The modification of wood cell walls is based on the characteristics of the chemical composition and structure of the cell wall. Various physical and chemical modifications to these characteristics enhance the original properties of the cell wall and give additional functionality. Through complex modification, wood has also obtained the opportunity to become a multifunctional material. Scholars have paid more attention to the microscopic properties of the cell wall with continuous enrichment of modification methods and improvement of modification mechanisms. This article summarizes the methods of cell wall modification in recent years and proposes prospects for future development: (1) innovation of modifiers and combination with modification mechanism, as well as improvement of cell wall permeability; (2) the application directions of cell wall structures; and (3) the application of nano-technologies in cell wall modification. This review provides further ideas and technologies for wood modifications. Wood is a renewable and biological material, which is widely used in various fields ,2,3,4, rWood cell walls are composed of cellulose, hemicellulose, and lignin. Celluloses construct the skeletons of the cell wall, and the space between the skeletons is occupied by the hemicelluloses and by lignin . The celIn wood modification, the cell walls, as a carrier, not only reacts with the added modifiers but also fix the modifier using its structure to produce a physical combination with the reagent to enhance performance. For the modification of wood cell walls, the particularly important points are the moisture absorption and permeability of wood cell walls. A lot of studies have proved that moisture can change the properties of wood, resulting in great shrink and swell of wood products . TherefoThis article summarizes the methods of wood cell wall modification and the application of modified materials in recent years and proposes a prospect for the development of wood cell wall modification in the future.Thermal modification (TM) of wood enhances wood performance by reducing moisture absorption, improving dimensional stability, and biological durability ,13,14. WTM enhances the function of wood by changing the composition of wood cell walls. The chemical composition changes through the degradation of cell wall materials and extracts at high temperatures. The degradation of cell walls materials  leads toWood in steam TM, the steam can not only prevent the wood from burning but also participates in a certain chemical reaction. Tian et al. improved the bonding performance of Masson pine using steam TM. Although the surface of wood cell walls undergoes a series of changes, such as collapse, shrink, deformation, etc., wood performance  improved. Masson pine wood treated at the temperature between 160 °C to 180 °C has a higher surface wettability, while the wood obtained good hydrophobicity when treated at 200 °C to 220 °C. The reason for this phenomenon is that the surface energy of wood cell walls decreases with an increase in temperature and the loss of hydroxyl groups during TM . Elin etOther thermal modifications use gases as heat transfer media, such as nitrogen, which rarely reacts with wood. Bytner et al. thermally modified Populus Nigra L. in a nitrogen atmosphere to improve its dimensional stability. He also believes that higher modification temperatures and longer processing times contributed to a lower swelling anisotropy .On the other hand, liquid can also be used as a heat conduction medium in wood thermal modification. In the study of oil heat treatment, Wang et al. found that the results of his study confirmed that chemical reactions in the wood resulting from the heat treatment account for the main improvements of wood properties in reduced hygroscopicity and improved dimensional stability, while the oil absorbed by wood reduces the rate of water absorption .The vacuum environment can effectively prevent the wood from burning during the TM process. Sivrikaya et al. impregnated wood under vacuum condition (0.08 MPa) for 1 h with dissolved glycerin before vacuum TM . The advThe chemical composition of wood cells contains a large number of hydroxyl groups, especially the polysaccharides, leading to dimensional instability of wood material . In orde2 sol and paraffin emulsion to impregnate the wood, and then TM the samples (Pinus sylvestris L. sapwood) at a high temperature. The anti-weathering performance of TMW was greatly improved by applying a combined post-treatment of TiO2 sol and paraffin emulsion resulting from simultaneous control of ultraviolet and water [Hevea brasiliensis) and then modified the wood thermally. The results show that PEG is physically adsorbed on the walls and pits of the wood, and there is no new chemical reaction between PEG and wood [TM improves wood dimensional stability and decay resistance, but darkens wood color . The surnd water . Lin useand wood . Peg penand wood . These mThermo-hydro and thermo-hydro-mechanical processes, in an orthodox definition, no additives are used in the processes beyond water in combination with wood, heat, and external forces to shape the wood . ProceduE. nitens, saw-log