Mechanochemical Transduction Research Articles

Polymer mechanochemistry: from single molecule to bulk material.

The field of polymer mechanochemistry has experienced a renaissance over the past decades, primarily propelled by the rapid development of force-sensitive molecular units (i.e., mechanophores) and principles governing the reactivity of polymer networks for mechanochemical transduction or material strengthening. In addition to fundamental guidelines for converting mechanical energy input into chemical output, there has also been increasing focus on engineering applications of polymer mechanochemistry for specific functions, mechanically adaptive material systems, and smart devices. These endeavors are made possible by multidisciplinary approaches involving the development of multifunctional mechanophores for mechanoresponsive polymer systems, mechanochemical catalysis and synthesis, three-dimensional (3D) printed mechanochromic materials, reasonable design of polymer network topology, and computational modeling. The aim of this minireview is to provide a summary of recent advancements in covalent polymer mechanochemistry. We specifically focus on productive mechanophores, mechanical remodeling of polymeric materials, and the development of theoretical concepts.

Caveolae-associated cAMP/Ca2+-mediated mechano-chemical signal transduction in mouse atrial myocytes

Caveolae are tiny invaginations in the sarcolemma that buffer extra membrane and contribute to mechanical regulation of cellular function. While the role of caveolae in membrane mechanosensation has been studied predominantly in non-cardiomyocyte cells, caveolae contribution to cardiac mechanotransduction remains elusive. Here, we studied the role of caveolae in the regulation of Ca2+ signaling in atrial cardiomyocytes. In Langendorff-perfused mouse hearts, atrial pressure/volume overload stretched atrial myocytes and decreased caveolae density. In isolated cells, caveolae were disrupted through hypotonic challenge that induced a temporal (<10 min) augmentation of Ca2+ transients and caused a rise in Ca2+ spark activity. Similar changes in Ca2+ signaling were observed after chemical (methyl-β-cyclodextrin) and genetic ablation of caveolae in cardiac-specific conditional caveolin-3 knock-out mice. Acute disruption of caveolae, both mechanical and chemical, led to the elevation of cAMP level in the cell interior, and cAMP-mediated augmentation of protein kinase A (PKA)-phosphorylated ryanodine receptors (at Ser2030 and Ser2808). Caveolae-mediated stimulatory effects on Ca2+ signaling were abolished via inhibition of cAMP production by adenyl cyclase antagonists MDL12330 and SQ22536, or reduction of PKA activity by H-89. A compartmentalized mathematical model of mouse atrial myocytes linked the observed changes to a microdomain-specific decrease in phosphodiesterase activity, which disrupted cAMP signaling and augmented PKA activity. Our findings add a new dimension to cardiac mechanobiology and highlight caveolae-associated cAMP/PKA-mediated phosphorylation of Ca2+ handling proteins as a novel component of mechano-chemical feedback in atrial myocytes.

MECHANOLUMINESCENCE OF WALKER-256 CARCINOSARCOMA CELLS INDUCED BY MAGNETO-MECHANOCHEMICAL EFFECTS OF Fe3O4–Au NANOCOMPOSITE

Magnetic fields have been used to deliver magnetic nanocomposites (MNCs) and alter mechanochemical transduction pathways in malignant tumors. We study mechanoluminescence (ML) of Walker-256 carcinosarcoma cells induced by the magneto-mechanochemical effects of Fe3O4–Au MNCs under a nonuniform rotating magnetic field (RMF). Photoluminescence (PL) and Raman spectra were recorded to investigate the optical response of MNCs. The PL spectrum of MNCs showed three broad emission bands with peaks at 525, 570 and 680 nm. MNCs underwent a phase transition attributed to localized surface plasmon resonance as indicated by the Raman spectra. ML intensity recorded from MNCs[Formula: see text][Formula: see text][Formula: see text]cells[Formula: see text][Formula: see text][Formula: see text]RMF was 3.5 and 1.4 times greater than chemiluminescence (CL) of MNCs[Formula: see text][Formula: see text][Formula: see text]cells and cells alone, respectively ([Formula: see text] 0.05). ML exhibited lesser variation than CL. The nonuniform distribution of a magnetic force exerted on MNCs resulted in more symmetric distributions of ML signals. Therefore, the observed ML emission could originate from the magneto-mechanochemically and light-induced free radical reactions in cancer cells in response to MNCs[Formula: see text][Formula: see text][Formula: see text]RMF. The magneto-mechanochemical effects have the possibility to translate ML to cancer diagnosis and treatment by providing additional information about changes in breaking asymmetry to symmetric processes at the quantum level.

