In the era of the “Industry 4.0” revolution, self-adjusting and unmanned machining systems have gained considerable interest in high-value manufacturing industries to cope with the growing demand for high productivity, standardized part quality, and reduced cost. Tool condition monitoring (TCM) systems pave the way for automated machining through monitoring the state of the cutting tool, including the occurrences of wear, cracks, chipping, and breakage, with the aim of improving the efficiency and economics of the machining process. This article reviews the state-of-the-art TCM system components, namely, means of sensing, data acquisition, signal conditioning and processing, and monitoring models, found in the recent open literature. Special attention is given to analyzing the advantages and limitations of current practices in developing wireless tool-embedded sensor nodes, which enable seamless implementation and Industrial Internet of Things (IIOT) readiness of TCM systems. Additionally, a comprehensive review of the selection of dimensionality reduction techniques is provided due to the lack of clear recommendations and shortcomings of various techniques developed in the literature. Recent attempts for TCM systems’ generalization and enhancement are discussed, along with recommendations for possible future research avenues to improve TCM systems accuracy, reliability, functionality, and integration. The benefits of advances in digital technologies, along with the development of the Industrial Internet of Things (IIoT) have expanded at a rapid rate over the last two decades. This is due to the development of smart sensing technologies and data storage capacities that has led to the ‘Industry 4.0’ revolution, where advanced manufacturing techniques are combined with IIoT systems to drive further intelligent action back in the physical world, motivating unmanned manufacturing. This drives competitive industrial advantages in terms of reducing cost, increasing productivity, improving quality, and preventing damage to machined parts during processing. An intelligent tool condition monitoring (TCM) system is a building block in this framework to achieve such automated machining systems. It provides a digitalized feedback estimation of the tool condition based on analytical or sensor-based models to safeguard the machined part, and to enable process optimization and quality control in real-time. Therefore, tremendous efforts have been exerted towards developing new methods and implementing innovative technologies to improve the performance of TCM systems and to introduce solutions to the challenges facing manufacturers.Tool condition monitoring systems can be applied offline, online, or in real-time. An offline TCM system entails interrupting the machining process and examining the tool health state using inspection equipment such as an optical microscope at unregulated periods . In onliMany techniques have been presented to model the tool health states in TCM systems, which can be classified into two categories: physics-based, and data-driven models. Physics-based models usually simplify the cutting processes using a semi-empirical law or mechanistic model . They caHigh-performance machining involves overall process optimization through fully utilizing the machine capabilities to minimize production costs, boost productivity, meet pre-defined component quality characteristics, and maximize tool life. It encompasses continuous optimization of the cutting speed, feedrate, and strategies, either offline or online. Therefore, a real-time autonomous TCM system with high degree of generalization and robustness is essential to accommodate this continuous change with minimum calibration efforts and without process disturbance. In this paper, more than 200 recent publications have been analyzed to furnish the knowledge of recent advancements in TCM. Furthermore, research gaps and limitations of the recently developed approaches are highlighted. Despite the numerous literature reviews on the development of TCM systems ,16,17,18The article is organized as follows: As indicated earlier, indirect methods are preferred, as real-time tool health indicators, by establishing a correlation between the measured process parameters and the tool health state. Commonly monitored indirect parameters in TCM systems include cutting forces , vibratiDue to its high sensitivity to tool conditions, the cutting force signal is the most reliable and stable variable in machining operations, which makes it the most commonly utilized signal to detect tool wear ,25. As tThe cutting tool vibrations are measured by piezoelectric or micro-electromechanical system MEMS accelerometers to predict the tool edge wear and the surface roughness of the machined surface, among others ,35. SharAcoustic emission AE sensors are used to capture the radiation of the acoustic waves released from irreversible processes within a material, such as wear, chipping, and breakage of the cutting tool, chip formation, and thermal reaction. Since the frequency bandwidth of the AE waves (100 kHz–1 MHz) is higher than that of machine vibrations and ambient noises (1 Hz–10 kHz), the AE signal is widely considered as one of the most effective methods for detecting tool wear and breakage . In addiThe primary source of energy in cutting operations is the spindle motor current, which is linked to changes in the cutting zone, including the tool health state. With the progression in the tool edge wear, the cutting forces increase, which increases the drawn current . The ineDespite being able to monitor the tool wear level, temperature sensors utilization in real-time TCM systems is rare owing to the high thermal inertia, the low response of the embedded conventional thermocouples , and theThe repetitive shocks and friction between the cutting tool and the workpiece are the primary source of the spindle speed fluctuations . Very feA multi-sensor approach, in which the TCM system considers monitoring several process and machine parameters, is preferable to increase the TCM accuracy and reliability . This haWhen designing a multi-signal TCM system, the acquired data are fused at either the raw signal, feature, or model levels , as showWireless TCM systems provide high implementation flexibility, accessibility, and connectivity compared to wired sensor-based systems. Wireless sensor networks (WSN) provide an efficient and effective solution for TCM systems and other condition monitoring applications ,73,74,75Mounting the sensing unit at a far physical distance from the signal source weakens the acquired data and introduces attenuation and noise to measurements by other components of the machine, such as spindle bearings and collet interfaces ,82. For More reliable AE signals can be gained by mounting the AE sensor on the tool holder close to the signal source, which avoids multiple acoustic wave reflections and shortens the transmission path . To the To overcome the limited practicality of commercial dynamometers, tool-embedded thin-film force sensors have been proposed within the wireless tool-embedded sensor node concept . NumerouSeveral wireless sensor nodes have been integrated with multiple sensors, as provided in 2C protocols used in other designs.The common wireless technologies, utilized to transmit data to the host computer in TCM systems, include Wi-Fi ,115,116,Rechargeable batteries are widely used as a power source for wireless sensor nodes. The wireless module and the microcontroller are the dominant power consumers compared to the sensing unit, which usually has the least power consumption at levels of milliwatt . The powTo reduce the needed battery sizes and prolong its cycle life, energy harvesting techniques have been utilized to continuously charge the utilized battery based on mechanical vibration energy ,129,130,Amplification: At an early step, the signal is typically amplified due to the low-level output signal of the used sensor, which increases the signal-to-noise ratio and reduces the unwanted interference. The maximum voltage range of the signal should meet the maximum input range condition of the analog–digital converter to achieve the best level of accuracy .Sampling: After amplifying the signal, the acquired signal should be sampled at a sampling rate more than two times the highest frequency of interest seen in the signal according to the Nyquist–Shannon sampling theorem . In pracFiltering: Digital or analog filtering is used to exclude the undesired signal frequencies while preserving the correlation between sensor data and process variables, such as studying the cutting force signals at the tool-pass frequency . FilteriSegmentation: As an optional technique for pre-processing sensor data, segments of the signal are extracted when the tool is engaged with the workpiece material as only these segments include information about the tool condition ,131. TheSignal pre-processing is typically needed and executed by a sensor-specific conditioner before or after signal digitalization due to sensor characteristics and the interference caused by mechanical, electrical, and ambient disturbances. The common signal conditioning approaches adopted in the signal pre-processing stage are:In machining processes, the acquired signals are nonlinear and nonstationary, as well as noisy . MoreoveOne of the most crucial stages in TCM systems is feature construction, which determines the success of any classification model . PhysicaTime domain features are the most common and simplest features in terms of extraction and required computations. The most common time-domain statistical features are the average, maximum/minimum, root-mean-square, and peak-to-peak amplitude of the signal. In addition, the probabilistic distribution of acquired data are usually represented through extracting the variance, crest factor, skewness, and kurtosis ,140. MorFrequency domain features are constructed by transforming time-series signals into the frequency domain to evaluate the dominant frequency component. The fast Fourier transform (FFT) or its enhanced variants, the discrete Fourier transform (DFT), and discrete cosine transform (DCT) have been commonly used and reported in the literature ,143,144.Time–frequency domain features can evaluate the signal localization in both time and frequency domains. This domain has attracted considerable attention for TCM systems compared to the aforementioned domains ,18,25. TOne of the most effective methods for time–frequency domain analysis is the empirical mode decomposition EMD that was developed explicitly for nonlinear nonstationary signals using an adaptive data-driven approach ,152,153.The values of constructed features change as a result of variation in cutting conditions, cutting tools and workpiece materials, the type and units of various signals and features, as well as the deterioration of the cutting tool health, among others . They arHigh-dimensional data are another issue in TCM systems that results from constructing features in multiple domains, which increases the computational cost in the training stage and degrades the classifier’s accuracy if insignificant noisy features are included . A modelFilter techniques are open-loop computational methods that only consider the relationship between features and class label without involving the subsequent tool wear classification model, as shown in Wrapper techniques are closed-loop techniques, in which the tool wear model is used for selecting the most discriminative features by minimizing the misclassification error of the model, as shown in Hybrid techniques are the result of merging a wrapper technique and a filter technique to inherit the complementary