Cellular Responses to Mechanical Cues Across Scales: From Fundamental Insights to Translational Potential.

Abstract

Soft biomaterials strongly influence cellular behavior by transmitting mechanical cues via well-characterized mechanotransduction pathways. However, translating insights from simplified in vitro systems to complex in vivo responses remains a challenge. This review provides a framework for assessing the translational relevance of mechanobiological studies across different scales-from single cells and organoids to tissues and organs. First, we categorize soft biomaterials based on their architecture and mechanical features to establish consistent terminology. We then investigate how cells interpret the transmitted mechanical signals in advanced in vitro systems that simulate physiologically relevant mechanical environments. To discuss the translational potential, we present a scoring system and a comparative analysis demonstrating that physiological specificity, rather than experimental complexity, determines predictive value. Simple systems can yield highly translatable outcomes when mechanical cues mimic native conditions, while advanced models require careful validation to ensure their relevance. By integrating biomechanics, electrophysiology, and systems biology, we outline principles and validation strategies that enhance the predictive utility of mechanobiological findings and ultimately support the design of more effective biomaterials and tissue-engineered systems.