From tensegrity to human organs-on-chips: implications for mechanobiology and mechanotherapeutics.

The field of mechanobiology, which focuses on the key role that physical forces play in control of biological systems, has grown enormously over the past few decades. Here, I provide a brief personal perspective on the development of the tensegrity theory that contributed to the emergence of the mechanobiology field, the key role that crossing disciplines has played in its development, and how it has matured over time. I also describe how pursuing questions relating to mechanochemical transduction and mechanoregulation can lead to the creation of novel technologies and open paths for development of new therapeutic strategies for a broad range of diseases and disorders.

Caveolae-restricted mechano-chemical signal transduction in mouse atrial myocytes.

Atrial fibrillation (AF) is commonly observed in patients with hypertension and is associated with pathologically elevated cardiomyocyte stretch. AF triggers have been linked to subcellular Ca2+ abnormalities, while their association with stretch remains elusive. Caveolae are mechanosensitive membrane structures, that play a role in both Ca2+ and cyclic adenosine monophosphate (cAMP) signaling. Therefore, caveolae could provide a mechanistic connection between cardiomyocyte stretch, Ca2+ mishandling, and AF. In isolated mouse atrial myocytes, cell stretch was mimicked by hypotonic swelling, which increased cell width (by ∼30%, p<0.05), but not cell length. Swelling induced a temporal rise (1-5 min) in Ca2+ transient (CaT) amplitude and spontaneous Ca2+ sparks frequency (CaSpF). Electron microscopy analysis revealed a 2-fold decrease in caveolae density in stretched cells. Alternatively, disruption of caveolae via (1) 10 mM methyl-β-cyclodextrin (MβCD) or (2) genetic knockout of caveolin-3 augmented both CaT and CaSpF, similar to swelling. Immunofluorescent analysis revealed the augmentation of protein kinase A (PKA)-phosphorylated ryanodine receptors (at both Ser2030 and Ser2808) in swelled and MβCD-treated cells as compared to isotonic ones (p<0.05). CaSpF in swelled and MβCD-treated cells was reduced to the unstretched level via (1) inhibition of cAMP production by 100 μM SQ22536, or (2) reduction of PKA activity by 1 μM H-89. Transfection of myocytes with either sarcolemma- or cytosol-targeted Epac2-camps FRET sensors revealed a sharp decrease of cAMP signal in the submembrane compartment and a transient rise in the cytosol during the stretch. Atrial myocytes from pressure-overloaded hearts (4-weeks transaortic constriction) showed 1.6 times higher CaSpF than wild-type cells (p<0.01), which was significantly reduced after incubation with SQ22536 (p<0.05). Our findings demonstrate that short-time cell swelling augments Ca2+ handling in atrial myocytes via caveolae/cAMP/PKA mechano-chemical signal transduction, which could contribute to atrial arrhythmogenesis under pathological conditions.

Mechanochemical induction of nuclear condensates during cell confined migration.