strengths of both models, as shown in Embedded techniques are built-in feature selection techniques, in which the feature selection and the model training processes are merged . During Subset feature selection techniques are used to select the most discriminative features of the tool health state to minimize the computational effort and to increase the accuracy of the classification model. No relevant information can be lost during the feature selection process. Typically, conventional feature selection techniques rank the extracted features based on their sensitivity to tool condition and then choose the top-ranked features. The feature selection techniques can be categorized as follows :Filter tThe feature transformation methods implement algebraic feature transformation to the input feature set, according to some optimization criteria, to develop a low-dimensional representation to reduce the required computational resources . The outAlgorithms for feature transformation can be classified as linear or nonlinear algorithms . Linear PCA is a popular linear unsupervised feature transformation algorithm that orthogonally projects features into a synthetic feature domain, based on their variances in which features with low variance are disregarded ,179,206.Classifier-based machine learning algorithms have been extensively applied to support the decision-making stage, particularly to monitor the progressive tool wear . PromisiIn addition to the conventional machine learning techniques, researchers have employed adaptive neuro-fuzzy inference system (ANFIS) , relevanRecently developed advanced deep learning methods, such as convolutional neural network (CNN) , recurreTo reduce the learning effort, deep transfer learning approach has been proposed recently in TCM applications, where a classification model that was developed for a specific application is reused as a starting point to develop a new model for another application ,229,230.AI model interpretation increases trust in the rendered decisions as they can be logically assessed. Several conventional classification models, such as linear or tree-based models, are easy to interpret and, hence, can be physically linked to the cutting process. However, this comes at the expense of their biased performance, which reduces the model accuracy. Deep machine learning algorithms overcome this performance limitation but are difficult to interpret and, hence, are not the recommended approach in industrial applications, where a false rendered decision could have a high cost impact on the industrial facility. A desirable solution would use an interpretable model with low-variant key features that are directly linked to tool wear and insensitive to the cutting conditions.Low computational and decision-rendering times are essential for successful real-time implementation of TCM systems. Hassan et al. benchmarked the computational time needed by different machine learning algorithms, including SVM, LDA, ANN, and KNN using the same set of features to define the tool condition . The KNNDespite the utilization of the most advanced conventional and deep learning algorithms, no comprehensive, reliable, and friendly solution to monitor tool wear in real-time has been found yet in the open literature to satisfy the industrial environment requirements. They are commonly trained and validated on a single machine tool, with a single cutting tool-workpiece combination, and under a limited set of cutting conditions ,232, as after it has taken place. They cannot predict and prevent the tool failure, which jeopardizes the economics of the machining operations. Duo et al. collected several external and machine internal signals to predict the tool breakage due to excessive tool wear in drilling operations [High stresses and excessive heat at the tool cutting edge are the common causes for sudden tool failures in the form of chipping or/and breakage, particularly when machining a difficult-to-cut material ,234. Earerations . They coVery few studies have been concerned with providing an online prediction and prevention of sudden tool chipping or breakage through monitoring the unstable crack propagation in the pre-failure stage, which has been presented by Hassan et al. ,237. TheData acquisition: Until recently, previous TCM research has adopted a conventional approach, in which the sensors are mounted on the machine spindle or the workpiece. In this approach, vibration and acoustic emission AE sensors were preferred in industrial TCM applications, since monitoring cutting forces using a table dynamometer is impractical due to the high intrusiveness and investment cost. Although the cutting tool temperature is correlated to tool wear in the milling operations of difficult-to-cut materials, such as Ti6Al4V alloy, it is not widely monitored and used as an indicator of tool wear. The quality of the vibration and AE signals are impacted by the long signal transmission path and multiple reflective surfaces, particularly when they are mounted on the machine spindle. This problem can be alleviated by using a universal wireless tool-embedded sensor node in the TCM system. The application of this approach is still limited. Recently, some researchers were able to integrate force, vibration, and temperature sensors into the tool holder to increase the universality of the TCM system. To date, AE has not been integrated yet on a rotating tool for milling operations, due to the complex signal conditioning electronics needed to fit in a confined space on the tool holder. For the conventional multi-sensor approach, optimizing the sensors’ selection and location need to be further investigated, based on the availability and ease of integration of the sensors, as well as the TCM system performance and economics. In the reported commercial and academic designs of TCM tool-embedded sensor nodes, no optimization has been attempted for the selection of the sensors type, proximity, and orientation. Additionally, none of the reported designs have been tailored for machining difficult-to-cut materials, where high cutting forces and concentrated heat can be encountered, causing sensor drift. The sampling rate and the reduced structural stiffness are still the main obstacles for developing a reliable universal wireless sensor node. Furthermore, a comprehensive solution for the power management of the senor node has not been realized yet to reduce the interruptions and/or the intrusiveness to the machining process.Feature construction and dimensionality reduction: The TCM research to date has focused on using conventional features constructed from the time, frequency, and time–frequency domains, rather than discovering novel features that correlate to the tool health state, while being independent of the cutting parameters. The compatibility of such features with the most up-to-date tool wear modeling algorithms should be investigated. The time–frequency domain has attracted attention of many researchers in TCM applications, particularly the EMD technique and its variants due to its ability to handle nonlinear nonstationary signals. This technique is, however, susceptible to mode mixing and mode splitting. The fast iterative filtering technique can tackle these issues but its application is still limited in TCM. The generality, adaptability, and computational cost of AI algorithms can be improved by monitoring new variables or discovering new features. Based on the reviewed literature, there has been no detailed investigation of the tool wear impact on the chip segmentation and its consequences on the acquired signals, rubbing force, tooth-pass frequency, and the direction of the resultant cutting force. Such investigation may help to explore a robust feature or variable that decreases the learning effort and increases the generality of the developed model. Due to the great impact of dimensionality reduction on the performance and accuracy of machine learning algorithms, a wide variety of dimensionality reduction strategies have been proposed in recent decades to address the problem of high-dimensional data in TCM applications. The two main adopted techniques are feature selection and feature transformation. However, there is currently no universal strategy for dimensionality reduction that can be applied to all scenarios. Future TCM research should consider developing techniques that are tailored for the nature of acquired sensory data in machining operations to improve the accuracy and robustness of the TCM system.before it happens. Only one research work has been found that can monitor the unstable crack propagation stage in stationary tools before the occurrence of chipping and/or breakage in intermittent machining operations using an AE sensor by pre-setting a threshold based on experimental results. A fully automated and comprehensive solution for milling operations still needs to be developed. There is also a need for establishing a correlation between the AE bursts and the chipped material, as well as optimizing the location of mounting the AE in the milling machine to reduce the signal transmission path and multiple acoustic wave reflections.Decision making for tool health state monitoring: A remarkable interest has been given to tool wear monitoring with the anticipated increase in utilizing more advanced artificial intelligence AI techniques. Conventional algorithms such as ANNs became more popular for tool wear modeling. Choosing the appropriate algorithm is impacted by the information content and quality of the processed signal. This necessitates extensive research into the efficacy of various signal features and signal processing techniques before implementing the monitoring AI algorithms needed to reduce the learning effort and improve the TCM system generalization. The complex nonlinear and nonstationary nature of machining processes has led to utilizing advanced deep learning algorithms. To overcome their main limitation, few studies have recently been conducted to propose a practical deep learning algorithms with low training efforts to increase the possibility of adopting them for industrial TCM systems. The vast majority of the previous research has focused on exploiting process-feedback signals to identify changes in cutting parameters following tool chipping and/or breakage in machining operations. However, it is crucial to predict and prevent sudden tool failures by chipping and/or breakage Numerous TCM systems have been developed to detect tool wear, chipping, and breakage in laboratories around the world. Various data acquisition, processing, and decision-making AI techniques have been proposed in an attempt to develop an industry-oriented TCM system. Despite the fact that TCM research has made significant progress, components of the TCM system have several shortcomings that require further investigation. The following are the conclusions and future recommendations for an industry oriented TCM system:Other issues that require additional developments for the acceptance and implementation of TCM systems by industry include: (a) handling the quantity of data required to effectively train the available data-driven models, (b) any feature selection/transformation and threshold value pre-setting should be handled entirely by the TCM system with minimum intervention from the operator, and (c) optimizing the tool remaining life so that it can complete at least one continuous machined feature before being replaced. This can be achieved by integrating a TCM system with an adaptive control (AC) system, in which the signal behaviors are learnt to manipulate the operating conditions. Such integration is effective and robust but more complex and needs further research.


