A definitive understanding of the interplay between protein binding/migration and membrane curvature evolution is emerging but needs further study. The mechanisms defining such phenomena are critical to intracellular transport and trafficking of proteins. Among trafficking modalities, exosomes have drawn attention in cancer research as these nano-sized naturally occurring vehicles are implicated in intercellular communication in the tumor microenvironment, suppressing anti-tumor immunity and preparing the metastatic niche for progression. A significant question in the field is how the release and composition of tumor exosomes are regulated. In this perspective article, we explore how physical factors such as geometry and tissue mechanics regulate cell cortical tension to influence exosome production by co-opting the biophysics as well as the signaling dynamics of intracellular trafficking pathways and how these exosomes contribute to the suppression of anti-tumor immunity and promote metastasis. We describe a multiscale modeling approach whose impact goes beyond the fundamental investigation of specific cellular processes toward actual clinical translation. Exosomal mechanisms are critical to developing and approving liquid biopsy technologies, poised to transform future non-invasive, longitudinal profiling of evolving tumors and resistance to cancer therapies to bring us one step closer to the promise of personalized medicine.

Multiplex ultrasensitive detection of low abundance proteins remains a significant challenge in clinical applications, necessitating the development of innovative solutions. The integration of bead-based microfluidic chip platforms with their efficient target capture and separation capabilities, along with the advantages of miniaturization and low reagent consumption, holds great promise for building an integrated point-of-care testing (POCT) system that enables seamless sample input-result output. This review presents a comprehensive overview of recent advancements in bead-based microfluidic platforms for multiplex and ultrasensitive immunoassays, along with their potential applications in clinical diagnosis and treatment, which is organized into four sections: encoding techniques, the role of microfluidic platforms, applications, and future prospects.

Distal metastasis is the main cause of clinical treatment failure in patients with colon cancer. It is now known that the invasion and metastasis of cancer cells is precisely regulated by chemical and physical factors in vivo. However, the role of extracellular matrix (ECM) stiffness in colon cancer cell (CCCs) invasion and metastasis remains unclear. Here, bioinformatical analysis suggested that a high expression level of yes associated protein 1 (YAP1) was significantly associated with metastasis and poor prognosis in colon cancer patients. We further investigated the effects of polyacrylamide hydrogels with different stiffnesses (3, 20, and 38 ​kPa), which were simulated as ECM, on the mechanophenotype (F-actin cytoskeleton organization, electrophoretic rate, membrane fluidity, and Young's modulus) of CCCs. The results showed that a stiffer ECM could induce the maturation of focal adhesions and formation of stress fibers in CCCs, regulate their mechanophenotypes, and promote cell motility. We also demonstrated that the expression levels of YAP1 and paxillin were positively correlated in patients with colon cancer. YAP1 knockdown reduces paxillin clustering and cell motility and alters the cellular mechanophenotypes of CCCs. This is of great significance for an in-depth understanding of the invasion and metastatic mechanisms of colon cancer and for the optimization of clinical therapy from the perspective of mechanobiology.

Given the tremendous increase in the risks of cartilage defects in the sports and aging population, current treatments are limited, and new repair strategies are needed. Cartilage tissue engineering (CTE) is a promising approach to handle this burden and several fabrication technologies and biomaterials have been developed these years. The extracellular matrix (ECM) of cartilage consists of a tissue-specific 3D microenvironment with excellent biomechanical and biochemical properties, which regulates cell proliferation, adhesion, migration, and differentiation, thus attracting a great deal of attention to the rapid development of CTE based on ECM components. New generations of biomaterials are being developed rapidly for use as scaffolds to mimic the natural ECM environment. In this review, we discuss such CTE scaffolds based on ECM-derived biomaterials by reviewing the biomaterials for CTE, the applications in different scaffolds and their processing approaches, as well as the current clinical applications of those ECM-based CTE scaffolds.

Mechanobiology is an interdisciplinary discipline combining biology, engineering, chemistry, physics, and medicine. Mechanobiology research comprehensively discusses, the role of mechanical factors in various life processes and the occurrence and development of associated and diseases at the whole organism, organ, cell, protein and gene levels. The cellular and molecular mechanisms of mechanical signal transduction and response are elucidated, in addition to the discovery of novel biomarkers and potential drug targets, which are mechanosensitive molecules. This paper reviews the development of mechanobiology research in China since the new century, while focusing on the research achievements of Chinese scientists in the field of mechanobiology over the last three years, including cardiovascular, bone and joint, tumor, cellular, and molecular mechanobiology. Meanwhile, it has been suggested that in the future, mechanobiology research should include are indicated detailed studies on the mechanobiological mechanism of diseases at the cellular and molecular levels firstly, so that the newly discovered biomarkers or potential targets can gradually achieve clinical transformation. Second, future research should strengthen the qualitative and quantitative combination of biological experiments and mechanical and mathematical modeling analyses, especially at cellular, subcellular and molecular scales. Mechanobiological studies are of great theoretical and practical significance for our understanding of the mechanical mechanisms and natural laws of growth and senility of the human body, expounding pathological mechanisms of diseases, and researching and developing new medicines and technologies to promote biomedical and clinical research for human health.