Cell movement through small constrictions is important in many physiological and disease contexts, such as in cancer metastasis. Such migration is rate-limited by squeezing the cell nucleus through the constriction, with associated deformation of the nuclear lamina and chromatin. However, other subnuclear structures are similarly deformed, including membraneless nuclear bodies or condensates, where the impact of cell mechanics on their formation by liquid-liquid phase separation is largely unknown. Here we investigate the response of chromatin-embedded nuclear condensates under mechanical stress using a microfluidic device. We find that the DNA damage response protein 53BP1 undergoes a switch in phase behavior at the rear of migrating breast cancer cell nucleus, independent of DNA damage response. Interestingly, confined migration does not induce nuclear condensation of phase-separated prone FET family proteins. We hypothesize that 53BP1 and potentially other nuclear condensates can sense mechanical stimuli by changing their phase behavior, which is thereby closely coupled to the heterogeneity of the chromatin network they are embedded in. By quantitatively mapping the displacement field of chromatin, we found that chromatin forms spatially distinct domains of correlated motions as well as different strain magnitudes. Our finding highlights the mechanical interplay between nuclear condensates and chromatin under physiological deformations, and suggests the potential role of LLPS in mechanochemical transduction.

Effect of strand molecular length on mechanochemical transduction in elastomers probed with uniform force sensors

The impact of strand molecular length on mechanical response is elucidated through the incorporation of uniform mechanochromic force probes.

Abstract SY23-02: Elevated cellular stiffness sensitizes metastatic cells to destruction by mechanosurveillance: The mechanical mode of immune surveillance

Abstract Tumor evolution is coupled to profound biophysical changes in cancer cells and understanding how these changes impact metastasis can reveal novel therapeutic targets. One prominent biophysical characteristic of cancer cells is their stiffness. At the early steps of the metastatic cascade, transformed cells become physically softer and this allows them to invade into and to navigate through the surrounding extracellular matrix. Conversely, cancer cells that later intravasate into circulation need to maintain a higher degree of biophysical stiffness in order to withstand shear forces that otherwise cause mechanical rupture of cancer cells during hematogenous dissemination. However, the impact of cellular stiffness on the final stage of metastatic colonization in vital secondary organs is not well understood. We recently found that increasing stiffness of disseminated cancer cells sensitizes them to destruction by cytotoxic lymphocytes. Specifically, we found that myocardin related transcription factor (MRTFA/B) activity in cancer cells increases cancer cell stiffness, which then biophysically stimulates apoptotic cytokine production and cytolytic granule secretion in the adjoining CD8+ T- and Natural Killer (NK) cells for improved cytotoxicity. Our data highlighted the in vivo prevalence of the fundamental concepts in lymphocyte mechanobiology, which posit that increasing the stiffness of the surfaces that oppose T- and NK cells increases their cytolytic function through mechano-chemical signal transduction. We termed this mechanical mode of immune surveillance “mechanosurveillance” and showed that the expression of its molecular mediators cooperates with immune checkpoint blockade therapies in melanoma models and is associated with better patient survival in the clinic. In our current work, we utilized a series of novel biophysical approaches to measure the stiffness of metastatic foci in situ and to demonstrate that physically stiffer metastatic foci are eliminated by the immune surveillance. Furthermore, we used bioinformatics analyses of patient data and loss-of-function and gain-of-function experiments to identify therapeutically actionable proteins that increase cancer cell stiffness. Our findings revealed pharmacological manipulations that increase cancer cell stiffness and provided a road map for promoting mechanosurveillance in metastatic niches. Citation Format: Ekrem Emrah Er. Elevated cellular stiffness sensitizes metastatic cells to destruction by mechanosurveillance: The mechanical mode of immune surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY23-02.

Programmed mechano-chemical coupling in reaction-diffusion active matter.

Embryo morphogenesis involves a complex combination of self-organization mechanisms that generate a great diversity of patterns. However, classical in vitro patterning experiments explore only one self-organization mechanism at a time, thus missing coupling effects. Here, we conjugate two major out-of-equilibrium patterning mechanisms—reaction-diffusion and active matter—by integrating dissipative DNA/enzyme reaction networks within an active gel composed of cytoskeletal motors and filaments. We show that the strength of the flow generated by the active gel controls the mechano-chemical coupling between the two subsystems. This property was used to engineer a synthetic material where contractions trigger chemical reaction networks both in time and space, thus mimicking key aspects of the polarization mechanism observed in C. elegans oocytes. We anticipate that reaction-diffusion active matter will promote the investigation of mechano-chemical transduction and the design of new materials with life-like properties.

