Biomechanical Signals Research Articles

Potential Efficacy of Proteasome Inhibitor, Delanzomib, for the Treatment of Renal Fibrosis.

Renal fibrosis is scarring and tissue hardening caused by the excess deposition of extracellular matrix proteins in response to chronic inflammation. Renal fibrosis is the primary cause of a progressive loss of renal function, and is an important therapeutic target because it ultimately leads to end-stage renal failure, which can be treated only by either dialysis or kidney transplantation. There is no effective treatment that specifically targets renal fibrosis. Myofibroblasts are known to evade apoptosis by activating molecular mechanisms in response to pro-survival biomechanical and growth factor signals from the fibrotic microenvironment. In this study, we screened and selected compounds that selectively cause cell death in myofibroblasts in vitro and studied their possible potency against renal fibrosis in a mouse model. Several proteasome inhibitors induced selective cell death in myofibroblasts differentiated from the human fibroblast cell line (MRC5). The in vivo antifibrotic effect of Delanzomib (Dz), one of the proteasome inhibitors most sensitive to myofibroblasts in vitro, was investigated in a Unilateral Ureteric Obstruction (UUO) mouse model. Treatment with Dz decreased the expression levels of the actin-alpha-2 (ACTA2) and collagen-type-1-alpha-1 (COL1A1) genes in the kidney, which are common fibrosis markers. These results suggest that Dz might be a compound that suppresses renal fibrosis by inducing selective cell death of myofibroblasts, although further investigation is required.

Mechanisms underlying divergent relationships between Ca2+ and YAP/TAZ signalling.

Yes-associated protein (YAP) and its homologue TAZ are transducers of several biochemical and biomechanical signals, integrating multiplexed inputs from the microenvironment into higher level cellular functions such as proliferation, differentiation and migration. Emerging evidence suggests that Ca2+ is a key second messenger that connects microenvironmental input signals and YAP/TAZ regulation. However, studies that directly modulate Ca2+ have reported contradictory YAP/TAZ responses: in some studies, a reduction in Ca2+ influx increases the activity of YAP/TAZ, while in others, an increase in Ca2+ influx activates YAP/TAZ. Importantly, Ca2+ and YAP/TAZ exhibit distinct spatiotemporal dynamics, making it difficult to unravel their connections from a purely experimental approach. In this study, we developed a network model of Ca2+ -mediated YAP/TAZ signalling to investigate how temporal dynamics and crosstalk of signalling pathways interacting with Ca2+ can alter the YAP/TAZ response, as observed in experiments. By including six signalling modules (e.g. GPCR, IP3-Ca2+ , kinases, RhoA, F-actin and Hippo-YAP/TAZ) that interact with Ca2+ , we investigated both transient and steady-state cell response to angiotensin II and thapsigargin stimuli. The model predicts that stimuli, Ca2+ transients and frequency-dependent relationships between Ca2+ and YAP/TAZ are primarily mediated by cPKC, DAG, CaMKII and F-actin. Simulation results illustrate the role of Ca2+ dynamics and CaMKII bistable response in switching the direction of changes in Ca2+ -induced YAP/TAZ activity. A frequency-dependent YAP/TAZ response revealed the competition between upstream regulators of LATS1/2, leading to the YAP/TAZ non-monotonic response to periodic GPCR stimulation. This study provides new insights into underlying mechanisms responsible for the controversial Ca2+ -YAP/TAZ relationship observed in experiments. KEY POINTS: YAP/TAZ integrates biochemical and biomechanical inputs to regulate cellular functions, and Ca2+ acts as a key second messenger linking cellular inputs to YAP/TAZ. Studies have reported contradictory Ca2+ -YAP/TAZ relationships for different cell types and stimuli. A network model of Ca2+ -mediated YAP/TAZ signalling was developed to investigate the underlying mechanisms of divergent Ca2+ -YAP/TAZ relationships. The model predicts context-dependent Ca2+ transient, CaMKII bistable response and frequency-dependent activation of LATS1/2 upstream regulators as mechanisms governing the Ca2+ -YAP/TAZ relationship. This study provides new insights into the underlying mechanisms of the controversial Ca2+ -YAP/TAZ relationship to better understand the dynamics of cellular functions controlled by YAP/TAZ activity.