Radiation therapy is one of the most effective therapeutic modalities for tumors. The changes in matrix stiffness of tumors and associated tissues are important consequences of side effects after radiotherapy. They are documented to induce the radio-resistance of cancer cells and promote the recurrence and metastasis of tumors, resulting in poor patient prognosis. Identifying the relationship between radiation and matrix stiffness is beneficial to optimize clinical treatment schemes and ultimately improve the patient prognosis. Herein, this review includes knowledge regarding the specific cellular, molecular processes and relevant clinical factors of the changes in matrix stiffness of tumors or associated tissues induced by radiation. The effects of altered matrix stiffness on the behaviors of cancer cells and associated normal cells are further detailed. It also reviews literatures to elucidate the mechanical signal transduction mechanism in radiotherapy and proposes some strategies to enhance the efficacy of radiotherapy based on matrix mechanics.

Among the various families of G protein-couple receptors (GPCR), the adhesion family of GPCRs is specialized by its expansive extracellular region, which facilitates the recruitment of various ligands. Previous hypothesis proposed that aGPCRs are activated by mechanical force, wherein a Stachel peptide is liberated from the GPCR autoproteolysis-inducing (GAIN) domain and subsequently binds to the transmembrane domain (7TM) upon activation. In this review, we summarize recent advancements in structural studies of aGPCRs, unveiling a conserved structural change of the Stachel peptide from the GAIN domain-embedded β-strand conformation to the 7TM-loaded α-helical conformation. Notably, using single-molecule studies, we directly observed the unfolding of GAIN domain and the release of Stachel peptide under physiological level of force, precisely supporting the mechanosensing mechanism for aGPCRs. We observed that the current complex structures of aGPCR adhesion domains with their respective ligands share a common pattern with the C-termini of each binding partner extending in opposite directions, suggesting a similar shearing stretch geometry for these aGPCRs to transmit the mechanical force generated in the circulating environment to the GAIN domain for its unfolding. Outstanding questions, including the relative orientations and interactions between 7TM and its preceding GAIN and adhesion domains of different aGPCRs, may require further structural and mechanical studies at the full-length receptor scale or cell-based level. Our analysis extends the current view of aGPCR structural organization and activation and offers valuable insights for the development of mechanosensor based on aGPCRs or discovery of mechanotherapy against aGPCRs.

Micropatterning is a sophisticated technique that precisely manipulates the spatial distribution of cell adhesion proteins on various substrates across multiple scales. This precise control over adhesive regions facilitates the manipulation of architectures and physical constraints for single or multiple cells. Furthermore, it allows for an in-depth analysis of how chemical and physical properties influence cellular functionality. In this comprehensive review, we explore the current understanding of the impact of geometrical confinement on cellular functions across various dimensions, emphasizing the benefits of micropatterning in addressing fundamental biological queries. We advocate that utilizing directed self-organization via physical confinement and morphogen gradients on micropatterned surfaces represents an innovative approach to generating functional tissue and controlling morphogenesis in vitro. Integrating this technique with cutting-edge technologies, micropatterning presents a significant potential to bridge a crucial knowledge gap in understanding core biological processes.

Covalent organic frameworks (COFs) are emerging crystalline porous materials composed of covalently linked and periodically arranged organic molecules, which exhibit mechanical properties mediated by structural diversity. Meanwhile, the tunable mechanical properties of COFs have been widely applied in drug delivery and cancer therapy. Herein, we first summarize the regulation strategies of COFs with different mechanical strengths, such as structural dimensions, pore sizes, and host-guest interaction forces. Then, the remarkable achievements of COFs with different mechanical properties in drug delivery and cancer therapy in recent years are introduced. Finally, the mechanical strength regulation of COFs and the remaining challenges for biomedical applications are presented. This review provides a more comprehensive understanding of the application of COFs systems with tunable mechanical properties in the field of biomedicine, and promotes the development of interdisciplinary research between COFs materials and nanomedicine.