Electrophysiological and Molecular Mechanisms of Sinoatrial Node Mechanosensitivity.

The understanding of the electrophysiological mechanisms that underlie mechanosensitivity of the sinoatrial node (SAN), the primary pacemaker of the heart, has been evolving over the past century. The heart is constantly exposed to a dynamic mechanical environment; as such, the SAN has numerous canonical and emerging mechanosensitive ion channels and signaling pathways that govern its ability to respond to both fast (within second or on beat-to-beat manner) and slow (minutes) timescales. This review summarizes the effects of mechanical loading on the SAN activity and reviews putative candidates, including fast mechanoactivated channels (Piezo, TREK, and BK) and slow mechanoresponsive ion channels [including volume-regulated chloride channels and transient receptor potential (TRP)], as well as the components of mechanochemical signal transduction, which may contribute to SAN mechanosensitivity. Furthermore, we examine the structural foundation for both mechano-electrical and mechanochemical signal transduction and discuss the role of specialized membrane nanodomains, namely, caveolae, in mechanical regulation of both membrane and calcium clock components of the so-called coupled-clock pacemaker system responsible for SAN automaticity. Finally, we emphasize how these mechanically activated changes contribute to the pathophysiology of SAN dysfunction and discuss controversial areas necessitating future investigations. Though the exact mechanisms of SAN mechanosensitivity are currently unknown, identification of such components, their impact into SAN pacemaking, and pathological remodeling may provide new therapeutic targets for the treatment of SAN dysfunction and associated rhythm abnormalities.

Re-Entrant Conformation Transition in Hydrogels.

Hydrogels are attractive materials not only for their tremendous applications but also for theoretical studies as they provide macroscopic monitoring of the conformation change of polymer chains. The pioneering theoretical work of Dusek predicting the discontinuous volume phase transition in gels followed by the experimental observation of Tanaka opened up a new area, called smart hydrogels, in the gel science. Many ionic hydrogels exhibit a discontinuous volume phase transition due to the change of the polymer–solvent interaction parameter χ depending on the external stimuli such as temperature, pH, composition of the solvent, etc. The observation of a discontinuous volume phase transition in nonionic hydrogels or organogels is still a challenging task as it requires a polymer–solvent system with a strong polymer concentration dependent χ parameter. Such an observation may open up the use of organogels as smart and hydrophobic soft materials. The re-entrant phenomenon first observed by Tanaka is another characteristic of stimuli responsive hydrogels in which they are frustrated between the swollen and collapsed states in a given solvent mixture. Thus, the hydrogel first collapses and then reswells if an environmental parameter is continuously increased. The re-entrant phenomenon of hydrogels in water–cosolvent mixtures is due to the competitive hydrogen-bonding and hydrophobic interactions leading to flow-in and flow-out of the cosolvent molecules through the hydrogel moving boundary as the composition of the solvent mixture is varied. The experimental results reviewed here show that a re-entrant conformation transition in hydrogels requires a hydrophobically modified hydrophilic network, and a moderate hydrogen-bonding cosolvent having competitive attractions with water and polymer. The re-entrant phenomenon may widen the applications of the hydrogels in mechanochemical transducers, switches, memories, and sensors.