Cerebral ischemia is one of the major diseases associated with death or disability among patients. To date, there is a lack of effective treatments, with the exception of thrombolytic therapy that can be administered during the acute phase of ischemic stroke. Cerebral ischemia can cause a variety of pathological changes, including microvascular basal membrane matrix, endothelial cell activation, and astrocyte adhesion, which may affect signal transduction between the microvessels and neurons. Therefore, researchers put forward the concept of neurovascular unit, including neurons, axons, astrocytes, microvasculature , and oligodendrocytes. Numerous studies have demonstrated that exercise can produce protective effects in cerebral ischemia, and that exercise may protect the integrity of the blood-brain barrier, promote neovascularization, reduce neuronal apoptosis, and eventually lead to an improvement in neurological function after cerebral ischemia. In this review, we summarized the potential mechanisms on the effect of exercise on cerebral ischemia, by mainly focusing on the neurovascular unit, with the aim of providing a novel therapeutic strategy for future treatment of cerebral ischemia. Research on neuroprotective therapy for cerebral ischemia has been a hot topic worldwide. Ischemic tolerance refers to a short period when patients experience cerebral ischemia before the onset of a severe ischemic stroke, thus enhancing the tolerance of brain tissue to the subsequent ischemic injury . This suA neurovascular unit (NVU), which was initially proposed by The mechanism of neuronal injury caused by cerebral ischemia is complex. Neuronal apoptosis, after cerebral ischemia, is regulated by many different events and may develop by initiating the internal cellular death mechanism. Many studies have discovered that cerebral ischemia can induce cell apoptosis, and most apoptotic cells are neurons, with a few glial cells and vascular endothelial cells . Delayedvia RIPK1 ubiquitination, and neuronal necroptosis could be reduced by upregulation of Pellino3 -mixed lineage kinase domain-like protein (MLKL) signaling pathway is involved in the onset of neuronal necrosis after injury by cerebral ischemia , 2020. TPellino3 . Zhang ePellino3 .The autophagy signaling pathway in cerebral ischemia is complex, is connected to necrosis and apoptosis, and affects the degree of brain injury . Su et aAfter cerebral ischemia, the blood-brain barrier (BBB) not only has abnormal function but also suffers from structural damage . The micMatrix metalloproteinases (MMPs) are a group of zinc-dependent enzymes that have the ability to degrade the extracellular matrix. Under physiological conditions, MMPs are known to be involved in embryo development, angiogenesis, nerve development, and regulation of tissue remodeling . After tThe pathological process after the onset of cerebral ischemia is complex, and the substances and factors that are released post-stroke have different roles. Each component of the NVU becomes damaged after stroke and maintains the microvascular-neuronal connection. The integrity of NVU is key to the prevention and treatment of ischemic stroke. Exercise, as a neuroprotective method, has been validated to be involved in protecting NVU during ischemic stroke .After cerebral ischemia, a series of cascade reactions cause BBB dysfunction and an increase in cerebrovascular permeability, leading to brain edema. MMP-9 degrades the extracellular matrix, which is directly related to BBB dysfunction. Previous studies have indicated that MMP-9 reaches its peak at 48 h after ischemia, causing irreversible damage to BBB . InhibitAfter the occurrence of an ischemic stroke, cell death, especially neuronal death, occurs in the core area of ischemia. Furthermore, the extent of infarction is related to the degree of interruption of blood supply. Reducing neuronal apoptosis can help improve the neurological function after the onset of cerebral ischemia .Extracellular-regulated protein kinase 1/2 functions in the neuroprotective mechanism of exercise preconditioning. After the occurrence of ischemic stroke, heat shock protein (HSP)-70 (HSP-72) can protect neuronal apoptosis, caused by ischemia and hypoxia, and play an important role in cell survival and recovery. The increased synthesis of HSP-70 (HSP-72) can be utilized as an indicator of active repair and compensate for nerve reconstruction; it can also promote the recovery of neurological dysfunction after ischemia . Recent Since the discovery of BDNF , its rolNumerous clinical and animal studies have suggested that regular aerobic exercise can increase the neuroprotective effect by enhancing the secretion of neurotrophins, including BDNF and insulin-like growth factor (IGF)-1, in the brain. Low concentrations of IGF-1 in the serum are found among chronic hemiparesis patients after they suffer from stroke . In a raStudies have demonstrated that exercise can protect the cerebrovascular system. Nitric oxide (NO) can help relax vascular smooth muscle cells and inhibit smooth muscle cell proliferation, which has an important function in inhibiting elevated blood pressure and vascular remodeling. Exercise can help stimulate phosphorylation and activation of AMP-activated protein kinase (AMPK) in vascular endothelial cells. This can promote phosphorylation of endothelial nitric oxide synthase (eNOS), increase the release of NO, improve endothelium-dependent relaxation function, and can be activated by shear force during exercise. Therefore, eNOS can increase NO production and enhance endothelium-dependent relaxation function . Nitric Vascular endothelial growth factor (VEGF) plays an important role during the process of exercise-induced angiogenesis. Exercise can induce the gene and protein expression of VEGF  and decrInfusion of endothelin-1 (ET-1), as a potent vasoconstrictor, into the animal’s hippocampus using stereotaxic surgery is a method that is frequently used to develop an ischemia model . A cliniExercise is an important method of preventing and rehabilitating cerebral ischemia, as it can not only reduce the incidence of stroke, but also play a protective role in the development of stroke, thereby reducing the severity and improving stroke outcome. Based on the current review, exercise can alleviate the damage of NVU after cerebral ischemia by inhibiting neuronal apoptosis, reducing BBB dysfunction, and promoting angiogenesis and synaptic plasticity. Elucidating the neuroprotective mechanism of exercise will be helpful in improving people’s understanding of exercise, and encourage patients that are at high risk of stroke to actively participate in exercise. They will also provide new therapeutic strategies and potential drug targets for the prevention and treatment of cerebral ischemia in the future. Many challenges and issues remain to be solved and emphasized in the further study, including, but not limited to, exploring optimal duration, initiating time, intensity of exercise, varying responses of different brain regions and cell types to exercise, and the discrepancy of gender and age in response to exercise. Another existing difficulty is the low long-term compliance of patients. Therefore, it is necessary to strengthen health education for the target high-risk population and improve their understanding and attention to the significance of exercise intervention.HZ designed and conceptualized this review. JH drafted and revised the manuscript. HZ and QX edited the manuscript. All authors contributed to the manuscript and approved the final version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Atherosclerosis is a progressive insidious chronic disease that underlies most of the cardiovascular pathologies, including myocardial infarction and ischemic stroke. The malfunctioning of the lysosomal compartment has a central role in the etiology and pathogenesis of atherosclerosis. Lysosomes are the degradative organelles of mammalian cells and process endogenous and exogenous substrates in a very efficient manner. Dysfunction of these organelles and consequent inefficient degradation of modified low-density lipoproteins (LDL) and apoptotic cells in atherosclerotic lesions have, therefore, numerous deleterious consequences for cellular homeostasis and disease progression. Lysosome dysfunction has been mostly studied in the context of the inherited lysosomal storage disorders (LSDs). However, over the last years it has become increasingly evident that the consequences of this phenomenon are more far-reaching, also influencing the progression of multiple acquired human pathologies, such as neurodegenerative diseases, cancer, and cardiovascular diseases (CVDs). During the formation of atherosclerotic plaques, the lysosomal compartment of the various cells constituting the arterial wall is under severe stress, due to the tremendous amounts of lipoproteins being processed by these cells. The uncontrolled uptake of modified lipoproteins by arterial phagocytic cells, namely macrophages and vascular smooth muscle cells (VSMCs), is the initial step that triggers the pathogenic cascade culminating in the formation of atheroma. These cells become pathogenic “foam cells,” which are characterized by dysfunctional lipid-laden lysosomes. Here, we summarize the current knowledge regarding the origin and impact of the malfunctioning of the lysosomal compartment in plaque cells. We further analyze how the field of LSD research may contribute with some insights to the study of CVDs, particularly how therapeutic approaches that target the lysosomes in LSDs could be applied to hamper atherosclerosis progression and associated mortality. Cardiovascular diseases (CVDs) are a group of disorders affecting the function of the heart and blood vessels and constitute the current leading cause of death worldwide, claiming more lives than all forms of cancer combined . AtherosAtherosclerotic lesions are predominantly located in the intima layer of middle-sized and large elastic and muscular arteries, especially at branch points and in areas of high vessel curvature . These aIn the early stages of atherosclerosis intima thickening becomes pathological (PIT), as the ECM facilitates the binding, retention, and deposition of further lipoprotein-derived lipids. The LDLs are subsequently modified by numerous mechanisms including oxidation and enzymatic cleavage, transforming them into pro-inflammatory oxidized LDL (oxLDL). These modified lipoproteins damage the endothelium, triggering a pro-inflammatory cascade initiated by the activation