# Topology Outweighs Stiffness: Self-Reinforced Cell Mechanotransduction via Multiaxial Curvature Engineering of Ultrasoft Hydrogels

## TL;DR

Researchers show that curved surfaces on soft materials can strongly influence cell behavior, even more than material stiffness.

## Contribution

A new method creates stable curvatures on ultrasoft hydrogels to study how topology affects cell mechanosensing.

## Key findings

- Curved hydrogels induce focal adhesion maturation and cytoskeletal changes in stem cells.
- Curvature enhances osteogenesis and nuclear mechanosensing like rigid substrates.
- Curvature-driven mechanosensing works in 3D microgels, independent of stiffness.

## Abstract

Geometric curvature
critically regulates cellular behavior
in soft
tissue microenvironments, yet its role in mechanotransduction is underexplored
due to stiffness-centric paradigms and challenges in creating stable
curvatures on ultrasoft materials. We developed a solvent-induced
buckling strategy to engineer multiaxial curvatures on ultrasoft hydrogels
(500–750 Pa), recapitulating the anisotropic topologies of
natural tissues such as cerebral gyri and breast lobules. Human mesenchymal
stem cells on these surfaces exhibit robust focal adhesion maturation,
cytoskeletal reorganization, nuclear mechanosensing (e.g., elevated
Lamin A/C), and enhanced osteogenesisphenotypes typically
seen on rigid substrates but markedly attenuated on flat ultrasoft
controls. This curvature-dominated mechanosensing persists in 3D injectable
microgels, decoupling topological cues from the substrate stiffness.
Mechanistic studies and energy minimization modeling reveal that curvature
segregates stress fiber functions: basal fibers align circumferentially
in high-curvature regions to enhance Rho-mediated contractility and
focal adhesions, while apical fibers orient radially in low-curvature
zones to minimize the bending energy. These findings establish topology
as a primary driver of cellular tension and fate, providing fundamental
insights into designing biomaterials and biointerfaces for soft tissue
repair and regenerative medicine.