Effects Of Mechanical Forces Research Articles

The Role of Biophysical Factors in Organ Development: Insights from Current Organoid Models.

Biophysical factors play a fundamental role in human embryonic development. Traditional in vitro models of organogenesis focused on the biochemical environment and did not consider the effects of mechanical forces on developing tissue. While most human tissue has a Young's modulus in the low kilopascal range, the standard cell culture substrate, plasma-treated polystyrene, has a Young's modulus of 3 gigapascals, making it 10,000-100,000 times stiffer than native tissues. Modern in vitro approaches attempt to recapitulate the biophysical niche of native organs and have yielded more clinically relevant models of human tissues. Since Clevers' conception of intestinal organoids in 2009, the field has expanded rapidly, generating stem-cell derived structures, which are transcriptionally similar to fetal tissues, for nearly every organ system in the human body. For this reason, we conjecture that organoids will make their first clinical impact in fetal regenerative medicine as the structures generated ex vivo will better match native fetal tissues. Moreover, autologously sourced transplanted tissues would be able to grow with the developing embryo in a dynamic, fetal environment. As organoid technologies evolve, the resultant tissues will approach the structure and function of adult human organs and may help bridge the gap between preclinical drug candidates and clinically approved therapeutics. In this review, we discuss roles of tissue stiffness, viscoelasticity, and shear forces in organ formation and disease development, suggesting that these physical parameters should be further integrated into organoid models to improve their physiological relevance and therapeutic applicability. It also points to the mechanotransductive Hippo-YAP/TAZ signaling pathway as a key player in the interplay between extracellular matrix stiffness, cellular mechanics, and biochemical pathways. We conclude by highlighting how frontiers in physics can be applied to biology, for example, how quantum entanglement may be applied to better predict spontaneous DNA mutations. In the future, contemporary physical theories may be leveraged to better understand seemingly stochastic events during organogenesis.

Mechanical Strain Induces and Increases Vesicular Release Monitored by Microfabricated Stretchable Electrodes

AbstractExocytosis involving the fusion of intracellular vesicles with cell membrane, is thought to be modulated by the mechanical cues in the microenvironment. Single‐cell electrochemistry can offer unique information about the quantification and kinetics of exocytotic events; however, the effects of mechanical force on vesicular release have been poorly explored. Herein, we developed a stretchable microelectrode with excellent electrochemical stability under mechanical deformation by microfabrication of functionalized poly(3,4‐ethylenedioxythiophene) conductive ink, which achieved real‐time quantitation of strain‐induced vesicular exocytosis from a single cell for the first time. We found that mechanical strain could cause calcium influx via the activation of Piezo1 channels in chromaffin cell, initiating the vesicular exocytosis process. Interestingly, mechanical strain increases the amount of catecholamines released by accelerating the opening and prolonging the closing of fusion pore during exocytosis. This work is expected to provide revealing insights into the regulatory effects of mechanical stimuli on vesicular exocytosis.

Mechanical Strain Induces and Increases Vesicular Release Monitored by Microfabricated Stretchable Electrodes.

Exocytosis involving the fusion of intracellular vesicles with cell membrane, is thought to be modulated by the mechanical cues in the microenvironment. Single-cell electrochemistry can offer unique information about the quantification and kinetics of exocytotic events; however, the effects of mechanical force on vesicular release have been poorly explored. Herein, we developed a stretchable microelectrode with excellent electrochemical stability under mechanical deformation by microfabrication of functionalized poly(3,4-ethylenedioxythiophene) conductive ink, which achieved real-time quantitation of strain-induced vesicular exocytosis from a single cell for the first time. We found that mechanical strain could cause calcium influx via the activation of Piezo1 channels in chromaffin cell, initiating the vesicular exocytosis process. Interestingly, mechanical strain increases the amount of catecholamines released by accelerating the opening and prolonging the closing of fusion pore during exocytosis. This work is expected to provide revealing insights into the regulatory effects of mechanical stimuli on vesicular exocytosis.