of ECs, which start secreting chemo-attractants   and adheThe pro-inflammatory plaque macrophages give rise to local inflammation by secreting pro-inflammatory cytokines  , which rInitially, the necrotic core is surrounded by a thick fibrous cap composed of VSMCs, which protects the vulnerable plaque . HoweverDuring plaque development, one organelle in particular endures a sheer amount of stress. Lysosomes, the recycling centers of the cell, must cope with the unrestrained amounts of lipoproteins taken up by foam cells, process the mounting apoptotic bodies engulfed by phagocytes and, as a nutrient sensing platform, regulate the unbalanced cellular metabolic status and growth rate. The giant task of these small organelles in atherosclerotic plaques was first recognized by the pioneering work of Christian De Duve , Nobel pThese small cytoplasmic organelles are spherical membrane-bound vesicles containing numerous acidic hydrolytic enzymes that can breakdown biological polymers, such as lipids, proteins, carbohydrates, and nucleic acids . LysosomTo this date, four members of the MiT/TFE family have been identified: microphthalmia-associated transcription factor (MITF), transcription factor EB (TFEB), TFE3, and TFEC . All fouLysosomes are comprised by more than 70 hydrolases, 200 membrane proteins and numerous other associated proteins . Of the The most severe cardiovascular manifestations in LSDs have prenatal onset, for example, cardiomyopathy in infantile-onset Pompe disease , while other manifestations occur more subtly at later stages and become more life-threatening over time, in conditions such as Fabry disease  . In the The concept of LSD has been broadened to encompass acquired pathologies in which malfunction of the autophagy-lysosomal system plays a significant etiological role . ExternaIn early atherosclerotic lesions, monocyte-derived macrophages take up the retained lipoproteins through receptor-mediated endocytosis and fluid-phase pinocytosis . Native in vivo . Regardless of their origin, these modifications decrease the ability of LDL to bind to the LDLR  modifications, which are associated with increased atherogenicity. These cholesterol-containing structures may be oxidized, aggregated, or enzymatically modified. These modifications significantly affect the physicochemical and biological properties of the lipoproteins . One of in vivo . The preactivity . In the the LDLR . The prothe LDLR , althougthe LDLR , 2021.As the lesion progresses, foam cells arise as the result of the uncontrolled uptake and defective metabolization of modified-LDL accumulated in the vessel wall by cells. The uptake of modified lipids by phagocytes, namely macrophages and VSMCs, is mediated by alternate SRs . These rA large number of open questions still surround the mechanisms by which oxLDL triggers lysosomal lipidosis. Nonetheless, considerable advances have been made in recent years concerning the characterization of the multiple processes driving the impairment of lysosomal homeostasis in atherosclerotic plaque cells. Numerous studies have demonstrated that oxLDL, CC, and other modified lipids are able to alkalize lysosomal pH, impair the degradative capacity of lysosomal hydrolases and cause damage to the lysosomal membrane .Each cell contains different populations of lysosomes, which can be distinguished by their position, size, acidification and reformation properties . HydrolyAll lysosomal hydrolases, responsible for the catabolism of endogenous and exogenous substrates, have optimal activity at acidic pH. The raise in lysosomal pH observed in foam cells impairs the ability of these enzymes to break down the incoming modified lipoproteins . This drInflammation” section) and cell death responses [for information on lysosomal-mediated cell death pathways see Autophagy” section), autophagy is disturbed in atherosclerosis, and the removal of damaged lysosomes may thus be impaired, contributing to the aggravation of the pathogenic cascade.OxLDL and CC, formed as a consequence of lysosomal FC accumulation, can cause damage to the lysosomal membrane. In macrophages, oxLDL- and CC-mediated lysosomal membrane permeabilization (LMP) causes loss of proton gradient and a massive release of lysosomal hydrolases into the cell cytosol . DownstrLysosomes are indispensable players in several mechanisms that affect atherosclerotic disease progression, including inflammation, efferocytosis, exocytosis, autophagy, mTOR signaling, and iron metabolism. The irreversible lipid accumulation taking place in the lumen of lysosomes of advanced plaque cells severely affects the ability of the autophagy-lysosomal axis to perform these fundamental functions, further aggravating the pathological cascade through, for example: iron-mediated lysosomal oxidation of lipoproteins, exocytosis of partially degraded oxLDL, inefficient disposal of apoptotic bodies and inflammasome activation. Next, we will discuss the most relevant consequences of lysosomal dysfunction for plaque development.in vivo. Indeed, the lysosomal acidic environment increases the solubility of iron facilitating oxidation  . The LYNIn the case of macrophages, the mTOR pathway is not only a key sensor of nutrient status, but also the coordinator of metabolic and inflammatory signals determining activation of these cells . Macroph2+-independent manner   leads to marked increases in atherosclerosis . The grosection) .In ECs, oxLDL and other atherogenic insults stimulate autophagy to promote cell survival . This prEfferocytosis is a multistep process of engulfment of dead cells by phagocytes that allows multicellular organisms to recycle cellular components . The remAs discussed earlier, autophagy, if not excessive, protects macrophages against cell death. This is illustrated by the fact that blocking autophagy worsens the recognition and clearance of dead cells by efferocytes and promotes plaque necrosis . PresentScientists in the LSD field have been developing strategies to circumvent the defects in lysosomal function associated with the pathologies. These pharmacological and genetic strategies may aim to directly correct the protein defect, to ameliorate pernicious secondary effects or to provide a general boost in lysosome function . DespiteThere is currently no curative treatment for LSDs. Although gene therapy has made significant strides toward this goal in the last years, the standard of care for most LSDs (particularly the non-neuronopathic forms) is still enzyme replacement therapy (ERT). ERT consists in the supplementation with exogenous recombinantly produced lysosomal hydrolases delivered intravenously  . ERT witSubstrate reduction therapy (SRT) is an alternative therapeutic approach often employed in LSDs whenever treatment by ERT is not feasible. Approved SRT strategies involve the pharmacological inhibition of the synthesis of glycosphingolipids (GSLs), a class of membrane lipids that undergo lysosomal breakdown and that is often a primary or secondary storage product of LSDs . Multipl–/– mice by reprogramming macrophages   . Additio efflux) . Despite efflux) . New for efflux) , c.Recent studies have demonstrated that mTOR inhibitors have unique anti-atherosclerotic effects, including induction of autophagy, depletion of plaque macrophages, activation of cholesterol efflux and inhibition of pro-inflammatory signaling . HoweverLysosomal cathepsins, particularly when present in the extracellular milieu, have been implicated in the etiology of CVDs . The extIn vitro studies have demonstrated that increasing lysosomal biogenesis through TFEB overexpression can rescue the lipid-induced lysosomal dysfunction, reduce inflammasome activation and decrease atherosclerosis progression  and c-MYC . The uniAlmost 50 years after its publication, the original observation by De Duve, the scientific “father” of lysosomes, has been vindicated. A large body of evidence has been produced confirming the central role played by lysosomal dysfunction in atherogenesis. Such studies have demonstrated that lysosomes alone must process the lipoproteins trapped in the arterial wall during atherosclerotic plaque development. While their catalytic function in ECs, VSMCs and macrophages—the main cell types of the arterial wall—remains intact in the initial stages of plaque development, eventually the influx of substrates surpasses the capacity of these small organelles. The advent of extracellular and/or intracellular modifications in the lipoproteins, throws a final wrench into the endolysosomal compartment, halting its primary function as the degradative compartment of the cell and, as a consequence, its secondary  functions.Although significant progress has been made in the understanding of the etiology and the consequences of lysosomal dysfunction in arterial plaque cells, substantial questions remain. Scientists are still to clarify, among other questions: exactly where and how modifications in lipoproteins occur; which components of oxLDL underlie its atherogenic properties; and how the different transcription factors orchestrate the response to a dysfunctional lysosomal compartment. Here we argue that, in order to answer these questions, scientists in the field may benefit from the knowledge gathered since the 1950’s by researchers studying LSDs, monogenic inherited disorders affecting the functioning of lysosomes. The advantages of the cooperation between these domains of expertise are already evident. For example, initial observations by scientists investigating LSDs enabled researchers to study the key role of the transcription factor TFEB, the master regulator of lysosome biogenesis, in the development of atherosclerosis. Additionally, many markers of autophagy-lysosomal dysfunction may also be employed as (bio)markers for atherosclerosis prognosis . Finally, this cooperation has already brought to light the fact that therapeutic interventions aiming to compensate the individual deficiencies in lysosomal proteins or to boost the autophagy-lysosomal machinery as a whole, hold considerable potential for the treatment of atherosclerosis. The knowledge thus gathered may assist in the ongoing efforts to minimize the morbidity and mortality associated to atherosclerosis.OV proposed and structured the outline of the manuscript. CR did the initial literature research. AM wrote the majority of the manuscript and designed the figures. All authors have contributed to the writing and reviewed the manuscript, read and agreed to the published version of the manuscript.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.


