Artificial articular cartilage (AC) is extensively applied in the repair and regeneration of cartilage which lacks self-regeneration capacity because of its avascular and low-cellularity nature. With advances in tissue engineering, bioengineering techniques for artificial AC construction have been increasing and maturing gradually. In this review, we elaborated on the advances of biological scaffold technologies in artificial AC including freeze-drying, electrospinning, 3D bioprinting and decellularized, and scaffold-free methods such as self-assembly and cell sheet. In the following, several successful applications of artificial AC built by scaffold and scaffold-free techniques are introduced to demonstrate the clinical application value of artificial AC. Articular cartilage (AC) is a connective tissue covered on the ends of bones in an articulating joint. It provides a low-friction surface to facilitate movements of the joints and serves as the load-bearing part which absorbs and distributes loads applied to the joint to protect the subchondral bones. AC tissue is mainly composed of water, chondrocytes, predominantly type II collagen, and proteoglycans . HoweverNotwithstanding various surgical approaches have been introduced in clinics and some of them had receive positive therapeutic outcomes, current surgical strategies are designed to treat small cartilage defects, but they lack long-term durable and sufficient clinical outcomes . TherefoIn this review, we highlighted several mature techniques including scaffold-based and scaffold-free approaches to constructing artificial, presented the applications of artificial AC formed by different techniques and compared their advantages and disadvantages, aiming to provide a reference for the application of artificial articular cartilage in the repair treatment of the defect in knee, hip, temporomandibular joint (TMJ) and other joints .Decellularized cartilage matrix from cartilage is an ideal natural scaffold for artificial AC tissue engineering. However, traditional decellularized techniques such as physical, chemical, and enzymatic treatments can decellularize the cartilage matrix , but allFreeze-drying is a traditional method to manufacture porous scaffolds for tissue engineering and biological applications. In this method, the water in the material is first converted into ice at a low temperature, then the ice is sublimated by a vacuum environment to remove water before the dehydrated porous structure is obtained . MoreoveElectrospinning is a manufacturing process broadly applied in tissue engineering, textile industry, energy harvesting, etc. , which iIn a previous study , the gelHowever, due to the loss in the electrospinning process, only 40–50% of the growth factors loaded on the material can be released by the scaffold, resulting in a decrease in the efficiency of AC regeneration and an increase in manufacturing cost . Therefovia cell suspension and via cell aggregate. The results indicated that the former tended to present fibrochondrocyte phenotype, whereas the latter showed hyaline cartilage phenotype, suggesting that it may be possible to build different types of AC on an extrusion-bioprinted scaffold by changing the ways of cell seeding. Coaxial extrusion printing derived from extrusion printing enables direct printing of cell-loaded hydrogels by changing the hydrogels in the shell and the core, and can build the layered structure of cartilage, namely, transparent cartilage and calcified cartilage, to better mimic the inhomogeneities and anisotropies of AC and promote Osteochondral tissue regeneration  software, which allows precise regulation of the size and structure of biological scaffolds by printing according to a preset program . In the neration . Howeverneration . Stereolneration . Aisenbrneration . Developin vitro culture to targeted sites in vivo  is obtained by culturing stem cells and transplanted into the defective area after detached with external force to promote tissue recovery through gradual differentiation and proliferation of the stem cell tissue. Cell sheet technology maintains cell functionality as scaffold-free constructs by ECM while enabling direct cell transplantation from  in vivo . Thorp eIn bioengineering, self-assembly is regarded as one of the promising tissue-engineering techniques in which the basic structural units in a material spontaneously form an ordered, stable and regular structure under the interaction of non-covalent bonds . In scafAdditionally, 3D bioprinting can also be applied in assembling stem cells and tissue spheroids to precisely control and maintain a scaffold-free construct shape. in vitro and resulted in neocartilage and better structural restoration, which also combines the virtues of high fidelity and good mechanical properties  loading MSCs as core and HA-GelMA bioink with photoinitiator as shell to coaxial print scaffold in the cartilage defects of sheep in situ, realizing the simultaneous coaxial extrusion of bioscaffold and cultured cells directly into the cartilage defect in vivo in a single-session surgery  such as bone marrow mesenchymal stem cells (BMSCs), adipose mesenchymal stem cells, etc. are widely used as seed cells because of their strong proliferative ability . To promThe scaffold-free technique is mainly used to repair and regenerate cartilage by sending a mixture of seed cells and ECM or pure tissue spheroids into the site of AC damage and loss without forming an exogenous scaffold. Compared with the construction of a cartilage scaffold, the scaffold-free technique is simple and easy to construct tissue-engineered cartilage, avoiding the negative effects such as potential toxicity response of exogenous materials, but the resulting engineered cartilage is limited in mechanical properties, while the mechanical properties of cartilage scaffold can be controlled by adjusting the materials and manufacturing process .For clinical application, artificial AC made by tissue engineering with and without scaffolds have potential in the clinical treatment of OA and other joint injuries and degeneration. However, the clinical transformation of the tissue engineering-based approaches needs further animal and human clinical trials to ensure the safety and effectiveness of clinical application, which is lacking in some clinical feasible technologies of forming artificial AC . Moreove


Chromosomes inside the nucleus are not located in the form of linear molecules. Instead, there is a complex multilevel genome folding that includes nucleosomes packaging, formation of chromatin loops, domains, compartments, and finally, chromosomal territories. Proper spatial organization play an essential role for the correct functioning of the genome, and is therefore dynamically changed during development or disease. Here we discuss how the organization of the cancer cell genome differs from the healthy genome at various levels. A better understanding of how malignization affects genome organization and long-range gene regulation will help to reveal the molecular mechanisms underlying cancer development and evolution. The genome is distinctly organized in the nucleus by various architectural proteins. This organization is essential for genome functioning by the colocalization of genes and the regulatory elements, as well as by the establishment of efficient replication origins and an initiation repair-prone chromatin compartment. Cancer driver mutations, including structural variations and point mutations, lead to a global disruption of the cell program that has an impact in destruction of the genome organization.Understanding how chromosomes are folded in the nucleus is a key issue in molecular biology. Chromosomes occupy separate but interacting chromosome territories within the cell nucleus. Euchromatin and heterochromatin are two major types of chromatin into which all chromosome territories can be divided. According to genome-wide chromatin conformation capture (Hi-C) data, they correspond to compartments A and B, respectively . CompartHere we describe evidences of chromatin architecture alterations at different levels in cancer. Studies of chromosomal territories, chromatin compartments and topologically associating domains reveal key elements of transformed genome structure in cancer. Our analysis highlights the relationship between the structure and function of the genome in human cancer.The abnormal morphology of the nuclei is one of the attributes that is widely used to identify malignant cells. The most easily assessed feature is nuclear size, which is usually increased in malignant cells . The mecIn addition to the changes in size, cancer cell nuclei often display an atypical morphology, which supposes defects in the nuclear envelope structure. The inner layer of the nuclear envelope is the nuclear lamina, which is formed by a network of filament proteins called A- and B-type lamins. The proper expression of lamin genes is important to maintain the correct rigidity of the nucleus. Downregulation of lamin genes makes nuclei softer and increases nuclear deformability leading to the appearance of invaginations and nuclear blebbing , whereasOn the other hand, atypical morphology may be caused by changes in chromatin organization. In most of the eukaryotes, the heterochromatin is located on the periphery of the cell nucleus . It is bThe chromatin decompaction in cancer samples are well distinguishable by staining of tissue sections and tumor cells. Differences in the distribution of heterochromatin areas inside the nucleus are clearly visible, which is the basis for the diagnosis of several cancer subtypes . The speAt the same time, lamin gene disruption can be the direct reason of heterochromatin disorganization . ChromatTaken together, these observations show a complex mutual influence of nuclear lamina and chromatin in the cell nucleus. We believe that future studies will shed light on the root cause of the altered nuclear morphology in cancer cells. It is important as the atypical nuclear morphology can promote cancer cell invasion and metastatic dissemination by facilitate cell squeezing through narrow tissue spaces .The interphase nucleus is a highly ordered structure where each chromosome occupies a certain territory without global mixing with its neighbors. In accordance with the changes of nucleus size, the volume of chromosome territory increases in the cancer cell. However, enlargement of chromosome territories and nuclear volume is not proportional; as a result, relative volumes of chromosome territories are smaller in cancer cells than in normal cells . The obsBesides entire chromosome territories changing location within the nucleus simultaneously with the changes in transcription, individual genes also move within chromosome territories and, moreover, loop out. As it was mentioned the gene-poor chromosomes occupy the nucleus periphery; however, the distribution of genes within chromosome territories follows a different logic; namely, active genes are localized more peripherally within the chromosome territories . The loocis interactions, and increase in trans interactions. As a result of chromosome territories decompaction, translocations frequently occur in Cap-H2 depleted cells  is required for chromosome territory