CircPRKD3/miR-6783-3p responds to mechanical force to facilitate the osteogenesis of stretched periodontal ligament stem cells

BackgroundThe mechanotransduction mechanisms by which cells regulate tissue remodeling are not fully deciphered. Circular RNAs (circRNAs) are crucial to various physiological processes, including cell cycle, differentiation, and polarization. However, the effects of mechanical force on circRNAs and the role of circRNAs in the mechanobiology of differentiation and remodeling in stretched periodontal ligament stem cells (PDLSCs) remain unclear. This article aims to explore the osteogenic function of mechanically sensitive circular RNA protein kinase D3 (circPRKD3) and elucidate its underlying mechanotransduction mechanism.Materials and methodsPDLSCs were elongated with 8% stretch at 0.5 Hz for 24 h using the Flexcell® FX-6000™ Tension System. CircPRKD3 was knockdown or overexpressed with lentiviral constructs or plasmids. The downstream molecules of circPRKD3 were predicted by bioinformatics analysis. The osteogenic effect of related molecules was evaluated by quantitative real-time PCR (qRT‐PCR) and western blot.ResultsMechanical force enhanced the osteogenesis of PDLSCs and increased the expression of circPRKD3. Knockdown of circPRKD3 hindered PDLSCs from osteogenesis under mechanical force, while overexpression of circPRKD3 promoted the early osteogenesis process of PDLSCs. With bioinformatics analysis and multiple software predictions, we identified hsa-miR-6783-3p could act as the sponge of circPRKD3 to indirectly regulate osteogenic differentiation of mechanically stimulated PDLSCs.ConclusionsOur results first suggested that both circPRKD3 and hsa-miR-6783-3p could enhance osteogenesis of stretched PDLSCs. Furthermore, hsa-miR-6783-3p could sponge circPRKD3 to indirectly regulate RUNX2 during the periodontal tissue remodeling process in orthodontic treatment.

The Role of the Piezo1 Mechanosensitive Channel in Heart Failure.

Mechanotransduction (MT) is inseparable from the pathobiology of heart failure (HF). However, the effects of mechanical forces on HF remain unclear. This review briefly describes how Piezo1 functions in HF-affected cells, including endothelial cells (ECs), cardiac fibroblasts (CFs), cardiomyocytes (CMs), and immune cells. Piezo1 is a mechanosensitive ion channel that has been extensively studied in recent years. Piezo1 responds to different mechanical forces and converts them into intracellular signals. The pathways that modulate the Piezo1 switch have also been briefly described. Experimental drugs that specifically activate Piezo1-like proteins, such as Yoda1, Jedi1, and Jedi2, are available for clinical studies to treat Piezo1-related diseases. The only mechanosensitive ion-channel-specific inhibitor available is GsMTx4, which can turn off Piezo1 by modulating the local membrane tension. Ultrasound waves can modulate Piezo1 switching in vitro with the assistance of microbubbles. This review provides new possible targets for heart failure therapy by exploring the cellular functions of Piezo1 that are involved in the progression of the disease. Modulation of Piezo1 activity may, therefore, effectively delay the progression of heart failure.

Mechanisms of mechanical force aggravating periodontitis: Areview.

Periodontitis is a widespread oral disease accompanied by uncontrolled inflammation-related tissue destruction. Periodontitis is related to various factors. Among them, occlusal trauma can aggravate the severity of periodontitis and has been attracting a great deal of attention. We systematically searched PubMed and Web of Science databases for related articles. Keywords for the search were "mechanical force", "mechanical stress", "occlusal trauma" and "periodontitis". This review focuses on the effect of mechanical forces on periodontitis and discusses the possible pivotal targets participating in this process. We elucidated and summarized 21 articles that reported on our topic. Several biological processes and pathways that participate in enhancing the inflammatory response to mechanical stress have been studied, including the regulation of osteogenesis and osteoclastic resorption balance, Yes-associated protein signaling, induction of collagen destruction, and regulation of programmed cell death. Mechanical force enhances the process of periodontitis in multiple ways. However, currently, no studies have further examined its underlying mechanism. Understanding the specific roles of mechanical forces may assist in the treatment of periodontitis with traumatic occlusal trauma.

Effects of mechanical forces on the formation of cutaneous wounds during skin expansion and emerging therapies for wound healing and scar prevention.