The gastrointestinal (GI) tract's primary role is food digestion, relying on coordinated fluid secretion and bowel movements triggered by mechanosensation. Enteroendocrine cells (EECs) are specialized mechanosensitive cells that convert mechanical forces into electrochemical signals, culminating in serotonin release to regulate GI motility. Despite their pivotal role, knowledge of EEC mechanical properties has been lacking due to their rarity and limited accessibility. In this brief report, we present the first single-cell mechanical characterization of human ECCs isolated from healthy intestinal organoids. Using single-cell optical tweezers, we measured EEC stiffness profiles at the physiological temperature and investigated changes following tryptophan metabolism inhibition. Our findings not only shed light on EEC mechanics but also highlight the potential of adult stem cell-derived organoids for studying these elusive cells.

Mechanical stimuli are known to play critical roles in mediating tissue repair and regeneration. Recently, this knowledge has led to a paradigm shift toward proactive programming of biological functionalities of biomaterials by leveraging mechanics-geometry-biofunction relationships, which are beginning to shape the newly emerging field of mechanobiomaterials. To profile this emerging field, this article aims to elucidate the fundamental principles in modulating biological responses with material-tissue mechanical interactions, illustrate recent findings on the relationships between material properties and biological responses, discuss the importance of mathematical/physical models and numerical simulations in optimizing material properties and geometry, and outline design strategies for mechanobiomaterials and their potential for tissue repair and regeneration. Given that the field of mechanobiomaterials is still in its infancy, this article also discusses open questions and challenges that need to be addressed.

Bone and immune cells typically inhabit the same microenvironment and engage in mutual interactions to collectively execute the functions of the “osteoimmune system.” Establishing a harmonized and enduring osteoimmune system significantly enhances bone regeneration, necessitating the maintenance of bone and immune homeostasis. Recently, mechanobiology has garnered increasing interest in bone tissue engineering, with matrix stiffness emerging as a crucial parameter that has been extensively investigated. The effect of matrix stiffness on bone homeostasis remains relatively clear. Soft substrates tend to significantly affect the chondrogenic differentiation of bone marrow mesenchymal stem cells, whereas increasing matrix stiffness is advantageous for osteogenic differentiation. Increased stiffness increases osteoclast differentiation and activity. Additionally, there is increasing emphasis on immune homeostasis, which necessitates dynamic communication between immune cells. Immune cells are crucial in initiating bone regeneration and driving early inflammatory responses. Functional changes induced by matrix stiffness are pivotal for determining the outcomes of engineered tissue mimics. However, inconsistent and incomparable findings regarding the responses of different immune cells to matrix stiffness can be perplexing owing to variations in the stiffness range, measurement methods, and other factors. Therefore, this study aimed to provide a comprehensive review of the specific effects of matrix stiffness on diverse immune cells, with a particular focus on its implications for bone regeneration, which would offer theoretical insights into the treatment of large segmental bony defects and assist in the clinical development of new engineering strategies.

Bone adapts to mechanical loading by changing its shape and mass. Osteocytes, as major mechanosensors, are critical for bone modeling/remodeling in response to mechanical stimuli. Intracellular calcium oscillation is one of the early responses in osteocytes, and this further facilitates bone cell communication through released biochemical signals. Our previous study has found that mechanically induced calcium oscillations in osteocytes enhance the release of extracellular vesicles (EVs), and those released EVs can elevate bone formation activity. However, the mechanism of mechanically stimulated EVs’ regulation of bone formation and resorption is still unclear. Here, using in vitro studies, we exposed OCY454 cells, with relatively high sclerostin expression, to steady fluid flow (SFF) and characterized the functions of rapidly released EVs in osteoblast and osteoclast regulation. Our study demonstrates that SFF stimulates intracellular calcium response in OCY454 cells and further induces sclerostin, osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL) inside or outside EVs to regulate osteoblast and osteoclast activities. This load-induced protein and EVs release is load-duration dependent. Moreover, stimulated osteocytes rapidly regulate osteoclast maturation through EVs capsulated RANKL. In contrast, other regulating proteins, OPG, and sclerostin, are mainly released directly into the medium without EV capsulation.

A recent study published in Science Advances¹ showed the influence of Yap on notochord formation and NT (neural tube) patterning in vertebrate embryonic development, and conducted an in-depth study from the perspective of biomechanical signal mechanotransduction. In addition, this study also explored the possible complex interaction between mechanical signals and gene expression. Together, this study provides new insights into the development mechanism of early vertebrate embryos.

Mechanobiology is the study of how mechanical forces affect biological systems, including cells and tissues. The two-photon lithography (TPL) as a powerful 3D printing technique allows the creation of 3D complex structures at a microscopic scale. By applying the TPL into the mechanobiology studies, researchers could create precise structures that mimic the mechanical properties of biological system, allowing for the study of mechanobiological processes in a controlled environment. This implies applications in tissue engineering, drug screening, and fundamental research into the mechanisms of mechanobiology. In this review, we highlight recent advances in TPL for mechanobiology studies, as well as the potential future directions for this promising field.