Quasi-Homogeneous and Hierarchical Electronic Textiles with Porosity-Hydrophilicity Dual-Gradient for Unidirectional Sweat Transport, Electrophysiological Monitoring, and Body-Temperature Visualization.

On-skin electronics based on impermeable elastomers and stacking structures often suffer from inferior sweat-repelling capabilities and severe mechanical mismatch between sub-layers employed, which significantly impedes their lengthy wearing comfort and functionality. Herein, inspired by the transpiration system of vascular plants and the water diode phenomenon, a hierarchical nonwoven electronic textile (E-textile) with multi-branching microfibers and robust interlayer adhesion is rationally developed. The layer-by-layer electro-airflow spinning method and selective oxygen plasma treatment are utilized to yield a porosity-hydrophilicity dual-gradient. The resulting E-textile shows unidirectional, nonreversible, and anti-gravity water transporting performance even upon large-scale stretching (250%), excellent mechanical matching between sub-layers, as well as a reversible color-switching ability to visualize body temperature. More importantly, the conducting and skin-conformal E-textile demonstrates accurate and stable detecting capability for biomechanical and bioelectrical signals when applied as an on-skin bioelectrode, including different human activities, electrocardiography, electromyogram, and electrodermal activity signals. Further, the E-textile can be efficiently implemented in human-machine interfaces to build a gesture-controlled dustbin and a smart acousto-optic alarm. Hence, this hierarchically-designed E-textile with integrated functionalities offers a practical and innovative method for designing comfortable and daily applicable on-skin electronics.

Biocompatible cracked reduced graphene oxide strain sensors: enhancing implantable strain sensing performance and durability

A soft and implantable cracked reduced graphene oxide strain sensor with high strain sensitivity and durability was demonstrated, allowing for accurate measurement of in vivo biomechanical signals.

Aortic Stress Activates an Adaptive Program in Thoracic Aortic Smooth Muscle Cells That Maintains Aortic Strength and Protects Against Aneurysm and Dissection in Mice.

When aortic cells are under stress, such as increased hemodynamic pressure, they adapt to the environment by modifying their functions, allowing the aorta to maintain its strength. To understand the regulation of this adaptive response, we examined transcriptomic and epigenomic programs in aortic smooth muscle cells (SMCs) during the adaptive response to AngII (angiotensin II) infusion and determined its importance in protecting against aortic aneurysm and dissection (AAD). We performed single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analyses in a mouse model of sporadic AAD induced by AngII infusion. We also examined the direct effects of YAP (yes-associated protein) on the SMC adaptive response in vitro. The role of YAP in AAD development was further evaluated in AngII-infused mice with SMC-specific Yap deletion. In wild-type mice, AngII infusion increased medial thickness in the thoracic aorta. Single-cell RNA sequencing analysis revealed an adaptive response in thoracic SMCs characterized by upregulated genes with roles in wound healing, elastin and collagen production, proliferation, migration, cytoskeleton organization, cell-matrix focal adhesion, and PI3K-PKB/Akt (phosphoinositide-3-kinase-protein kinase B/Akt) and TGF-β (transforming growth factor beta) signaling. ScATAC-seq analysis showed increased chromatin accessibility at regulatory regions of adaptive genes and revealed the mechanical sensor YAP/transcriptional enhanced associate domains as a top candidate transcription complex driving the expression of these genes (eg, Lox, Col5a2, Tgfb2). In cultured human aortic SMCs, cyclic stretch activated YAP, which directly bound to adaptive gene regulatory regions (eg, Lox) and increased their transcript abundance. SMC-specific Yap deletion in mice compromised this adaptive response in SMCs, leading to an increased AAD incidence. Aortic stress triggers the systemic epigenetic induction of an adaptive response (eg, wound healing, proliferation, matrix organization) in thoracic aortic SMCs that depends on functional biomechanical signal transduction (eg, YAP signaling). Our study highlights the importance of the adaptive response in maintaining aortic homeostasis and preventing AAD in mice.