To update a possible role of cosmeceutical topic treatment to obtain a better scar. This is a preliminary supportive study. A total of 14 patients who went to the General Hospital of Mexico City, Mexico, between May and December 2020, for breast reconstruction were included in the current study. The biopsies were carried out to the scar area of the previous I° and II° surgery. The patients were thus divided into 2 groups: those who used Cicolea cream® as a treatment supplement and those who used only petrolatum. Collagen fibers arranged in a regular pattern in the group treated with Cicolea compared to dispersed collagen fibers in the group treated with pure petrolatum. Furthermore, the patients who presented hypertrophic or keloid scars secondary to mastectomy, developed after insertion of breast expanders an organized scarring process, with improvement of scar if treated with Cicolea. Based on our observations, it is possible to propose that the action of the polyphenols present in the different components of Cicolea® cream leads to a better evolution of the wound healing compared to the action of petrolatum composition.

Mechanical forces: The missing link between idiopathic pulmonary fibrosis and lung cancer

Patients with idiopathic pulmonary fibrosis (IPF) have a high risk of developing lung cancer compared with the general population. The morbidity of lung cancer in IPF patient ranges from 3% to 22%, and in some cases exceeds 50%, and these patients have a reduced survival time. However, the mechanisms through which IPF increases the morbidity and mortality in lung cancer remain unclear.By carefully analyzing the pathological features of these two diseases, we uncovered that, first, similar to IPF, lung carcinomas are more frequently found in the peripheral area of the lungs and, second, lung cancers tend to develop from the honeycomb areas in IPF. In accordance with the above pathological features, due to the spatial location, the peripheral areas of the lung experience a high stretch force because the average distance between adjacent alveolar cells in this area tends to be larger than that at the central lung when inflated; furthermore, the honeycomb areas, comprised of condensed fibrous tissue, are characterized by increased stiffness. Both of these pathological features of lung cancer and IPF are coincidentally related to abnormal mechanical forces (stretch and tissue stiffness). Therefore, we believe that the aberrant mechanical forces that are generated in the lung with IPF may contribute to the onset and progression of lung cancer.In this review, we discuss the possible effects of mechanical forces that are generated in IPF on the initiation and progression of lung cancer from the perspective of the hallmarks of cancer, including proliferation, metastasis, angiogenesis, cancer stem cells, immunology, epigenetics, and metabolism, so as to advance our understanding of the pathogenesis of IPF-related lung cancer and to harness these concepts for lung cancer mechanotherapies.

Effect of mechanical force on dissociation characteristics of cathode materials in spent lithium-ion batteries

With the rapid growth of the demand for lithium-ion batteries (LIBs), the treatment challenges of spent LIBs continue to increase. The dissociation characteristics of the electrode materials by impact crushing and shear crushing were studied. The liberation characteristics of each size particles and over crushing rule of aluminum (Al) foil were analyzed. The results show that both shear crushing and impact crushing can achieve effective liberation of electrode materials. The rapid liberation of cathode material can be achieved by shear crushing in 5 s, the particle size of the shear crushed products is mainly concentrated in + 2 mm and − 0.074 mm, and the degree of liberation increases to 69.29% at 40 s. Meanwhile, the liberation caused by impact crushing mainly occurs within 5–20 s, the liberation degree increases sharply from 1.36% to 49.51%, and final liberation degree can reach 62.68% with 40 s crushing. In addition, the over crushing of Al foil is inevitable in impact crushing and shear crushing, and the Al content of − 0.074 mm crushing products of shear crushing and impact crushing fluctuates within 2.4%− 3.5%. This study provides a feasible technical approach for the safe and environmentally friendly dissociation of electrode materials in spent LIBs.

Mechanical force-sensitive lncRNA SNHG8 inhibits osteogenic differentiation by regulating EZH2 in hPDLSCs