A recent study published in Cell Stem Cell [1] showed that matrix stiffness critically regulates hematopoietic stem cell (HSC) niche, and successfully engineered a soft bone marrow (BM) organoid to maintain and rejuvenate HSCs ex vivo. In addition, BM stiffening was also identified as a novel aging hallmark of the hematopoietic system. Together, these important findings implicate matrix stiffness as a fundamental biomechanical factor governing cell fate determination and aging of tissue-specific stem cells.

Cellular behaviors such as migration, spreading, and differentiation arise from the interplay of cell-matrix interactions. The comprehension of this interplay has been advanced by the motor-clutch model, a theoretical framework that captures the binding-unbinding kinetics of mechanosensitive membrane-bound proteins involved in mechanochemical signaling, such as integrins. Since its introduction and subsequent development as a computational tool, the motor clutch model has been instrumental in elucidating the impact of biophysical factors on cellular mechanobiology. This review aims to provide a comprehensive overview of recent advances in the motor-clutch modeling framework, its role in elucidating the relationships between mechanical forces and cellular processes, and its potential applications in mechanomedicine.

Neural stem cells in vivo receive information from biochemical and biophysical cues of their microenvironment that affect their survival, proliferation and differentiation toward specific lineages. Recapitulation of these conditions in vitro is better achieved in 3D cell cultures. Especially the cells that grow in scaffold-dependent 3D cultures establish more complex cell-cell and cell-material interactions enabling the study of the various signaling pathways. The biochemical signaling from growth factors and hormones has been extensively studied over the years. More recently cumulative evidence demonstrates that cell sensing and response to mechanical stimuli is mediated through mechanotransduction pathways. Although individual signaling pathways activated by biochemical or mechanical cues in cells are well-studied, synergistic or antagonistic effects among them need further research to be fully understood. The understanding of the alteration of the cell behavior due to a microenvironmental cues would be greatly enhanced by the study of key elements that lie in the convergence of biochemical and mechanical pathways. Here we analyzed the effect of the substrate topography on the nerve growth factor (NGF) induced differentiation of PC12 cells. Our results showed that the topography interferes with NGF-induced neuronal differentiation and this is reflected in the reduced activation of the integrin-mediated mechanotransduction.

Type 1 hypersensitivity involves an exaggerated immune reaction triggered by allergen exposure, leading to rapid release of inflammatory mediators. Meanwhile, mechanobiology explores how physical forces influence cellular processes, and recent research underscores its relevance in allergic reactions. This review provides a concise overview of Type 1 hypersensitivity, highlighting the pivotal role of mast cells and immunoglobulin E (IgE) antibodies in orchestrating allergic reactions. Recognizing the dynamic nature of cellular responses in allergies, this study subsequently delves into the emerging field of mechanobiology and its significance in understanding the mechanical forces governing immune cell behavior. Furthermore, molecular forces during mast cell activation and degranulation are explored, elucidating the mechanical aspects of IgE binding and cytoskeletal rearrangements. Next, we discuss the intricate interplay between immune cells and the extracellular matrix, emphasizing the impact of matrix stiffness on cellular responses. Additionally, we examine key mechanosensitive signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway, Rho guanosine triphosphatase (GTPase) and integrin-mediated focal adhesion signaling, shedding light on their contributions to hypersensitivity reactions. This interplay of mechanobiology and Type 1 hypersensitivity provides insights into potential therapeutic targets and biomarkers, paving the way for better clinical management of Type 1 hypersensitivity reactions.

Mechanical models offer a quantitative framework for understanding scientific problems, predicting novel phenomena, and guiding experimental designs. Over the past few decades, the emerging field of cellular mechanobiology has greatly benefited from the substantial contributions of new theoretical tools grounded in mechanical models. Within the expansive realm of mechanobiology, the investigation of how cells sense and respond to their microenvironment has become a prominent research focus. There is a growing acknowledgment that cells mechanically interact with their external surroundings through an integrated machinery encompassing the cell membrane, cytoskeleton, and nucleus. This review provides a comprehensive overview of mechanical models addressing three pivotal components crucial for force transmission within cells, extending from mechanosensitive receptors on the cell membrane to the actomyosin cytoskeleton and ultimately to the nucleus. We present the existing numerical relationships that form the basis for understanding the structures, mechanical properties, and functions of these components. Additionally, we underscore the significance of developing mechanical models in advancing cellular mechanobiology and propose potential directions for the evolution of these models.

