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The extracellular matrix (ECM)-and its mechanobiology-regulates key cellular functions that drive tumor growth and development. Accordingly, mechanotherapy is emerging as an effective approach to treat fibrotic diseases such as cancer. Through restoring the ECM to healthy-like conditions, this treatment aims to improve tissue perfusion, facilitating the delivery of chemotherapies. In particular, the manipulation of ECM is gaining interest as a valuable strategy for developing innovative treatments based on nanoparticles (NPs). However, further progress is required; for instance, it is known that the presence of a dense ECM, which hampers the penetration of NPs, primarily impacts the efficacy of nanomedicines. Furthermore, most 2D in vitro studies fail to recapitulate the physiological deposition of matrix components. To address these issues, a comprehensive understanding of the interactions between the ECM and NPs is needed. This review focuses on the main features of the ECM and its complex interplay with NPs. Recent advances in mechanotherapy are discussed and insights are offered into how its combination with nanomedicine can help improve nanomaterials design and advance their clinical translation., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Mechanomedicine is an interdisciplinary field that combines different areas including biomechanics, mechanobiology, and clinical applications like mechanodiagnosis and mechanotherapy. The emergence of artificial intelligence (AI) has revolutionized mechanomedicine, providing advanced tools to analyze the complex interactions between mechanics and biology. This review explores how AI impacts mechanomedicine across four key aspects, i.e., biomechanics, mechanobiology, mechanodiagnosis, and mechanotherapy. AI improves the accuracy of biomechanical characterizations and models, deepens the understanding of cellular mechanotransduction pathways, and enables early disease detection through mechanodiagnosis. In addition, AI optimizes mechanotherapy that targets biomechanical features and mechanobiological markers by personalizing treatment strategies based on real-time patient data. Even with these advancements, challenges still exist, particularly in data quality and the ethical integration into AI in clinical practice. The integration of AI with mechanomedicine offers transformative potential, enabling more accurate diagnostics and personalized treatments, and discovering novel mechanobiological pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mechanotherapy has emerged as a promising treatment for tissue injury. However, existing robots for mechanotherapy are often designed on intuition, lack remote and wireless control, and have limited motion modes. Herein, through topology optimization and hybrid fabrication, wireless magneto-active soft robots are created that can achieve various modes of programmatic deformations under remote magnetic actuation and apply mechanical forces to tissues in a precise and predictable manner. These soft robots can quickly and wirelessly deform under magnetic actuation and are able to deliver compressing, stretching, shearing, and multimodal forces to the surrounding tissues. The design framework considers the hierarchical tissue-robot interaction and, therefore, can design customized soft robots for different types of tissues with varied mechanical properties. It is shown that these customized robots with different programmable motions can induce precise deformations of porcine muscle, liver, and heart tissues with excellent durability. The soft robots, the underlying design principles, and the fabrication approach provide a new avenue for developing next-generation mechanotherapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The skin, the outermost organ of the human body, is vital for sensing and responding to stimuli through mechanotransduction. It is constantly exposed to mechanical stress. Consequently, various mechanical therapies, including compression, massage, and microneedling, have become routine practices for skin healing and regeneration. However, these traditional methods require direct skin contact, restricting their applicability. To address this constraint, we developed shear wave stimulation (SWS), a contactless mechanical stimulation technique. The effectiveness of SWS was compared with that of a commercial compression bioreactor used on reconstructed skin at various stages of maturity. Despite the distinct stimulus conditions applied by the two methods, SWS yielded remarkable outcomes, similar to the effects of the compression bioreactor. It significantly increased the shear modulus of tissue-engineered skin, heightened the density of collagen and elastin fibers, and resulted in an augmentation of fibroblasts in terms of their number and length. Notably, SWS exhibited diverse effects in the low- and high-frequency modes, highlighting the importance of fine-tuning the stimulus intensity. These results unequivocally demonstrated the capability of SWS to enhance the mechanical functions of the skin in vitro, making it a promising option for addressing wound healing and stretch mark recovery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mechano-rehabilitation, also known as mechanotherapy, represents the forefront of noninvasive treatment for musculoskeletal (MSK) tissue disorders, encompassing conditions affecting tendons, cartilage, ligaments, and muscles. Recent emphasis has underscored the significance of macrophage presence in the healing of MSK tissues. However, a considerable gap still exists in comprehending how mechanical strains associated with mechanotherapy impact both the naïve and pro-inflammatory macrophage phenotypes within the three-dimensional (3D) tissue matrix, as well as whether the shift in macrophage phenotype is contingent on the mechanical strains inherent to mechanotherapy. In this study, we delineated alterations in mechano-adaptation and polarization of both naive and M1 macrophages within 3D matrices, elucidating their response to varying degrees of mechanical strain exposure (3%, 6%, and 12%). To evaluate macrophage mechano-adaptation and mechano-sensitivity within 3D collagen matrices under mechanical loading, we employed structural techniques (scanning electron microscopy, histology), quantitative morphological measures for phenotypic assessment, and genotypic methods such as quantitative real-time polymerase chain reaction. Our data reveal that the response of macrophages to mechanical loading is not only contingent on their specific sub-phenotype but also varies with the amplitude of mechanical strain. Notably, although supra-mechanical loading (12% strain) was requisite to induce a phenotypic shift in naive (M0) macrophages, as little as 3% mechanical strain proved sufficient to prompt phenotypic alterations in pro-inflammatory (M1) macrophages. These findings pave the way for leveraging the macrophage mechanome in customized and targeted applications of mechanical strain within the mechano-therapeutic framework. Considering the prevalence of MSK tissue injuries and their profound societal and economic implications, the development of well-informed and effective clinical mechanotherapy modalities for MSK tissue healing becomes an imperative endeavor. Impact statement Mechanotherapy is a primary noninvasive treatment for musculoskeletal (MSK) tissue injuries, but the effect of mechanical strain on macrophage phenotypes is not fully understood. A recent study found that macrophage response to mechanical loading is both sub-phenotype specific and amplitude-dependent, with even small strains enough to induce phenotypic changes in pro-inflammatory macrophages. These findings could pave the way for using macrophage mechanome in targeted mechanotherapy applications for better MSK tissue healing.