managed P. radiata, and native eucalypt species from Tasmania) at 170 °C for 3 min and then heated them at a pressure of 300 kN, finally increasing the basic density of the three samples. The results showed that there were obvious differences among different varieties, and the application of fiber-grown E. nitens also showed good wood properties [The thermo-hydro-mechanical (THM) process has a positive effect on low-density wood, the elastic modulus and rupture modulus of dense wood increased, and the hardness of dense wood was also increased compared to normal wood . Michelloperties . And Wanoperties .2 laser modification, although the absorption coefficient of wood components is different, 355 nm is the best wavelength for modification [Laser TM to the wood surface is different from traditional TM. A laser as a heat source is used to radiate wood surface, different components of wood materials  color; the plasticization of lignin and the increase of crystallinity of cellulose reduced the wettability of wood surface; the decrease of nutrient content such as sugar and protein in wood can improve the corrosion resistance of wood . Fukuta fication . Laser Tfication . Laser TIn the chemical modification of wood, modifiers are mainly used to affect the process of hydrolysis, oxidation, reduction, dehydration, or reaction with free radicals to improve the functionality of wood . ImproviAcetylation modification technology is an earlier modification method , which cYang et al. modified wood cell walls using dimethyldichlorosilane (DMDCS) to improve the hydrophobicity and mechanical properties . The modAnother chemical modification method is based on the graft polymerization of cellulose, which creates wood polymer composites (WPCs) using a single grafting of vinyl on the molecular structure of celluloses. The modified wood has both the excellent properties of wood and monomeric polymers, such as good decay resistance and physical properties. However, many monomers used for this modification are difficult to penetrate wood cell walls . To reduGuo et al. found that the preparation of wood-polymer composites by polymerization of active monomers could not make full use of the properties of the polymer. They proposed a two-step method to improve the problem of poor interface compatibility of wood-polymer. They firstly immersed the water-soluble vinyl monomer into the cell walls, then reacted with the active double bond of the water-soluble vinyl monomer in the treated wood using styrene. The modified wood has a higher swelling resistance, hydrophobicity, and mechanical properties .Ding studied the effect of composite modifier impregnation on the multi-function of wood. They prepared a multi-functional composite modifier using methyl urea, dimethyl dihydroxy ethylene urea (DMDHEU), urea, and silica sol as raw materials and treated wood. A cross-linking reaction occurs between wood cell walls and the composite modifier. Spectral analysis proves that this chemical modification has no significant effect on the crystal structure of cell wall cellulose, the hydroxyl groups are reduced, the thermal stability and mechanical properties of modified wood increase, and the moisture absorption decrease .Different from acetylation, part of the modification of wood is to modify the pores in wood cell walls . ModifieThe relevant modification methods also include furfurylation, thermosetting resin impregnation, etc. , and eleMahumut et al. used UV light to create a hydrogel by polymerizing polyethylene glycol diacrylate free radicals into the pores of the wood cell walls, and then modified wood using the hydrogel. The cross-links of polyethylene glycol diacrylate and hydrogels in the cell walls and cell cavities of wood were observed through confocal Raman microscopy, spectroscopy, and electron microscopy. This polymerization and cross-linking in the form of the hydrogel can react in water in a short time . Wang alThe commonly used flame retardants substances in wood and bamboo include inorganic salts, phosphoric acid, phosphate, ammonium sulfate, ammonium chloride, borax, boric acid, etc. . The proThe mineralization process of the wood in nature takes millions of years, in which the silicic acid penetrates the cell walls and further transforms into a crystalline state through a polycondensation reaction . Modern Modern wood products are developing towards higher wood quality and performance. Multiple modification methods are developed to meet the needs of wood industries. The above-mentioned modification methods are also accompanied by other treatments in practical applications to finally obtain satisfactory modified wood. For the improvement of the cell wall, more research has focused on the multi-function, wide-areas, high-tech, and more comprehensive performance of wood.Wood carbonization is associated with the TM technology of wood. Excessive temperature leads to the carbonization of wood components. The carbonized wood has lost a lot of its properties of wood, leaving more of the skeleton structure of wood cell walls. Xu studied some transformation characteristics of wood cell walls under carbonization using scanning thermal microscopy. This