Microsphere Sensors for Charactering Stress Fields within Three-Dimensional Extracellular Matrix

Stress in the three-dimensional extracellular matrix is one of the key cues in regulating multiscale biological processes. Thus far, noticeable progress in methods and technologies (e.g., micropipette aspiration, AFM, and molecule probes) has been made to quantify forces/stresses in cell microenvironment at different length scales. Among them, the microsphere sensor-based method (MSS-based method) has emerged as an advantageous approach over conventional techniques in quantifying stress in situ and in vivo at the cellular and supra-cellular scales. This method is implemented by seven sequential steps, including fabrication, modification, characterization, cell adhesion, imaging, displacement field extraction, and stress calculation. Precise control of each step and inter-tunning between steps can provide quantitative characterization of stress field. However, detailed procedural information associated with each step and process has been scattered. This review aims to provide a comprehensive overview of MSS-based characterization of stress fields within 3D ECM, systematically summarizing the principles and research progresses. Firstly, the basic principles are introduced, and the specific experiment and calculation processes of the MSS-based method are presented in detail. Then, recent advances and applications of this method are summarized. Moreover, the selection of materials and techniques for the MSS-based method needs to be adjusted independently according to the research objectives and requirements (e.g., specific tissue, length scale, time scale and resolution). Finally, perspectives of the limitations and development trends of the MSS-based method are discussed. This specific and comprehensive review would provide a guideline for the widespread application of MSS-based method as an advantageous method for in situ and in vivo stress measurement over both cellular and supra-cellular scale within 3D ECM.