A Portable and Low-Cost Triboelectric Nanogenerator for Wheelchair Table Tennis Monitoring

With progress in fifth-generation techniques, more advanced techniques are available for disabled people. Disability table tennis has also benefited from the new technology. In this paper, a portable and low-cost triboelectric nanogenerator for wheelchair table tennis monitoring systems is proposed. It was applied for wheelchair table tennis athletes’ monitoring. The portable and low-cost triboelectric nanogenerator consists of Kapton, polyurethane triboelectric films, and a foam supporting layer. The materials have flexible and low-cost characteristics. Therefore, the device has no influence on exercise performance. Due to triboelectric and electrostatic induction, the portable and low-cost triboelectric nanogenerator can convert biomechanical signals into electric signals. The electric signal is used as a sensing signal and is transformed in a computer by an Analog-to-Digital acquisition module. The coach acquires motion information in real time from a terminal device regarding force, exercise amplitude, and stability of the athlete. Meanwhile, the electric signal provides also sustainable energy for the microelectronic device. It can light 20 LEDs easily and power a calculator and a watch. This portable and low-cost self-powered triboelectric nanogenerator offers a new approach to the field of motion monitoring for disabled people.

Ultrasoft and Biocompatible Magnetic-Hydrogel-Based Strain Sensors for Wireless Passive Biomechanical Monitoring.

Implantable flexible mechanical sensors have exhibited great potential in health monitoring and disease diagnosis due to continuous and real-time monitoring capability. However, the wires and power supply required in current devices cause inconvenience and potential risks. Magnetic-based devices have demonstrated advantages in wireless and passive sensing, but the mismatched mechanical properties, poor biocompatibility, and insufficient sensitivity have limited their applications in biomechanical monitoring. Here, a wireless and passive flexible magnetic-based strain sensor based on a gelatin methacrylate/Fe3O4 magnetic hydrogel has been fabricated. The sensor exhibits ultrasoft mechanical properties, strong magnetic properties, and long-term stability in saline solution and can monitor strains down to 50 μm. A model of the sensing process is established to identify the optimal detection location and the relation between the relative magnetic permeability and the sensitivity of the sensors. Moreover, an in vitro tissue model is developed to investigate the potential of the sensor in detecting subtle biomechanical signals and avoiding interference with bioactivities. Furthermore, a real-time and high-throughput biomonitoring platform is built and implements passive wireless monitoring of the drug response and cultural status of the cardiomyocytes. This work demonstrates the potential of applying magnetic sensing for biomechanical monitoring and provides ideas for the design of wireless and passive implantable devices.

Biomechanical Forces Determine Fibroid Stem Cell Transformation and the Receptivity Status of the Endometrium: A Critical Appraisal.

Myometrium cells are an important reproductive niche in which cyclic mechanical forces of a pico-newton range are produced continuously at millisecond and second intervals. Overproduction and/or underproduction of micro-forces, due to point or epigenetic mutation, aberrant methylation, and abnormal response to hypoxia, may lead to the transformation of fibroid stem cells into fibroid-initiating stem cells. Fibroids are tumors with a high modulus of stiffness disturbing the critical homeostasis of the myometrium and they may cause unfavorable and strong mechanical forces. Micro-mechanical forces and soluble-chemical signals play a critical role in transcriptional and translational processes' maintenance, by regulating communication between the cell nucleus and its organelles. Signals coming from the external environment can stimulate cells in the format of both soluble biochemical signals and mechanical ones. The shape of the cell and the plasma membrane have a significant character in sensing electro-chemical signals, through specialized receptors and generating responses, accordingly. In order for mechanical signals to be perceived by the cell, they must be converted into biological stimuli, through a process called mechanotransduction. Transmission of fibroid-derived mechanical signals to the endometrium and their effects on receptivity modulators are mediated through a pathway known as solid-state signaling. It is not sufficiently clear which type of receptors and mechanical signals impair endometrial receptivity. However, it is known that biomechanical signals reaching the endometrium affect epithelial sodium channels, lysophosphatidic acid receptors or Rho GTPases, leading to conformational changes in endometrial proteins. Translational changes in receptivity modulators may disrupt the selectivity and receptivity functions of the endometrium, resulting in failed implantation or early pregnancy loss. By hypermethylation of the receptivity genes, micro-forces can also negatively affect decidualization and implantation. The purpose of this narrative review is to summarize the state of the art of the biomechanical forces which can determine fibroid stem cell transformation and, thus, affect the receptivity status of the endometrium with regard to fertilization and pregnancy.