experimental method can effectively study the changes in the composition and structure of cell walls after carbonization, and provide ideas for the application of carbonized wood . The devThe wood energy storage materials are high-performance capacitors  which ar2 solution), NaOH (7 wt%), or NaCIO2 (3 wt%), wood sponges with a porosity of 96.47% were obtained, which has good resilience and excellent adsorption properties [Aerogel-based wood matrix composites are also named wood sponges. Wood has a natural porous cell structure, cellulose causes cell walls to be strong and tough, and lignin is the main component that causes wood discoloration and brittleness . Moreoveoperties . Mi et aoperties .Wang et al. prepared a composite hydrogel based on wood-matrix using delignified wood, which shows good performance in strength and swelling properties. He also delignifies balsa wood using sodium hypochlorite to obtain a transparent structure with a highly arranged nano-cellulose in the cell walls, then penetrates modified gelatin into wood cell walls to completely glue and cross-link the composite material . Their wRecently, some studies focus on the transparent wood ,89,90. THomalium foetidum TM at 190 °C results in enhanced sound absorption [Wood has special natural acoustic characteristics due to its unique structure and thus it is used in various musical instruments. Despite the excellent sound performance, wood also has great sound absorption capacity and is used for noise control. Kang et al. changed the original porosity of wood through the steam explosion and increased the sorption coefficient of wood by 79%. Wang et al. increased the permeability of the pores on the cell wall using microwave treatment, and significantly enhanced the mid-frequency sound absorption performance of the modified wood. When microwave intensity, the thickness of the wood, and processing time were controlled at 18 kW, 30 mm, and 80 s, respectively, the optimal sound absorption was achieved for the treated wood . TM at hsorption .A very important step in cell wall modification is to allow the modifier to penetrate cell walls or cell cavities before reacting. The channels through which the modifiers penetrate the cell walls are the pores and cavities on the cell walls. These pores are composed of pits and gaps among microfibrils . These p2, and ZnO, and they all can improve wood decay resistance [2 was absorbed on the surfaces of wood through dip coating and annealing treatment, and the antibacterial properties, ultraviolet resistance, and a certain degree of self-cleaning ability of wood were improved [In the application of nanotechnology modification, nanoparticles can penetrate the cell wall through certain means, but there are still technical difficulties. If the modifier does not penetrate the cell wall, the modifications to the wood are weak . Mahr prsistance  and flamsistance . The sodsistance . TiO2 waimproved . The strWood cell walls play a key role in their physical, chemical, and mechanical properties. Modifications are applied to wood using various physical, chemical, and biological approaches to modify wood cell walls and improve additional functions and properties in previous studies and industry applications. Current modifications have been studied in new fields and ideas along with the further development of nanotechnology and microscopic observation technology. In this article, we list some interesting things and summarize the different modification methods. Some of them are creative, and because of their good performance, we think the modifications of wood and wood-based composites in the future should focus on three prospects: innovation of modifiers and combination with modification mechanism; wood cell walls, such as permeability, pore size and structures of wood cell walls; and application of nano-technologies.(1)The research on traditional modification of TM, acetylation, and furfuralization should pay more attrition to the modifier innovation and combination of modifier and modification mechanisms. The permeability of wood is critical for modifiers penetrating; therefore, novel permeability improvement theory and technology should be developed in future research.(2)Wood sponge, transparent wood, and energy storage materials are developed based on the modification to the wood cell wall and its structures. Future work should focus on the directional modification to the cell walls due to the particular anisotropic characteristic, the longitudinal, tangential, and radial mechanical properties of the cell wall can be individually enhanced to meet some special applications.(3)Nanotechnology has been used in wood modification and provides more ideas for cell wall modification. Nanotechnology can not only be applied to modifiers to provide new ideas for solving the problem of cell wall permeability, but it can also be applied to cell wall structures. It is of great significance to study the cross-linking process of modifiers in cell walls from the nanoscale. The modification mechanism of nano-modifier particles, the distribution within the cell wall, and the nanostructure of the cell wall should be the key directions in future research.