Long non-coding RNAs (lncRNAs) play important roles in various physiological and pathophysiological processes. However, the effect of mechanical force on lncRNAs and their role in osteogenic differentiation of periodontal ligament stem cells (PDLSCs) remains unclear. Here, we showed that the expression of lncRNA small nucleolar RNA host gene 8 (SNHG8) was steadily declined in PDLSCs under mechanical force. This reduced expression of SNHG8 promoted osteogenic differentiation of PDLSCs under mechanical force. After knockdown of SNHG8 by shRNA, the expression of osteogenic-related genes was increased in PDLSCs under mechanical force. Regarding the osteogenic regulatory ability of SNHG8, PDLSCs with lower level of expression of SNHG8 under osteogenic induction had a higher level of expression of osteogenic-related genes, higher level of alkaline phosphatase (ALP), and more mineralised nodules. In rats, the expression of the homolog, Smim4, was decreased during tooth movement. PDLSCs with lower expression of SNHG8 in nude mice also showed better bone formation ability during ectopic osteogenesis. Mechanistically, downregulation of SNHG8 led to lower expression of enhancer of zeste homolog 2 (EZH2), which negatively regulated the osteogenic differentiation of PDLSCs. Our study indicated that the mechanically sensitive lncRNA SNHG8 regulates the osteogenic differentiation of PDLSCs through epigenetic pathways. Our results provided solid evidence for the regulation of cell differentiation by non-coding genes, which might serve as potential therapeutic targets for bone reconstruction or periodontal tissue regeneration during orthodontics.

Recent Advances and Emerging Challenges in the Molecular Modeling of Mechanobiological Processes.

Many biological processes result from the effect of mechanical forces on macromolecular structures and on their interactions. In particular, the cell shape, motion, and differentiation directly depend on mechanical stimuli from the extracellular matrix or from neighboring cells. The development of experimental techniques that can measure and characterize the tiny forces acting at the cellular scale and down to the single-molecule, biomolecular level has enabled access to unprecedented details about the involved mechanisms. However, because the experimental observables often do not provide a direct atomistic picture of the corresponding phenomena, particle-based simulations performed at various scales are instrumental in complementing these experiments and in providing a molecular interpretation. Here, we will review the recent key achievements in the field, and we will highlight and discuss the many technical challenges these simulations are facing, as well as suggest future directions for improvement.

Optimization of Mechanical Tissue Dissociation Using an Integrated Microfluidic Device for Improved Generation of Single Cells Following Digestion.

The dissociation of tissue and cell aggregates into single cells is of high interest for single cell analysis studies, primary cultures, tissue engineering, and regenerative medicine. However, current methods are slow, poorly controlled, variable, and can introduce artifacts. We previously developed a microfluidic device that contains two separate dissociation modules, a branching channel array and nylon mesh filters, which was used as a polishing step after tissue processing with a microfluidic digestion device. Here, we employed the integrated disaggregation and filtration (IDF) device as a standalone method with both cell aggregates and traditionally digested tissue to perform a well-controlled and detailed study into the effect of mechanical forces on dissociation, including modulation of flow rate, device pass number, and even the mechanism. Using a strongly cohesive cell aggregate model, we found that single cell recovery was highest using flow rates exceeding 40 ml/min and multiple passes through the filter module, either with or without the channel module. For minced and digested kidney tissue, recovery of diverse cell types was maximal using multiple passes through the channel module and only a single pass through the filter module. Notably, we found that epithelial cell recovery from the optimized IDF device alone exceeded our previous efforts, and this result was maintained after reducing digestion time to 20 min. However, endothelial cells and leukocytes still required extended digestion time for maximal recover. These findings highlight the significance of parameter optimization to achieve the highest cell yield and viability based on tissue sample size, extracellular matrix content, and strength of cell-cell interactions.

Re-thinking benign inflammation of the lactating breast: A mechanobiological model.

Despite the known benefits of breastfeeding for both infant and mother, clinical support for problems such as inflammation of the lactating breast remains a research frontier. Breast pain associated with inflammation is a common reason for premature weaning. Multiple diagnoses are used for inflammatory conditions of the lactating breast, such as engorgement, blocked ducts, phlegmon, mammary candidiasis, subacute mastitis, mastitis and white spots, which lack agreed or evidence-based aetiology, definitions and treatment. This is the first in a series of three articles which review the research literature concerning benign lactation–related breast inflammation. This article investigates aetiological models. A complex systems perspective is applied to analyse heterogeneous and interdisciplinary evidence elucidating the functional anatomy and physiology of the lactating breast; the mammary immune system, including the human milk microbiome and cellular composition; the effects of mechanical forces during lactation; and the interactions between these. This analysis gives rise to a mechanobiological model of breast inflammation, in which very high intra-alveolar and intra-ductal pressures are hypothesized to strain or rupture the tight junctions between lactocytes and ductal epithelial cells, triggering inflammatory cascades and capillary dilation. Resultant elevation of stromal tension exerts pressure on lactiferous ducts, worsening intraluminal backpressure. Rising leucocyte and epithelial cell counts in the milk and alterations in the milk microbiome are signs that the mammary immune system is recruiting mechanisms to downregulate inflammatory feedback loops. From a complex systems perspective, the key mechanism for the prevention or treatment of breast inflammation is avoidance of excessively high intra-alveolar and intra-ductal pressures, which prevents a critical mass of mechanical strain and rupture of the tight junctions between lactocytes and ductal epithelial cells.