STEM-25. IN VIVO FUNCTIONAL GENOMICS IDENTIFIES ESSENTIALITY OF POTASSIUM HOMEOSTASIS IN MEDULLOBLASTOMA

Abstract Distinguishing cancer maintenance genes—i.e. genes essential and specific to tumor survival—from initiation, progression, and passenger genes is critical for developing effective cancer therapeutics. We engineered the Lazy Piggy genetic screening system, which uses a Sleeping Beauty / piggyBac hybrid transposon to dysregulate and later restore gene expression. In vivo spatiotemporal control of Lazy Piggy transposon insertion and remobilization depletes insertions that are non-essential for tumor survival while enriching for maintenance driver insertions. Using this functional genomic approach, we identify potassium channels as a regulator for medulloblastoma, the most common pediatric brain malignancy. Loss of potassium channel Kcnb2 diminishes the pool of medulloblastoma-propagating cells by hampering their replication potential, thereby prolonging the survival of tumor-bearing mice. Mechanistically, Kcnb2 governs potassium homeostasis to regulate plasma membrane tension-gated EGFR signaling, which drives the proliferative expansion of medulloblastoma-propagating cells. Our in vivo functional genomics reveals potassium homeostasis as a tumor maintenance essentiality, establishes a link between potassium channel activity and plasma membrane tension, and defines a mechanism by which ion homeostasis integrates biomechanical and biochemical signaling to promote medulloblastoma aggression.

Biomimetic Hierarchical Nanocomposite Hydrogels: From Design to Biomedical Applications

Natural extracellular matrix (ECM) is highly heterogeneous and anisotropic due to the existence of biomacromolecule bundles and pores. Hydrogels have been proposed as ideal carriers for therapeutic cells and drugs in tissue engineering and regenerative medicine. However, most of the homogeneous and isotropic hydrogels cannot fully emulate the hierarchical properties of natural ECM, including the dynamically spatiotemporal distributions of biochemical and biomechanical signals. Biomimetic hierarchical nanocomposite hydrogels have emerged as potential candidates to better recapitulate natural ECM by introducing various nanostructures, such as nanoparticles, nanorods, and nanofibers. Moreover, the nanostructures in nanocomposite hydrogels can be engineered as stimuli-responsive actuators to realize the desirable control of hydrogel properties, thereby manipulating the behaviors of the encapsulated cells upon appropriate external stimuli. In this review, we present a comprehensive summary of the main strategies to construct biomimetic hierarchical nanocomposite hydrogels with an emphasis on the rational design of local hydrogel properties and their stimuli-responsibility. We then highlight cell fate decisions in engineered nanocomposite niches and their recent development and challenges in biomedical applications.

An Elastic and Damage-Tolerant Dry Epidermal Patch with Robust Skin Adhesion for Bioelectronic Interfacing.

On-skin patches that record biopotential and biomechanical signals are essential for wearable healthcare monitoring, clinical treatment, and human-machine interaction. To acquire wearing comfort and high-quality signals, patches with tissue-like softness, elastic recovery, damage tolerance, and robust bioelectronic interface are highly desired yet challenging to achieve. Here, we report a dry epidermal patch made from a supramolecular polymer (SESA) and an in situ transferred carbon nanotubes' percolation network. The polymer possesses a hybrid structure of copolymerized permanent scaffold permeated by multiple dynamic interactions, which imparts a desired mechanical response transition from elastic recoil to energy dissipation with increased elongation. Such SESA-based patches are soft (Young's modulus ∼0.1 MPa) and elastic within physiologically relevant strain levels (97% elastic recovery at 50% tensile strain), intrinsically mechanical-electrical damage-resilient (∼90% restoration from damage after 5 min), and interference-immune in dynamic signal acquisition (stretch, underwater, sweat). We demonstrate its versatile physiological sensing applications, including electrocardiogram recording under various disturbances, machine-learning-enabled hand-gesture recognition through electromyogram measurement, subtle radial artery pulse, and drastic knee kinematics sensing. This epidermal patch offers a promising noninvasive, long-duration, and ambulant bioelectronic interfacing with anti-interference robustness.

Wearable respiratory sensors for COVID-19 monitoring.