The well-known immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) are the reason why they are being used for the treatment of many diseases. Because they are considered hypoimmunogenic, MSCs treatments are performed without considering histocompatibility barriers and without anticipating possible immune rejections. However, recent preclinical studies describe the generation of alloantibodies and the immune rejection of MSCs. This has led to an increasing number of clinical trials evaluating the immunological profile of patients after treatment with MSCs. The objective of this systematic review was to evaluate the generation of donor specific antibodies (DSA) after allogeneic MSC  therapy and the impact on safety or tolerability. Data from 555 patients were included in the systematic review, 356 were treated with allo-MSC and the rest were treated with placebo or control drugs. A mean of 11.51% of allo-MSC-treated patients developed DSA. Specifically, 14.95% of these patients developed DSA and 6.33% of them developed cPRA. Neither the production of DSA after treatment nor the presence of DSA at baseline (presensitization) were correlated with safety and/or tolerability of the treatment. The number of doses administrated and human leucocyte antigen (HLA) mismatches between donor and recipient did not affect the production of DSA. The safety of allo-MSC therapy has been proved in all the studies and the generation of alloantibodies might not have clinical relevance. However, there are very few studies in the area. More studies with adequate designs are needed to confirm these results. In 2006 the International Society for Cell and Gene Therapy (ISCT) set up minimal criteria defining mesenchymal stromal cells (MSCs). Firstly, MSCs must be plastic-adherent when maintained in standard culture conditions. Secondly, they must express CD73, CD90 and CD105 and lack expression of hematopoietic and endothelial markers CD11b, CD14, CD19, CD34, CD45, CD79alpha and HLA-DR. Finally, MSC must be capable of in vitro differentiation into adipocyte, chondrocyte and osteoblast lineages [Among the various sources of MSCs, perinatal tissues have special interest. Tissues associated with birth, such as the placenta, umbilical cord blood, amniotic fluid and amnion, are widely available and can be used for therapeutic purposes . Adult MMSCs treatment can be autologous, allogeneic and xenogeneic. Xenogeneic MSCs treatment is often unsuccessful due to irreconcilable inter-species differences. Auto-MSCs treatment involves donor site morbidity. Age and disease state of the patient can also adversely affect the quality of the cells . FurtherFurthermore, MSCs have been considered “immunoprivileged”, as they do not activate aggressive immune responses. Numerous in vitro and in vivo studies have shown that MSC therapy promotes angiogenesis and the growth and differentiation of local progenitor cells. MSC therapy prevents fibrosis and apoptosis, attracts immune cells to the site of injury and modulates immune responses. There is current evidence showing that MSCs achieve a therapeutic effect in vivo not due to their proliferative and immunomodulatory capacity but also through paracrine signaling ,7,8. In On the other hand, MSCs secrete paracrine factors, including growth factors, exosomes, cytokines and chemokines, which promote the formation of a regenerative environment by inhibiting B and T cell proliferation and monocyte maturation. MSCs also stimulate the generation of regulatory T cells and M2 macrophages ,13,14. SAlthough the majority of in vitro studies have highlighted the immunosuppressive properties of MSCs, several studies have provided evidence that mismatched MSCs are immunogenic . MismatcRegarding clinical translation of MSCs, MSCs therapies are effective in many diseases such as GVHD ,31, ischRecent data indicate that MSC treatment may provoke donors’ humoral and cellular immune responses, especially in allogeneic transplants. Detection of donor specific antibodies (DSA) in the serum of transplant recipients provides clear evidence of alloantigen recognition by B cells . The genAt present, few studies address aspects of the safety or tolerability of allo-MSCs therapy to their immunogenicity. This systematic review aims to analyze the studies that evaluate the alloantibodies’ development in humans, including level of evidence, in order to estimate if the production of DSA is relatively common in the allo-MSC therapy, and if this alloantibodies’ production influences the safety or tolerability of the treatment.−What is the prevalence of alloantibodies’ development in patients treated with allo-MSCs?−Does the route of administration of allo-MSCs influence the development of alloantibodies?−Does the tissue of origin of the MSCs influence the development of alloantibodies?−Is the total dose of allo-MSCs associated with increased alloantibodies response?−Are repeated doses of treatment associated with higher frequency of alloantibodies or impact of treatment?−Does the presensitization status of patients influence the development of alloantibodies?