# Automation of electrothermal cell sheet manipulator for seamless tissue assembly and handling

## TL;DR

This paper introduces an automated system for handling fragile cell sheets, which preserves their structure and enables precise tissue assembly for regenerative medicine.

## Contribution

The novel contribution is an automated electrothermal manipulator that enables gentle, damage-free handling of cell sheets using a thermoresponsive hydrogel.

## Key findings

- The automated system preserves cell sheet flatness and minimizes wrinkling compared to manual methods.
- Human iPSC-derived neural sheets were successfully transferred onto endothelial cell monolayers using the system.
- The system enables reproducible, hands-free operation with synchronized thermal and mechanical control.

## Abstract

The manipulation of fragile biological tissues such as engineered cell sheets remains a major challenge for regenerative medicine and tissue engineering. Manual handling with tools like tweezers often induces wrinkling or tearing, compromising tissue integrity. Here, we present an automated cell sheet manipulator that integrates a thermoresponsive microchanneled poly(N-isopropylacrylamide) (PNIPAAm) hydrogel with an embedded microheater, mounted on a programmable three-axis motorized stage. Upon localized heating and cooling, the hydrogel undergoes rapid, reversible volumetric transitions that enable suction-based gripping and release of cell sheets within a few seconds. The custom LabVIEW interface synchronizes stage movement and thermal cycling, allowing reproducible, hands-free operation. A compliance-based Z-axis apparatus ensured uniform low-magnitude contact forces, preventing mechanical damage during transfer. Using this system, human iPSC-derived neural sheets were reliably transferred onto human brain microvascular endothelial cell (hBMEC) monolayers. Compared to manual transfer, the automated manipulator preserved cell sheet flatness and minimized micro-wrinkling, resulting in safe retention of intercellular architecture and structural integrity. This work demonstrates a robust, user-friendly platform for automated and gentle handling of delicate biological sheets. By enabling the precise stacking of engineered tissues while preserving their morphology, this system provides a promising tool for advanced biofabrication workflows, supporting defect-free 3D tissue assembly and implantation.

The online version contains supplementary material available at 10.1007/s10544-025-00781-y.