formation in Drosophila cells, promotes long distance interactions within the chromosome territory, and, at the same time, prevents chromosomes from intermingling . In Drosed cells . In conted cells . This obed cells . Thus, ied cells , are liked cells . As desced cells  and chroed cells .Intermingling of chromosome territories observed during malignancy can lead to secondary oncogenic events associated with tumor progression, facilitating translocations between certain chromosomes , dependiTo sum up, changes in chromosome territories position and volume, as well as relocation of specific loci outside their chromosome territories and increasing intermingling are observed in cancer cells . These cGenomic compartments can be distinguished within chromosome territories as clusters of specific chromatin subtypes. At low resolution, compartments can be identified as megabase-scale genomic regions that are either euchromatic with high gene density (A-type) or heterochromatic with low gene density (B-type). The chromatin interactions between the different types of compartments are dramatically reduced. Increase in resolution provides a more detailed view of chromatin composition of compartments, allowing to identify spatially segregated subtypes of active- and repressed chromatin .It is assumed that chromatin compartments allow to locally increase the concentration of enzymes required for specific molecular processes, such as transcription initiation and elongation, RNA splicing, gene silencing, etc. . CompartOne mechanism explaining compartment switching in cancer cells is overexpression of an oncogenic transcription factor, which is normally absent or expressed at low level. The protein binds its DNA targets, and engages them to an active compartment. This results in a dramatic shift of DNA compartmentalization profile, and accompanied changes of gene expression and cellular properties. For example, activation of the KLF5 transcription factor results in spatial clustering of its binding sites, recruitment of CBP/EP300, BRD4 and eventually Polymerase II complexes into these clusters, leading to numerous transcriptional changes . This onAnother mechanism altering chromatin clustering and causing transcription changes in cancer cells is associated with gain- or loss-of-function mutations of architectural proteins, which affect their ability to form chromatin condensates . It is avice versa up-regulated after B to A switching. At the same time, there are some examples showing that getting into the active compartment is not always accompanied by the activation of gene expression  can be distinguished as the regions of chromatin with a high grade of self-interaction. As well as other genes, proto-oncogenes and tumor-suppressors are sequestered in such domains, which borders protect these genes from miscellaneous enhancer interactions . Thus, Tvice versa, the score decreases when TAD moves from A to B (TAD boundaries can change not only their position, disappearing or appearing in new loci, but also change insulator properties in cancer cells . Unlike m A to B . AltogetTAD changes arise in the cancer genome through a variety of mechanisms including somatic mutation, CTCF binding site alterations, CTCF inferiority. The genome distribution of point mutations is closely related to the spatial chromatin organization with increasing probability near the TAD boundaries and especially around the boundaries between transcriptionally distinct domains . TAD bouFusion of TADs in different epigenetic states could lead to the formation of new regulatory landscape and upregulation of repressed genes . WhereasAnother mechanism of TAD disturbance observed in cancer cells is CTCF binding change. CTCF is one of the key players establishing chromatin organization. It is a DNA-binding protein required to maintain genome architecture by mediating both short and long chromosome contacts . The redThe CTCF occupancy reduction may happen due to mutations in the binding sites, which undergo a high mutational load in different types of cancer . The mosHigh levels of DNA methylation are associated with nucleosome compaction and reduced chromatin accessibility for different TFs, including CTCF . The genThus, changes in TAD boundaries potentially underlie tumorigenesis by altering the spatial architecture of regulatory elements and proximity to genes, leading to aberrant expression of cancer related genes.During the last decades, key principles of chromatin organization and their role in genome function have been gradually discovered. At the moment, there is an understanding of the importance of chromatin folding in the processes of development and diseases. It makes possible to integrate knowledge about the principles of chromatin architecture organization into a comprehensive understanding of cancer development and the risks of its progression. Results discussed here suggest that malignization affects every level of genomic organization and chromatin organization alterations can contribute to cancer progression. The main changing vector that can be found at different levels is chromatin mixing . This is


In addition to many other functions, the placenta is a source of a vast number of autocrine, paracrine and endocrine factors. However, the spectrum of placental regulatory factors, their concentrations, gestational profiles and roles may differ considerably even between phylogenetically closely related species. Depending on the species, placental regulatory factors of a broad range of molecule classes have been found including (glyco-)proteins, peptides, steroids and prostaglandins. Local placental regulatory factors are especially important for the dialogue between the fetal and the maternal compartment immediately at the feto-maternal borderline and for the control of growth, differentiation and functions of the placenta itself. Moreover, placental hormones in a proper sense may also have effects in more remote targets within the maternal compartment, serving functions such as pregnancy-specific adaptations of maternal circulation, provision of hemotrophe to the fetus or the development and function of the mammary gland. Functions of placental hormones in the fetus proper are less clear but may be especially important before the establishment of a functional fetal endocrine system and near term within the highly species-specific networks of signals preparing and initiating parturition. This review takes a comparative view on the situation in different domestic animals focusing on ruminants and on placental hormones occurring at significant concentrations in the maternal circulation. There is probably no other organ which shows such a structural diversity comparable to that of the placenta , and theDue to the large variety of placental signaling molecules and considerable species specific peculiarities, a detailed review on placental endocrine function in a larger number of species would clearly go beyond the scope of this article. Thus, here we focus predominantly on domestic ruminants  and those regulatory factors which have been measured at significant concentrations in fetal or maternal blood. According to the specific expertise of the authors special emphasis is placed on placental steroidogenesis.et al., 2006) and to larger syncytial plaques in sheep and goat  or antiluteolytic  are considered as a prominent class of hormones. However, they are also involved in the regulation of numerous processes outside the reproductive system , which cProgesterone is commonly considered indispensable for mammalian pregnancy, as it is involved in the control of numerous essential pregnancy-related functions including endometrial differentiation, myometrial quiescence, closure of the cervix and local immunotolerance in the pregnant uterus . With reIn many mammalian species, especially in primates and ungulates, the placenta produces significant amounts of estrogens. However, observations made so far with respect to the type of estrogens formed, concentrations, gestational profiles in maternal blood and synthetic pathways point to significant species differences. Different from follicular steroidogenesis with estradiol-17β generally being the sole relevant estrogen identified so far, during pregnancy frequently other estrogens are quantitatively dominating in maternal blood. In many ungulate species estrone is the major estrogen and sulfonated forms frequently exceed by far the concentrations of their free counterparts in maternal blood , whereas placentae in other species such as the cow  or sulfonated DHEA (DHEAS) which are devoid of any noteworthy activity at the androgen receptor but may serve as precursors for the synthesis of bioactive androgens. It is clear that in species exhibiting placental estrogen production aromatizable C19-steroids must be available as precursors. Due to a lack of considerable CYP17A1 expression, the human and equine placentae depend on the provision of C19-steroids from extraplacental sources . In the otherwise epitheliochorial equine placenta, eCG expression is restricted to a specialized trophoblast subpopulation which invades the maternal endometrium to form discrete structures named endometrial cups. By its strong and long-lasting LH activity in horses, eCG induces the transformation of large follicles, which develop during early pregnancy under the influence of pituitary FSH, into accessory corpora lutea (The pituitary gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) play an outstanding role in the hormonal regulation of gonadal function. Together with thyroid stimulating hormone (TSH), they belong to the family of glycoprotein hormones and are composed of a common α-subunit and a hormone-specific β-subunit. Depending on the species, LH-related glycoproteins are also expressed in the trophoblast. For a long time, chorionic gonadotrophin (CG) expression has only been reported in equids and primates  and prolactin (PRL) are structurally-related signaling molecules which have evolved from a common precursor. Their receptors  are also structurally related. Whereas in most mammals GH and PRL are evolutionarily conserved, in anthropoid primates, ruminants and muroid rodents either GH, PRL or both have undergone considerable evolutionary change and GH- (primates) or PRL-  gene derivatives are expressed in the trophoblast . MoreoveIn ruminants both GH- and PRL-encoding genes have undergone considerable evolution. Duplication of the PRL gene has been shown in all well- studied ruminants, leading to the formation of a cluster consisting of PRL, PL and PRP genes. Most ruminant species including cattle possess a single GH-like gene, which despite the absence of gene duplication has also undergone accelerated evolution. However, domestic sheep and goat have been found to be polymorphic for a GH-duplication (GH1/GH2-N and GH2-Z). Whereas in the bovine placenta there is no evidence for GH expression, in the ovine placenta GH was found to be expressed between days 35-75. In ovine haplotypes with two GH genes, one gene was expressed in the pituitary (GH2-N) and the other one in the placenta (GH2-Z). In addition to a role in the control of pregnancy-specific uterine gland differentiation and functions, GH transiently expressed in the ovine placenta has