−How relevant is alloantibodies’ development to the safety of the treatment?This review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA statement . A bibliRandomized clinical trials which evaluated the production of DSA after allo-MSC treatment were selected. The search was focused on studies published in English from conception on 10 May 2021. The exclusion criteria were review articles, preclinical research articles and other types of publications that were not clinical trials, non-randomized clinical trials and case reports. Stem cell sources other than mesenchymal stem cells were also excluded. Finally, a total of 13 randomized clinical trials in which DSA were measured after treatment with allo-MSCs were obtained.To carry out the study selection, a two-step review was applied. The titles and abstracts were screened independently by two authors (RST and MQV), and all publications reporting the measurement of DSA in the allo-MSC treated patients were included. Secondly, the entire publication was reviewed to ensure that it fulfilled the rest inclusion criteria. Disagreements about inclusion or exclusion of articles were discussed until a consensus was reached. If not reached, resolution was achieved by discussion with a third independent author (AFG).The variables assessed were study design, follow-up, author, country, age, disease, number of participants, controls, cell dose, number of injections, route of delivery and MSC origin. Safety and tolerability were also analyzed as well as the efficacy of MSC treatment. Severe adverse events were divided into two groups: adverse events general group and severe adverse events. Regarding efficacy, the main endpoints and the results obtained after therapy are highlighted. Finally, a correlation is established between the development of DSA and the safety of the treatment.The quality of the design was critically appraised using the Cochrane risk of bias assessment tool. This tool includes 7 specific domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias. Studies were classified as having a low, high or unclear risk of bias. Any discrepancies between reviewers were resolved in consultation with the third author until a consensus was reached.The literature search strategy identified 862 references. After screening the title and abstract and removing the articles which fulfilled the exclusion criteria , 31 recoThe main characteristics of the trials included in the study are summarized in Five studies carried out the measurement of alloantibodies after allo-MSC administration in patients with heart diseases, two studies in patients with ischemic cardiomyopathy (ICM) ,54, two All the studies included a random sequence generation. Regarding the allocation concealment, two studies were considered to have some concerns as they did not specify the allocation methodology. There were some concerns for the blinding of participants and personnel in just one study and the blinding of outcome assessment was considered of high level of risk in two studies where masking of evaluators was single or none. Eleven studies conducted a blinding of outcome assessment to avoid the detection bias. We identified a high risk of attrition bias in three studies where the missing data proportion exceeded 20%. Ten studies managed properly the incomplete outcome data. Overall, the studies exhibited low risk of bias. The details of risk-of-bias evaluation for each included study are presented in In the studies analyzed, a total of 555 patients have been entered into clinical trials with allo-MSC therapy. The main characteristics of the articles reviewed are summarized in -What is the prevalence of alloantibodies development in patients treated with allo-MSCs?-Does the route of administration of allo-MSCs influence the development of alloantibodies?The administration route for each study is shown in TESI injection in all studies led to the development of alloantibodies. The values were variable, ranging from one single patient ,47, two -Does the tissue of origin of the MSCs influence the development of alloantibodies?The tissue origin of the allo-MSCs is indicated in -Is the total dose of allo-MSCs associated with increased alloantibodies response?The cell dose is described in On the other hand, the highest dose was 300 M to treat DN. In this case, two patients developed alloantibodies . Panes ePerin et al. compared different doses to treat chronic HF. The response of DSA persisted longer in patients treated with the highest dose. Specifically, the antibody response was transient in three patients (two patients in the 25 M-treated group and one patient in the 150 M-treated group). However, the response of DSA persisted for ≤12 months in two patients in the 150 M-treated group .Tompkins et al. also compared different doses, in this case to treat FS. The highest production of alloantibodies occurred in patients treated with the highest dose. Specifically, three patients had a mild/moderate increase in cPRA (one mild in the 100 M-treated group and two moderates in the 200 M-treated group) .-Are repeated doses of treatment associated with higher frequency of alloantibodies or impact of treatment?The number of allo-MSC injections is described in -Does the presensitization status of patients influence the development of alloantibodies?The patient’s state of presensitization is described in -How relevant is alloantibodies development to the safety of the treatment?Adverse events (AEs) and severe adverse events (SAEs) collected in the clinical trials analyzed are summarized in In none of the analyzed studies was there a correlation established between the safety profile and the development of alloantibodies. The most frequently reported AEs in patients included in the analysis were infections, which are indicated as problems related to the injection process and not to the drug ,57,58. TOnly two studies ,50,51 anIn this systematic review, the production of alloantibodies after treatment with allo-MSCs was not correlated with safety or tolerability and did not have clinical relevance. Although a better understanding of MSC rejection is still needed, it is clear that MSCs are not immunoprivileged, but rather evade the immune system . However-What is the prevalence of alloantibodies development in patients treated with allo-MSCs?One out of eleven patients developed alloantibodies after allo-MSCs administration. In all the studies, specificity of DSA was against HLA class I antigens. Local treatments seem to have a lower