Peripheral nerve injuries lead to significant morbidity and adversely affect quality of life. The peripheral nervous system harbors the unique trait of autonomous regeneration; however, achieving successful regeneration remains uncertain. Research continues to augment and expedite successful peripheral nerve recovery, offering promising strategies for promoting peripheral nerve regeneration (PNR). These include leveraging extracellular vesicle (EV) communication and harnessing cellular activation through electrical and mechanical stimulation. Small extracellular vesicles (sEVs), 30-150 nm in diameter, play a pivotal role in regulating intercellular communication within the regenerative cascade, specifically among nerve cells, Schwann cells, macrophages, and fibroblasts. Furthermore, the utilization of exogenous stimuli, including electrical stimulation (ES), ultrasound stimulation (US), and extracorporeal shock wave therapy (ESWT), offers remarkable advantages in accelerating and augmenting PNR. Moreover, the application of mechanical and electrical stimuli can potentially affect the biogenesis and secretion of sEVs, consequently leading to potential improvements in PNR. In this review article, we comprehensively delve into the intricacies of cell-to-cell communication facilitated by sEVs and the key regulatory signaling pathways governing PNR. Additionally, we investigated the broad-ranging impacts of ES, US, and ESWT on PNR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Izhiman and Esfandiari.)

Mechanotransduction is a strictly regulated process whereby mechanical stimuli, including mechanical forces and properties, are sensed and translated into biochemical signals. Increasing data demonstrate that mechanotransduction is crucial for regulating macroscopic and microscopic dynamics and functionalities. However, the actions and mechanisms of mechanotransduction across multiple hierarchies, from molecules, subcellular structures, cells, tissues/organs, to the whole-body level, have not been yet comprehensively documented. Herein, the biological roles and operational mechanisms of mechanotransduction from macro to micro are revisited, with a focus on the orchestrations across diverse hierarchies. The implications, applications, and challenges of mechanotransduction in human diseases are also summarized and discussed. Together, this knowledge from a hierarchical perspective has the potential to refresh insights into mechanotransduction regulation and disease pathogenesis and therapy, and ultimately revolutionize the prevention, diagnosis, and treatment of human diseases., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Regenerative Rehabilitation represents a multifaceted approach that merges mechanobiology with therapeutic intervention to harness the body's intrinsic tissue repair and regeneration capacity. This review delves into the intricate interplay between mechanical loading and cellular responses in the context of musculoskeletal tissue healing. It emphasizes the importance of understanding the phases involved in translating mechanical forces into biochemical responses at the cellular level. The review paper also covers the mechanosensitivity of macrophages, fibroblasts, and mesenchymal stem cells, which play a crucial role during regenerative rehabilitation since these cells exhibit unique mechanoresponsiveness during different stages of the tissue healing process. Understanding how mechanical loading amplitude and frequency applied during regenerative rehabilitation influences macrophage polarization, fibroblast-to-myofibroblast transition (FMT), and mesenchymal stem cell differentiation is crucial for developing effective therapies for musculoskeletal tissues. In conclusion, this review underscores the significance of mechanome-guided strategies in regenerative rehabilitation. By exploring the mechanosensitivity of different cell types and their responses to mechanical loading, this field offers promising avenues for accelerating tissue healing and functional recovery, ultimately enhancing the quality of life for individuals with musculoskeletal injuries and degenerative diseases., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Stress urinary incontinence (SUI) presents as unintentional urine leakage associated with activities. It significantly affects quality of life (QoL) and is the most common type of incontinence in women. Current treatment options, particularly non-surgical therapies, are lacking., Objective: To assess the efficacy of mechanotherapy provided by the Flyte ® intra-vaginal device during pelvic floor muscle training (PFMT)., Design: This was a randomized, controlled, double-blinded trial., Materials and Methods: Flyte is a repeat use device for conditioning and strengthening the pelvic floor muscles (PFMs). It provides two-part mechanotherapy. Part 1 is the stretching and preloading of the PFM from the internal wand. Part 2 integrates mechanical pulses which elicit muscle cellular and tissue level responses that trigger cellular regeneration, improve neuromuscular facilitation and motor learning. Subjects used the device for 5 min/day for 12 weeks. Subjects (144) were randomized and evaluated at 6 and 12 weeks. Arm A (72) received both Part 1 and Part 2 mechanotherapy for 12 weeks, whereas Arm B (72) received Part 1 therapy for 6 weeks, then crossed over to full therapy. Mean age was 50, 49, respectively, prior pelvic/abdominal surgery 26%, 46%, and previous incontinence treatments 13%, 22%. The primary endpoint was 24-h pad weight (24-HR PW) at 6 weeks. Secondary endpoints were 24-HR PW at 12 weeks and QoL [International Consultation on Incontinence Questionnaire (ICIQ), Urinary Incontinence Quality of Life (IQOL)]., Results: Part 1 therapy had a greater than anticipated therapeutic effect. Thus, the study was underpowered to identify differences between study arms. Therefore, data were pooled to assess the effects of mechanotherapy. Twenty four-HR PW was significantly reduced at 6 weeks ( p  = <0.0001), with further reduction from 6 to 12 weeks ( p  = <0.0001). Data were stratified based on 24-HR PW severity. Significant reductions were noted in all severity groups (mild p  = <0.0001, moderate p  = <0.0001, severe p  = <0.01). QoL was similarly improved at 6 weeks (ICIQ p  = <0.0001, IQOL p  = <0.0001), and 12 weeks (ICIQ p  = <0.0001, IQOL p  = <0.0001). Compliance was >80% at 6 weeks and 70% at 12 weeks., Conclusion: Two-part mechanotherapy significantly improved 24-HR PW and QoL across all severities of SUI. Improvements were noted in as little as 2 weeks and appeared to be sustained through 2-year follow up., Trial Registration: Registered on ClinTrials.gov (NCT02954042)., Competing Interests: MM is a paid consultant for Pelvital USA, Inc. The other authors have no conflicts of interest to report., (© The Author(s), 2024.)