also been suggested to have effects in the fetal compartment before the onset of GH expression in the fetal pituitary  acts as agonist at PRLR-homodimers and at PRLR-/GHR- heterodimers, whereas it has antagonistic effects at GHR- homodimers . ExpressIn contrast to sheep and goat, maternal PL concentrations in cattle were only in the lower ng/ml range throughout gestation . In sterRuminant PLs have been postulated as factors involved in the normal physiological adjustments occurring during pregnancy in concert with other regulators. Observations especially from rodents suggest that activities of PRL paralogues may not be particularly in demand in unimpaired pregnancy but may become important during adaptations to stress . Concernin vitro studies suggest that it may stimulate placentomal angiogenesis . However, these non-classical members of the PRL/GH family are quite different in amino acid sequence from PL. In cattle on the protein level the expression of only PRP-1 has been confirmed, while mRNAs from more than ten different PRP genes are transcribed. The function of PRP-1 produced in TGCs  throughoAfter the discovery of relaxin by its softening effect on the pubic ligament in virgin guinea pigs , subsequDepending on the context RLN may act as a systemic hormone or as a local regulatory factor. In many mammalian species a pregnancy-specific increase of maternal RLN concentrations is observed. Generally, regarding quantities the corpus luteum and/or the placenta are the most important sources. However, their relative contributions to maternal blood levels may differ significantly between species. In a considerable number of species including rabbit, dog, cat, camelids and horse the placenta is the major or sole source of RLN at advanced stages of gestation. Different from the aforementioned species, in humans, rodents and pigs circulating RLN is of luteal origin throughout gestation. However, local effects of placental RLN may also occur in the absence of substantial concentrations in the maternal circulation. A multitude of RLN effects have been described during pregnancy such as decidualization, immunomodulation, quiescence of the myometrium, maternal circulatory adaptations of pregnancy, stimulation of angiogenesis, uterine and vaginal growth, development of the mammary gland and/or nipples. In the prepartal period, RLN has been related to the relaxation of the pubic ligament and the preparation of the maternal birth canal for parturition. However, observations concerning pregnancy-specific roles of RLN point to considerable differences between species . The facConcerning the physiology of the RLN/INSL family domestic ruminants hold a special position among mammals as they do not express RLN1. In cattle the RLN1 gene has obviously been lost during evolution and in goat, sheep and other ruminants only a pseudogene was identified. However, the bovine expresses fully functional receptors for RLN1 and INSL3, RXFP1 and RXFP2, respectively. Thus, it was suggested that in ruminants other members of the RLN/INSL family or non-relaxin ligands could compensate for the missing RLN1 .Mammalian parturition is controlled by a complex network of signals involving the fetus, the mother and the placenta. Important processes related to parturition are the withdrawal of progesterone (or progesterone effects), softening of the birth canal, opening of the cervix, increase in the excitability of the myometrium, release of uterotonic substances, rupture of the fetal membranes, expulsion of the fetus and finally the timely release of the placenta. Another process immediately linked to the prepartal endocrine changes is the onset of lactation. However, initiation and control of parturition has been studied in detail only in a limited number of species with the exact sequence or network of events being still widely unknown in most of them. Although some common motifs have been encountered in several species investigated, observations available so far indicate that even between closely related species significant differences may exist . As the According to the current general concept of initiation of parturition in domestic animals, after gradual maturation the fetus reaches a state of readiness for parturition. At this point a rapid mechanism of progesterone withdrawal is activated . The eff2. Besides promotion of the maturation of the fetal HPA axis by a positive feedback loop, placental PGE2 stimulates a pronounced up-regulation of the steroidogenic key enzyme CYP17A1 co-localized with PTGS2 in UTC. The increase in CYP17A1 expression enhances the synthesis of estrogens at the expense of progesterone production  observed a slight increase of maternal PGFM levels starting four days before parturition concomitant with the decline of progesterone. Although the increase of maternal PGFM levels became statistically significant only on the day before parturition, taking into account other observations from the literature , the situation of placental estrogens around parturition is very complex, which obscures the understanding of their definite effects. Moreover, information so far available demonstrates significant differences between species.in vitro , in many mammalian species pregnancy-associated increases of maternal RLN concentrations have been measured with the ovary and/or the placenta being the relevant source(s) depending on the individual species and stage of gestation. On the one hand, together with progesterone, generally RLN is considered as a pregnancy-retaining factor. On the other hand, towards the end of gestation, RLN is considered important for the preparation of the pelvic symphysis and the birth canal for parturition. The softening effect on connective tissue is obviously resulting from remodeling of the extracellular matrix brought about by the increased activity of collagenases .in vitro models nowadays available, for a significant progress in the field animal experiments performed in the respective target species are still considered indispensable. However, experiments in livestock animals are very expensive due to the high costs for the necessary facilities, purchase and keeping of experimental animals or large amounts of compounds applied, e.g. enzyme inhibitors or receptor blockers. Significant progress may be expected from the availability of new or refined analytical methods, e.g. mass spectrometry based methods for the specific simultaneous determination of multiple analytes in blood and tissues, or new efficient technologies to specifically suppress the expression of target genes in the placenta.Despite many studies in the field our knowledge on the endocrinology of pregnancy and parturition including the “placental endocrine function” is still very fragmentary or virtually lacking in most species, with the exception of the sheep. Due to significant species specific particularities, concepts put forward based on observations in a certain species may be largely inappropriate in others. The complex interdependencies in the endocrinology of pregnancy and parturition frequently involving different compartments and intricate hormone systems, which are themselves composed of several ligands and receptor types, are difficult to elucidate. Moreover, hormone measurements in the systemic fetal or maternal circulation may not provide the appropriate information about local roles of hormones, which may depend on local mechanisms of transport, activation of inactive precursors or inactivation. Although some aspects may be successfully studied in the refined


Immune dysfunction and inflammation are involved in autoimmune neurological and neurodegenerative disorders (NDs)  and ligand apolipoprotein E4 (ApoE4) has a role in the regulation of microglia. Liu et al. comprehensively reviewed the roles of mitophagy in the maintenance of microglial functions and the regulation of neuroinflammation in neurological disorders. Mitophagy contributes to mitochondrial homeostasis and clearance of damaged mitochondria, which reduce oxidative stress and restore ATP levels. The authors summarized the mechanisms of mitophagy regulation and the influence of the pathologic factors on mitophagy. In addition, they comprehensively summarized the role of microglial mitophagy in different NDs and aging. Furthermore, they described the regulation of mitophagy by multiple factors that modify microglial activity. Russo and Riessland discussed the relationships between cell senescence and inflammatory activation in PD. They summarized the evidence of cell senescence in neurons and different glial cells in the brain, as well as T cells in the periphery in PD. They discussed that senescence-associated secretory phenotype activates local glial cells as well as peripheral immune cells, which upregulates the expressions of inflammatory factors in blood and brain in PD patients, leading to the damage of dopaminergic neurons in the substantia nigra. In addition to NDs, Zhen-Gang et al. discussed crosstalk among glial cells or glial cells and peripheral immune cells that plays roles in spinal cord injury. Moreover, peripheral organs, including the spleen and gut, are involved in SCI under different conditions and promote or protect against spinal cord injury.In autoimmune disorders and NDs, microglia-associated neuroinflammation plays a crucial role in disease pathogenesis. Reactive microglia in a chronic state secrete multiple cytokines and inflammatory mediators into the surrounding microenvironment, leading to the activation of other glial cells and damage to neurons (Shi and Holtzman, Brandi et al. examined microglial heterogeneity in response to systemic inflammation and found brain region-specific activation of microglia and astrocytes. Moreover, they showed that CX3CR1 contributes to microglial activation after systemic lipopolysaccharide administration. Their study provided a novel mechanism, explaining that the brain region-specific heterogeneity of microglia may contribute to the susceptibility of midbrain dopaminergic neurons in PD.Heterogeneity in microglial phenotypes has received much attention in recent years due to the development of single-cell sequencing (Colonna and Brioschi, Zhang et al. reviewed the mechanisms underlying the regulation of the glymphatic system and the roles of the glymphatic pathway in neurological diseases. In addition, they discussed the relationship between sleep and the glymphatic system, emphasizing that impairment of the glymphatic system by pathological factors in glial cells may be an early event in sleep and mental disorders.The CNS was previously thought to lack the lymphatic vessels that are involved in the removal of metabolic waste products from the brain. Recent studies have shown that there is a specific type of lymphatic system called the “glymphatic system” that is composed of a glial-dependent perivascular network to support the drainage of waste in the brain (Plog and Nedergaard, Taken together, this Research Topic summarizes the mechanisms underlying glial cell dysfunction that contribute to neuroinflammation and the pathogenesis of NDs.RW drafted the manuscript. HR, L-FH, NS, LL, and ZY provided suggestions. GW revised and finalized the manuscript. All authors contributed to the article and approved the submitted version.