biodistribution and as they do not have systemic biodistribution . However-Does the presensitization status of patients influence the development of alloantibodies?Regarding the presence of presensitized patients, in the studies in which presensitization is analyzed, the percentage was 43% , 30% 5454 and 16Presensitized patients showed the highest frequency of DSA, but this did not have clinical relevance in the studies analyzed. Because of the lack of studies, it is difficult to draw a firm conclusion. If the development of DSA proves to be of clinical importance, MSCs from representative subsets of the population could be collected, typed, and expanded. The creation of an HLA typed allogenic MSC bank could be created due to MSCs expansion. This should improve MSC persistence and potentially therapeutic outcomes. It should also allow serial injection of MSCs without rejection or co-administration of immunosuppressive drugs .-Does allo-MSC treatment influence the safety of the treatment?Regarding the analyzed studies, the safety profile and the de-novo DSA development were not correlated. Although MSC therapy shows a favorable safety profile, long-term safety data are limited. It would be interesting to carry out a longer follow-up after this therapy in the safety profile, as well as to evaluate the possible long-term effects that the development of alloantibodies may have. In fact, Barnhoorn et al.  detected-What information do non-randomized studies give us?In our search, we found two case reports and six non-randomized clinical trials in which DSA was also measured after allo-MSC therapy. These were not included in this systematic review because they were non-randomized studies. Despite the fact that risk of alloimmunization by MSCs seems to be low in immunocompromised patients, numerous cases have been found that point out the opposite. For example, in the case report of Kaipe et al., after two infusions of MSCs, the severe junctional epidermolysis bullosa patient had developed multispecific anti-HLA class-I DSA . Sun et Only two studies ,50,51 anIn only 13 studies in which allo-MSCs were used as treatment, was the production of alloantibodies measured. Of these, just four studies evaluate the presence of DSA at baseline and two studies analyzed the number of HLA mismatches between donor and recipient. In future studies it may be interesting to analyze these parameters in order to extract firm conclusions about the immunogenicity of allo-MSC treatment. Importantly, anti-donor antibody measurements in clinical trials, which to date have been rare, should become routine, as they will allow to understand the relationship between the degree of HLA mismatch, MSC rejection, and the efficacy of treatment under specific conditions . In addiIn conclusion, parameters such as the administration route, the tissue origin or the size of the MSC dose can influence the subsequent development of alloantibodies. The IL administration route produced the greatest generation of alloantibodies. Allo-MSCs from UC did not produce any patient with alloantibodies, and high doses are generally associated with a high concentration of alloantibodies.Furthermore, no correlation between alloantibodies and the safety of allo-MSC therapy has been found. However, only 13 studies in which allo-MSCs were used as treatment measured the production of alloantibodies. This may be insufficient to extract firm conclusions about the immunogenicity of allo-MSC treatment and more studies are needed.


Spinal cord injuries (SCI) are disruptive neurological events that severly affect the body leading to the interruption of sensorimotor and autonomic pathways. Recent research highlighted SCI-related alterations extend beyond than the expected network, involving most of the central nervous system and goes far beyond primary sensorimotor cortices. The present perspective offers an alternative, useful way to interpret conflicting findings by focusing on the deafferented and deefferented body as the central object of interest. After an introduction to the main processes involved in reorganization according to SCI, we will focus separately on the body regions of the head, upper limbs, and lower limbs in complete, incomplete, and deafferent SCI participants. On one hand, the imprinting of the body’s spatial organization is entrenched in the brain such that its representation likely lasts for the entire lifetime of patients, independent of the severity of the SCI. However, neural activity is extremely adaptable, even over short time scales, and is modulated by changing conditions or different compensative strategies. Therefore, a better understanding of both aspects is an invaluable clinical resource for rehabilitation and the successful use of modern robotic technologies. Spinal cord injury (SCI) is a devastating neurological injury that mostly affects young individuals, severely limiting their normal life activities. SCIs are commonly attributed to sudden trauma, acute/chronic disease processes, or degeneration of the vertebrae . UnfortuWe provide a comprehensive yet concise summary of the current knowledge on how SCI impacts the representation of the entire body, both above and below the injury. The first section summarizes the main structural and functional neuroplastic events that typically occur throughout the CNS following SCI and that unfolds at different spatial and temporal scales. The second section discusses the most relevant studies relating to body representation for the three main parts of the body: (i) lower limbs, (ii) trunk and upper limbs, and (iii) head and face. Only a better understanding of the neurobiological and clinical/behavioral outcomes will allow the development of appropriate therapeutic strategies. At the neural systems level, an altered signal initiated at