A growing body of research has confirmed that nanoparticle (NP) systems can enhance delivery of therapeutic and imaging agents as well as prevent potentially damaging systemic exposure to these agents by modifying the kinetics of their release. With a wide choice of NP materials possessing different properties and surface modification options with unique targeting agents, bespoke nanosystems have been developed for applications varying from cancer therapeutics and genetic modification to cell imaging. Although there remain many challenges for the clinical application of nanoparticles, including toxicity within the reproductive system, some of these may be overcome with the recent development of biodegradable nanoparticles that offer increased biocompatibility. In recognition of this potential, this review seeks to present recent NP research with a focus on the exciting possibilities posed by the application of biocompatible nanomaterials within the fields of male reproductive medicine, health, and research. The last four decades have witnessed the development of a range of nanopharmaceuticals designed for the targeted, efficacious delivery of bioavailable drugs . The genThe reproductive system functions to arouse sexual interest, produce healthy gametes, facilitate fertilization of the egg, and to provide a nurturing environment for the resultant embryo until the time of parturition. The sophistication and complexity of this system increases its vulnerability to various forms of pathology, which commonly manifest in sub-/in- fertility phenotypes. Indeed, infertility afflicts an estimated 9% of the human population of reproductive age , represein vitro study of male gametes is complicated by their relative short lifespan ex vivo and the fact that they are highly sensitive to environmental exposures as diverse as excursions in temperature and pH as well as to a plethora of xenobiotic compounds , which separates the seminiferous tubules into basal and adluminal compartments. Sertoli cells secrete a number of cytokines, growth factors and immunoregulatory molecules thus protecting the haploid germ cells from the immune system . By estaAlong with LC , the intThere are a number of cellular insults that are capable of disrupting the redox status and thereby inducing germ cell ablation within the testes. Pro-oxidants and sources of intrinsic and extrinsic oxidative stress, such as autoimmune disease, exposure to radiation , xenobioThe field of nanopharmaceuticals encompasses the development and use of nanomaterials for therapeutic, diagnostic, and theragnostic modalities. The physicochemical properties of nanomaterials overcome some of the challenges and limitations posed by more traditional therapeutic agents thus enhancing their utility for drug delivery. Such properties include the ultra-small size  , antimicQuantum dots (QDs) are semiconductor nanocrystals of ultra- small hydrodynamic radius of <10 nm and are utilised for imaging applications rather than drug delivery. QDs possess very desirable qualities such as high yield and stable fluorescence, as well as being amenable to surface modification with targeting moieties. These attributes could make them invaluable in research  as well Arguably, the most promising of the biodegradable, metal based, nanoparticles are the iron oxide NPs.Iron oxide NPs (IONPs), which have been widely researched for drug delivery and as platforms for magnetic resonance imaging (MRI) contrast reagents. IONPs are biodegraded in vivo into iron ions , which iSilica nanoparticles (SNPs) are composed of porous silica  and can in vivo to silicic acid, which is then excreted via the kidneys  constitute a large proportion of the NP formulations that have been approved by the U.S. Federal Drug Administration (FDA) and are currently being marketed . Polymerin vitro and in vivo performance of PNPs as drug delivery agents. Furthermore, there are currently six polymeric pharmaceutical products in Phase I, II, and III clinical trials .Combined, the stability, responsiveness, tunability, facility for specific functionality via surface modification, along with biocompatibility and FDA approval status afforded to NPs composed of the amphiphilic block copolymers, poly(lactic acid) (PLA) or poly(lactic-co-glycolic acid) (PLGA), has identified this class of NP as the focus for intense scientific and clinical interest . As within vivo. One of these components, the cell-surface “do-not-eat-me” protein, CD47, binds to and signals phagocytes that the cell is “self” thereby inhibiting phagocytosis. in vivo clearance compared to that of PEGylated PLGA NPs  of endosomal origin formed by the fusion of multivesicular bodies with the plasma membrane  and are Exosomes possess a “homing” ability that facilities the targeting of particular recipient cell type(s). Together, their size and endowment with surface “self” proteins enable exosomes to evade recognition and removal by the immune system and bestows excellent biocompatibility . ExosomeThe current research in this use of biomimicry to produce safer and more effective EV and exosomal nanosystems for drug delivery was comprehensively reviewed by In summary, the major limitations to the wider use of exosomes as carriers include their unfavorable pharmacokinetics , lack ofCovalent attachment of targeting moieties such as peptides, antibodies or aptamers to the NP surface provides the opportunity for circulating NPs to bind to specific cell surface biomarkers. This, in turn, facilitates the delivery of the NP payload to selected cell types , 3. TargThis targeting strategy enables elevation of the local concentration of the drug whilst maintaining the systemic levels well below the maximum tolerated dose (MTD) and thus decreasing the chance of off-target effects. The targeting moieties can be coupled to PEGylated NPs via the PEG portion of the polymer before or after formation of PNPs . TargetiAdvantageously, the testes presents several uniquely expressed receptors for hormones such as the FSH, LH, and the Anti-Mullerian hormone (AMH), that are ideal for targeting using peptides or antibodies. The structure and kinetics of the FSH receptor, in particular, have been extensively studied. On binding of a ligand to its active site, both the FSH receptor and bound ligand are internalized via receptor mediated endocytosis . Indeed,There have been many recent review articles discussing the various aspects of reproductive research, health and medicine that might be addressed using specifically engineered nanosystems . Rather Cytotoxic cell ablation pharmaceuticals are currently used for a variety of scientific and medical applications to selectively ablate a single type of cell  with theAlmost all anticancer therapies rely on the enhanced permeability and retention (EPR) effect, that is, passive accumulation of therapeutics in the tumor . The advν β3 integrins over-expressed on the surface of cancer cells. When exposed to blue-light radiation, this nanosystem was able to increase the accumulation of the drug and to reverse antiapoptotic effects of survivin as well as to enhance ROS levels (Tripterygium wilfordii Hook F.) for use in ovarian cancer  payload that inhibits the translation of proteins involved in the resistance pathway. Examples of such dual-mode NPs include those described by S levels . AnotherS levels  or drugsn cancer . A recenn cancer . Therefon cancer .NPs can overcome the challenge of maximizing cytotoxicity within the tumor by incorporating all of the drugs in the one carrier and thereby delivering drug cocktails simultaneously to the cell. The use of nanotherapeutics may also obviate or reduce some of the long- and short-term side effects of chemotherapeutic drugs. For instance, the cardiotoxicity resulting from treatment with cisplatin or doxorubicin. The therapeutic potential of NP cisplatin-delivery strategies have been extensively discussed in review articles by Globally, prostate cancer (PC) is the second most commonly diagnosed cancer in men  and is rin vitro and in in vivo xenograft models of the PSMA-positive/androgen-receptor negative LNCaP cell line and the PSMA-negative/androgen-receptor positive CRPC PC-3 cell line , distribution to off-target tissues was reduced, and a significant inhibition of growth of xenograft tumors was observed.NPs may better facilitate the detection of ultra-small clusters of tumor cells by MRI than traditional contrast reagents. With this in mind,  Resovit . SimilarDespite being relatively uncommon, accounting for only 1% of all cancers, testicular cancer (TC) is the most prevalent solid malignancy in 15–30 year old males. Like PC, TC is more prevalent in developed countries where altered environmental factors and higher exposure to xenobiotics, both pre- and postnatally, are believed to be responsible for its increasing prevalence . TC is uTreatment of TC usually involves removal of the effected testis (orchiectomy) or chemotherapy followed by orchiectomy in the case of metastasis . Testis in vitro  baby in 1978, the field of assisted reproduction technology (ART) has made much progress. However, among the many challenges that remain in this field, at least some may be addressed using nanotechnology. Thus, non-human models have been used to test the efficacy and safety of nanotechnology in improving ART outcomes. The selection of good quality, healthy spermatozoa for use in artificial insemination (AI), IVF, and intracytoplasmic sperm injection (ICSI) may improve the health of the embryos, the chances of conception, and the viability of the resulting pregnancies. After undergoing a selection process, the sperm sample should show improved motility, and morphology and should exhibit lower levels of DNA fragmentation, DNA oxidative damage and contamination with apoptotic sperm or other cell types  for the purpose of contraception. Additionally, imaging is an emerging application for NPs, which can be engineered to deliver any cargo including MRI contrast reagents and fluorescent tags. This may be particularly useful for such diverse clinical applications as the assessment of the ovarian reserve for family planning or to image metastatic cell clusters of reproductive origin.in vivo use of NPs will only be possible if they present with minimal toxicity/immunogenicity. In this regard, minimization of off-target effects and increased safety indices could perhaps be best addressed via functionalization of the NP surface to ensure it is engineered with the highest levels of target cell specificity and/or differential uptake efficiency into the targeted, as opposed to non-targeted cells. As additional criteria for clinical use, the NPs would benefit from an extended half-life in vivo as well as a long shelf-life.This review has sought to highlight the breadth and variety of applications to which NPs may be applied to expand and enhance existing imaging and treatment options for conditions of the male reproductive system. Besides their use in diagnostics, reproductive cancer, contraception, ART and reproductive health are all fields that stand to benefit from future developments in NP technologies. In guiding these developments, important considerations include the formulation of biocompatible, well characterized materials that are soluble or colloidal under aqueous conditions. Similarly, in vivo half-life and biocompatibility, presents many possibilities and would have a wide application in tailored cancer therapy, gene manipulation in germ cells, as well as a wide range of reproductive biology research applications.The use of exosomes, which are furnished with specific ligands targeting them to particular cell types, could be arguably among the most exciting developments in nanotechnology. Potentially, molecular engineering of the source cell to express a desired cargo or targeting peptides to then be packaged into or expressed on the membrane surface of exosomes may result in ingenious delivery agents that are customized to the patient. Innovative hybridisation of exosomes to create a new breed of “stealthy” NPs, with increased in vitro and in vivo research as well as in