Since its outbreak in 2019, COVID-19 becomes a pandemic, severely burdening the public healthcare systems and causing an economic burden. Thus, societies around the world are prioritizing a return to normal. However, fighting the recession could rekindle the pandemic owing to the lightning-fast transmission rate of SARS-CoV-2. Furthermore, many of those who are infected remain asymptomatic for several days, leading to the increased possibility of unintended transmission of the virus. Thus, developing rigorous and universal testing technologies to continuously detect COVID-19 for entire populations remains a critical challenge that needs to be overcome. Wearable respiratory sensors can monitor biomechanical signals such as the abnormities in respiratory rate and cough frequency caused by COVID-19, as well as biochemical signals such as viral biomarkers from exhaled breaths. The point-of-care system enabled by advanced respiratory sensors is expected to promote better control of the pandemic by providing an accessible, continuous, widespread, noninvasive, and reliable solution for COVID-19 diagnosis, monitoring, and management.

Delineating cooperative effects of Notch and biomechanical signals on patterned liver differentiation

Controlled in vitro multicellular culture systems with defined biophysical microenvironment have been used to elucidate the role of Notch signaling in the spatiotemporal regulation of stem and progenitor cell differentiation. In addition, computational models incorporating features of Notch ligand-receptor interactions have provided important insights into Notch pathway signaling dynamics. However, the mechanistic relationship between Notch-mediated intercellular signaling and cooperative microenvironmental cues is less clear. Here, liver progenitor cell differentiation patterning was used as a model to systematically evaluate the complex interplay of cellular mechanics and Notch signaling along with identifying combinatorial mechanisms guiding progenitor fate. We present an integrated approach that pairs a computational intercellular signaling model with defined microscale culture configurations provided within a cell microarray platform. Specifically, the cell microarray-based experiments were used to validate and optimize parameters of the intercellular Notch signaling model. This model incorporated the experimentally established multicellular dimensions of the cellular microarray domains, mechanical stress-related activation parameters, and distinct Notch receptor-ligand interactions based on the roles of the Notch ligands Jagged-1 and Delta-like-1. Overall, these studies demonstrate the spatial control of mechanotransduction-associated components, key growth factor and Notch signaling interactions, and point towards a possible role of E-Cadherin in translating intercellular mechanical gradients to downstream Notch signaling.

Advances in non-invasive biosensing measures to monitor wound healing progression

Impaired wound healing is a significant financial and medical burden. The synthesis and deposition of extracellular matrix (ECM) in a new wound is a dynamic process that is constantly changing and adapting to the biochemical and biomechanical signaling from the extracellular microenvironments of the wound. This drives either a regenerative or fibrotic and scar-forming healing outcome. Disruptions in ECM deposition, structure, and composition lead to impaired healing in diseased states, such as in diabetes. Valid measures of the principal determinants of successful ECM deposition and wound healing include lack of bacterial contamination, good tissue perfusion, and reduced mechanical injury and strain. These measures are used by wound-care providers to intervene upon the healing wound to steer healing toward a more functional phenotype with improved structural integrity and healing outcomes and to prevent adverse wound developments. In this review, we discuss bioengineering advances in 1) non-invasive detection of biologic and physiologic factors of the healing wound, 2) visualizing and modeling the ECM, and 3) computational tools that efficiently evaluate the complex data acquired from the wounds based on basic science, preclinical, translational and clinical studies, that would allow us to prognosticate healing outcomes and intervene effectively. We focus on bioelectronics and biologic interfaces of the sensors and actuators for real time biosensing and actuation of the tissues. We also discuss high-resolution, advanced imaging techniques, which go beyond traditional confocal and fluorescence microscopy to visualize microscopic details of the composition of the wound matrix, linearity of collagen, and live tracking of components within the wound microenvironment. Computational modeling of the wound matrix, including partial differential equation datasets as well as machine learning models that can serve as powerful tools for physicians to guide their decision-making process are discussed.

The path to a hemocompatible cardiovascular implant: Advances and challenges of current endothelialization strategies.