the lesion’s origin in the spinal cord spreads until the endpoint of the sensorimotor tract ,8,9 in tIn addition, cortical reorganization after SCI has also been associated with neuropathic or phantom limb pain ,38,39. TImportant information on the over time evolution of SCI also comes from the perceptual symptoms reported by patients. Phantom limb sensations are common after SCI , both foThis analysis introduces new factors that may help disentangle the complex dynamics of brain adaptation post-SCI and may assist in understanding phenomena such as phantom limbs or the long-term somatotopic stability of the deafferented body.Currently, the most effective technique for addressing body-brain disconnection in SCI is brain activity registration  during tThe traditional view of this problem suggests that severe sensorimotor impairment should correspond to shifts, loss of extension, and reductions in cortical thickness and/or activation in lower-limb corresponding areas of the brain. However, this represents an over-simplification caused mainly by over-interpreting the results of early studies in the field due to the clinical need to categorize sensory and motor residual functions. According to the American Spinal Cord Injury Association (ASIA) classification, a complete SCI lesion is classified as AIS Grade A, meaning that the patient does not feel any sensation—or cannot produce any motor activity—in the part of the body below the lesion. Meanwhile, an AIS Grade B lesion means that while body sensations from below the SCI are spared, complete motor loss is present. AIS grades C–E describe different levels of sensorimotor impairment. However, more recent evidence suggests that at least one more level exists between AIS grade A and B; over 30 years ago, such a condition was known as a discomplete lesion whereby at least sensory information was able to reach the brain, even in the absence of a patient’s awareness . ImportaA procedure seeking to identify changes in the cortical representation of the lower limbs consists of simple sensory stimulation. Gentle toe brushing of patients with clinically complete SCIs (AIS Grade A) was used to evoke S1 activation, making it possible to discriminate between complete and incomplete lesions . In 11 oDepending on the level and severity of SCI, researchers have used various experimental paradigms, including motor activity, motor attempt, and mental/motor imagery tasks, to study lower limb-related brain activity in humans. For example, Sharp et al.  using fMThe upper body, specifically the upper limbs, offers a wider range of experimental opportunities to assess changes in body representations in the brain following a SCI, when compared to the lower limbs. TMS is a non-invasive brain stimulation technique that produces different effects depending on the target area. For example, stimulation of the primary motor cortex with TMS produces motor-evoked potentials that can be recorded in the muscles . TMS hasIn the primary motor area, only the movement of the fingers produced a change, which consisted of more extensive activations that expand medially and laterally compared to that in the controls. Movements of both the wrist and elbow in SCI patients are related to greater activation of non-primary cortical areas involved in movement, such as the supplementary motor area, the dorsal premotor area, the primary somatosensory cortex, and the cerebellum. Just a few years earlier, a PET study, using a hand movement task to control a joystick, identified, albeit in less detail, differences in activation patterns, also differentiating paraplegic and tetraplegic participants in comparison with healthy controls . The actIn addition, the ability of plastic reorganization is maintained to allow these areas to participate in long-lost motor activity , even when using a muscle that was previously not directly involved in this movement. After some time, in the same group of patients, it was possible to study the morphological changes in the cortical areas involved in thumb movement. That is, the primary motor cortex showed a general condition of atrophy, but when specifically considering only the area “reactivated”, because of the tendon transfer procedure, there was no difference in cortical thickness between tetraplegic patient and healthy controls .Dorsal column lesions ,62,63,64In fact, somatotopic remapping processes occur with the establishment of new connections between the face and the deafferented hand region in the primary somatosensory cortex ,68. ReorOverlapping fMRI scans of the SCI patient and the control revealed that the active facial region was similarly active in the two participants; however, in the SCI subject, it invaded the hand area. While reorganization patterns following SCI in humans suggest a topographical remapping in the region closer to the site of deafferentation, the tactile threshold required to elicit a neural response of the new face map, and whether reorganization of face representation occurs in higher somatosensory areas, remains unknown in humans after cervical SCI. However, behaviorally, greater susceptibility to the modified rubber hand illusion paradigm (applying sensory stimulation to the face with the observed touches on the fake hand) seems to drive tetraplegics’ sense of hand ownership , supportThe studies discussed in this paper show that peripheral and CNS lesions can induce neural reorganization within the central somatosensory and motor/body representations. However, how the brain processes the flow of signals following a body-brain disconnection due to a complete SCI remains largely unknown. How deep severe neurological traumas affect typical sensory and motor signals of single body parts and their appropriate integration by brain mechanisms and structures is unclear. In fact, there are discrepancies in the observed brain activity changes in patients with SCI. This can be attributed to heterogeneity in the extent of the neurological injury and lesion severity, to disease duration, age, as well as to the degree of altered sensory and pain experience, to compensatory learning, and to exposure to rehabilitation . Importa