diagnostic imaging, offering higher yield and in vivo stability in comparison to other fluorescent tags. In reproductive biology research, possible applications for ligand-modified QDs may include gamete labelling for in vivo and in vitro tracking, as envisaged by in vivo imaging of germ cells within the testes, and particle tracking. Additionally, in vivo tumour imaging using targeted QDs may aid in cancer treatments and also detect cancer cells for early diagnosis in vivo and in ex vivo samples.The other exciting developments lie in the field of imaging. Recently, researchers have sought to synthesize quantum dots based on carbon  or silicIn the field of reproductive science, IONPs present a number of applications, including the aforementioned use in MACS-facilitated sperm selection, superparamagnetic IONPs may facilitate cell MR imaging and magnetic fluid hyperthermia for targeted cell ablation. Additionally, safer alternatives to QDs, based on IONPs may be developed. For instance, Vasquez et al. used a composite luciferase magnetic NP to label sperm which could then be detected using bioluminescent and UV-Vis-NIR microscopy . FinallyRA conceived the review topic, edited all sections, and proposed modifications to section organization and figure preparation. BF prepared the manuscript, organized all sections, and made revisions as proposed by co-authors. AP prepared all figures. JS contributed early editing of reproductive system section of manuscript. ML edited nanoparticle sections. DR contributed to co-writing the male reproductive system section. BN edited all sections and proposed modifications to section organization and figure preparation. All authors contributed to the article and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The definition of the term “biomaterial” dates back to 1991, during the 2nd Consensus Conference on the Definitions in Biomaterials organized by the European Society of Biomaterials in Chester (UK). In detail, as an outcome of the Consensus Conference a biomaterial has been defined as “a material intended to interface with biological systems to evaluate, treat, augment or replace any tissue, organ or function of the body” [The interaction of biomaterials with biological systems occurs at different length-scales, namely at the macro-, micro- and nano-scales. In particular, the design of materials and structures with nanometric precision has demonstrated its enormous potential in controlling cellular processes such as adhesion, proliferation and differentiation . On the co-glycolic acid), or polyethylene, which are widely used in bone, dental and maxillofacial engineering, are bioinert in their native form and, importantly, unsuitable for traditional procedures applied for HA coating deposition . Taking into account this important issue, Riau and colleagues surveyed in their review the available approaches for HA deposition on the surface of low melting temperature polymers , focusing on their key features, pros and cons, with the final aim of providing readers with an in-depth overview useful in decision making processes during bone tissue engineering device development [in loco. A notable example in this field is provided in the work by Boffito, Laurano et al. that embedded ibuprofen-loaded mesoporous carbons into an injectable thermosensitive hydrogel based on a customized Poloxamer 407-based poly(ether urethane) [Staphylococcus aureus and Staphylococcus epidermidis. Finally, in the wide plethora of nanomaterials investigated for biomedical applications, those of natural origin or based on naturally derived building blocks  hold a huge promise due to their biomimetic and bioactive properties and their excellent biological activity. For instance, extracellular vesicles (EVs) are nanoscale heterogeneous cell-secreted membrane vesicles, with a tremendous potential in the biomedical field thanks to their no tumorigenicity, low immunogenic potential and high stability. In this regard, Saludas and colleagues provided a thorough overview on the application of EVs in the treatment of cardiac damage after myocardial infarction [In this scenario, the Special Issue “Biomaterials Tailoring at the Nanoscale for Tissue Engineering and Advanced Therapies” offers to the readers a series of articles describing breakthrough research in the field of bionanotechnology and its exploitation in tissue engineering/regenerative medicine as well as in drug delivery and cell therapy. The issue is comprised of 11 peer-reviewed manuscripts  focused on different fields addressing the selected topic, namely drug carrier design and consequent payload delivery, surface property tuning at the nanoscale through functionalization and fabrication procedures, and stimuli-sensitive nanoparticle design and application. The development of nano-features thus represents the narrative thread of the whole manuscripts comprised in the Special Issue. Interestingly, the 80 contributors, scientists from universities and research institutes from nine countries , described, collectively, biomaterials with nano-scale features exploited in different aspects of the whole medical device development pipeline. For instance, Fiorilli et al. developed smart nano-biomaterials by providing mesoporous bioactive glasses with chemical and biological cues exerting promising therapeutic effects  for the management of patients with compromised bone remodeling, such as those affected by osteoporosis fractures . In detaelopment . Anotherelopment . Additioelopment . The devrethane) . Particlrethane) . Even atfarction . Peptidefarction . The ApoIn summary, this Special Issue reflects the high diversity, versatility and existing creativity in the design of nano-biomaterials and their application in the biomedical field. Although this paper collection cannot be completely exhaustive, the reader will find a comprehensive overview of the latest advancements in biomaterials tailoring at the nanoscale for advanced applications in tissue engineering and drug delivery. Moreover, the reader will easily appreciate that the addressed topic is broad in nature and represents a still open question in the biomedical field. The available tools for the development of nano-biomaterials are continuously expanding and the strict collaboration among researchers with different know-how  will allow in the near future to further advance the fascinating and supradisciplinary field of bionanotechnology, finally leading to the translation of basic research results from the bench to the bedside.


It is uncertain whether the treatment of mild gestational diabetes mellitus (GDM) improves pregnancy outcomes. The aim of this systemic review and meta-analysis was to investigate the effect of mild GDM treatment on adverse pregnancy outcomes.A comprehensive literature search was conducted on the databases of PubMed, Scopus, and Google Scholar to retrieve studies that compared interventions for the treatment of mild GDM with usual antenatal care. The fixed/random effects models were used for the analysis of heterogeneous and non-heterogeneous results. Publication bias was assessed using the Harbord test. Also, the DerSimonian and Laird, and inverse variance methods were used to calculate the pooled odds ratio of events. The quality assessment of the included studies was performed using the Modified Newcastle–Ottawa Quality Assessment scale and the CONSORT checklist. In addition, the risk of bias was evaluated using the Cochrane Collaboration’s tool for assessing risk of bias.The systematic review and meta-analysis involved ten studies consisting of 3317 pregnant women who received treatment for mild GDM and 4407 untreated counterparts. Accordingly, the treatment of mild GDM significantly reduced the risk of macrosomia , large for gestational age , shoulder dystocia , caesarean-section , preeclampsia , elevated cord C-peptide , and respiratory distress syndrome  compared to untreated counterparts. Moreover, the risk of induced labor significantly increased in the treated group compared to the untreated group . However, no statistically significant difference was observed between the groups in terms of small for gestational age, hypoglycemia, hyperbilirubinemia, birth trauma, admission to the neonatal intensive care unit, and preterm birth. Sensitivity analysis based on the exclusion of secondary analysis data was all highly consistent with the main data analysis.Treatment of mild GDM reduced the risk of selected important maternal outcomes including preeclampsia, macrosomia, large for gestational age, cesarean section, and shoulder dystocia without increasing the risk of small for gestational age. Nevertheless, the treatment could not reduce the risk of neonatal metabolic abnormalities or several complications in newborn. Gestational diabetes mellitus (GDM) is defined as diabetes diagnosed in the second or third trimester of pregnancy without the presence of overt diabetes prior to gestation . GDM is Lifestyle modifications including diet therapy, physical exercise, and pharmacological treatments such as oral antidiabetic medications and/or insulin are suggested for the treatment of GDM . HoweverStudies on the treatment of mild GDM and its effect on adverse pregnancy outcomes have shown controversial results. A modest benefit from the identification and treatment of women with mild carbohydrate intolerance during pregnancy has been shown . On the Given the lack of conclusive evidence regarding the benefits of the treatment of mild GDM, this systematic review and meta-analysis investigated the effect of mild GDM treatment on adverse pregnancy outcomes. Accordingly, the review question was as follows: does the treatment of mild GDM through diet therapy and antidiabetic medications improve adverse pregnancy outcomes in terms of maternal and neonatal adverse outcomes compared to untreated women?This systematic review and meta-analysis was informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . The revP: pregnant women with mild GDM; I: treatment through diet therapy and medications; C: treatment effect on adverse pregnancy outcomes; O: maternal and neonatal adverse outcomes.The objectives of this review were to assess:o the pooled risk of adverse single and composite maternal outcomes among those pregnant women who received the treatment of mild GDM compared to untreated counterparts;o the pooled risk of adverse single and composite neonatal outcomes among those pregnant women who received the treatment of mild GDM compared to untreated counterparts;o sensitivity analysis based on the exclusion of secondary analysis studies.Studies were identified eligible if: (I) they presented a clear definition of mild GDM or gestational hyperglycemia; (II) described the details of screening strategies and the threshold of blood sugar in screening tests; (III) reported at least one of the short-term single maternal and neonatal outcomes of GDM; (IV) reported the number or prevalence of adverse events; (V) described the treatment process; (VI) compared adverse pregnancy outcomes between those women who received treatment for mild GDM and untreated counterparts.Exclusion criteria were non-original studies including reviews, commentaries, editorials, letters, meeting abstracts, case reports, and conference proceedings that did not provide accurate and clear data on research variables, and the presence of preexisting glucose intolerance or diabetes in studies’ samples.A comprehensive literature search was conducted on the databases of PubMed (including Medline), Web of Science, and Scopus to retrieve original studies published in English language and on the prevalence and incidence of adverse maternal and neonatal outcomes among women with mild GDM up to May-2020. Further, a manual search in the references list of the selected studies and other relevant reviews was carried out to maximize the identification of eligible studies.The following keywords, alone or in combination using the Boolean method, were used in the search:  AND .The screening of titles, abstracts and full texts of studies was conducted independently by two authors based on the