Accumulating evidence strongly suggests that cell chirality plays a pivotal role in driving left-right (LR) symmetry breaking, a widespread phenomenon in living organisms. Whole embryos and excised organs have historically been employed to investigate LR symmetry breaking and have yielded exciting findings. In recent years, in vitro engineered platforms have emerged as powerful tools to reveal cellular chiral biases and led to uncovering molecular and biophysical insights into chiral morphogenesis, including the significant role of the actin cytoskeleton. Establishing a link between observed in vivo tissue chiral morphogenesis and the determined chiral bias of cells in vitro has become increasingly important. In this regard, computational mathematical models hold immense value as they can explain and predict tissue morphogenic behavior based on the chiral biases of individual cells. Here, we present the formulations and discoveries achieved using various computational models spanning different biological scales, from the molecular and cellular levels to tissue and organ levels. Furthermore, we offer insights into future directions and the role of such models in advancing the study of asymmetric cellular mechanobiology.

Mechanical force often has clear effects on tissue niche remodeling. However, the changes in stem cells and their roles in clinical treatment remain unclear. Orthodontic tooth movement (OTM), the primary approach to treating dental-maxillofacial malformations, involves reconstruction of periodontal tissue. Herein, lineage tracing revealed that Col1⁺ cells are distributed in the periodontal ligament and are sensitive to mechanical forces during OTM. Immunofluorescence analysis confirms that Col1⁺ cells can differentiate into osteoblasts and fibroblasts under orthodontic force. Moreover, Col1⁺ cells may be involved in angiogenesis. These findings suggest that Col1⁺ cells play a crucial role in the mechanical remodeling of periodontal tissue during OTM and may serve as a valuable tool for studying the mechanism of OTM.

A recent study published in Nature Communications introduces a novel mechanically-mediated reaction involving ZnO nanoparticles that autonomously react, forming Zn/S mineral microrods within an organogel. These microrods selectively reinforce synthetic polymer composites, offering a unique approach to material strengthening. The method provides a distinctive pathway for mechanical mineralization in composite materials.

As local regions in the tumor outstrip their oxygen supply, hypoxia can develop, affecting not only the cancer cells, but also other cells in the microenvironment, including cancer associated fibroblasts (CAFs). Hypoxia is also not necessarily stable over time, and can fluctuate or oscillate. Hypoxia Inducible Factor-1 is the master regulator of cellular response to hypoxia, and can also exhibit oscillations in its activity. To understand how stable, and fluctuating hypoxia influence breast CAFs, we measured changes in gene expression in CAFs in normoxia, hypoxia, and oscillatory hypoxia, as well as measured change in their capacity to resist, or assist breast cancer invasion. We show that hypoxia has a profound effect on breast CAFs causing activation of key pathways associated with fibroblast activation, but reduce myofibroblast activation and traction force generation. We also found that oscillatory hypoxia, while expectedly resulted in a “sub-hypoxic” response in gene expression, it resulted in specific activation of pathways associated with actin polymerization and actomyosin maturation. Using traction force microscopy, and a nanopatterned stromal invasion assay, we show that oscillatory hypoxia increases contractile force generation vs stable hypoxia, and increases heterogeneity in force generation response, while also additively enhancing invasibility of CAFs to MDA-MB-231 invasion. Our data show that stable and unstable hypoxia can regulate many mechnobiological characteristics of CAFs, and can contribute to transformation of CAFs to assist cancer dissemination and onset of metastasis.

Anisodamine and anisodine have been used in treatment of septic shock, but the underlying mechanism are still unclear. In the present study, the effects of anisodamine hydrobromide (Ani HBr) and anisodine hydrobromide (AT3) on the mesenteric hemodynamics in septic shock rats were performed. The rat model of septic shock was established by intravenous tail vein injection of 5 ​mg/kg lipopolysaccharide (LPS), and then treated with Ani HBr, AT3, racemic anisodine (Race Ani) or atropine (ATP). The mesenteric microcirculation was observed using the intravital microscopy. Then, the flow pattern of the microcirculation, leukocytes dynamics and the plasma levels of cytokines tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) were analyzed. Compared with the control rats, reduced mean arterial pressure, increased heart rate, and slow microcirculatory blood flow was found in septic shock rats. The main abnormal flow patterns were intermittent and reciprocating motions. Ani HBr, AT3, Race Ani and ATP elevated the mean arterial pressure and reduced heart rate in septic shock rats. Ani HBr and AT3 not only restored the velocity of microcirculatory blood flow and improved the microcirculatory flow patterns, but also suppressed the LPS-induced leukocyte-endothelium interaction and releases of TNF-α and IL-6. Therefore, Ani HBr and AT3 improves hemodynamics in both macro- and microcirculation, which provide a novel experimental basis for exploring the mechanobiological mechanisms in septic shock.

