# A Human Neural Tube Model Using 4D Self‐Folding Smart Scaffolds

## TL;DR

Scientists created a 4D self-folding scaffold model of the human neural tube using stem cells to study brain development and disorders.

## Contribution

A novel 4D bioprinted neural tube model that mimics human neural development and can be used to study neurodevelopmental disorders.

## Key findings

- The 4D-NT scaffold self-folds upon hydration, mimicking the spatial complexity of the human neural tube.
- iPSC-derived neuroprogenitors efficiently develop on the 4D-NT, recapitulating early neural development.
- The model successfully replicates disease features associated with WDR62 mutations in microcephaly.

## Abstract

The human brain originates from the neural tube that detaches from the ectodermal layer and gradually develops into a mature structure through highly regulated molecular and cellular processes. Here, stem cell technology is combined with 4D bioprinting, a fabrication process that utilizes additive manufacturing, to generate a 4D‐neural tube (4D‐NT). This consists of a scaffold that can self‐fold over time, which is then populated with iPSC‐derived neuroprogenitors, mimicking neural tube cellular architecture. The scaffold's “smart” self‐folding behavior is driven by the differential swelling properties of bilayer films, which create a deformation gradient upon hydration. Cellular analyses reveal a highly efficient induction of neuroprogenitors on 4D‐NTs, demonstrating the ability of this model to mimic the spatial and structural complexity of the developing human neural tube. Furthermore, 4D‐NTs seeded with iPSCs with a mutation in WDR62, associated with autosomal recessive primary microcephaly (MCPH), recapitulate the earlier observations obtained in 2D/3D neural cultures, thereby validating the newly developed 4D‐NT platform and suggesting it represents a tool that can facilitate understanding of human neural development and disease.

Induced pluripotent stem cells (iPSCs) exhibit features comparable to the inner cell mass of the human embryo. iPSCs are applied to a novel self‐folding 4D‐Neural Tube (4D‐NT) structure that mimics the neurulation process. This 4D‐NT model recapitulates early events of human neural development and represents a platform to explore neurodevelopmental disorders.