eligibility criteria and the following data was extracted from eligible studies: the first author’s name; journal title; publication year; country; study design; sample size; population characteristics including age and body mass index (BMI); mild GDM screening strategy; mild GDM criteria and laboratory values of blood sugar tests; treatment details; quality assessment and outcome measurements including the number and prevalence of adverse outcomes. To prevent bias in the data extraction and data entry, the accuracy of data before the meta-analysis was assessed through double checking the data extraction process.For the purpose of the present review, a composite outcome of adverse maternal outcomes and the important maternal events of labor induction, cesarean section, preeclampsia was selected. Also, a composite outcome of adverse neonatal outcomes and the single neonatal events of macrosomia, large for gestational age (LGA), small for gestational age (SGA), hypoglycemia, hyperbilirubinemia, elevated cord C-peptide, admission to the neonatal intensive care unit (NICU), respiratory distress syndrome (RDS), shoulder dystopia, and preterm birth was selected. Mild GDM was defined as any glucose intolerance during pregnancy, which was lower than the criteria for the diagnosis of GDM.Quality of the selected studies was critically appraised in terms of the methodological structure and presentation of results. Two authors who were blinded to the study’s author and institution, and the journal’s title evaluated the quality of each study independently. The modified consolidated standards of reporting trials (CONSORT) as a validated quality assessment checklist for RCTs was used for the appraisal. Studies with scores ≥70% of the highest score of the CONSORT checklist were judged as high quality, 40–70% as moderate quality, 20–40% as low quality, and <20% as very low quality . The ris2 index and P < 0.05 was interpreted as heterogeneity. Heterogeneous and non-heterogeneous results were analyzed using the random/fixed effects models for calculating the pooled effect, respectively. Publication bias was assessed through the Harbord test. The DerSimonian and Laird, and inverse variance methods were used to calculate the pooled odds ratio  of events. Meta-regression was performed to explore the effect of maternal age as the source of heterogeneity. In addition, sensitivity analysis was run to investigate the influence of each individual study on the overall meta-analysis summary estimate. A graph of the results of an influence analysis in which the meta-analysis was re-estimated omitting each study in turn was presented. P < 0.05 was set as significance level.The software package STATA  was used for statistical data analysis. Heterogeneity between the studies was assessed using the IThe quality assessment of the included studies has been presented in , A statistically significant difference between the treatment group and the control group in the risk of the composite maternal and neonatal perinatal outcomes was observed  and , respectively, , 3.In term of maternal outcomes, the pooled OR of cesarean section  and shoulder dystocia  as well as preeclampsia  were significantly reduced in the treated group compared with the untreated group. In contrast, the pooled OR of labor induction among the treated women was significantly 1.3 folds higher than that of the untreated women  4.–In terms of neonatal outcomes, the adverse events of SGA, hypoglycemia, hyperbilirubinemia, birth trauma, admission to the NICU, and preterm birth were not significantly different between the groups 9. HowevSince three of the included studies used a secondary analysis design, sensitivity analysis was performed after their exclusion from the data analysis process. The results were highly consistent with the main data analysis’ results (No substantial publication bias for meta-analyses based on the Harbord test was observed Tables 2The results of the current systematic review and meta-analysis showed that although the treatment of mild GDM did not reduce the risk of selected neonatal outcomes including hypoglycemia, hyperbilirubinemia, birth trauma, admission to the NICU, and preterm birth, it reduced the risks of macrosomia, LGA, elevated cord C-Peptide and RDS as well as maternal outcomes of cesarean section, shoulder dystocia and preeclampsia, without causing any significant increase in the risk of SGA. However, the risk of labor induction among the treated women was higher than the untreated women.Despite the unquestionable evidence and the wide range of recommendations regarding the benefit of treatment for women with GDM , 26, 27,Diet therapy along with glucose monitoring was mentioned as the primary therapeutic choice in all studies meeting our inclusion criteria for inclusion to our meta-analysis. Pharmacotherapy and mainly insulin therapy were initiated if dietary modification failed to control glycemic levels. The treatment significant decreased the risk of adverse outcomes related to fetal overgrowth including macrosomia and LGA, which in turn reduced the risk of shoulder dystocia and caesarean section among the treated women with mild GDM compared to untreated counterparts. It is suggested that maternal hyperglycemia therapy can regulate fetal hyperinsulinemia and subsequently decrease the body fat storage in fetus . It shouOur review findings showed that treatment significantly decreased the elevated cord C-peptide as a marker of fetal hyperinsulinemia , but it This is the largest and the most updated systematic review and meta-analysis of RCTs conducted on the most stringent method of determining whether a cause-effect relationship exists between the intervention and outcome. In addition, the included studies showed consistency across all outcomes of interest and no statistically significant publication bias was identified. However, some limitations should be considered during the interpretation of the results. For instance, given a lack of a uniform standard for defining mild GDM during pregnancy, individual studies on the topic has produced a varying definition for mild GDM, implying that women with different degrees of glucose intolerance are involved. A lack of unique definition for each adverse pregnancy outcome might have affected the review findings. Most of the included studies had a small sample size and the results were dominated by the secondary analysis of one study . HoweverIn conclusion, the treatment of mild GDM using diet therapy and insulin is likely to reduce the risk of several key adverse outcomes of interest such as macrosomia and LGA, shoulder dystocia, cesarean section, preeclampsia as well as newborn RDS, without causing any significant increase in the risk of SGA. Also, our review findings indicated that the treatment of mild GDM might not reduce other adverse neonatal outcomes. Further studies with larger sample sizes are required in different population and ethnicities to examine the effect of treatment on other important adverse pregnancy outcomes with low prevalence.The original contributions presented in the study are included in the article/SB-G conceptualized the study and was involved in study design, search in databases, study selection, data extraction, drafting the manuscript, and revising it critically for important intellectual content. MV was involved in manuscript drafting, editing, and revising it critically for important intellectual content. RB-Y contributed to quality assessment, data analysis, and interpreting data. MP contributed to quality assessment, data analysis, and interpreting data. All authors contributed to the article and approved the submitted version.Nord University, Bodø, Norway covered the article processing charge.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.


Background: Recently, artificial intelligence (AI) with computerized imaging analysis is attracting the attention of clinicians, in particular for its potential applications in improving cancer diagnosis. This review aims to investigate the contribution of radiomics and AI on the radiological preoperative assessment of patients with uterine sarcomas (USs). Methods: Our literature review involved a systematic search conducted in the last ten years about diagnosis, staging and treatments with radiomics and AI in USs. The protocol was drafted according to the systematic review and meta-analysis preferred reporting project (PRISMA-P) and was registered in the PROSPERO database (CRD42021253535). Results: The initial search identified 754 articles; of these, six papers responded to the characteristics required for the revision and were included in the final analysis. The predominant technique tested was magnetic resonance imaging. The analyzed studies revealed that even though sometimes complex models included AI-related algorithms, they are still too complex for translation into clinical practice. Furthermore, since these results are extracted by retrospective series and do not include external validations, currently it is hard to predict the chances of their application in different study groups. Conclusion: To date, insufficient evidence supports the benefit of radiomics in USs. Nevertheless, this field is promising but the quality of studies should be a priority in these new technologies. The potential refinement of risk stratification systems resulting from this new scenario will require the ability to manage and analyse large databases. To this purpose, analyses based on artificial intelligence (AI) systems could be able to overcome the human cognitive possibilities and therefore are considered very attractive [Uterine body tumours (UBTs) are represented by endometrial carcinomas (ECs) and sarcomas (USs). ECs are the most common female cancers of the reproductive system in high-income countries, with a favourable prognosis in most patients ,2. On thtractive ,9. Over tractive ,11. Thertractive .Given the clinical management issues of USs, AI and more specifically radiomics could promote a more efficient identification of new biomarkers and new diagnostic and prognostic criteria, playing a key role in improving the currently available prognostic stratification systems and developing new ones.Therefore, the purpose of this systematic review was to assess the state of the art of imaging-based AI techniques (including radiomics) applied to USs.The PICOS framework  was used to formulate the questions for this study: (1) patients with malignant uterine sarcomas (population), (2) assessed with radiomics/AI (interventions), (3) and/or with standard radiological exams (comparisons), (4) diagnosis, and/or prognosis (outcomes), and (5) all types of cohort studies, including randomized controlled trials, case series and case reports (study design). The focused question was “What are the potential contributing factors on diagnosis and prognosis of radiomics/AI compared to standard radiological imaging in malignant uterine sarcomas?”