Mechanotransduction, the transfer of mechanical stimuli into various biological signals, is a vital biological process in multiple organ systems. The osteoclast (OC) plays a vital role in bone metabolism and repair. The role of mechanotransduction in osteoclasts and other bone cells is emerging. This commentary highlights a recent research report on a novel strategy for the precise regulation of OC formation via modulating matrix stiffness. Modulation of the mechanotransduction pathways in the skeletal system will pave the way for the development of a matrix stiffness-based strategy for bone tissue regeneration.

Tumor models in vitro are conventional methods for developing anti-cancer drugs, evaluating drug delivery, or calculating drug efficacy. However, traditional cell line-derived tumor models are unable to capture the tumor heterogeneity in patients or mimic the interaction between tumors and their surroundings. Recently emerging patient-derived preclinical cancer models, including of patient-derived xenograft (PDX) model, circulating tumor cell (CTC)-derived model, and tumor organoids-on-chips, are promising in personalized drug therapy by recapitulating the complexities and personalities of tumors and surroundings. These patient-derived models have demonstrated potential advantages in satisfying the rigorous demands of specificity, accuracy, and efficiency necessary for personalized drug therapy. However, the selection of suitable models is depending on the specific therapeutic requirements dictated by cancer types, progressions, or the assay scale. As an example, PDX models show remarkable advantages to reconstruct solid tumors in vitro to understand drug delivery and metabolism. Similarly, CTC-derived models provide a sensitive platform for drug testing in advanced-stage patients, while also facilitating the development of drugs aimed at suppressing tumor metastasis. Meanwhile, the demand for large-scale testing has promoted the development of tumor organoids-on-chips, which serves as an optimal tool for high-throughput drug screening. This review summarizes the establishment and development of PDX, CTC-derived models, and tumor organoids-on-chips and addresses their distinctive advantages in drug discovery, sensitive testing, and screening, which demonstrate the potential to aid in the selection of suitable models for fundamental cancer research and clinical trials, and further developing the personalized drug therapy.

The use of mechanical biology and biomechanical signal transduction is a novel approach to attenuate biological tissue degeneration, whereas the understanding of specific cellular responses is critical to delineate the underlying mechanism. Dynamic mechanical signals with optimized loading signals, i.e., intensity and frequency, have been shown to have the potential to regulate adaptation and regeneration. Mechanotransduction pathways are of great interest in elucidating how mechanical signals produce such observed effects, including reduced tissue mass loss, increased healing and formation, and cell differentiation. While mechanobiology in the adaptation of cells and tissues is observed and recorded in the literature, its application in disease mechanism and treatment is under development. We would congratulate the opening of the Mechanobiology in Medicine journal, which provides an effective platform for advanced research in basic mechanotransduction and its translation in disease diagnosis, therapeutics, and beyond. This review aims to develop a cellular and molecular understanding of the mechanotransduction processes in tissue regeneration, which may provide new insights into disease mechanisms and the promotion of healing. Particular attention is allotted to the responses of mechanical loading, including potential cellular and molecular pathways, such as mechanotransduction associated with mechanotransduction pathways (e.g., Piezo ion channels and Wnt signaling), immune-response, neuron development, tissue adaptation and repair, and stem cell differentiation. Altogether, these discussed data highlight the complex yet highly coordinated mechanotransduction process in tissue regeneration.

The dynamic protrusions of lamellipodia and filopodia have emerged as crucial players in tumor progression and metastasis. These membrane structures, governed by intricate actin cytoskeletal rearrangements, facilitate cancer cell migration, invasion, and interaction with the tumor microenvironment. This review provides a comprehensive examination of the structural and functional attributes of lamellipodia and filopodia, shedding light on their pivotal roles in mediating cancer invasion. Navigating through the intricate landscape of cancer biology, the review illuminates the intricate signaling pathways and regulatory mechanisms orchestrating the formation and activity of these protrusions. The discussion extends to the clinical implications of lamellipodia and filopodia, exploring their potential as diagnostic and prognostic markers, and delving into therapeutic strategies that target these structures to impede cancer progression. As we delve into the future, the review outlines emerging technologies and unexplored facets that beckon further research, emphasizing the need for collaborative efforts to unravel the complexities of lamellipodia and filopodia in cancer, ultimately paving the way for innovative therapeutic interventions.

The significance of early detection and isolation of infected individuals, along with the quantitative assessment of antibodies against the virus, has gained widespread recognition during the ongoing covid-19 pandemic. This necessitates the development of cost-effective, user-friendly, decentralized testing methods characterized by both high sensitivity and specificity. In this article, we present a comprehensive review of an innovative, low-cost rapid decentralized immunoassay technology, applicable across various diagnostic and quantitative testing scenarios. Distinguishing itself from conventional immunoassay technologies, this method is featured with mechanically enhanced specificity without compromising sensitivity. We delve into the basic principle of the technology and a comparative analysis of this technology in relation to other immunodiagnostic methods, highlighting its potential applications in a wide spectrum of diagnostic tests.

