Many genes and molecules that drive tissue patterning during organogenesis and tissue regeneration have been discovered. Yet, we still lack a full understanding of how these chemical cues induce the formation of living tissues with their unique shapes and material properties. Here, we review work based on the convergence of physics, engineering and biology that suggests that mechanical forces generated by living cells are as crucial as genes and chemical signals for the control of embryological development, morphogenesis and tissue patterning.

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Mechanical control of tissue and organ development

Mechanical forces play important roles in the regulation of various biological processes at the molecular and cellular level, such as gene expression, adhesion, migration, and cell fate, which are essential to the maintenance of tissue homeostasis. In this review, we discuss emerging bioengineered tools enabled by microscale technologies for studying the roles of mechanical forces in cell biology. In addition to traditional mechanobiology experimental techniques, we review recent advances of microelectromechanical systems (MEMS)-based approaches for cell mechanobiology and discuss how microengineered platforms can be used to generate in vivo–like micromechanical environment in in vitro settings for investigating cellular processes in normal and pathophysiological contexts. These capabilities also have significant implications for mechanical control of cell and tissue development and cell-based regenerative therapies.

/pdf/microengineered-platforms-for-cell-mechanobiology-403ur5va6e.pdf

Microengineered Platforms for Cell Mechanobiology

All cells are influenced by mechanical forces. In the brain, force-generating and load-bearing proteins twist, turn, ratchet, flex, compress, expand and bend to mediate neuronal signalling and plasticity. Although the functions of mechanosensitive proteins have been thoroughly described in classical sensory systems, the effects of endogenous mechanical energy on cellular function in the brain have received less attention, and many working models in neuroscience do not currently integrate principles of cellular mechanics. An understanding of cellular-mechanical concepts is essential to allow the integration of mechanobiology into ongoing studies of brain structure and function.

The mechanobiology of brain function

Ultrasonic neuromodulation is a rapidly growing field, in which low-intensity ultrasound (US) is delivered to nervous system tissue, resulting in transient modulation of neural activity. This review summarizes the findings in the central and peripheral nervous systems from mechanistic studies in cell culture to cognitive behavioral studies in humans. The mechanisms by which US mechanically interacts with neurons and could affect firing are presented. An in-depth safety assessment of current studies shows that parameters for the human studies fall within the safety envelope for US imaging. Challenges associated with accurately targeting US and monitoring the response are described. In conclusion, the literature supports the use of US as a safe, non-invasive brain stimulation modality with improved spatial localization and depth targeting compared with alternative methods. US neurostimulation has the potential to be used both as a scientific instrument to investigate brain function and as a therapeutic modality to modulate brain activity.

Ultrasound Neuromodulation: A Review of Results, Mechanisms and Safety.

Biological cells are well known to respond to a multitude of chemical signals. In the nervous system, chemical signaling has been shown to be crucially involved in development, normal functioning, and disorders of neurons and glial cells. However, there are an increasing number of studies showing that these cells also respond to mechanical cues. Here, we summarize current knowledge about the mechanical properties of nervous tissue and its building blocks, review recent progress in methodology and understanding of cellular mechanosensitivity in the nervous system, and provide an outlook on the implications of neuromechanics for future developments in biomedical engineering to aid overcoming some of the most devastating and currently incurable CNS pathologies such as spinal cord injuries and multiple sclerosis.

https://www.annualreviews.org/doi/pdf/10.1146/annurev-bioeng-071811-150045

Mechanics in neuronal development and repair.

Memory and learning in animals are mediated by neurotransmitters that are released from vesicles clustered at the synapse. As a synapse is used more frequently, its neurotransmission efficiency increases, partly because of increased vesicle clustering in the presynaptic neuron. Vesicle clustering has been believed to result primarily from biochemical signaling processes that require the connectivity of the presynaptic terminal with the cell body, the central nervous system, and the postsynaptic cell. Our in vivo experiments on the embryonic Drosophila nervous system show that vesicle clustering at the neuromuscular presynaptic terminal depends on mechanical tension within the axons. Vesicle clustering vanishes upon severing the axon from the cell body, but is restored when mechanical tension is applied to the severed end of the axon. Clustering increases when intact axons are stretched mechanically by pulling the postsynaptic muscle. Using micro mechanical force sensors, we find that embryonic axons that have formed neuromuscular junctions maintain a rest tension of ≈1 nanonewton. If the rest tension is perturbed mechanically, axons restore the rest tension either by relaxing or by contracting over a period of ≈15 min. Our results suggest that neuromuscular synapses employ mechanical tension as a signal to modulate vesicle accumulation and synaptic plasticity.

https://www.pnas.org/content/pnas/106/31/12611.full.pdf

Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals.

This paper employs MEMS force sensors to explore the role of mechanical tension in neuro transmission. Here, the nervous system of Drosophila (fruit fly) embryo is examined. The accumulation of vesicles that carry neuro transmitter at the synapse between the axons and muscle tissue is measured using florescent technique. The tensile force on axons are measured in vivo. The rest tension in axons is found to be about 1 nN. Increasing the tension by mechanical probing results in increasing vesicle accumulation. The results suggests that nature employs mechanical tension as a means of tuning neuro transmission efficiency, and hence memory formation.

Scott Siechen

Papers

Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals.

MEMS based sensors to explore the role of tension in axons for neuro-transmission

2009 GEM4 Summer School - University of Illinois at Urbana-Champaign: Lecture 1: Fundamentals of cell and molecular biology