Hemostatic materials are very important for the treatment of a large number of bleeding trauma patients in battlefield and disaster environments. Different types of hemostatic materials need to be used for emergency hemostasis according to different injury parts and severity. At present, the first-aid hemostatic materials have been well applied to the bleeding of body surface wounds, limbs, and junctions, but there are still no ideal hemostatic materials in the early treatment of first aid for the deep and incompressible bleeding of thoracoabdominal cavity and visceral organs. This paper reviews the classification and mechanism of hemostatic materials, as well as the application and research progress in trauma emergency, so as to provide reference for the application of hemostatic materials in early first-aid emergency. Massive blood loss is one of the main causes of death caused by war and disaster accidents. 80% of the deaths of patients occur within 1 hour after trauma. If the bleeding can be stopped immediately or early, the mortality can be reduced to 20%∼30% –6. In reIn order to understand the application and research progress of different types of hemostatic materials in trauma first aid, we searched MEDLINE, CINAHL, EMBASE, AMED, ProQuest Hospital Collection, NHS Healthcare Databases Advanced Search to search AMED, British Nursing Index, CINAHL, EMBASE.HMIC, PsycINFO, Health Business Elite with “hemostatic material,” “hemostatic hydrogel,” “hemostatic dressing,” and “hemostatic powder” as keywords. The search period is from January 2005 to August 2022. The literature inclusion criteria are as follows: (1) the research object is hemostatic materials for first aid; (2) the research objects are hemostatic materials for clinical use and newly developed hemostatic materials of various types, with emphasis on hemostatic materials suitable for noncompressible blood loss; (3) the literature types are articles and reviews. The literature exclusion criteria are as follows: (1) literature with duplicate or obsolete content; (2) lectures and comments. Finally, 40 papers were included. We reviewed the classification and mechanism of existing hemostatic materials, as well as the application and research progress in trauma first aid, so as to provide reference for the application of hemostatic materials in early trauma first aid.There are many kinds of hemostatic materials –17, whicPatch hemostatic materials are a kind of sheet-like materials that cover wounds, adhere to bleeding sites, and prevent further damage. The main hemostatic mechanism of patch hemostatic materials is to close the wound by fitting and covering with the damaged tissue, exert certain pressure on the wound, and form an effective physical barrier, and then use its internal pore structure to quickly absorb blood and water, activate the rapid aggregation of platelets, so as to achieve the hemostatic effect , 12 Fig. The patGranular powder hemostatic materials are also a kind of materials that have been studied earlier, usually small particle size materials obtained by grinding and freeze-drying after raw materials are synthesized. The granular powder hemostatic material can better cover wounds of different shapes and depths. Its mechanism of action mainly relies on the small particle structure of hemostatic powder to absorb water in blood, effectively concentrate blood, closely adhere to damaged tissues under the action of external forces, and electrostatically interact with negatively charged red blood cells with the help of some self-positively charged components such as chitosan, so as to promote the formation of local blood clots and accelerate hemostasis  Figure .http://www. z-medica.com/), Celox gauze , and ChitoGauze . These hemostatic dressings have been recommended in the US military Tactical Combat Casualty Care guidelines and have been covered in a recent systematic review.Because of its convenient use and strong shape plasticity, granular powder hemostatic materials are suitable for large and deep body surface wounds or on-site emergency hemostasis with limited treatment conditions. At present, granular powder materials in use include zeolite, microfibril collagen powder (MFC), and chitosan hemostatic powder (celox). Zeolite has excellent adsorption capacity due to its high specific surface area. It can quickly adsorb blood after contacting with wounds and promote blood coagulation through exothermic action. It is well used in emergency hemostasis of battlefield body surface injury, but high temperature may cause damage to damaged tissues . The maiFluid sealing hemostatic materials are new materials that have emerged in recent years. These materials are usually stored in the form of liquid. After contacting the wound by local injection/spraying, they form glue or film to close the wound. Its mechanism of action mainly relies on the high adhesion of the material to closely combine with the damaged tissue and close the wound. While forming a physical barrier, it uses some components that can promote the aggregation of red blood cells and platelets to accelerate hemostasis –16 Figu.Fluid sealing hemostatic materials are suitable for deep and irregular wound bleeding in the body due to their high fluidity and adhesion, especially for uncontrollable wound bleeding such as internal defect bleeding of the organs and bones. Clinically used fluid sealing hemostatic materials such as cyanoacrylate tissue adhesive are often used for puncture wound bleeding in the cavity. It can react anionically with the water in the tissue or blood and solidify into glue to seal the wound, so as to achieve the rapid hemostatic effect, but it will lead to a certain degree of inflammation and tissue necrosis , 29. HemTrigger inflation hemostatic materials are also a research hotspot in recent years. These materials usually have macroporous structure and shape memory function. Its mechanism of action is mainly through the unique shape memory macroporous structure of the material to highly fit the size of the wound and quickly absorb blood and water, effectively seal the bleeding position and promote coagulation.X-ray [Trigger inflation hemostatic material has the characteristics of rapid expansion and strong water absorption, which is very suitable for hemostasis of large noncompressible wounds. It has great application potential in the hemostatic direction of penetrating wound bleeding at the junction of the trunk , 36, 44.X-ray . This maX-ray , 38. ThiX-ray  synthesiX-ray . At the Rapid hemostasis in trauma first aid has always been the focus of medical attention at home and abroad, and the related research of various hemostatic materials has also increased year-by-year. Based on the difference of the external morphology of the existing hemostatic materials, the author divides them into patch type, particle powder type, fluid sealing type, and trigger expansion type, and analyzes and summarizes the hemostatic mechanism, application scenarios, and research status of each type of hemostatic materials. Based on the above analysis, the hemostatic mechanism of these hemostatic materials includes forming a physical barrier with the wound to close the wound, absorbing the blood and water of the wound, promoting the aggregation of red blood cells and platelets, and accelerating the coagulation process. Different types of hemostatic materials have their own characteristics in hemostatic mechanism, such as high-strength wound coverage of patch type, small particle size structure of particle powder type fitting blood loss point, gel forming and film forming characteristics of fluid seal type, and shape memory function of trigger expansion type. Different types of hemostatic materials are suitable for different trauma situations in trauma emergency treatment because of their respective characteristics and advantages and disadvantages. Patch hemostatic materials are suitable for bleeding from wounds on the surface of the body and organs due to their strong adhesion and high coverage. The granular powder hemostatic material is suitable for emergency hemostasis of small blood loss and irregular shape because of its small particle size and easy to fill wounds. Because of its high fluidity and strong adhesion, the fluid sealed hemostatic material can highly fit the wound and play an effective sealing role, which is suitable for blood loss in noncompressible wounds such as deep wound and organ and bone damage. The rapid shape adaptation of trigger inflation hemostatic materials endows them with the ability to cope with uncompressed bleeding, which is especially suitable for penetrating injuries and massive blood loss at the junction of the limbs and trunk. Therefore, in trauma first aid, suitable hemostatic materials and methods should be selected according to the injured site and bleeding characteristics.In addition, wound infection and secondary multiple organ dysfunction are the causes of the third wave of death peak after trauma. The repair of the wound tissue is a dynamic and multistage process. The author believes that ideal first-aid hemostatic materials should have antibacterial, repair promoting, degradable, and other characteristics, and can respond intelligently according to the physiological microenvironment of the wound (such as temperature and pH changes). For noncompressible bleeding such as abdominal bleeding, in addition to developing targeted hemostatic materials, we should also study intelligent, portable, and miniaturized diagnosis and treatment equipment that can be used on-site. For example, intelligent blood transfusion equipment, intelligent hemostasis equipment integrating accurate diagnosis and laparoscopy, intelligent life monitoring and support system, etc. will significantly improve the efficiency and level of on-site treatment of trauma patients.None of the current hemostatic products meet all the criteria for an ideal hemostatic agent. There is still a tremendous impetus for the development of diverse and more efficacious hemostatic technologies and biomaterials for emergency scenarios, not only in both civilian and military traumatic settings but also during variable therapeutic interventions. Alternatively, large randomized trials, particularly direct head-to-head clinical trials comparing the current hemostatic agents, are needed to show which is more effective in prehospital hemorrhage control. There is also a need for studies that would enable the selection of appropriate hemostatic agents based on the mechanism and location of injuries. Finally, nanotechnology has been applied for hemostasis . Some no