A recent study published in Nature Communications showed that essential modulatory roles of interfacial adhesion and mechanical microenvironments such as geometric constraints and extracellular matrix stiffness, in microbe-host cell interactions. This study utilized single-cell force spectroscopy and RNA sequencing to gain insight into the intrinsic mechanisms by which the mechanical microenvironment regulates bacterial-host interactions and therefore reveal potential interventions against bacterial invasion. Meanwhile, the adhesion forces involved in the bacterial-host interactions were recognized as a new indicator for assessing the extent of bacterial infection. Taken together, these findings demonstrate that interfacial adhesion forces and mechanical microenvironments play a dominant role in modulating functions and behaviors of microorganisms and host cells, which also provide a mechanobiology-inspired idea for the development of subsequent drug-resistant antimicrobials and broad-spectrum antiviral drugs.

A recent study published in Nature Communications demonstrated that restoring SERCA2 pump deficiency can enhance bone mechano-responsiveness in type 2 diabetes (T2D) by modulating osteocyte calcium dynamics. The findings revealed that in T2D mice, the ability of the bone to respond to mechanical stress is compromised, primarily due to attenuated calcium oscillatory dynamics within osteocytes rather than in osteoblasts or osteoclasts. The underlying mechanism of this reduction in bone mechano-responsiveness in T2D was identified as a specific decrease in osteocytic SERCA2 expression mediated by PPARα. Additionally, mice overexpressing SERCA2 in osteocytes exhibited reduced deterioration of bone mechano-responsiveness induced by T2D. Collectively, this study provides mechanistic insights into T2D-induced deterioration in bone mechano-responsiveness and identifies a promising therapeutic approach to counteract T2D-associated fragility fractures.

Osteoarthritis (OA) is a progressive degenerative joint sickness related with mechanics, obesity, ageing, etc., mainly characterized by cartilage degeneration, subchondral bone damage and synovium inflammation. Coordinated mechanical absorption and conduction of the joint play significant roles in the prevalence and development of OA. Subchondral bone is generally considered a load-burdening tissue where mechanosensitive cells are resident, including osteocytes, osteoblast lineage cells, and osteoclast lineage cells (especially less concerned in mechanical studies). Mechano-signaling imbalances affect complicated cellular events and disorders of subchondral bone homeostasis. This paper will focus on the significance of mechanical force as the pathogenesis, involvement of various mechanical force patterns in mechanosensitive cells, and mechanobiology research of loading devices in vitro and in vivo, which are further discussed. Additionally, various mechanosensing structures (e.g., transient receptor potential channels, gap junctions, primary cilia, podosome-associated complexes, extracellular vesicles) and mechanotransduction signaling pathways (e.g., Ca²⁺ signaling, Wnt/β-catenin, RhoA GTPase, focal adhesion kinase, cotranscriptional activators YAP/TAZ) in mechanosensitive bone cells. Finally, we highlight potential targets for improving mechanoprotection in the treatment of OA. These advances furnish an integration of mechanical regulation of subchondral bone homeostasis, as well as OA therapeutic approaches by modulating mechanical homeostasis.

A recent study published in Nature Communications presents a unique approach using an osteoinductive intramedullary (IM) implant as an adjunctive therapy for bone transport distraction osteogenesis. The study demonstrates that this innovative technique achieves early bony bridging, eliminates pin tract infections, and prevents docking site non-union, offering significant potential for the treatment of large bone defects. The study also highlights an additive effect of the osteoinductive IM implant on distraction osteogenesis for managing bone defect.

The mechanical microenvironment strongly affects cell state and decisions. Cell mechanosensing has been described by a molecular clutch which gets progressively engaged depending upon the stiffness of the extracellular material. Through the actuation of pulling forces exerted by actin fibres on the mechanosensitive talin-integrin molecular complex, cells sense and react to the stiffness of their surroundings. However, whether the truly cell mechanosensing is regulated by the pure elastic stiffness or by the strain energy density of the ECM is still debated. Here we report that the cell response to change of strain energy density out of loading induced deformation (purely elastic) can be accounted for by including, within the same frame of the molecular clutch model, the residual strain/stress to which the ECM could be subjected before establishing any interaction with the molecular clutches. To include the contribution of residual stresses, an additional spring orthogonal to the ones already present in the original clutch model has been introduced; this spring takes memory of the ECM strain energy when axially deformed before any interaction with cell molecular clutches can occur. To evaluate the influence of strain on the optimum number of clutches, the model has been implemented with different levels of strain. Results suggest that cells undergo a reinforcement process, stiffening the cytoskeleton in response to the ECM stress/strain energy.

