Microsphere sensors for characterizing 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 techniques (e.g., micropipette aspiration, AFM, and molecule probes) has been made to quantify stress 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 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 method, systematically summarizing the principles and research progresses. Firstly, the basic principles are introduced, and the specific experiment and calculation processes of MSS-based method are presented in detail. Then, recent advances and applications of this method are summarized. Finally, perspectives of the limitations and development trends of 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 characterization at cellular and supra-cellular scale within three-dimensional extracellular matrix. STATEMENT OF SIGNIFICANCE: In this review, a method based on a microsphere sensor (MSS-based method) as an advantageous approach over conventional techniques in quantifying stress in situ and in vivo at cellular and supra-cellular scales is introduced and discussed. This technique is implemented by seven sequential steps, including fabrication, modification, characterization, cell junction, imaging, displacement field extraction, and stress calculation. Precise control of each step and inter-tunning between steps can provide quantitative stress field. However, detailed procedural information associated with each step has been scattered. Thus, a comprehensive review collating recent advances and perspective discussions is a necessity to introduce a better option for quantifying the stress field in biological processes at the cellular and supra-cellular scales.