Ischemic stroke is one of the leading causes of death and disability. Ischemia triggers a cascade of events leading to cell death and cerebral infarction. Mesenchymal stem cell (MSC) therapy is a promising treatment modality to promote the development of nerve and blood vessels and improve nerve function. However, MSCs have a limited therapeutic effect in the harsh microenvironment of ischemic brain tissue. Modified MSC therapy shows better therapeutic effect under different pathological conditions, and is expected to be translated into clinical practice. In this article, we review the latest advances in the development of modified MSCs for the treatment of cerebral ischemia. In particular, we summarize the targets involved in migration, homing, antioxidant stress, anti-inflammatory, nerve and vascular regeneration, providing new ideas for clinical transformation. Stroke is the second leading cause of death in the world after ischemic heart disease Currently, there is a paucity of effective treatments for IS. Tissue plasminogen activator (T-PA) is administered intravenously to unblock the blocked blood vessels. However, the time window for T-PA treatment is short (≤4.5 hours) and there is a risk of secondary intracerebral hemorrhage Mesenchymal stem cells (MSCs) are multipotent cells that can specialize into several cell types from different lineages. Intravenously administered MSCs can migrate to the site of tissue damage and promote angiogenesis, growth, and differentiation of local progenitor cells MSC therapy has been shown to promote post-stroke functional recovery and neurological outcomes There are several therapeutic challenges in the use of MSC therapy for treatment of IS. The key issues include whether MSCs and their exosomes (microvesicles) can migrate to the target organ and play a role, their ability to survive for a long time in the ischemic and hypoxic brain tissue, and their ability to successfully transform into functional nerve cells in the damaged area Figure .It is generally believed that the homing ability of MSCs at the site of target lesions and their implantation determines the therapeutic effect of MSC therapy Secondly, in the experimental middle cerebral artery occlusion (MCAO) model, only a small part of intravenously injected MSCs entered the ischemic brain tissue, and most of them were trapped in the lung and spleen UBIAD1, SOCS-3, CUEDC2, SRC3) or specific miRNAs  can target specific antioxidant enzymes During brain ischemia and hypoxia, the adverse microenvironment induced by excessive oxidative stress leads to the death of a large number of transplanted MSCs, which further hinders the therapeutic effect of MSC therapy In the acute stage of cerebral ischemia, the progression of cerebral infarction and the formation of cerebral edema are closely related to the strong inflammatory response. It is characterized by rapid microglial activation, production of pro-inflammatory mediators, and infiltration of inflammatory cells into injured brain tissue As mentioned above, MSCs play an anti-inflammatory role by secreting IL-6 and reducing the pro-inflammatory factor TNF-α. This signaling pathway may be related to the inhibition of NF-κB by MSCs MSCs can induce pro-inflammatory M1 microglia to differentiate into anti-inflammatory M2 microglia after IS. It has been reported that MSCs cause low expression of microglia activation markers (ED1 and Iba) and astrocyte proliferation markers (GFAP) MSCs can reduce the release of neutrophil matrix metalloproteinase-9 (MMP-9), maintain the integrity of the blood-brain barrier, and reduce the infiltration of inflammatory cells in brain parenchyma Overexpression of anti-inflammatory factors enhanced the anti-inflammatory effect of MSCs, leading to enhanced neuroprotective function. In addition, IL-10 overexpressed MSCs can delay the time window for MSC therapy without affecting serum IL-10 levels, which may reduce the risk of systemic IL-10-induced adverse reactions such as anemia, thrombocytopenia, and immunosuppression It is generally believed that the paracrine effect of MSCs plays a role in endogenous neural differentiation and proliferation In conclusion, modification of MSCs by sensitive targets has shown a more significant effect in the treatment of IS stroke than MSCs alone.Clinical trials have demonstrated the safety of MSC therapy in IS. MSCs derived from allofat were found to be safe for treatment in the acute phase of ischemia Some experimental studies suggest the feasibility of use of modified MSCs for the treatment of IS. In particular, genetically modified MSCs have shown promising therapeutic effects, but not much work has been done in clinical transformation. The key challenges to clinical transformation include the cytotoxicity of vectors such as lentiviruses, adenoviruses or retroviruses, and carcinogenicity and immunogenicity of viral DNA integration into the host genome. However, clinical studies in the context of other diseases have demonstrated the safety of the treatment process and good results have been achieved. For example, in a clinical study of neuroblastoma In conclusion, allogeneic MSC therapy for IS appears safe and feasible. The safety and effectiveness of genetically-modified MSCs has been demonstrated in clinical trials. The available evidence suggests a promising outlook of the use of various gene targets or preconditioning of modified allogeneic MSCs for the treatment of IS at all stages.Advances in the field of biotechnology have helped improve the treatment of a wide range of diseases. In recent years, the development of crisPR-Cas9 and other gene technologies has made rapid progress in the treatment of metabolic diseases and cancers. Modification of MSCs appears a particularly promising approach as a therapeutic modality. In conclusion, modification of MSCs for ischemic stroke to enhance their targeting ability is a feasible and highly applicable research direction for future clinical transformation.Ischemic stroke is a disease characterized by high morbidity, disability, and mortality. Complex pathological changes occurring in the damaged brain tissue including inflammatory storm, oxidative stress, and nerve cell apoptosis lead to severe neurological dysfunction. MSC therapy is a promising treatment for IS. However, the harsh ischemic and hypoxic microenvironment limits the effectiveness of this treatment modality. Modification of MSCs to improve their therapeutic ability represents a feasible and applicable research direction in clinical transformation.


The plastic forming process involves many influencing factors and has some inevitable disturbance factors, rendering the multi-objective collaborative optimization difficult. With the rapid development of big data and artificial intelligence (AI) technology, intelligent process optimization has become one of the critical technologies for plastic forming. This paper elaborated on the research progress on the intelligent optimization of plastic forming and the data-driven process planning and decision-making system in plastic forming process optimization. The development trend in intelligent optimization of the plastic forming process was researched. This review showed that the intelligent optimization algorithm has great potential in controlling forming quality, microstructure, and performance in plastic forming. It is a general trend to develop an intelligent optimization model of the plastic forming process with high integration, versatility, and high performance. Future research will take the data-driven expert system and digital twin system as the carrier, integrate the optimization algorithm and model, and realize the multi-scale, high-precision, high-efficiency, and real-time optimization of the plastic forming process. Plastic forming is a manufacturing method that realizes volume transfer and obtains shape, size, and performance that meet the requirements via plastic deformation by simultaneously applying a force field or temperature field . As an eThe traditional optimization methods mainly include trial and error methods based on experience and orthogonal experimental design based on theory and simulation. The trial-and-error method depends entirely on personal experience, with high uncertainty and non-interpretability. Based on probability theory, mathematical statistics, and practical experience, the orthogonal experimental design uses a standardized orthogonal table to arrange the experimental scheme. It calculates and analyzes the results to quickly find a design method for the optimal experimental scheme . HoweverIntelligent optimization is essentially an optimization method that determines optimization strategy and solves the optimal model based on the assumption space, and finally predicts or analyzes new data using the learned optimization model. It has attracted increasing research interest in various fields, such as material design ,7,8, macThere are many review articles about intelligent manufacturing, but few focus on intelligent process optimization of plastic forming. Li et al.  summarizPlastic forming must first ensure the required shape and dimension of parts. The forming defects that may be caused by the improper plastic forming process include surface cracks, folds, surface pits, surface bubbles, and orange peel surface. The forming quality can be controlled by adjusting process parameters. However, there are usually many process parameters for plastic forming, and there is usually a coupling relationship between parameters. The selection of main parameters and reasonable optimization methods are the most critical. Secondly, the microstructure and performance must also be optimized to ensure that the parts have good mechanical properties. Finally, it is necessary to optimize the workshop scheduling to reasonably arrange production resources and improve production efficiency for the whole production workshop. This section discusses research progress on the intelligent optimization of plastic forming in terms of parts forming quality, performance, and workshop scheduling according to different optimization objectives. Cloud computing in plastic forming and hybrid physics-informed and data-driven modeling are also introduced.The intelligent optimization of forming quality and performance is mainly carried out by optimizing process parameters. Plastic forming has many different types of processes, such as stamping, forging, rolling, and spinning, characterized by different forming features and problems. Therefore, it is necessary to formulate the corresponding intelligent optimization scheme for different forming processes to achieve optimal optimization.The primary defects that arise in sheet stamping are cracks, springback, thinning, and wrinkling. These defects are significantly related to blank holder force (BHF), draw-bead geometric parameters, die radius, die gap, and punching speed. Various types of multi-object optimization problems could be generated due to the complex interaction of process parameters. The traditional orthogonal test and Taguchi methods cannot solve all the problems well. Optimizing the stamping process parameter is of great significance in improving the forming quality of stamped parts using intelligent optimization. Liu and Yang  optimizeMany scholars achieved some optimization results using the deterministic optimization scheme, while this optimization may not be stable since the disturbance changes of property of raw material, surface roughness, and forming parameters such as forming temperature, and BHF would give rise to the inevitable quality fluctuation. The internal variability in the forming process should thus be considered. Gantar and Kuzman  proposedThe above optimization schemes are all based on scalar methods. When the number of noise factors or design variables to be considered increases, the dimension of the problem usually increases sharply, which will bring a great difficulty to the training and solution of the model and result in low generalization ability. Image-based convolutional neural network (CNN) may effectively handle such problems. Attar et al.  proposedIn addition to optimizing the stamping process parameters to obtain stamping parts with excellent forming quality, some scholars have also predicted the microstructure of stamping parts to acquire important information related to mechanical properties. Chokshi et al.  proposedr = 100, and continue the decision of the next action after updating the DQN network in small batches. Otherwise, set the reward r = −1, and restart the decision-making with the current state as the initial state. This algorithm realizes the intelligence of the traditional free-form sheet metal stamping process without prior professional knowledge guidance. RL is also applied to directly output the optimal process parameters according to the target shape of the stamping part, which brings great convenience to the early design of the stamping process. Recently, some scholars have used RL to optimize the manufacturing process parameters of a component with variable shapes. Unlike the classical optimization based on the surrogate model and CNN model, this method trains a function that directly evaluates the optimal process parameters (output) with the workpiece geometric structure as the input. It combines RL with surrogate-assisted optimization (SAO) to effectively explore the