Tumor progression is accompanied by complex structural changes in the extracellular matrix (ECM), which decrease the effective exposure of tumors to drugs. Breast cancer are highly heterogeneous with a typically high degree of ECM remodeling and stiffening. Therefore, it is especially important to explore the influence of ECM stiffness on breast cancer chemotherapy. Here, we fabricated 3D Methacrylate Gelatin (GelMA) hydrogels with varying stiffness by photo-crosslinking to simulate the change of tissue stiffness during the development of breast cancer. These 3D hydrogels were used to evaluate how MDA-MB-231 cells responded to the chemotherapy drug doxorubicin (DOX), the mechanical regulatory mechanism involved has also been investigated. The findings demonstrated that 15% GelMA hydrogel (9 ​kPa) increased the activity of EGFR to block the Hippo signaling pathway and activate Yes-associated protein (YAP). Activated YAP allowed cytosolic EGFR transport into the nucleus via binding with it, up-regulated the expression of their respective transcriptional targets, and thus generates drug resistance. Altogether, our study implicates that stiffness-dependent EGFR activation plays an important role in breast cancer drug resistance, indicating that targeting of both YAP and EGFR signals may present a promising therapeutic strategy for ECM stiffness-induced drug resistance.

Coronavirus disease-19 (COVID-19) is the ongoing pandemic affecting millions of people worldwide. Several vaccine candidates have been designed and developed for the causative virus, SARS-CoV-2. However high mutation rate in the viral genome and the emergence of new variants have challenged the effectiveness of these vaccines developed for previous strains. Hence, screening and identification of anti-SARS-CoV-2 agents having multi-target potency would be more impactful in the prevention of the disease. Epicatechin gallate (ECG) is a green tea polyphenol having various medicinal properties, including anti-oxidative and anti-inflammatory effects. However its role as anti-SARS-CoV-2 agent is not clear. Hence the present in silico study aims to investigate the binding potential of ECG with several proteins which are critical to SARS-CoV-2 entry and replication within the host cell. Molecular docking analyses have revealed that ECG could potentially block several amino acid residues of entry factors in host cells, spike protein, and many non-structural proteins through Hydrogen bonds and hydrophobic interactions. Such interactions with vital proteins could inhibit SARS-CoV-2 entry and its subsequent replication into the host. Therefore, ECG could be a potential therapeutic agent for the prevention of COVID-19. However, the findings of the present study demand further validation in animal models.

Increased matrix stiffness is a common phenomenon in solid tumor tissue and is regulated by both tumor and mesenchymal cells. The increase in collagen and lysyl oxidase family proteins in the extracellular matrix leads to deposition, contraction, and crosslinking of the stroma, promoting increased matrix stiffness in tumors. Matrix stiffness is critical to the progression of various solid tumors. As a mechanical factor in the tumor microenvironment, matrix stiffness is involved in tumor progression, promoting biological processes such as tumor cell proliferation, invasion, metastasis, angiogenesis, drug resistance, and immune escape. Reducing tissue stiffness can slow down tumor progression. Therefore targeting matrix stiffness is a potential option for tumor therapy. This article reviews the detailed mechanisms of matrix stiffness in different malignant tumor phenotypes and potential tumor therapies targeting matrix stiffness. Understanding the role and mechanisms of matrix stiffness in tumors could provide theoretical insights into the treatment of tumors and assist in the clinical development of new drug therapies.

Tumor state transitions between the excited (high-concentration) and nonexcited (low-concentration) basins under the Gaussian white noise and non-Gaussian colored noise are investigated via the most probable steady states (MPSS) and the first escape probability (FEP)-based stochastic basin of attraction (SBA), respectively. Reducing the non-Gaussian colored noise and then utilizing the unified colored noise approximation (UCNA), the Markov system is derived. The extremal controlling equation of stationary probability density function (SPDF) is derived to analyze the impacts of noise on transitions in terms of MPSS. The existence of the ‘color’ of the non-Gaussian colored noise induces the reappearance of the uncorrelated additive white noise parameter that had vanished from the extremal controlling equation, completely reversing the inability of the uncorrelated additive Gaussian white noise to operate on transitions. The FEP-dependent SBA characterizing the excited basin stability is performed to further analyze the role of noise on the likelihood of escaping to the nonexcited state. Results show that the cross-correlated noises play a dual role in regulating SBA. The increased SBA indicating more difficulty to escape to the nonexcited state reflects a worse therapeutic effect. Therefore, enhancing the negatively correlated noise intensities and augmenting the non-Gaussian noise correlation time is essential for destabilizing the excited basin and achieving optimal therapeutic efficacy.