Human pluripotent stem cells have emerged as a promising in vitro model system for studying the brain. Two-dimensional and three-dimensional cell culture paradigms have provided valuable insights into the pathogenesis of neuropsychiatric disorders, but they remain limited in their capacity to model certain features of human neural development. Specifically, current models do not efficiently incorporate extracellular matrix-derived biochemical and biophysical cues, facilitate multicellular spatio-temporal patterning, or achieve advanced functional maturation. Engineered biomaterials have the capacity to create increasingly biomimetic neural microenvironments, yet further refinement is needed before these approaches are widely implemented. This Review therefore highlights how continued progression and increased integration of engineered biomaterials may be well poised to address intractable challenges in recapitulating human neural development.
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The authors thank members of the Heilshorn, Paşca, Bao and Cui laboratories for helpful discussions. Specifically, the authors acknowledge B. L. LeSavage and M. J. Kratochvil for their constructive feedback. The authors acknowledge financial support from the US National Institutes of Health (R21NS114549, R01EB027666 and R01EB027171 (S.C.H.)), the US National Science Foundation (DMR1808415 and CBET2033302 (S.C.H.)), the National Science Foundation Future Manufacturing Program under award no. 2037164 (V.R.F., Y.J. and Z.B.), the National Science Foundation Graduate Research Fellowship Program under grant no. DGE-1656518 (J.G.R. and M.S.H.), the Stanford Smith Family Graduate Fellowship (J.G.R.), the Stanford ChEM-H O’Leary-Thiry Graduate Fellowship (M.S.H.), a Stanford Bio-X seed grant (V.R.F., Y.J. and Z.B.) and the Stanford Brain Organogenesis Program in the Wu Tsai Neurosciences Institute (B.C., H.T.G., Z.B., S.P.P. and S.C.H.).
The authors declare no competing interests.
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Nature Reviews Neuroscience thanks I.-H. Park, who co-reviewed with B. Cakir, T. Segura, who co-reviewed with J. Samal, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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- Human pluripotent stem cells
(Human PS cells). A broad category of human stem cells that includes both embryonic stem cells and induced pluripotent stem cells. Stem cells are defined by their capacity to continuously divide into identical, undifferentiated daughter cells and to differentiate into cells from any of the three germ layers.
Three-dimensional clusters of organ-specific cells of multiple subtypes that self-organize and exhibit some organ-appropriate functions.
Three-dimensional, self-organizing cultures derived by fusion of organoids with other organoids or cell lineages.
- Neural progenitor cell
(NPC). A neural stem cell with limited capacity for self-renewal.
- Natural biomaterials
Biomaterials derived from natural sources, including proteins, polysaccharides and decellularized tissue matrices.
- Neural stem cells
(NSCs). Multipotent cells that maintain the capacity to undergo limitless self-renewing cell divisions and create progeny of restricted lineages that differentiate into mature neural and glial cells.
- Synthetic biomaterials
Biomaterials derived from synthetic sources, including metals, ceramics, synthetic polymers and composites.
The process of isolating tissue-specific extracellular matrix by removing cell content.
- Protein engineering
The process of modifying existing protein sequences through substitution, insertion or deletion of nucleotides in an encoding gene.
- Neuroepithelial cells
(NECs). Early neural stem cells emerging from neuroectoderm that ultimately give rise to radial glia and other cells in the early developing central nervous system.
(OoC). A class of microphysiological systems wherein specialized cells are cultured within microfluidic chips.
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Roth, J.G., Huang, M.S., Li, T.L. et al. Advancing models of neural development with biomaterials. Nat Rev Neurosci 22, 593–615 (2021). https://doi.org/10.1038/s41583-021-00496-y