implicit relationship among process parameters, geometric parameters, and forming quality [Scholars usually use surrogate models to establish the response between stamping process parameters and forming goals and then solving the model through different optimization algorithms. This kind of optimization scheme can solve the forming of simple stamping parts under specific conditions. Still, the generalization ability and interpretability are poor, and when optimizing a new stamping process such as HFQ, it is often impossible to optimize due to insufficient empirical data. The CNN model optimizes the stamping process based on images, which can often extract more information from the original data. Previous studies have proved that the surrogate model based on CNN has higher accuracy than the traditional models such as Kriging and radial basis function (RBF) ,33. The  quality . In addi quality .Forging can produce structural parts with complex shapes and excellent mechanical properties and is a critical forming technology for large structural components in automobiles, aerospace, and national defense. However, it is difficult to gain an accurate shape with tailored microstructures due to the complex deformation and microstructural evolution behavior. Meanwhile, the forging process involves many disturbances such as multi-field coupling, fluctuations in ambient temperature, and complex heat transfer between the workpiece and the die, making it an arduous task to control the process-structure-property relationships of the forging process. It also reduces the life of the forging die and equipment when an inappropriate process is adopted. Traditional optimization mainly relies on empirical trial and error and finite element analysis. Such methods are very blind and time-consuming, often resulting in a severe waste of materials and equipment . TherefoPre-forging design is one of the important optimization problems in forging. A good pre-forging shape can obtain high-quality forgings, reduce forming resistance, and improve the service life of molds and equipment. Zhang et al.  establisThe above optimization case shows that the surrogate model is widely used in the pre-forging design. Most researchers have improved the accuracy of the model by using intelligent optimization algorithms. However, process optimization must consider the interpretability of the model and improve its applicability, which has brought challenges to the SAO with its “black box” nature. It is expected to obtain the most accurate prediction model with minor process parameters while ensuring the running speed of the model. Similar to the stamping process above, the intelligent optimization scheme based on CNN has also been applied in pre-forging design. Lee et al.  proposedIn addition to pre-forging design, there is also substantial research on the optimization of process parameters. Kitayama et al.  adopted It can be seen from the above research that in the process of optimizing the forming quality, there are many variables in the model. Although the accuracy of the model is improved through various optimization algorithms, the interpretability of the model becomes poor, and the model with more variables will generally be less robust, which brings great constraints to the actual production and application .Since the internal microstructure of parts usually cannot be measured directly, microstructure modeling is the important issue to solve in intelligent optimization. Bambach et al.  proposedThe soft sensing method or material model can estimate microstructure information, such as recrystallization volume fraction (RVG) and average grain size (AGS). The material microstructural model can accurately describe the evolution mechanism of material microstructure and facilitate the optimization of process parameters to control microstructure ,51. ChenIn addition to this soft sensor method, it is also possible to predict the properties of the component directly using the metallographic images after forging. Emmanouil et al.  proposedThe rolling process includes many variables, such as temperature, rolling reduction rate, rolling speed, and rolling force. The change of each process variable may have different degrees of influence on the forming quality. The traditional optimization method mainly calculates relevant parameters through dynamic planning combined with finite element analysis. Still, the accuracy and reliability of FES largely depend on human factors, such as constructing mathematical models and setting constraints. The optimization is inefficient since only one solution is obtained at a time using the finite element simulation. Rolling is easier to realize intelligent optimization and control than forging and stamping due to its incremental deformation nature. Wang et al.  establisThe above prediction model could not capture the influence of noise factors in the production process since it does not consider the impact and genetic dependence of the dynamic changes in the working conditions. Agarwal et al.  developeBoth single and hybrid models focus on the predictive accuracy of the model and ignore interpretability. Although the accuracy of the model is improved through various optimization algorithms, the interpretability of the model becomes poor, and the model with more variables will generally be less robust, which brings great constraints to the actual production and application . Ji et aThe spinning process has the advantages of low forming load, simple processing technology, and near-net shape and is widely used in the production of axisymmetric parts and structures in aviation, automobile, and other industries . In the Gondo et al.  proposedL of the whole optimization, can be expressed as [The optimization of workshop scheduling in the plastic forming process optimization is also an important problem. Workshop scheduling plays an essential role in the production system by reasonably arranging production resources to shorten production time and improve resource utilization. essed as :(1)L=minThere are few cases that conform to the workshop scheduling model in actual production, mainly including flow shop scheduling problem (FSP) and flexible job scheduling problem (FJSP). FSP stipulates that each workpiece has the same processing route. FJSP allows multiple machines to be selected for a process, and the processing time on different machines may be different. Both of them are nondeterministic polynomial hard problems . MetaheuSeng et al.  proposedQ network (DQN) was developed by Luo et al. [With the development of AI, DRL, which combines the ability of DL to extract high-dimensional features and the ability of RL decision-making learning, has attracted the attention of researchers. It can deal with decision-making problems in high-dimensional state space and high-dimensional action space and mine the characteristics of the problem independently. It uses only the original input instead of artificial features to generate output to realize end-to-end learning. It has been widely used in games, robots, automatic driving, and dialogue systems. Various practical problems have been successfully solved ,77. Luo o et al.  to solveIn summary, various intelligent optimization algorithms can be used in job shopping scheduling optimization. Compared with the optimization of forming quality microstructures in plastic forming, workshop scheduling optimization is more general and can be applied to various workshops. DRL can solve some problems and meet some primary goals. However, there are still problems in the interpretability, convergence, and reusability of the model, so it has not been widely used in actual production. In the future, green flexible workshop scheduling under intelligent manufacturing could be studied in combination with the current development trend of intelligent manufacturing and concepts such as big data, digital twins, the internet of things, and cloud computing. Conducting real-time monitoring of workshop conditions and using intelligent equipment to record carbon emissions and energy consumption during product processing and transportation are needed. The data obtained through supervision are of great research value. Only accurate underlying data can ensure the feasibility and robustness of scheduling .Data are the core of intelligent optimization. With the development of computers and industrial production, many companies have accumulated vast amounts of data. However, due to the different data flows and complex data types, data analysis and calculation face great difficulties, which affect not only users’ acquisition of effective information, but also the economic benefits and future development of enterprises. Therefore, cloud computing technology and AI technology were born to deal with the analysis and calculation of massive data. Cloud computing refers to the computing of data information by utilizing virtualized resources. Compared with ordinary computers, its computing power has been dramatically improved. Cloud computing divides the computing process into several parts, which are finally integrated and stored in the cloud to support the efficient processing of data information ,82. BecaWang et al.  developeOver the past decades, trial-and-error experiments and physics-informed modeling have been widely employed to optimize the plastic forming processes. However, the trial-and-error method is time-consuming and has a high expense of experimental tests because of many processes and material parameters . PhysicsIt is worth noting that the data-driven method has emerged as a promising alternative due to its enhanced data accessibility and parallel computing, but it relies on a substantial amount of labeled high-fidelity data, which are difficult to obtain by experiments or simulations . This grThe hybrid physics-informed and data-driven machine learning model has been developed to integrate the advantages of the data-driven method, classical physics-informed modeling and experimental data. Zhang et al.  proposedThe above investigations indicate that compared with a conventional data-driven machine learning model, the predictions of which could be physically inconsistent or im-plausible, owing to the poor generalization performance caused by extrapolation or observational biases, the hybrid physics-informed and data-driven modeling method has better development prospects in terms of AI. However, since there are also limitations in the method, including the development of new algorithms and computational frameworks for diverse multi-scale and multiphysics problems, the reports presently mainly focus on the characterization of constitutive behavior. Therefore, applying hybrid physics-informed and data-driven modeling in the intelligent optimization and decision of plastic forming can be another important research direction.ES refers to a computer system storing a large number of specific domain knowledge. It can make inferences and draw specific suggestions according to user needs. As with human experts, it can give advice and explain the logic behind it if necessary . ES is aThe computer-aided manufacturing system (CAPP) based on part feature modeling is an essential tool in the process of integrated design and manufacturing. It is also one of the widely used fields of ES. Osakada and Yang  utilizedChul Kim and Chul Woo Park  developePrevious research found that ES is usually used in the stamping process, while fewer forging ES is developed since the forging process is more complex. It is urgent to develop a universal ES to guide production in this field. ES integrates various theoretical knowledge, traditional experience, optimization algorithm, and machine learning. It carries out the preliminary design and optimization decisions for the plastic forming process, significantly improving product production efficiency and quality. Developing user-friendly KBS combined with a modern DL-based decision-making algorithm and adaptive control method is a future research