The application of lipid-based nanoparticles for COVID-19 vaccines and transthyretin-mediated amyloidosis treatment have highlighted their potential for translation to cancer therapy. However, their use in delivering drugs to solid tumors is limited by ineffective targeting, heterogeneous organ distribution, systemic inflammatory responses, and insufficient drug accumulation at the tumor. Instead, the use of lipid-based nanoparticles to remotely activate immune system responses is an emerging effective strategy. Despite this approach showing potential for treating hematological cancers, its application to treat solid tumors is hampered by the selection of eligible targets, tumor heterogeneity, and ineffective penetration of activated T cells within the tumor. Notwithstanding, the use of lipid-based nanoparticles for immunotherapy is projected to revolutionize cancer therapy, with the ultimate goal of rendering cancer a chronic disease. However, the translational success is likely to depend on the use of predictive tumor models in preclinical studies, simulating the complexity of the tumor microenvironment (e.g., the fibrotic extracellular matrix that impairs therapeutic outcomes) and stimulating tumor progression. This review compiles recent advances in the field of antitumor lipid-based nanoparticles and highlights emerging therapeutic approaches (e.g., mechanotherapy) to modulate tumor stiffness and improve T cell infiltration, and the use of organoids to better guide therapeutic outcomes., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: The Basas Spanish Squat with electrical stimulation (E-stim) has shown promising results as a potential key exercise in treatment of athletes with patellar tendinopathy. Gold standard exercise therapy for tendon injuries consists of tendon loading exercises, or exercises that appropriately applies high levels of mechanical strain to the tendon. The theoretical pathway in which the Basas Spanish Squat with E-stim improves tendinopathy has been speculated to be the additional strain applied through the patellar tendon during superimposition of E-stim. This theory, however, has yet to be confirmed., Purpose: The purpose of this case series was to compare patellar tendon strain, during the Basas Spanish Squat with, and without E-stim, and open kinetic chain knee extension., Methods: Four healthy participants performed the three exercises while a physical therapist collected simultaneous unilateral ultrasound images from the patellar tendon. Strain was calculated as the change in patellar tendon length during contraction divided by the resting length., Results: Amongst all participants, patellar tendon strain was smallest during the Basas Spanish Squat without E-stim, followed by the open kinetic chain knee extension at 60% maximum voluntary isometric contraction. The Basas Spanish Squat with E-stim yielded approximately double or more strain compared to the without E-stim condition and demonstrated higher level of strain compared to open kinetic chain knee extension in all participants., Conclusion: The findings reflect a clear trend of increased strain through the patellar tendon when E-stim was superimposed. The results support the theory that the Basas Spanish Squat with E-stim increases patellar tendon strain and could explain the reported clinical benefits in individuals with patellar tendinopathy., Level of Evidence: 4, Case series., Competing Interests: The authors report no conflicts of interest., (© The Author(s).)

Over the past 2 decades, cancer stem cells (CSCs) have been identified as the root cause of cancer occurrence, progression, chemoradioresistance, recurrence, and metastasis. Targeting CSCs is a novel therapeutic strategy for cancer management and treatment. Liver cancer (LC) is a malignant disease that can endanger human health. Studies are increasingly suggesting that changes in the liver mechanical microenvironment are a primary driver triggering the occurrence and development of liver cancer. In this review, we summarize current understanding of the roles of the liver mechano-microenvironment and liver cancer stem cells (LCSCs) in liver cancer progression. We also discuss the relationship between the mechanical heterogeneity of liver cancer tissues and LCSC recruitment and metastasis. Finally, we highlight potential mechanosensitive molecules in LCSCs and mechanotherapy in liver cancer. Understanding the roles and regulatory mechanisms of the mechano-microenvironment and LCSCs may provide fundamental insights into liver cancer progression and aid in further development of novel therapeutic strategies., Competing Interests: No potential conflicts of interest are disclosed., (Copyright © 2023 Cancer Biology & Medicine.)

Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Garcia-Aznar reports was provided by University of Zaragoza School of Engineering and Architecture. Garcia-Aznar reports a relationship with University of Zaragoza School of Engineering and Architecture that includes: employment.

Mechanotherapy is proposed as a new option for cancer treatment. Increasing evidence suggests that characteristic differences are present in the nuclear mechanics and mechanotransduction of cancer cells compared with those of normal cells. Recent advances in understanding nuclear mechanics and mechanotransduction provide not only further insights into the process of malignant transformation but also useful references for developing new therapeutic approaches. Herein, we present an overview of the alterations of nuclear mechanics and mechanotransduction in cancer cells and highlight their implications in cancer mechanotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Mechanotherapy is a groundbreaking approach to impact carcinogenesis. Cells sense and respond to mechanical stimuli, translating them into biochemical signals in a process known as mechanotransduction. The impact of stress on tumor growth has been studied in the last three decades, and many papers highlight the role of mechanics as a critical self-inducer of tumor fate at the in vitro and in vivo biological levels. Meanwhile, mathematical models attempt to determine laws to reproduce tumor dynamics. This review discusses biological mechanotransduction mechanisms and mathematical-biomechanical models together. The aim is to provide a common framework for the different approaches that have emerged in the literature from the perspective of tumor avascularity and to provide insight into emerging mechanotherapies that have attracted interest in recent years., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Juan Soler reports financial support was provided by University of Granada. Juan Soler reports a relationship with Spanish Scientific Research Council that includes: funding grants., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The extracellular matrix (ECM) provides physical support and imparts significant biochemical and mechanical cues to cells. Matrix stiffening is a hallmark of liver fibrosis and is associated with many hepatic diseases, especially liver cirrhosis and carcinoma. Increased matrix stiffness is not only a consequence of liver fibrosis but is also recognized as an active driver in the progression of fibrotic hepatic disease. In this article, we provide a comprehensive view of the role of matrix stiffness in the pathological progression of hepatic disease. The regulators that modulate matrix stiffness including ECM components, MMPs, and crosslinking modifications are discussed. The latest advances of the research on the matrix mechanics in regulating intercellular signaling and cell phenotype are classified, especially for hepatic stellate cells, hepatocytes, and immunocytes. The molecular mechanism that sensing and transducing mechanical signaling is highlighted. The current progress of ECM stiffness's role in hepatic cirrhosis and liver cancer is introduced and summarized. Finally, the recent trials targeting ECM stiffness for the treatment of liver disease are detailed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Guo, Wantono, Tan, Deng, Duan and Liu.)

Mechanotherapy, the application of various mechanical forces on injured or diseased tissue, is a viable option for tissue regenerative rehabilitation. Recent advances in tissue engineering (i.e., engineered materials and 3D printing) and soft-robotic technologies have enabled systematic and controlled studies to demonstrate the therapeutic impacts of mechanical stimulation on severely injured tissue. Along with innovation in actuation systems, improvements in analysis methods uncovering cellular and molecular landscapes during tissue regeneration under mechanical loading expand our understanding of how mechanical cues are translated into specific biological responses (i.e., stem cell self-renewal and differentiation, immune responses, etc.). Moving forward, the development of diversified actuation systems that are mechanically tissue friendly, easily scalable, and capable of delivering various modes of loading and monitoring functional biomarkers will facilitate systematic and controlled preclinical and clinical studies. Combining these future actuation systems with single-cell resolution analysis of cellular and molecular markers will enable detailed knowledge of underlying biological responses, and optimization of mechanotherapy protocols for specific tissues/injuries. These advancements will enable diverse mechanotherapy therapies in the future.

In 2020, cardiovascular diseases resulted in 25% of unnatural deaths in the United States. Treatment with long-term administration of medication can adversely affect other organs, and surgeries such as coronary artery grafts are risky. Meanwhile, sequential compression therapy (SCT) offers a low-risk alternative, but is currently expensive and unwieldy, and often requires the patient to be immobilized during administration. Here, we present a low-cost wearable device to administer SCT, constructed using a stacked lamination fabrication approach. Expanding on concepts from the field of soft robotics, textile sheets are thermally bonded to form pneumatic actuators, which are controlled by an inconspicuous and tetherless electronic onboard supply of pressurized air. Our open-source, low-profile, and lightweight (140 g) device costs $62, less than one-third the cost the least expensive alternative and one-half the weight of lightest alternative approved by the US Food and Drug Administration (FDA), presenting the opportunity to more effectively provide SCT to socioeconomically disadvantaged individuals. Furthermore, our textile-stacking method, inspired by conventional fabrication methods from the apparel industry, along with the lightweight fabrics used, allows the device to be worn more comfortably than other SCT devices. By reducing physical and financial encumbrances, the device presented in this work may better enable patients to treat cardiovascular diseases and aid in recovery from cardiac surgeries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schara, Zeng, Jumet and Preston.)