Abstract 2825: Mechanosurveillance by immunity targets mechanical compliance of metastatic cells

Abstract Metastatic dissemination of cancer cells to vital secondary organs pose a lifelong lethal threat unless they can successfully be eliminated by the immune system. Interestingly, despite their ability to evade immunity at primary organs, the vast majority of disseminated cancer cells are killed at secondary organs, suggesting that the process of dissemination renders cancer cells sensitive to immunity. Understanding how dissemination renders cancer cells sensitive to immunity would therefore provide exciting new opportunities to target metastases, but the relationship between dissemination and the immune response is not clear. In our effort to study this relationship, we manipulated cancer cells' expression of myocardin related transcription factors A and B (MRTFA/B), which are central in regulation of actin cytoskeleton and are indispensable for metastatic invasion, dissemination and colonization. Surprisingly, despite MRTFA/B's established roles in promoting metastasis, we found that MRTFA/B expression in cancer cells downregulated metastatic colonization in fully immuno-competent mouse models. MRTFA/B mediated decrease in colonization was completely reversed upon immune cell depletion suggesting that the immune cells exploit MRTFA/B expression in cancer cells for cytotoxicity. Among various cancer cell parameters involved in immune cell activation, T- and NK cell activation most prominently correlated with MRTFA/B driven mechanical compliance of cancer cells. Mechanical compliance, also known as stiffness, of antigen presenting cells and synthetic substrates are well-known to activate T- and NK cells through biophysical and mechano-chemical signal transduction. As such, perturbing cancer cells' stiffness downregulated the immune response and cytotoxicity. Thus, we termed this process mechanosurveillance. Our work on mechanosurveillance will help us understand how disseminated cancer cells are targeted by immunity and how they evade it at secondary organs. Importantly the concept of mechanosurveillance will help guide the use of existing therapeutics that alter tissue stiffness and immune boosting therapies to combat metastases. Citation Format: Maria Tello-Lafoz, Katja Srpan, Jing Hu, Yevgeniy Romin, Annalisa Calo, Katharine C. Hsu, Joan Massagué, Morgan Huse, Ekrem Emrah Er. Mechanosurveillance by immunity targets mechanical compliance of metastatic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2825.

A reversible shearing DNA probe for visualizing mechanically strong receptors in living cells.

In the last decade, DNA-based tension sensors have made significant contributions to the study of the importance of mechanical forces in many biological systems. Albeit successful, one shortcoming of these techniques is their inability to reversibly measure receptor forces in a higher regime (that is, >20 pN), which limits our understanding of the molecular details of mechanochemical transduction in living cells. Here, we developed a reversible shearing DNA-based tension probe (RSDTP) for probing molecular piconewton-scale forces between 4 and 60 pN transmitted by cells. Using these probes, we can easily distinguish the differences in force-bearing integrins without perturbing adhesion biology and reveal that a strong force-bearing integrin cluster can serve as a 'mechanical pivot' to maintain focal adhesion architecture and facilitate its maturation. The benefits of the RSDTP include a high dynamic range, reversibility and single-molecule sensitivity, all of which will facilitate a better understanding of the molecular mechanisms of mechanobiology.

Abstract LT016: Mechanosurveillance eliminates disseminated cancer cells by sensing their mechanical compliance