direction.DT is one of the most promising enabling technologies to realize intelligent manufacturing and industry 4.0. In the field of manufacturing. Garetti et al.  defined Tao et al.  proposedThe DT model can be applied to many automated process manufacturing systems, such as customized furniture production lines, 3C product production lines, and the plastic forming line. Based on the case study of sheet metal assembly, Söderberg et al.  describeThe DT-driven PHM is also highly applicable to the prediction of crack initiation. Cerrone et al.  proposedTo date, the DT systems for plastic forming are very limited, and most focus on monitoring the production line and PHM problems. The DT-based optimization and decision for the plastic forming process, which is most important for quality control of the product, is still unavailable. The architecture of a DT system for the plastic forming process is shown in In sum, DT is mainly used in PHM. It is expected to realize the online detection of part damage and the online observation of microstructure evolution by establishing a multi-scale DT model based on microstructure. DT has developed rapidly in recent years, and the relevant literature has increased. However, the development of DT is still at the conceptual stage, and its popularity in many small and medium-sized enterprises is not as good as that of an expert system. The core of DT is modeling, but there is currently no unified DT modeling method. In addition, how to filter, optimize and transmit a large amount of data are urgent problems for DT. DT has little research on plastic forming, mainly related to the high complexity of the plastic forming process itself. It can be preferentially applied to simple process and production line design optimization in the future.For some complex processes, the SAO method is widely used, and the optimization is gradually moving towards a diversified intelligent design with a multi-objective combination of multiple optimization algorithms and multiple optimization models. These methods complement each other and have been paid more and more attention to and applied in the field of forming process optimization design in recent years.The combination of RL and DL has become the current trend of optimal design due to their excellent decision-making performance and feature extraction performance. Meanwhile, the optimization design of the whole plastic forming process is changing to universality, integrity, rapidity, and user operability. The development based on ES and DT system is the outstanding performance of this characteristic.The DT system has shown great potential in production design and PHM. It enables the online detection of parts and the online observation of microstructure evolution by establishing a multi-scale model. However, the DT systems for plastic forming are very limited, especially for the overall process optimization and decision.Considering the many advantages and potential of intelligent plastic forming, scholars have conducted a series of studies on geometric parameters, process parameters, microstructure and mechanical properties, and workshop scheduling optimization. In this paper, the research progress in the field of plastic forming was investigated. The conclusions and prospects are as follows:Although intelligent optimization of the plastic forming process brings many conveniences, many problems also need to be addressed.Intelligent optimization combining machine learning and global searching algorithms lacks intrinsic mechanisms and interpretability. It is then difficult to generate universal knowledge that can be transferred to guide the forming process design of other products. It is essential to couple the physical rules into the optimization method and develop an interpretable approach to process modeling and optimization, changing the optimization process from a black box to a glass box.The optimization of the plastic forming process is closely related to the implicit relationship between material composition, process, microstructure, and properties. All the optimization design of material composition and process schemes aiming at performance must be closely combined with microstructures to truly grasp the essential law of process optimization. This means that the objective of design optimization has changed from macro parameters to macro micro coupling parameters, the dimension of design optimization has increased sharply, the response of the objective is highly nonlinear, and the difficulty of modeling and calculation has increased greatly. Therefore, with the increasing demand for intelligent optimization design of plastic forming, the field of multi-scale design optimization urgently needs to be studied.With the development of plastic forming technology, the contradiction between the accuracy and efficiency of design optimization has become increasingly prominent. Various results can be obtained in terms of efficiency and accuracy using different optimization methods, combined with diverse sample selection, numerical simulation, and optimization algorithms. In order to achieve an efficient optimization design of the forming process, it is urgent to develop alternative models for simplifying sequential modeling and large-scale parallel computing.Although some knowledge-based automatic design optimization methods and integrated computing platforms have been developed to integrate sample selection, numerical modeling, and optimization algorithms, most methods are still based on manual operation and model-driven optimization. There are substantial data, rules, and various knowledge in the forming production, which is far from meeting the urgent requirements for online real-time design optimization. Therefore, there is an urgent need to develop general expert systems based on emerging AI technologies such as big data, cloud computing, and machine learning to promote the development of digital twins, from model-driven to data-driven ,107,108.The critical technology for the DT system is still at a premature stage. To establish a high-fidelity digital model of workpiece and forming equipment, and realize the real-time control of PE and VE, the following key technologies should be developed: (1) intelligent detection accompanied by the fast intelligent reconstruction of macro and micro physical field ; (2) data fusion technology for multi-source and heterogenous data; (3) fieldbus technology for the real-time communication between each module of DT system; (4) a hybrid prediction model driven by data and intrinsic mechanism multi-filed for accurate and fast simulation of multi-field and whole process simulation of plastic forming.


The glycocalyx is a fluffy sugar coat covering the surface of all mammalian cells. While glycocalyx at endothelial cells is a barrier to tumor cell adhesion and transmigration, glycocalyx at tumor cells promotes tumor metastasis. Angiogenesis at primary tumors and the growth of tumor cells at metastatic sites are all affected by the tumor microenvironment, including the blood vasculature, extracellular matrix (ECM), and fibroblasts. Extracellular vesicles (EVs) secreted by the tumor cells and tumor-associated endothelial cells are also considered to be the components of the tumor microenvironment. They can modify tumor vasculature, ECM, and fibroblasts. But how the EVs are generated, secreted, and up taken by the endothelial and tumor cells in the development of the tumor microenvironment are unclear, especially after anti-angiogenic therapy (AAT). The objective of this short review is to summarize the role of the glycocalyx in EV biogenesis, secretion, and uptake, as well as the modulation of the glycocalyx by the EVs.Angiogenesis in tumor growth and progression involves a series of complex changes in the tumor microenvironment. Extracellular vesicles (EVs) are important components of the tumor microenvironment, which can be classified as exosomes, apoptotic vesicles, and matrix vesicles according to their origins and properties. The EVs that share many common biological properties are important factors for the microenvironmental modification and play a vital role in tumor growth and progression. For example, vascular endothelial growth factor (VEGF) exosomes, which carry VEGF, participate in the tolerance of anti-angiogenic therapy (AAT). The glycocalyx is a mucopolysaccharide structure consisting of glycoproteins, proteoglycans, and glycosaminoglycans. Both endothelial and tumor cells have glycocalyx at their surfaces. Glycocalyx at both cells mediates the secretion and uptake of EVs. On the other hand, many components carried by EVs can modify the glycocalyx, which finally facilitates the development of the tumor microenvironment. In this short review, we first summarize the role of EVs in the development of the tumor microenvironment. Then we review how the glycocalyx is associated with the tumor microenvironment and how it is modulated by the EVs, and finally, we review the role of the glycocalyx in the synthesis, release, and uptake of EVs that affect tumor microenvironments. This review aims to provide a basis for the mechanistic study of AAT and new clues to address the challenges in AAT tolerance, tumor angiogenesis and metastasis. Moreover, the vascular system has important functions such as maintaining nutrient and oxygen supply, waste removal, and immune surveillance. Therefore, anti-angiogenic therapies (AATs) that target tumor vasculature to inhibit the growth and metastasis of solid tumors have been widely used in the clinic [Malignant tumors remain a major threat to human health. Two key challenges facing conventional oncology therapies such as surgery, radiation, and chemotherapy are the local invasion of primary tumors and the metastasis of primary tumors to form secondary tumors, and the development of tumor cell tolerance to therapies . Angiogee clinic . Howevere clinic . After te clinic . Althouge clinic . AngiogeRecently, we reviewed the following several mechanisms of AAT resistance in tumors ,7: (1) hThe tumor microenvironment provides a suitable soil for tumor angiogenesis and growth. Tumor vasculature is disorganized and tortuous, with abnormal vascular ECs and leaky vascular walls. Tumor angiogenesis arises from the stimulation of a complex set of genetic and microenvironmental factors. Interstitial fluid pressure, hypoxia, and acidosis can regulate tumor angiogenesis . EVs areVascular ECs and their luminal side of the endothelial glycocalyx layer (EGL) are the basic barrier and regulator of material exchange between circulating blood and tissues . PreviouThe tumor microenvironment is an interactive cellular environment surrounding the tumor whose main function is to establish cellular communication pathways supporting tumorigenesis . EVs secThe EVs derived from tumor cells contribute to the formation of cancer-associated fibroblasts, inducing the remodeling of tumor stroma via transfer of pro-metastatic factors such as non-coding oncogenic micro ribonucleic acids (miRNAs) . EV-mediIn turn, tumor cells utilize EVs to evade the immune surveillance by inducing apoptosis in immune cells through the transfer of immunosuppressive molecules such as HSP72 , and FasThe EVs secreted by tumor cells within the tumor microenvironment transfer angiogenic factors such as EGFR and VEGF into ECs, inducing a pro-angiogenic niche to support the pathological angiogenesis and tumor growth ,39. The The EVs can promote endothelial cell invasion into tissues and accelerate neovascularization, which is closely associated with the secretion of matrix metalloproteinases (MMPs) . In turnMoreover, tumor-derived exosomes contain various miRNAs that participate in the tumor and stromal cell interaction, thus contributing to the tissue remodeling of the tumor microenvironment. Under hypoxia, miR-23a was significantly upregulated in lung cancer exosomes, which increases angiogenesis and vascular permeability by targeting prolyl hydroxylase and the tight junction protein