Excessive extracellular matrix deposition drives fibroblasts into a state of high mechanical stress, exacerbating pathological fibrosis and hypertrophic scar formation, leading to tissue dysfunction. This study reports a minimally invasive and convenient approach to obtaining scarless tissue using a silk fibroin microneedle patch (SF MNs). We found that by tuning the MN size and density only, the biocompatible MNs significantly decreased the scar elevation index in the rabbit ear hypertrophic scar model and increased ultimate tensile strength close to regular skin. To advance our understanding of this recent approach, we built a fibroblast-populated collagen lattice system and finite element model to study MN-mediated cellular behavior of fibroblasts. We found that the MNs reduced the fibroblasts generated contraction and mechanical stress, as indicated by decreased expression of the mechanical sensitive gene ANKRD1. Specifically, SF MNs attenuated the integrin-FAK signaling and consequently down-regulated the expression of TGF-β1, α-SMA, collagen I, and fibronectin. It resulted in a low-stress microenvironment that helps to reduce scar formation significantly. Microneedles' physical intervention via the mechanotherapeutic strategy is promising for scar-free wound healing.

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., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Aging is accompanied by reduced remodeling of skeletal muscle extracellular matrix (ECM), which is exacerbated during recovery following periods of disuse atrophy. Mechanotherapy has been shown to promote ECM remodeling through immunomodulation in adult muscle recovery, but not during the aged recovery from disuse. In order to determine if mechanotherapy promotes ECM remodeling in aged muscle, we performed single cell RNA sequencing (scRNA-seq) of all mononucleated cells in adult and aged rat gastrocnemius muscle recovering from disuse, with (REM) and without mechanotherapy (RE). We show that fibroadipogenic progenitor cells (FAPs) in aged RE muscle are highly enriched in chemotaxis genes ( Csf1 ), but absent in ECM remodeling genes compared to adult RE muscle ( Col1a1 ). Receptor-ligand (RL) network analysis of all mononucleated cell populations in aged RE muscle identified chemotaxis-enriched gene expression in numerous stromal cell populations (FAPs, endothelial cells, pericytes), despite reduced enrichment of genes related to phagocytic activity in myeloid cell populations (macrophages, monocytes, antigen presenting cells). Following mechanotherapy, aged REM mononuclear cell gene expression resembled adult RE muscle as evidenced by RL network analyses and KEGG pathway activity scoring. To validate our transcriptional findings, ECM turnover was measured in an independent cohort of animals using in vivo isotope tracing of intramuscular collagen and histological scoring of the ECM, which confirmed mechanotherapy-mediated ECM remodeling in aged RE muscle. Our results highlight age-related cellular mechanisms underpinning the impairment to complete recovery from disuse, and also promote mechanotherapy as an intervention to enhance ECM turnover in aged muscle recovering from disuse., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Physiological Society.)

Purpose: This review aims to summarize the evidence for the role of mechanotherapies and rehabilitation in supporting the synergy between regeneration and repair after an orthobiologic intervention., Methods: A selective literature search was performed using Web of Science, OVID, and PubMed to review research articles that discuss the effects of combining mechanotherapy with various forms of regenerative medicine., Results: Various mechanotherapies can encourage the healing process for patients at different stages. Taping, bracing, cold water immersion, and extracorporeal shockwave therapy can be used throughout the duration of acute inflammatory response. The regulation of angiogenesis can be sustained with blood flow restriction and resistance training, whereas heat therapy and tissue loading during exercise are recommended in the remodeling phase., Conclusion: Combining mechanotherapy with various forms of regenerative medicine has shown promise for improving treatment outcomes. However, further studies that reveal a greater volume of evidence are needed to support clinical decisions., (© 2021. The Author(s), under exclusive licence to The Author(s) under exclusive licence to SICOT aisbl.)

Cells sense the biophysical properties of the tumor microenvironment (TME) and adopt these signals in their development, progression, and metastatic dissemination. Recent work highlights the mechano-responsiveness of cells in tumors and the underlying mechanisms. Furthermore, approaches to mechano-modulating diverse types of cell have emerged aiming to inhibit tumor growth and metastasis. These include targeting mechanosensitive machineries in cancer cells to induce apoptosis, intervening matrix stiffening incurred by cancer-associated fibroblasts (CAFs) in both primary and metastatic tumor sites, and modulating matrix mechanics to improve immune cell therapeutic efficacy. This review is envisaged to help scientists and clinicians in cancer research to advance understanding of the cellular mechano-responsiveness in TME, and to harness these concepts for cancer mechanotherapies., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The literature review analyzed 20 Russian and 69 foreign publications on the rehabilitation of elderly patients with osteoporotic vertebral fractures. The article deals in detail with the prevalence, medical and social significance of pathological osteoporotic fractures, including vertebral deformities. The data confirming the importance of osteoporosis for physical and rehabilitation medicine specialists are presented. Changes in the quality of life, functional and gate disorders associated with osteoporotic vertebral fractures are described. Based on the available literature data, the principles of rehabilitation of patients with osteoporotic vertebral compression fractures are formulated, including the effectiveness of various methods of physical therapy, mechanotherapy and apparatus physiotherapy. From the standpoint of evidence-based medicine, the role of orthotics in the complex rehabilitation of such patients is described. Based on the analysis of literature data, it was concluded that the problem of osteoporosis is relevant for physicians working in the field of rehabilitation medicine; osteoporotic vertebral fractures are characterized by a high prevalence over the age of 50 years and are associated with a decrease in the quality of life, motor and functional limitations, and an increased risk of death, and well-planned medical rehabilitation programs including physical exercises, physiotherapy and orthotics can significantly improve patient functionality.