Abstract Metastatic dissemination of cancer cells to vital secondary organs pose a lifelong lethal threat unless they can successfully be eliminated by the immune system. Interestingly, despite their ability to evade immunity at primary organs, the vast majority of disseminated cancer cells are killed at secondary organs, suggesting that the process of dissemination renders cancer cells sensitive to immunity. Understanding how dissemination renders cancer cells sensitive to immunity would therefore provide exciting new opportunities to target metastases, but the relationship between dissemination and the immune response is not clear. In our effort to study this relationship, we manipulated cancer cells’ expression of myocardin related transcription factors A and B (MRTFA/B), which are central in regulation of actin cytoskeleton and are indispensable for metastatic invasion, dissemination and colonization. Surprisingly, despite MRTFA/B’s established roles in promoting metastasis, we found that MRTFA/B expression in cancer cells downregulated metastatic colonization in fully immuno-competent mouse models. MRTFA/B mediated decrease in colonization was completely reversed upon immune cell depletion suggesting that the immune cells exploit MRTFA/B expression in cancer cells for cytotoxicity. Among various cancer cell parameters involved in immune cell activation, T- and NK cell activation most prominently correlated with MRTFA/B driven mechanical compliance of cancer cells. Mechanical compliance, also known as stiffness, of antigen presenting cells and synthetic substrates are well-known to activate T- and NK cells through biophysical and mechano-chemical signal transduction. As such, perturbing cancer cells’ stiffness downregulated the immune response and cytotoxicity. Thus, we termed this process mechanosurveillance. Our work on mechanosurveillance will help us understand how disseminated cancer cells are targeted by immunity and how they evade it at secondary organs. Importantly the concept of mechanosurveillance will help guide the use of existing therapeutics that alter tissue stiffness and immune boosting therapies to combat metastases. Citation Format: Maria Tello-Lafoz, Katja Srpan, Jing Hu, Yevgeniy Romin, Annalisa Calò, Katharine C. Hsu, Joan Massagué, Morgan Huse, Ekrem Emrah Er. Mechanosurveillance eliminates disseminated cancer cells by sensing their mechanical compliance [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT016.

Binding Dynamics of α-Actinin-4 in Dependence of Actin Cortex Tension

Mechanosensation of cells is an important prerequisite for cellular function, e.g., in the context of cell migration, tissue organization, and morphogenesis. An important mechanochemical transducer is the actin cytoskeleton. In fact, previous studies have shown that actin cross-linkers such as α-actinin-4 exhibit mechanosensitive properties in their binding dynamics to actin polymers. However, to date, a quantitative analysis of tension-dependent binding dynamics in live cells is lacking. Here, we present a, to our knowledge, new technique that allows us to quantitatively characterize the dependence of cross-linking lifetime of actin cross-linkers on mechanical tension in the actin cortex of live cells. We use an approach that combines parallel plate confinement of round cells, fluorescence recovery after photobleaching, and a mathematical mean-field model of cross-linker binding. We apply our approach to the actin cross-linker α-actinin-4 and show that the cross-linking time of α-actinin-4 homodimers increases approximately twofold within the cellular range of cortical mechanical tension, rendering α-actinin-4 a catch bond in physiological tension ranges.

Modeling strategy for dynamic-modal mechanophore in double-network hydrogel composites with self-growing and tailorable mechanical strength

Smart materials with self-growing and tailorable mechanical strength have wide-range potential applications in self-healing, self-repairing, self-assembly, artificial muscle, soft robots and intelligent devices. However, their working mechanisms and principles are not fully understood yet and mathematically and physical modeling is a huge challenge, as traditionally synthesized materials cannot self-grow and reconstruct themselves once formed or deformed. In this study, a phenomenological constitutive model was developed to investigate the working mechanisms of self-growing and tailorable mechanical strength in double-network (DN) hydrogel composites, induced by mechanochemical transduction of dynamic-modal mechanophore. An extended Maxwell model was firstly employed to characterize the mechanical unzipping of hydrogel composites, and then mechanochemically induced destruction and reconstruction processes of brittle network in the hydrogel composite were formulated. The enhanced mechanical strength of brittle network has been identified as the key driving force to generate self-growing and tailorable mechanical strength in the hydrogel composite. Finally, a stress-strain constitutive relationship was developed for the dynamic-modal mechanophorein the hydrogel composite. Simulation results obtained from the proposed model were compared with the experimental data, and a good agreement has been achieved. This study provides an effective strategy for modelling and exploring the working mechanism in the mechanoresponsive DN hydrogel composites with self-growing and tailorable mechanical strength.

Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress

The intermediate filament (IF) cytoskeleton has been proposed to regulate morphogenic processes by integrating the cell fate signaling machinery with mechanical cues. Signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) through the Notch pathway regulates arterial remodeling in response to changes in blood flow. Here we show that the IF-protein vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic forces. Vimentin is important for Notch transactivation by ECs and vimentin knockout mice (VimKO) display disrupted VSMC differentiation and adverse remodeling in aortic explants and in vivo. Shear stress increases Jagged1 levels and Notch activation in a vimentin-dependent manner. Shear stress induces phosphorylation of vimentin at serine 38 and phosphorylated vimentin interacts with Jagged1 and increases Notch activation potential. Reduced Jagged1-Notch transactivation strength disrupts lateral signal induction through the arterial wall leading to adverse remodeling. Taken together we demonstrate that vimentin forms a central part of a mechanochemical transduction pathway that regulates multilayer communication and structural homeostasis of the arterial wall.

The plasma membrane as a mechanochemical transducer.

Cells are constantly submitted to external mechanical stresses, which they must withstand and respond to. By forming a physical boundary between cells and their environment that is also a biochemical platform, the plasma membrane (PM) is a key interface mediating both cellular response to mechanical stimuli, and subsequent biochemical responses. Here, we review the role of the PM as a mechanosensing structure. We first analyse how the PM responds to mechanical stresses, and then discuss how this mechanical response triggers downstream biochemical responses. The molecular players involved in PM mechanochemical transduction include sensors of membrane unfolding, membrane tension, membrane curvature or membrane domain rearrangement. These sensors trigger signalling cascades fundamental both in healthy scenarios and in diseases such as cancer, which cells harness to maintain integrity, keep or restore homeostasis and adapt to their external environment.This article is part of a discussion meeting issue ‘Forces in cancer: interdisciplinary approaches in tumour mechanobiology’.

High-intensity focused ultrasound-induced mechanochemical transduction in synthetic elastomers

While study in the field of polymer mechanochemistry has yielded mechanophores that perform various chemical reactions in response to mechanical stimuli, there is not yet a triggering method compatible with biological systems. Applications such as using mechanoluminescence to generate localized photon flux in vivo for optogenetics would greatly benefit from such an approach. Here we introduce a method of triggering mechanophores by using high-intensity focused ultrasound (HIFU) as a remote energy source to drive the spatially and temporally resolved mechanical-to-chemical transduction of mechanoresponsive polymers. A HIFU setup capable of controlling the excitation pressure, spatial location, and duration of exposure is employed to activate mechanochemical reactions in a cross-linked elastomeric polymer in a noninvasive fashion. One reaction is the chromogenic isomerization of a naphthopyran mechanophore embedded in a polydimethylsiloxane (PDMS) network. Under HIFU irradiation evidence of the mechanochemical transduction is the observation of a reversible color change as expected for the isomerization. The elastomer exhibits this distinguishable color change at the focal spot, depending on ultrasonic exposure conditions. A second reaction is the demonstration that HIFU irradiation successfully triggers a luminescent dioxetane, resulting in localized generation of visible blue light at the focal spot. In contrast to conventional stimuli such as UV light, heat, and uniaxial compression/tension testing, HIFU irradiation provides spatiotemporal control of the mechanochemical activation through targeted but noninvasive ultrasonic energy deposition. Targeted, remote light generation is potentially useful in biomedical applications such as optogenetics where a light source is used to trigger a cellular response.

Mechanochemical transduction and hygroelectricity in periodically stretched rubber

This work reports the rubber electrostatic potential due to repeated strain as a function of time for periods as long as the lifetime of the sample. Rubber potential depends on two main contributions: hygroelectricity added to the mechanochemical reactions evidenced by spectroscopy and microscopy/microanalytical experiments. Hygroelectricity produces fast periodic charging in phase with rubber strain, while a slower charging process is assigned to the mechanochemical reaction products, in conjunction with residual hygroelectricity. This result explains the significant negative potential displayed by rubber over long periods in the absence of any external applied voltage. These findings may contribute to improving dielectric elastomer performance in many applications that are currently of great interest in robotics and energy harvesting. Additionally, electric potential real-time measurements show desirable features as a tool for real-time, non-contact detection of rubber structural change and fatigue.