Cardiovascular (CV) implants are still associated with thrombogenicity due to insufficient hemocompatibility. Endothelialization of their luminal surface is a promising strategy to increase their hemocompatibility. In this review, we provide a collection of research studies and review articles aiming to summarize the recent efforts on surface modifications of CV implants, including stents, grafts, valves, and ventricular assist devises. We focus in particular on the implementation of micrometer or nanoscale surface modifications, physical characteristics of known biomaterials (such as wetness and stiffness), and surface morphological features (such as gratings, fibers, pores, and pits). We also review how biomechanical signals originating from the endothelial cell for surface interaction can be directed by topography engineering approaches toward the survival of the endothelium and its long-term adaptation. Finally, we summarize the regulatory and economic challenges that may prevent clinical implementation of endothelialized CV implants.

Role of extracellular matrix architecture and signaling in melanoma therapeutic resistance.

The extracellular matrix (ECM) is critical for maintaining tissue homeostasis therefore its production, assembly and mechanical stiffness are highly regulated in normal tissues. However, in solid tumors, increased stiffness resulting from abnormal ECM structural changes is associated with disease progression, an increased risk of metastasis and poor survival. As a dynamic and key component of the tumor microenvironment, the ECM is becoming increasingly recognized as an important feature of tumors, as it has been shown to promote several hallmarks of cancer via biochemical and biomechanical signaling. In this regard, melanoma cells are highly sensitive to ECM composition, stiffness and fiber alignment because they interact directly with the ECM in the tumor microenvironment via cell surface receptors, secreted factors or enzymes. Importantly, seeing as the ECM is predominantly deposited and remodeled by myofibroblastic stromal fibroblasts, it is a key avenue facilitating their paracrine interactions with melanoma cells. This review gives an overview of melanoma and further describes the critical roles that ECM properties such as ECM remodeling, ECM-related proteins and stiffness play in cutaneous melanoma progression, tumor cell plasticity and therapeutic resistance. Finally, given the emerging importance of ECM dynamics in melanoma, future perspectives on therapeutic strategies to normalize the ECM in tumors are discussed.

Microfluidic evidence of synergistic effects between mesenchymal stromal cell-derived biochemical factors and biomechanical forces to control endothelial cell function

A functional vascular system is a prerequisite for bone repair as disturbed angiogenesis often causes non-union. Paracrine factors released from human bone marrow derived mesenchymal stromal cells (BMSCs) have angiogenic effects on endothelial cells. However, whether these paracrine factors participate in blood flow dynamics within bone capillaries remains poorly understood. Here, we used two different microfluidic designs to investigate critical steps during angiogenesis and found pronounced effects of endothelial cell proliferation as well as chemotactic and mechanotactic migration induced by BMSC conditioned medium (CM). The application of BMSC-CM in dynamic cultures demonstrates that bioactive factors in combination with fluidic flow-induced biomechanical signals significantly enhanced endothelial cell migration. Transcriptional analyses of endothelial cells demonstrate the induction of a unique gene expression profile related to tricarboxylic acid cycle and energy metabolism by the combination of BMSC-CM factors and shear stress, which opens an interesting avenue to explore during fracture healing. Our results stress the importance of in vivo - like microenvironments simultaneously including biochemical, biomechanical and oxygen levels when investigating key events during vessel repair. Statement of significanceOur results demonstrate the importance of recapitulating in vivo - like microenvironments when investigating key events during vessel repair. Endothelial cells exhibit enhanced angiogenesis characteristics when simultaneous exposing them to hMSC-CM, mechanical forces and biochemical signals simultaneously. The improved angiogenesis may not only result from the direct effect of growth factors, but also by reprogramming of endothelial cell metabolism. Moreover, with this model we demonstrated a synergistic impact of mechanical forces and biochemical factors on endothelial cell behavior and the expression of genes involved in the TCA cycle and energy metabolism, which opens an interesting new avenue to stimulate angiogenesis during fracture healing.

Biomechanical forces and signals operating in the ovary during folliculogenesis and their dysregulation: implications for fertility.