Mechanical Deformation of Microtubules on a Two-Dimensional Elastic Medium.

Microtubule, the most rigid filamentous protein in cytoskeleton, plays significant roles in cellular mechano-transduction and mechano-regulation of cellular functions. In cells, the mechanical stress serves as a prevalent stimulus to frequently cause deformation of the microtubules participating in various cellular events. While the experimental and simulation-based approaches have confirmed the role of mechanical stress to tune mechanical properties of microtubule. Yet, the effect of mechanical force on the structural stability and the mechanism of microtubule deformation have remained obscure. Here, we describe the mechanical stress-induced deformation of microtubules using a custom-made mechanical device. We designed the device in a way which allows the microtubules to undergo deformation as response to the applied stress while attached on a two-dimensional elastic substrate through interaction with microtubule-associated motor protein, kinesin. We provide here the method to cause controlled bucking or fragmentation of microtubules by applying compressive or tensile stress on the microtubules, respectively. Such study is crucial to understand the mechanism of deformation in microtubules in cellular environment and their consequences in physiological activities.

Development of a multianalyte electrochemical sensor for depression biomarkers based on a waste of the steel industry for a sustainable and one-step electrode modification

This study aimed to reuse waste from the steel industry as a sustainable electrode modifier material in a simple and one-step modification approach for the electrochemical monitoring of the neurotransmitters dopamine (DA), serotonin (5-HT), and tryptophan (TRP), biomarkers related to depression diagnostics. Iron oxides constitute the mill scale (MS), composed of wüstite (FeO), magnetite (Fe3O4), and hematite (Fe2O3). This material was generated from the hot rolling process, and later it was ball milled using a high-energy shaker mill. X-ray powder diffraction (XRPD) was used to investigate the structural and microstructural evolution of the MS with milling time. Effects of mechanical force on solids include a reduction in the crystalline size by controlling the milling time, with consequently peculiar properties and chemical reactivity. The magnetic measurements show superparamagnetic characteristics in the samples, governed mainly by small crystallites of iron oxides. Two samples (milled for 2 and 30 min) were applied in the construction of new sensors. The MS carbon paste electrode (MS/CPE) with 30 min-sample allowed more defined oxidation peaks through a simple and one-step electrode modification step. Selectivity for the detection of the multianalytes was achieved after the modification of the carbonaceous substrate with the mixture of metal oxides with magnetic properties; overlapping peaks were observed for DA and 5-HT using the unmodified electrode. Under optimum conditions of square wave voltammetry, a linear relationship was observed between the peak current intensities and the concentrations of the analytes. Linear responses were obtained for DA, 5-HT, and TRP in the 0.49–21, 0.49–13.6, and 2.9–25 µmol L−1 concentration ranges, with detection limits of 0.21, 0.13, and 2.18 µmol L−1, respectively. The reuse of waste as a sustainable electrode modifier material for clinical and biomedical applications, with improved selectivity and sensibility, is hereby present.

Dynamic stability evolution of viscoelastic dielectric elastomers with continuously varying electromechanical parameters

Under an actuation of alternating voltage, dielectric elastomer (DE) based actuators are widely utilized as dynamic devices and robots, accompanying with the possible dynamic instabilities. In this article, based on a deduced dynamics model, we develop an analysis on the dynamic performance and stability evolution of a viscoelastic DE, using the continuous method. Effects of mechanical force and applied voltage are considered, respectively. The spectrum of dynamic deformation with the relevant parameters is presented. The evolution of phase paths is simultaneously provided to detect the dynamic stability of the viscoelastic DE.

Role of mechanosignaling on pathology of varicose vein.

