Advanced 3D biomaterials and bioprinting strategies for in vitro modeling of neurodegenerative diseases

Abstract

Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) remain a major global health challenge due to their progressive nature and lack of curative treatments. Traditional animal models and 2D cell cultures fail to recapitulate the complex microenvironment and human-specific pathophysiology of these disorders. In response, advanced 3D in vitro models incorporating functional biomaterials have emerged as promising platforms for replicating disease mechanisms, enabling personalized medicine, and accelerating therapeutic discovery. This review highlights recent progress in the design and application of bioinspired and engineered biomaterials, including natural, synthetic, and hybrid scaffolds, which mimic the extracellular matrix and guide neural cell behavior. Hydrogels, stimuli-responsive polymers, and conductive nanocomposites are increasingly used in scaffold fabrication and 3D bioprinting. Integration with patient-derived induced pluripotent stem cells (iPSCs) and microfluidic platforms enables the creation of physiologically relevant models that replicate key pathological features. We discuss the importance of quantitative materials characterization including porosity, stiffness, swelling, degradation, and wettability in ensuring scaffold reproducibility and translational relevance. Despite challenges like vascularization and culture stability, innovations are addressing these barriers. Advanced biomaterials enable precise cell placement and structure. High-precision bioprinting and microfluidics support perfusable vessels. AI-driven data integration enhances scalability, optimizes conditions, analyzes large datasets, and improves reproducibility by minimizing batch variability in 3D in vitro models. Recent advances in bioelectric and electrochemical biomaterials including piezoelectric PLLA membranes, wirelessly self-powered Zn/Ag₂O scaffolds, 3D-printed carbon nanoelectrodes, and conductive POSS-PCL/graphene nanocomposites offer promising multifunctional platforms for 3D neurodegenerative disease models.