ZO-1 . MiR-21-The intercellular cleft between vascular ECs is a major pathway for water and hydrophilic molecule exchange in microcirculation and a major site for tumor cell adhesion and transmigration. The endothelial glycocalyx layer is located at the vascular luminal surface, in direct contact with blood, covers the intercellular cleft, and is a natural barrier for tumor cells to metastasize across the vascular wall or endothelium. EGL has a complex structure and is comprised of many components. Heparan sulfate proteoglycan (HSPGs), syndecan-1 (SDC1), syndecan-2 (SDC2), syndecan-4 (SDC4), and glypican-1 (GPC1), and their glycosaminoglycan side chains, including heparan sulfate (HS), hyaluronic acid (HA), and chondroitin sulfate (CS), are important components of EGL .Both vascular endothelial and tumor cells in the tumor microenvironment are involved in tumorigenesis and metastasis. The microenvironmental modification and glycocalyx remodeling of vascular endothelium and tumor cells are prerequisites for tumor angiogenesis, tumor cell invasion, and metastasis. Tumor cell adhesion to and transmigration across the vessel wall are accompanied by the degradation of endothelial glycocalyx and disruption of EC junctions ,14,15,16The glycocalyx on different cells may have different changes in response to external stimuli. Vascular ECs co-cultured with tumor cells secrete EVs carrying vascular endothelial cadherin (VE-cadherin), which are reused by tumor cells and promote tumor angiogenesis . VE-cadhChemotherapy-driven shedded SDC1 stimulates IL-11 via enhancing HGF/c-met signaling, and it might bind to bone marrow ECM molecules such as collagen and fibronectin, worsening the bone disease in myeloma . SDC1 ovA recent single-cell RNA-seq analysis demonstrated that CCL5-SDC1/4 receptor-ligand interaction mediates the T cells’ crosstalk with tumor cells in pancreatic ductal adenocarcinoma . SDC2 enIt has been shown that SDC1 promotes the transformation of tumor ECs into an angiogenic phenotype . SDC1 siMoreover, whether vascular endothelial glycocalyx participates in the tumor angiogenesis and tumor metastasis remains unclear. Further investigation is required. VEGF not only selectively regulates the proliferation and motility of vascular ECs but also enhances vascular permeability, leading to fibrin gel deposition and providing a suitable microenvironment for tumor metastasis . VEGF caFor intracellular communication, tumor cells capture and endocytose the EVs. This process requires the glycocalyx ,19. CurrThe stimulatory effect that heparanase has on exosome biogenesis is related to its ability to promote intraluminal budding and the formation of exosomes by enzymatically altering the heparan sulfate chain of syndecans ,73. TranHeparanases that are enhanced in human cancer cells such as myeloma, lymphoblastoid, and breast cancer, induces exosome secretion and increases levels of protein cargo in exosomes, which stimulate the migration of tumor cells on fibronectin and the invasion of endothelial cells through the ECM . For exaThe degradation of heparan sulfate contributes to the remodeling of the ECM that alters tumor and host cell behaviors, which likely contributes to chemoresistance and eventual relapse . AdditioInterestingly, higher levels of SDC1, VEGF, and hepatocyte growth factor (HGF) are present in exosomes secreted by heparanase high-expressing cells as compared with heparanase-low-expressing cells. The exosomes from heparanase-high-expressing cells could enhance the endothelial cell invasion . ReinforHere, we review the role of the glycocalyx in EV synthesis, release, and uptake, and the modification or modulation of the glycocalyx by the cargo of EVs. The present evidence supports that syndecans, their heparan sulfate chains, and the modification enzyme heparanase all play critical roles in the secretion and uptake of EVs. The function of EVs, which is closely associated with their compositions, is regulated by the glycocalyx. Given the importance of exosomes in the microenvironment of diseases such as cancer and inflammation, the glycocalyx compositions that are responsible for exosome secretion and uptake are viable targets. As exosomes diffuse through the tumor microenvironment, the ability of exosomal heparanase to shed heparan sulfate could be critical for cell-ECM interaction during tumor metastasis and/or inflammation. Application of the heparanase inhibitor Roneparstat can enhance anticancer chemotherapy efficacy and overcome drug resistance  and alsoParticularly, our previous studies have shown that VEGF can disrupt endothelial intercellular junctions, promote the adhesion of tumor cells to microvessels, and enhance microvascular permeability through the VEGFR2 pathway ,46. It iAs previously reviewed, the heterogeneity of the EVs, the lack of isolation and purification standards, and the unknown optimal storage conditions and pharmacokinetics or biodistribution patterns are major obstacles to the development of exosomal agents . There aTumor-derived EVs modulate the tumor microenvironment by inducing ECM remodeling, neovascularization, and immune escape. The glycocalyx is closely associated with the tumor microenvironment and plays critical roles in the synthesis, and packaging of the cargos that regulate crucial processes such as migration, invasion, and premetastatic niche formation, uptake, and internalization of EVs. Thus, glycocalyx acts as a central player in the development of the tumor microenvironment by EVs for tumor angiogenesis and metastasis.


The detection of cancer biomarkers has recently become an established method for the early diagnosis of cancer. The sensitive analysis of specific biomarkers can also be clinically applied for the determination of response to treatment and monitoring of disease progression. Because of the ultra-low concentration of cancer biomarkers in body fluids, diagnostic tools need to be highly sensitive and specific. Conducting polymers (CPs) are particularly known to exhibit numerous features that enable them to serve as excellent materials for the immobilization of biomolecules and the facilitation of electron transfer. Their large surface area, porosity, and the presence of functional groups provide CPs with binding sites suitable for capturing biomarkers, in addition to their sensitive and easy detection. The aim of this review is to present a comprehensive summary of the available electrochemical biosensors based on CPs and their composites for the ultrasensitive detection of selected cancer biomarkers. We have categorized the study based on different types of targeted biomarkers such as DNAs, miRNAs, proteins, enzymes, neurotransmitters and whole cancer cells. The sensitivity of their detection is enhanced by the presence of CPs, providing a limit of detection as low as 0.5 fM (for miRNA) and 10 cells (for the detection of cancer cells). The methods of multiplex biomarker detection and cell capture are indicated as the most promising category, since they furnish more accurate and reliable results. Ultimately, we discuss the available CP-based electrochemical sensors and promising approaches for facilitating cancer diagnosis and treatment. Cancer is undoubtedly one of the leading reasons for global deaths. In 2020,, there were 4 million new cases of cancer and 1.9 million cancer-related deaths reported in the European Union . Th. Th12]. Circulating tumor cells and circulating cell-free DNA (cfDNA) are important for the early detection and screening of cancer, as they can be used to identify tumors and genetic alterations  31]. Th. Th31]. Wang et al.  reportedThe changes in the miRNA expression within a tissue are often associated with disease states. The involvement of miRNA in human cancer was first reported by Caline et al. , who desIn a similar study, the ruthenium oxide-tagged miRNAs-initiated polymerization of aniline was executed for the voltammetric quantification of miRNA in lung cancer cells . A templImmunosensing is a method of biosensing where the sensitive detection is based on the specific binding between an antigen and an antibody to form a stable complex. Immunosensors combine the advantages of good sensitivity and high selectivity. Furthermore, they allow the progress of immunoreactions on detector surfaces to be followed in real-time . A cruci−1 . El. El54]. −1, respectively. The accuracy of the sensor was found to be 90%, and similar results were obtained when compared with conventional clinical methods such as ELISA [4 was chosen as the oxidant [−1 and 0.006 ng mL−1, respectively.Due to the complexity of the biological systems, an accurate diagnosis is not usually possible by the analysis of a single biomarker alone. Consequently, an improved accuracy for cancer detection is achievable through the simultaneous detection of multiple biomarkers. There are few reports on the fabrication of biosensors for multiple biomarkers based on conducting polymer matrices. For instance, a PPy-modified gold electrode was reported for the electrochemical detection of the oral cancer biomarkers interleukin (IL)-8 mRNA and IL-8 protein. Under optimized conditions, the LOD of salivary IL-8 mRNA and IL-8 protein reached 3.9 fM and 7.4 pg mLas ELISA . On the  oxidant . AuNPs-dIn the previous section, a detailed discussion of the available electrochemical biosensors based on CPs was presented. An overview of the reported results, including electrode material, biomarkers, sensing technique, range of linearity, limit of detection, and biomarker source is presented in The development of biosensors for the early detection of cancer biomarkers has been reported in recent years by focusing on the sensitive detection of DNAs, miRNAs, enzymes, proteins, etc., related to the presence of cancerous cells in the human body. Although electrochemical biosensors are able to provide rapid and continuous detection, the practicability of the electrochemical methods is restricted due to biofouling effects and thereby limited stability. Researchers are currently devoting great efforts to achieve the maximum sensitivity and selectivity of biosensors and to avoid the biofouling effect from proteins and biomolecules present in blood serum samples during practical applications.CPs and their composites have been the subject of intensive studies, particularly in the development of electrochemical sensors, for the ultrasensitive detection of cancer biomarkers. Their large surface area, porosity, and the presence of functional groups provide CPs with binding sites suitable for capturing biomarkers, as well as enabling sensitive and easy detection. Consequently, CPs have been found to act as excellent electrode materials able to immobilize a wide range of molecular recognition elements allowing for the ultrasensitive recognition (with LOD as low as 0.5 fM) of DNAs, miRNAs, proteins, enzymes, neurotransmitters, as well as whole cancer cells (LOD of 10 cells). More importantly, functionalized CP surfaces have been found to limit the biofouling effect, allowing for sensitive detection in real patient samples. The anti-fouling property of a sensor material is a supreme character in the practical applications of biomarker detection. Similarly, from the development of biosensors for a single biomarker, researchers have now reached the stage where a single biosensor can detect multiple biomarkers at a time. In this way, it is possible to provide the detailed encryption of the cancerous initiation and growth. Additionally, CPs furnish the direct cell capturing and sensing, which will make the cancer diagnosis more accurate and efficient. Nevertheless, apart from the laboratory methods, no devices are reported elsewhere for the point of care diagnosis of cancer biomarkers. The fabrication of stable, sensitive, selective and antifouling cancer biomarker biosensing devices, particularly those based on CPs, is expected to be a positive new development in the field of cancer diagnosis to replace the conventional analytical methods.