Varicose veins are the most common vascular disease in humans. Veins have valves that help the blood return gradually to the heart without leaking blood. When these valves become weak, blood and fluid collect and pool by pressing against the walls of the veins, causing varicose veins. In the cardiovascular system, mechanical forces are important determinants of vascular homeostasis and pathological processes. Blood vessels are constantly exposed to a variety of hemodynamic forces, including shear stress and environmental strains caused by the blood flow. In varicose veins within the leg, venous blood pressure rises in the vein of the lower extremities due to prolonged standing, creating a peripheral tension in the vessel wall thereby causing mechanical stimulation of endothelial cells and vascular smooth muscle. Studies have shown that long-term increased exposure to vascular wall tension is associated with the overexpression of HIF-1α and HIF-2α and increased levels of MMP-2 and MMP-9, thereby reducing venous contraction and progressive venous dilatation, which is involved in the development of varicose veins. Following the expression of metalloproteinase, the expression of type 1 collagen increases, and the amount of type 3 collagen decreases. Therefore, collagen imbalance will cause the varicose veins to not stretch. Loss of structural proteins (type 3 collagen and elastin) in the vessel wall causes the loss of the biophysical properties of the varicose vein wall. This review article tries to elaborate on the effect of mechanical forces and sensors of these forces on the vascular wall in creating the mechanism of mechanosignaling, as well as the role of the onset of molecular signaling cascades in the pathology of varicose veins.

Preparation of effective carvacrol/attapulgite hybrid antibacterial materials by mechanical milling

A green antibacterial material was successfully prepared using natural attapulgite and carvacrol by a facile mechanical milling. The stable hybrid nanocomposites were formed after the zeolitic water molecules of attapulgite was substituted by the carvacrol molecules under the effect of mechanical force. It was found that the 30 wt% of carvacrol added amount and the 30 min of grinding time were the appropriate parameters for preparation a stable hybrid. Furthermore, the fast release behavior of carvacrol molecules provided good antibacterial property for the obtained antibacterial material, and the minimum inhibitory concentration values against both Staphylococci aureus and Escherichia coli were 2.0 mg/mL. Therefore, it is expected to develop a facile and promising strategy for preparation green antibacterial material to replace the synthetic antibiotic used in animal feeding.

How mechanical forces can modulate the metal affinity and selectivity of metal binding sites in proteins.

Mechanical forces play a key role in essential biological processes including cell growth, division, deformation, adhesion, migration and intra-cell interactions. The effect of mechanical forces in modulating the structure and properties of metal-occupied protein binding sites has not been fully understood. Here, by employing a combination of density functional theory (DFT) calculations and polarizable continuum model (PCM) computations applied on model metal-loaded EF-hand binding sites, we shed light on the intimate mechanism of the Mg2+/Ca2+ competition impacted by the application of mechanical stimuli. Applying mechanical force with a specific directionality and magnitude may shift the balance between the competing metal cations in favor of a given contestant depending on the composition and strength of the coordinative bonds and robustness of the metal binding site. Furthermore, the calculations help to determine the range of mechanical rupture forces typical for these structures: these range from 0.4 to 1.5 nN depending on the nature of the metal and amino acid residue. This positions the strength of the Mg2+-O and Ca2+-O coordinative bonds between that of typical covalent and hydrogen bonds. The bonds between the metal cation and the charged amino acid residue rupture at higher forces (∼1.2-1.5 nN) relative to those of their metal-noncharged counterparts which dissociate at ∼0.2-0.4 nN.

Mathematical analysis the effect of traffic bump shocking and layer position on the physical properties of Strawberry fruit (Fragaria x ananassa) during transportation

Strawberry is known as a perishable fruit, it is very easy to be damaged as the effect of mechanical force, and this is one of the main problem in postharvest of this fruit. In Indonesia, it is often encountered a traffic bump across the road, this may create a shocking force that may affect the damage of the fruit during transportation. This research was intended to find out the effect of duration of shocking and layer position in the packing box on the physical properties of strawberry fruit. Application of shocking force was done using a special shocking apparatus to the strawberry samples inside wood package box which was arranged in three layers for a certain determined time. After shocking process the sample were then stored at room temperature and continuously monitored. It was found that both the duration of shocking and layer position in the box were significantly affect some of physical properties of the fruit, such as respiration rate, weight loss, brix content, firmness, and lightness of the fruit. The rate of change of physical properties of the fruit could be described appropriately using kinetics model of the zero or first order.