Underwater traction of the spine is a physiotherapeutic method that combines the effects of mechanical traction and fresh water of indifferent temperature and seems promising for the treatment of pain in the lower back, which is due to the physiological basis of the mechanism of action on the spinal motion segment by eliminating muscle spasm and restoring the biomechanics of the spine., Objective: To study the effectiveness of underwater horizontal traction in combination with mechanotherapy in patients with non-stenosing unstable degenerative spondylolisthesis of the lumbosacral spine of the 1st degree, accompanied by pain., Material and Methods: The clinical study included 14 patients (mean age 50.21 years). Patients underwent underwater horizontal traction of the spine according to the modified Pushkareva-Vozdvizhenskaya method in a variable mode, the procedures were performed every other day, for a course of 6 procedures. After completion of the traction procedure, patients were recommended to put on a fixing lumbosacral corset, in which they rested for 30 minutes in the supine position. At the end of the rest period, the patients performed training of the back muscles with biofeedback on the mechanotherapeutic complex of simulators for 30 minutes daily, except for weekends, for a course of 10 procedures., Results: All patients completed the course of treatment, during the procedures no side effects or deterioration were noted. During the treatment, motor and daily activity significantly improved according to the Oswestry scale ( p =0.002), the severity of the pain syndrome and its effect on the patient's activity decreased, according to the Roland-Morris questionnaire ( p =0.003). According to an objective assessment of the muscle strength of the lumbosacral spine at the initial level, no deviations from the normative parameters were revealed, however, during the treatment, a significant increase in strength was noted in all muscle groups., Conclusion: Underwater horizontal traction of the spine in variable mode according to Pushkareva-Vozdvizhenskaya is an effective and safe method of conservative treatment of unstable non-stenosing degenerative spondylolisthesis of the 1st degree, accompanied by back pain, which helps to reduce the intensity of the pain syndrome and improve the daily motor and social activity of patients. The traction method should be supplemented with therapeutic exercises using mechanotherapeutic simulators to achieve a clinical result.

As explained by Wolff's law and the mechanostat hypothesis, mechanical stimulation can be used to promote bone formation. Low intensity pulsed ultrasound (LIPUS) is a source of mechanical stimulation that can activate the integrin/phosphatidylinositol 3-OH kinase/Akt pathway and upregulate osteogenic proteins through the production of cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ). This paper analyzes the results of in vitro and in vivo studies that have evaluated the effects of LIPUS on cell behavior within three-dimensional (3D) titanium, ceramic, and hydrogel scaffolds. We focus specifically on cell morphology and attachment, cell proliferation and viability, osteogenic differentiation, mineralization, bone volume, and osseointegration. As shown by upregulated levels of alkaline phosphatase and osteocalcin, increased mineral deposition, improved cell ingrowth, greater scaffold pore occupancy by bone tissue, and superior vascularization, LIPUS generally has a positive effect and promotes bone formation within engineered scaffolds. Additionally, LIPUS can have synergistic effects by producing the piezoelectric effect and enhancing the benefits of 3D hydrogel encapsulation, growth factor delivery, and scaffold modification. Additional research should be conducted to optimize the ultrasound parameters and evaluate the effects of LIPUS with other types of scaffold materials and cell types.

The inability to fully recover lost muscle mass following periods of disuse atrophy predisposes older adults to lost independence and poor quality of life. We have previously shown that mechanotherapy at a moderate load (4.5 N) enhances muscle mass recovery following atrophy in adult, but not older adult rats. We propose that elevated transverse stiffness in aged muscle inhibits the growth response to mechanotherapy and hypothesize that a higher load (7.6 N) will overcome this resistance to mechanical stimuli. F344/BN adult and older adult male rats underwent 14 days of hindlimb suspension, followed by 7 days of recovery with (RE + M) or without (RE) mechanotherapy at 7.6 N on gastrocnemius muscle. The 7.6 N load was determined by measuring transverse passive stiffness and linearly scaling up from 4.5 N. No differences in protein turnover or mean fiber cross-sectional area were observed between RE and RE + M for older adult rats or adult rats at 7.6 N. However, there was a higher number of small muscle fibers present in older adult, but not adult rats, which was explained by a 16-fold increase in the frequency of small fibers expressing embryonic myosin heavy chain. Elevated central nucleation, satellite cell abundance, and dystrophin-/laminin+ fibers were present in older adult rats only following 7.6 N, while 4.5 N did not induce damage at either age. We conclude that age is an important variable when considering load used during mechanotherapy and age-related transverse stiffness may predispose older adults to damage during the recovery period following disuse atrophy., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There are non-invasive methods of correcting genu valgum (GV), but to date, there is no method to evaluate mechanotherapeutic intervention that does not restrict child's natural movements while the process is on-going so that timely decisions could be made on effectiveness of intervention. The aim of study was to develop and assess the comfortability of garments with elastic straps and pressure applicator (GESPA) and the reliability and user-friendliness of "GVcorrect" app, which aims to catch the elastic straps' pressure level (mN)., Methods: 6 children (5-7 y) with intermalleolar distance ≥5 cm wore GESPA daily for 3 months. Anthropometrical and goniometrical measurements were done according to standard technique; tone and biomechanical parameters of skeletal muscles determined with MyotonPRO; feedback about GESPA and "GVcorrect" collected via questionnaire., Results: Based on feedback from children and parents, new, more comfortable and user-friendly GESPA were designed; several updates were made to "GVcorrect" app; new goals were set for the next phase of the study., Conclusions: GESPA and the "GVcorrect" app serve their purpose, but there are still a number of important limitations that need to be removed before the product can be marketed. The study continues with product development until a medical device certificate is obtained.

