Tissue-like mechanical responses in biopolymer networks induced by aggregated cell-mimicking particles

Biological tissues commonly exhibit compression stiffening, a mechanical response where stiffness increases under compression. However, most biopolymer networks such as collagen and fibrin, the primary components of extracellular matrices, typically display the opposite behavior: compression softening. Previous studies using uniformly distributed monodisperse spherical particles have provided explanations for this contrast, but have overlooked the role of irregularly shaped and aggregated inclusions, which better represent biological tissue structures. In this study, we demonstrate a novel mechanism of tissue-like compression stiffening in biopolymer hydrogels, driven by aggregates of cell-mimicking carbonyl iron particles. This effect is substantial and occurs even at low inclusion volume fractions. We show that the stiffening is not due to jamming or increased particle quantity, and that the diverse morphologies of inclusions, rather than polydisperse sizes, are critical for inducing tissue-like mechanical responses. Furthermore, we demonstrate that the stiffening results from the interactions between the particles and the network, where biopolymer fibers undergo stretching due to a lower contact percolation threshold. This work provides new insights into how tissue mechanics are regulated during both physiological and pathological conditions and suggests potential strategies for engineering biomaterials with more physiologically relevant mechanical properties.