Review Cite This: ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX
pubs.acs.org/journal/abseba
Where No Hand Has Gone Before: Probing Mechanobiology at the Cellular Level Carlos Matellan and Armando E. del Río Hernań dez*
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Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom ABSTRACT: Physical forces and other mechanical stimuli are fundamental regulators of cell behavior and function. Cells are also biomechanically competent: they generate forces to migrate, contract, remodel, and sense their environment. As the knowledge of the mechanisms of mechanobiology increases, the need to resolve and probe increasingly small scales calls for novel technologies to mechanically manipulate cells, examine forces exerted by cells, and characterize cellular biomechanics. Here, we review novel methods to quantify cellular force generation, measure cell mechanical properties, and exert localized piconewton and nanonewton forces on cells, receptors, and proteins. The combination of these technologies will provide further insight on the effect of mechanical stimuli on cells and the mechanisms that convert these stimuli into biochemical and biomechanical activity. KEYWORDS: mechanotransduction, mechanosensing, cellular biomechanics, traction force microscopy, cell compliance, microrheology
1. INTRODUCTION: THE ROLE OF MECHANOBIOLOGY IN HEALTH AND DISEASE
Mechanical forces are also fundamental in the onset and progression of disease and understanding how abnormal mechanobiology interacts with a pathology is key to develop new therapeutic strategies that target the biomechanical drivers of disease. Fibrotic diseases, which can account for ∼45% of all deaths in industrialized countries, can be regarded as a process of abnormal wound healing through sustained extracellular matrix (ECM) deposition and activation of myofibroblasts via biochemical and biomechanical signaling.13,14 In a similar manner, while certain blood flow patterns have been shown to be athero-protective,15 oscillatory flow dynamics activate a variety of signaling pathways that lead to pathological phenotypes and, eventually, cardiovascular disease.8,16,17 Mechanobiology is also becoming an increasingly important factor in cancer. 18−20 Biomechanical and biochemical activation of cancer-associated fibroblasts (CAFs) leads to remodelling of the tumor matrix, abnormal collagen deposition, and formation of a stiff, fibrotic microenvironment that increases cell proliferation, promotes epithelial to mesenchymal transition (EMT) and chemoresistance, and facilitates invasion and migration of the cancer cells.21−23 Solid stresses generated by the hyperproliferating tumor and high interstitial fluid pressure also play a role in the development of cancer.19,24 Similarly, the formation of a fibrotic niche in a target organ is conducive to the engraftment of metastatic seeds.25
In the body, cells and tissues are constantly subjected to mechanical forces. Over the last two decades, research has found that cells can sense and respond to these mechanical stimuli and the changing mechanical properties of their local microenvironment. While these biomechanical signals and responses are not as well-characterized as their biochemical counterparts, the growing body of evidence suggests that mechanical forces have a profound impact on regulating cell behavior. Mechanobiology has emerged as a field that studies how cells sense external forces and mechanical signals from their environment (mechanosensing) and transform these biomechanical cues to biochemical and biological activity (mechanotransduction). The complex interplay between biomechanical and biochemical signals plays a regulatory role in a wide variety of cellular processes. Matrix stiffness, cell shape, and nanotopography can determine stem cell differentiation.1−5 Mechanical forces orchestrate embryonic development6 and tissue morphogenesis.7 Shear forces exerted by blood flow regulate endothelial function,8 as well as vascular smooth muscle and fibroblast activity when these are exposed to fluid flow.9 Mechanical loading is fundamental to maintain an adequate equilibrium between bone deposition and resorption during bone remodelling and fracture repair.10,11 Mechanical forces also play a critical role in wound healing, where a combination of growth factors and mechanical signals activate myofibroblasts, enabling the remodelling of the provisional matrix.12 © XXXX American Chemical Society
Special Issue: Biomaterials for Mechanobiology Received: October 3, 2018 Accepted: December 6, 2018 Published: December 7, 2018 A
DOI: 10.1021/acsbiomaterials.8b01206 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX
Review
ACS Biomaterials Science & Engineering Table 1. Summary of Conventional and Novel Methods To Characterize Cellular Traction Forces name conventional 2D TFM super-resolved traction force microscopy (STFM) holographic TFM quantum dots TFM elastic resonator interference stress microscopy (ERISM) elastic micropillar arrays nanowire arrays parallel plates and AFM
spatial resolution 1−2 μm 0.4−1 μm 6.7 μm 0.75−3 μm, 30−45 nm precision 1.6 μm 0.5−2 μm ∼0.5 μm total cell contraction force
DNA hairpin
∼200 nm
integrative tension sensor
0.4 μm
FRET sensors