Mechano-transduction is the procedure of mechanical stimulus translation via cells, among substrate shear flow, topography, and stiffness into a biochemical answer. TAZ and YAP are transcriptional coactivators which are recognized as relay proteins that promote mechano-transduction within the Hippo pathway. With regard to healthy cells in homeostasis, mechano-transduction regularly restricts proliferation, and TAZ and YAP are totally inactive. During cancer development a YAP/TAZ - stimulating positive response loop is formed between the growing tumor and the stiffening ECM. As tumor developments, local stromal and cancerous cells take advantage of mechanotransduction to enhance proliferation, induce their migratory into remote tissues, and promote chemotherapeutic resistance. As a newly progresses paradigm, nanoparticle-conjunctions (such as magnetic nanoparticles, and graphene derivatives nanoparticles) hold significant promises for remote regulation of cells and their relevant events at molecular scale. Despite outstanding developments in employing nanoparticles for drug targeting studies, the role of nanoparticles on cellular behaviors (proliferation, migration, and differentiation) has still required more evaluations in the field of mechanotherapy. In this paper, the in-depth contribution of mechano-transduction is discussed during tumor progression, and how these consequences can be evaluated in vitro., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Massage is a viable mechanotherapy to improve protein turnover during disuse atrophy and improve muscle regrowth during recovery from disuse atrophy in adult muscle. Therefore, we investigated whether massage can cause beneficial adaptations in skeletal muscle from aged rats during normal weight-bearing (WB) conditions, hindlimb suspension (HS), or reloading (RE) following HS. Aged (30 months) male Fischer 344/Brown Norway rats were divided into two experiments: (1) WB for 7 days (WB, n = 8), WB with massage (WBM, n = 8), HS for 7 days (HS7, n = 8), or HS with massage (HSM, n = 8), and (2) WB for 14 days (WB14, n = 8), HS for 14 days (HS14, n = 8), reloading (RE, n = 10), or reloading with massage (REM, n = 10) for 7 days following HS. Deuterium oxide (D 2 O) labeling was used to assess dynamic protein and ribosome turnover in each group and anabolic signaling pathways were assessed. Massage did have an anabolic benefit during RE or WB. In contrast, massage during HS enhanced myofibrillar protein turnover in both the massaged limb and contralateral non-massaged limb compared with HS, but this did not prevent muscle loss. Overall, the data demonstrate that massage is not an effective mechanotherapy for prevention of atrophy during muscle disuse or recovery of muscle mass during reloading in aged rats.

Congenital diseases requiring reconstruction of parts of the gastrointestinal tract, skin, or bone are a challenge to alleviate especially in rapidly growing children. Novel technologies may be the answer. This article presents the state-of-art in regenerative robotic technologies, which are technologies that assist tissues and organs to regenerate using sensing and mechanotherapeutical capabilities. It addresses the challenges in the development of such technologies, among which are autonomy and fault-tolerance for long-term therapy as well as morphological conformations and compliance of such devices to adapt to gradual changes of the tissues in vivo. The potential as medical devices for delivering therapies for tissue growth and as tools for scientific exploration of regenerative mechanisms is also discussed., (© 2019 The Author. Birth Defects Research published by Wiley Periodicals, Inc.)

Aim: To assess the effect of the comprehensive rehabilitation, which includes mechanotherapy and cognitive stimulation based on tablet technologies, on emotional and behavioral disorders in patients in the acute stage of ischemic stroke., Material and Methods: The study enrolled 100 patients admitted to the hospital in the acute stage of ischemic stroke. The patients were randomized into treatment and control groups. Patients of the treatment group (n=50) underwent daily robotic mechanotherapy using the MOTOmed movement trainer and tablet technologies for self-training to improve memory, perception, reaction, counting. Patients of the control group (n=50) received standard therapy. The functional state of patients was assessed with the Rankin modified scale. Psychometric scales (the Beck Depression and Anxiety Inventories) were used to measure emotional and behavioral disorders., Results: The program of comprehensive rehabilitation in the acute stage of ischemic stroke helps to decrease emotional and behavioral disorders (p=0.0001). In patients of the treatment group, the severity of depressive disorders was lower at discharge from the hospital and continued to decrease for 6 months (p=0.001). The level of anxiety decreased over the study period (p=0.0001) compared with the patients of the control group who did not demonstrate improvement. Patients of the treatment group displayed better functional recovery reflected by significant changes in Rankin scale scores., Conclusion: The rehabilitation program, which includes mechanotherapy and cognitive stimulation based on tablet technologies, is an easy and accessible method for treatment of emotional and behavioral disorders in patients in the acute stage of ischemic stroke. The results are maintained during the study period with further improvement after 3 and 6 months.

