Beyond animal models: revolutionizing neurodegenerative disease modeling using 3D in vitro organoids, microfluidic chips, and bioprinting.

Neurodegenerative diseases (NDs) are characterized by uncontrolled loss of neuronal cells leading to a progressive deterioration of brain functions. The transition rate of numerous neuroprotective drugs against Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, leading to FDA approval, is only 8-14% in the last two decades. Thus, in spite of encouraging preclinical results, these drugs have failed in human clinical trials, demonstrating that traditional cell cultures and animal models cannot accurately replicate human pathophysiology. Hence, in vitro three-dimensional (3D) models have been developed to bridge the gap between human and animal studies. Such technological advancements in 3D culture systems, such as human-induced pluripotent stem cell (iPSC)-derived cells/organoids, organ-on-a-chip technique, and 3D bioprinting, have aided our understanding of the pathophysiology and underlying mechanisms of human NDs. Despite these recent advances, we still lack a 3D model that recapitulates all the key aspects of NDs, thus making it difficult to study the ND's etiology in-depth. Hence in this review, we propose developing a combinatorial approach that allows the integration of patient-derived iPSCs/organoids with 3D bioprinting and organ-on-a-chip technique as it would encompass the neuronal cells along with their niche. Such a 3D combinatorial approach would characterize pathological processes thoroughly, making them better suited for high-throughput drug screening and developing effective novel therapeutics targeting NDs.