrating 3D bioprinting and neural stem cell therapy for central nervous system repair: implications for...

The limited regenerative capacity of the central nervous system (CNS)poses a major challenge in neurosurgical interventions for spinal cord injuries, neurodegenerative diseases,and traumatic brain injuries. Traditional approaches offer structural stabilization but rarely achieve true neural tissue regeneration. Recent advances in regenerative medicine have spotlighted two promising strategies: 3D bioprinting and neural stem cell (NSC) therapy.3D bioprinting enables the fabrication of anatomically precise, biocompatible scaffolds that mimic native neural architecture, offering structural and biochemical support for tissue repair. Concurrently, NSCs capable of differentiating into neurons, astrocytes, and oligodendrocytes promote neurogenesis, synaptic integration,and immune modulation, making them attractive candidates for functional recovery. Despite extensive preclinical success, clinical translation of neural stem cell therapy remains inconsistent due to poor cell survival, uncontrolled differentiation, limited graft integration, and hostile post-injury microenvironments. This review critically examines why these limitations persist and argues that 3D bioprinting is not merely complementary, but essential for overcoming fundamental barriers to effective CNS regeneration. This review critically examines the convergence of 3D bioprinting and NSC therapy in neurosurgical applications. It discusses the design of bioinks, scaffold fabrication techniques,and the role of conductive and ECM-derived materials in supporting NSC viability and differentiation. The manuscript also explores preclinical and early-phase clinical trials (2015-2025), highlighting the therapeutic potential of NSC-loaded bioprinted constructs in spinal cord injury, Parkinson's disease,and stroke. Further, we analyze the biophysical and biochemical cues within scaffolds that shape NSC fate and describe how 3D bioprinted models are being used for disease modeling and drug screening. This review synthesizes findings from 53 preclinical and 18 clinical studies published between 2015 and 2025, providing a first-of-its-kind analysis that integrates bioink engineering principles with NSC-specific regenerative cues in neurosurgical applications. Our findings highlight that scaffold vascularization, immune compatibility,and GMP-standardized manufacturing remain the most pressing translational challenges,yet convergence of these technologies has the potential to redefine functional CNS repair. Despite promising outcomes, clinical translation faces challenges including cell survival, vascular integration, scaffold standardization,and regulatory compliance. Emerging technologies such as 4D bioprinting,CRISPR-engineered NSCs,and organoid-on-a-chip platforms are poised to overcome these barriers. By integrating structural bioengineering with cellular therapy, this interdisciplinary approach holds transformative potential for CNS repair. This review aims to provide a comprehensive overview of current advancements, translational bottlenecks,and future directions in regenerative neurosurgery using bioprinted NSC-based constructs.