Background: An implant used for stabilizing a fracture creates a mechanical construct, which directly determines the biology of bone healing. The stabilization of fractures places high mechanical demands on implants and therefore steel and titanium are currently almost exclusively used as the materials of choice., Objectives: The possible range of attainable mechanobiological stimulation for mechanotherapy as a function of plate stiffness depending on the selection of the plate material and the physical and mechanical properties of the material options are discussed., Material and Methods: An overview of the material properties of steel and titanium is given. For dynamically fixed long bone fractures as examples, various finite element models of plate osteosynthesis (steel/titanium) are created and the plate working length (PWL, screw configuration close to fracture) is varied. The interfragmentary movement (IFM) as a measure of mechanobiological stimulation is evaluated., Results: Stimulation in the form of IFM varies across the fracture and also as a function of the osteosynthesis material and the configuration. The influence of the material appears to be notably smaller than the influence of PWL but both lose their influence largely over a bridged fracture situation (contact). With a flexible titanium plate and large PSS, a greater mechanobiological stimulation is produced., Conclusion: An essential prerequisite for the secondary fracture healing is an appropriate mechanobiological environment, which can be controlled by the osteosynthesis material and the configuration and is also affected by the type of fracture and load.

Rehabilitation and regenerative medicine therapies has shown improved outcomes for tissue regeneration. Regenerative rehabilitation guides protocols regarding when to start therapy, types of stimuli administered, and graded exercise programs, taking into account biological factors and technologies designed to optimize healing potential. Although there are currently no evidence-based guidelines for rehabilitation, fundamental physical therapy principles likely apply. Immobilization tends to have deleterious effects on musculoskeletal tissues; mechanical loading promotes tissue healing and regeneration. Common physical therapy interventions may provide beneficial effects after the application of regenerative therapies. Research is needed to determine optimal rehabilitation protocols to enhance tissue healing and regeneration., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cells have the capacity to convert mechanical stimuli into chemical changes. This process is based on the tensegrity principle, a mechanism of tensional integrity. To date, this principle has been demonstrated to act in physiological processes such as mechanotransduction and mechanosensing at different scales (from cell sensing through integrins to molecular mechanical interventions or even localized massage). The process involves intra- and extracellular components, including the participation of extracellular matrix (ECM) and microtubules that act as compression structures, and actin filaments which act as tension structures. The nucleus itself has its own tensegrity system which is implicated in cell proliferation, differentiation, and apoptosis. Despite present advances, only the tip of the iceberg has so far been uncovered regarding the role of ECM compounds in influencing biotensegrity in pathological processes. Groups of cells, together with the surrounding ground substance, are subject to different and specific forces that certainly influence biological processes. In this paper, we review the current knowledge on the role of ECM elements in determining biotensegrity in malignant processes and describe their implication in therapeutic response, resistance to chemo- and radiotherapy, and subsequent tumor progression. Original data based on the study of neuroblastic tumors will be provided.

It has long been thought that the effectiveness and efficiency of physical therapy would improve if our understanding of the cell biology/biochemistry that participates in mechanics could be improved. Traditional physical therapy focuses primarily on rehabilitation, but recent developments in mechanobiology that illuminated the effects of physical forces on cells and tissues have led to the realization that the old therapy model should be updated. To achieve this here, the term mechanotherapy is proposed and recent studies showing how mechanotherapies target particular cells, molecules, and tissues are reviewed. These studies show how mechanical force modulates integrin-mediated processes and other mechanosensors such as gap junctions, hemichannels, primary cilia, transient receptor potential channels (cell targeting), and intracellular mechanosignaling pathways (molecule targeting). The role of mechanical force in various therapies, including microdeformation, shockwave, tissue expansion, distraction osteogenesis, and surgical tension reduction (tissue targeting) therapies, is reviewed. This review aims to jumpstart research into this field, which promises to generate a new era of viable and novel pharmacological and engineering interventions that can overcome human diseases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Physical medicine, which in the context of this article includes mechanotherapy, hydrotherapy, balneotherapy, electrotherapy, light therapy, air therapy, and thermotherapy, became a new field of labor in the healthcare domain in the Netherlands around 1900. This article gives an account of the introduction and development of mechanotherapy as a professional activity in the Netherlands in the 19(th) century. Mechanotherapy, which historically included exercises, manipulations, and massage, was introduced in this country around 1840 and became one of the core elements of physical medicine towards the end of that century. In contrast to what one might expect, mostly physical education teachers, referred to as "heilgymnasts," dedicated themselves to this kind of treatment, whereas only a few physicians were active in this field until the 1880s. When, in the last quarter of the 19(th) century, differentiation and specialization within the medical profession took place, physicians specializing in physical medicine and orthopaedics began to claim the field of mechanotherapy exclusively for themselves. This led to tensions between them and the group of heilgymnasts that had already been active in this field for decades. The focus of attention in this article is on interprofessional relationships, on the roles played by the different professional organizations in the fields of physical education and medicine, the local and national governments, and the judicial system, and on the social, political, and cultural circumstances under which developments in the field of mechanotherapy took place. The article concludes with the hypothesis that the intra- and inter-occupational rivalries discussed have had a negative impact on the academic development of physical medicine, orthopaedics, and heilgymnastics/physical therapy in the Netherlands in the first half of the 20(th) century.