. They were included in this review if they met the PICOS criteria.The protocol was drafted according to the systematic review and meta-analysis preferred reporting project (PRISMA-P) . The proRelevant studies were selected using the Boolean combination of the key terms reported in For each eligible article, the following data were sought and recorded: the study characteristics ; the patients’ characteristics ); methods applied .Finally, extracted data were crosschecked by the four investigators .The same authors  independently assessed the methodological quality of the selected studies. In cases of disagreement, they attempted to reach a consensus, and if they failed a senior author made the final decision. The overall quality of the included studies was critically evaluated based on the revised “Quality Assessment of Diagnostic Accuracy Studies” tool (QUADAS-2) . This toThe initial search yielded 754 articles. Ten studies were duplicates across PubMed and Scopus and thus eliminated, resulting in 744 studies to be screened. According to the previously described inclusion and exclusion criteria, 722 papers were excluded, and 6 full-text articles were included in this systematic review ,19,20,21Given the small number of the included papers and the heterogeneity of the available data, a meta-analysis to calculate the pooled results was not performed.As shown in As shown in The overall quality assessment of the included studies is reported in The main findings are reported in Clinical factors correlated with a diagnosis of USs included older age ,19, inteAlthough a complex algorithm showed 100% sensitivity, specificity and accuracy in the differentiation of myomas from leiomyosarcomas, this classifier was deemed too complicated for routine clinical practice ,20. The Finally, MRI-extracted AI-based methods were comparable to  or more This systematic review assessed the state of the art of imaging-based techniques  applied to USs. A few studies have shown that sometimes complex models, including AI-related algorithms, showed excellent accuracy in this setting . HoweverOur literature analysis showed a progressively growing interest in AI models in USs in recent years, including all studies published in the last two years. However, these studies are retrospective, and the lack of standardized protocols makes them very heterogeneous in terms of type of samples, of analysis and of segmentation. Moreover, the number of patients analysed is too small and the follow-up duration is too short to carry out reliable assessments.For all these reasons, it is a shared opinion of the authors that, currently, AI models cannot be used in clinical practice to solve the problems of differential diagnosis and risk stratification in USs.More recently, another systematic review on radiomics applied to uterine tumours was published . HoweverAs in radiomic studies on other organs, different strategies have also been adopted for the uterus in terms of inclusion in the analysis of the whole organ or of the macroscopic tumour only . Indeed,One of the main limitations of our systematic review is the “time factor”. In fact, given the interest in this topic, it is possible that additional studies have been published after our literature search and therefore have not been included in our analysis. The main limitations of our analysis were: (i) the small size and the heterogeneity of the included studies which obviously affects the levels of evidence of the review results; (ii) the low number of included studies; (iii) the wide range of inclusion criteria used to select patients in the analysed series that hindered the achievement of clear results. Moreover, none of the included articles provided an independent validation of the developed AI models, with obvious limits to their generalizability and thus to their external applicability. Finally, although multicentric and prospective studies are required to accurately assess the impact of AI on clinical outcomes, no analyses have been yet published.One of the strengths of our systematic review is the involvement of a multidisciplinary team of authors, including gynaecologists, radiologists, radiation oncologists, medical oncologists and experts in basic cancer research. Indeed, team members assessed the studies in detail, each based on their expertise and knowledge. Furthermore, this systematic review provides a comprehensive overview of radiomics and AI analyses currently used, alone or in combination with other dataflow, in order to build predictive models for US diagnosis and risk stratification. Finally, this analysis could improve the shared knowledge among different specialists involved in gynaecological oncology and could pave the way for future studies on USs.These future studies could have the purpose of: (i) defining the imaging methods in the USs, or their combinations, most appropriate for the development of AI models; (ii) evaluate the usefulness of integrated predictive models, including imaging, clinical, and molecular data; (iii) identify the most effective AI systems to produce reliable predictive models for diagnosis and risk stratification.In conclusion, the improvement of research quality should be the future focus in this field. a multidisciplinary approach could probably avoid several biases in patients’ selection and monitoring. Despite the lack of enough evidence on obvious advantages of radiomics and more generally of AI in USs at the moment, some preliminary data suggest a potential advantage from integrating these methods with human intelligence. Further studies are needed to refine AI techniques to enable their future use in the complex clinical management of USs.


In this paper, fracture behavior of four types of implants with different geometries  was studied in detail. Each implant fractured in the human body. The scanning electron microscopy (SEM) was used to determine the potential cause of implants fracture. It was found that the implants fracture mainly occurred in consequence of mechanical overloads resulting from repetitive, prohibited excessive limb loads or singular, un-intendent, secondary injures. Among many possible loading types, the implants were subjected to an excessive fatigue loads with additional interactions caused by screws that were mounted in their threaded holes. The results of this work enable to conclude that the design of orthopedic implants is not fully sufficient to transduce mechanical loads acting over them due to an increasing weight of treated patients and much higher their physical activity. Stainless steels and titanium alloys are widely used as implant materials in orthopedic surgery due to their good biocompatibility, corrosion resistance and durability ,2,3. The2O3) containing small amounts of Co and Mo oxides. Their mechanical properties could be tailored during cold working [Austenitic chromium-nickel steel doped with molybdenum  belongs to materials most extensively used in medicine. Nowadays, it is used to manufacture surgical instruments, surgical and cardiologic implants and joint prostheses ,12. Cr-N working ,13. Chro working ,18,19.Titanium and its alloys are well-tolerated in-between viable tissues. They are increasingly used in orthopedics as a material for production of trauma implants, including plates, screws, intramedullary nails, external fixators and joint prostheses. They are also used to manufacture surgical instruments . CommercIt should be mention however, that the main limitation of implant production with titanium is the difficulty in processing and making complex geometrical shapes. Additive manufacturing techniques allow to overcome such limitations. These specific techniques enable to produce functional, complex parts created directly by selectively melting layers of powder. Implants obtained from advanced additive methods, such as Direct Laser Forming and Selective Laser Melting, allow material to retain its strength properties ,24,25,26Despite the undeniable advantages of medical implants, their fractures remain a problem. Yu et al.  presenteFour different, exemplary implants were chosen out from 18 parts collected during last two years anteceding coronavirus pandemics to validate the observations independently from the type of an implant, its producer and an alloy itself. The study is focused on implants dedicated for the stabilization of long bone fractures, such as those that could be used temporarily, and possibly removed, when the fracture is healed; implants intended for bones subjected to mechanical loads in highest degree and implants representing materials the most often used for orthopedic purposes: steel, pure titanium and its alloy (Ti-6Al-4V).Pure titanium, angularly stabile, clavicular, locking plate  with energy-dispersive spectroscopy (EDS) attachment . Samples were obtained from the implant within the fracture zone. The fracture area was analyzed on both sides of the broken implant.The chemical composition of a titanium locking plate is presented in Nucleation of cracks was initiated on the side part of the implant and was followed by a progressive crack development b in cons2O3 (Analysis of the chemical composition of the implant material (2O3 . These pThe chemical composition of the titanium alloy locking plate is presented in Ti-6Al-4V titanium alloy femoral gamma nail with a full set of its components  was subjThe steel femoral condylar plate  was madeA visual analysis a revealeMicroscopic observations of the inner area of the fracture surface revealed dominant cracks in the inner aspect of the thread , showingA microstructural analysis of the fractured implants was performed in this paper. It should be mentioned, however, that it is hard to compare the results obtained in this work with the literature, since the knowledge on the implant fracture and its potential causes has not been reported in detail yet. More importantly, the complex loading states that the implants were subjected to were different for individual patients.The paper focused on the analysis of orthopedic trauma implant failure, which led to bone fracture destabilization. Implant fractures complicate orthopedic procedures, further disabling effective interventions. Clinical practice shows that they occur in a limited number of patients that usually present a fracture healing process or those who, due to unintended secondary injuries or in consequence of the transgression of postoperative recommendations, succumb to secondary limb traumatization. In those cases, implant fractures and bone break destabilization point to the causative impact of accidental or cumulative mechanical overloads of an implant.material impurities, where super-hard aluminum oxide acts as a mechanical strain concentrator, serving as the center of cracks propagating between the structure of an implant,the deficient adjustment of implant designs to the stresses acting on it,improper technology of implant production, especially in the case of drilling and threading of the holes serving as mounting areas of screws attaching it to the bone,inappropriate surgical technique during implantation,its mechanical overloads caused by excessive forces acting on limbs treated with this particular implant.Based on our investigations, it could be presumed that implant fractures are caused by: Nica et al.  analyzedIn the materials investigated, implant fractures most probably occurred in consequence to mechanical overloads resulting from repetitive, prohibitively excessive limb loads or singular, unintended secondary injures. The first mechanism subjected the implant to relatively mild but repetitive loads, which, when summarized, damaged it. The second one fractured due to forces acting with an amplitude enormously exceeding those that the implant could withstand. Based on a finite element analysis of the broken, steel condylar plate, Gervais et al.  concludeFor the observations given by our predecessors, we can add an additional one—namely, that the current design of orthopedic implants is not fully suitable to transduce mechanical loads acting on them due to the increasing weight of treated patients and, much more important, their physical activity.Moreover, the design of implants leads to the generation of stress concentrators that serve as initiators of cracks. An analysis of the surfaces of the fractured implants revealed that, regardless of the initial material state and geometry, the fracture was caused by the concentration of the stress forces in its holes, including the threaded parts, where the crack initiated and propagated within the material. Most probably, the implants were subjected to an excessive fatigue load with additional effects caused by the interaction between the screws and threaded holes. The very tight connection between the screws and threated holes of the implant initiated cracks that led to significant wear between the working surfaces. The wear of threads of screws and plates might reduce the rigidity of the connection between the bone and the implant, thus enhancing the temporary loads between them that promoted the propagation of the implant’s cracks.Taking into account the above observations, in order to reduce the risk of implant fracture, one can require to increase the thickness of their dimensions, especially in the areas with holes.