Folliculogenesis occurs in the highly dynamic environment of the ovary. Follicle cyclic recruitment, neo-angiogenesis, spatial displacement, follicle atresia and ovulation stand out as major events resulting from the interplay between mechanical forces and molecular signals. Morphological and functional changes to the growing follicle and to the surrounding tissue are required to produce oocytes capable of supporting preimplantation development to the blastocyst stage. This review will summarize the ovarian morphological and functional context that contributes to follicle recruitment, growth and ovulation, as well as to the acquisition of oocyte developmental competence. We will describe the changes occurring during folliculogenesis to the ovarian extracellular matrix (ECM) and to the vasculature, their influence on the mechanical properties of the ovarian tissue, and, in turn, their influence on the regulation of signal transduction. Also, we will outline how their dysregulation might be associated with pathologies such as polycystic ovary syndrome (PCOS), endometriosis or premature ovarian insufficiency (POI). Finally, for each of these three pathologies, we will highlight therapeutic strategies attempting to correct the altered biomechanical context in order to restore fertility. For each area discussed, a systematic bibliographical search was performed, without temporal limits, using PubMed Central, Web of Science and Scopus search engines employing the keywords extracellular matrix, mechanobiology, biomechanics, vasculature, angiogenesis or signalling pathway in combination with: ovary, oogenesis, oocyte, folliculogenesis, ovarian follicle, theca, granulosa, cumulus, follicular fluid, corpus luteum, meiosis, oocyte developmental competence, preimplantation, polycystic ovary syndrome, premature ovarian insufficiency or endometriosis. Through search engines queries, we yielded a total of 37 368 papers that were further selected based on our focus on mammals and, specifically, on rodents, bovine, equine, ovine, primates and human, and also were trimmed around each specific topic of the review. After the elimination of duplicates, this selection process resulted in 628 papers, of which 287 were cited in the manuscript. Among these, 89.2% were published in the past 22 years, while the remaining 8.0%, 2.4% or 0.3% were published during the 1990s, 1980s or before, respectively. During folliculogenesis, changes occur to the ovarian ECM composition and organization that, together with vasculature modelling around the growing follicle, are aimed to sustain its recruitment and growth, and the maturation of the enclosed oocyte. These events define the scenario in which mechanical forces are key to the regulation of cascades of molecular signals. Alterations to this context determine impaired folliculogenesis and decreased oocyte developmental potential, as observed in pathological conditions which are causes of infertility, such as PCOS, endometriosis or POI. The knowledge of these mechanisms and the rules that govern them lay a sound basis to explain how follicles recruitment and growth are modulated, and stimulate insights to develop, in clinical practice, strategies to improve follicular recruitment and oocyte competence, particularly for pathologies like PCOS, endometriosis and POI.

Collagen gel contraction assays: From modelling wound healing to quantifying cellular interactions with three-dimensional extracellular matrices

Cells respond to and actively remodel the extracellular matrix (ECM). The dynamic and bidirectional interaction between cells and ECM, especially their mechanical interactions, has been found to play an essential role in triggering a series of complex biochemical and biomechanical signal pathways and in regulating cellular functions and behaviours. The collagen gel contraction assay (CGCA) is a widely used method to investigate cell–ECM interactions in 3D environments and provides a mechanically associated readout reflecting 3D cellular contractility. In this review, we summarize various versions of CGCA, with an emphasis on recent high-throughput and low-consumption CGCA techniques. More importantly, we focus on the technique of force monitoring during the contraction of collagen gel, which provides a quantitative characterization of the overall forces generated by all the resident cells in the collagen hydrogel. Accordingly, we present recent biological applications of the CGCA, which have expanded from the initial wound healing model to other studies concerning cell–ECM interactions, including fibrosis, cancer, tissue repair and the preparation of biomimetic microtissues.

Index of Physical activity and Fall Efficacy scale classification through biomechanical signals and Machine Learning.

The rapid increase of the elderly population and chronic diseases have augmented disability in today's world. This situation has led researchers and engineers to create tools and technologies that allow health caregivers, physical trainers, and health policymakers to understand, measure, and treat people with disabilities. Nowadays, artificial intelligence techniques have been applied to improve the performance of these technologies. This article shows the development of a novel classifier that utilizes Machine Learning (ML) algorithms and biomechanical signals to predict a subject's International Physical Activity Questionnaire (IPAQ) and Falls Efficacy Scale (FES). Three ML algorithms were applied K-Nearest Neighbors (KNN), Decision tree, and Support Vector Machine (SVM). Results show the accuracy of classification over 95%, 99%, and 89%, respectively, and validate the correlation between qualitative scales and biomechanical responses in balance training. This classifier poses as an innovative tool to help professionals adjust and improve physical training programs.