The lymphatic system maintains homeostasis of the internal environment between the cells in tissues and the blood circulation. The coagulation state of lymph is determined by conditions of coagulation factors and lymphatic vessels. Internal obliteration, external compression or abnormally increased lymphatic pressure may predispose to localized lymphatic coagulation. In physiological conditions, an imbalance of antithrombin and thrombokinase reduces lymphatic thrombosis. However, the release of factor X by lymphatic endothelium injury may trigger coagulation casacade, causing blockage of lymphatic vessels and lymphedema. Heterogeneity of lymphatic vessels in various tissues may lead to distinct levels and patterns of coagulation in specific lymphatic vessels. The quantitative and qualitative measurement of clotting characteristic reveals longer time for clotting to occur in the lymph than in the blood. Cancer, infections, amyloidosis and lymph node dissection may trigger thrombosis in the lymphatic vessels. In contrast to venous or arterial thrombosis, lymphatic thrombosis has rarely been reported, and its actual prevalence is likely underestimated. In this review, we summarize the mechanisms of coagulation in lymphatic system, and discuss the lymphatic thrombosis-related diseases. The mammalian lymphatic system is a one-way transport system of draining fluid and proteins from the interstitialspaces to the blood circulation. The lymphatic circulation is composed of lymphatic vessels, lymph nodes, lymphocytes, and associated lymphoid organs . This syThe lymphatic system is a unidirectional transit network consisting of a network of vessels and nodes. The lymphatic system is responsible for the reabsorption of plasma components leaking from capillaries and postcapillaryvenules into extracellular spaces . When thThe lymphatic capillaries are composed of monolayers of discontinuous endothelial cells, which having a relatively flat, “oak leaf” shape . The basThe primary function of the lymphatic system is to replenish the vascular system by regulating tissue fluid balance, facilitating interstitial protein transport, and providing essential immune function . To accoThe normal blood coagulation process consists of three steps: vascular response, the initiation of platelet plugs, and the formation of fibrin clots . PlateleCoagulation includes both endogenous and exogenous pathways. Each pathway is initiated by different molecules, and both pathways converge into a common pathway that involves coagulation factors II, V, and X, leading to the formation of fibrin . CoagulaEndothelial cells produce anticoagulants and procoagulant molecules to form structures that rapidly activate platelets and clot blood . Von WilAn imbalance consisting of an excessive concentration of antithrombin in the lymph and a low concentration ofthrombokinase (activated coagulation factor X) greatly reduces the possibility of lymphatic thrombosis. The lack of anionic phospholipids on the cell surface and low concentrations of thrombinand TFPI also offset the production of fibrin in the lymph –44. ImmuTheoretically, any known cause of lymphatic vessel occlusion due to internal obliteration, external compression, or increased lymphatic pressure may predispose an individual to localized lymphatic thrombosis . The venLymphatic vasculature displays remarkable heterogeneity in structure and function. The primarylymphaticsare right lymphatic duct (RLD) and thoracic duct (TD). TD is the largest lymphatic vessel that drains chylous and lymphatic fluid from most of the human body including the limbs and abdomen . The livThe analyses of lymphatic vessels inembryos, an dual origin theory proposed that lymphatic endothelial cells originated from two sources , 62. TheIn contrast to blood, which is not in direct contact with the cellular layers of parenchymal organs, the lymph is derived directly from the organ interstitialfluid, whichbathes each organ's cellular layers , 67. ThaIt is well-known that the platelets play an essential role in the formation of white thrombus in circulating blood . The lymIn the coagulation cascade of the blood, the embolus is adherent to the vascular walls through platelet, leading to vessel occlusion . The intAccording to the existing literature, the ultrastructure of lymphatic vessels in healthy humans does not contain WPBs. Von Willebrand antigen was present in a very low concentration in the rabbit limb lymph, primarily as low molecular weight multimers . The preAs early as 1980, coagulation factors in thoracic-duct lymph of dogs were found to have significantly different coagulation activity from that typically measured in plasma . Both acThe concentrations of coagulation factors and anticoagulation factors in the lymph were much lower than those in the plasma, but the concentration of d-dimer in the lymph was higher than that in the plasma, often more than fivefold , 53. Bacin vivo , podoplanin, Vascular endothelial growth factor receptor-3 (VEGFR-3) and specific intracellular factors such as Prox-1 have been found –85. The Lymphedema is a chronic and persistent disease that can easily lead to a large number of comorbidities . It may In cases studies of amyloidosis, a total of 2% of patients diagnosed with all types of amyloidosis had lymph node amyloidosis , 100. BoIn an experiment on liver and gallbladder edema caused by cantharidin, liver lymphatic vessels expanded extensively. Lymphatic endothelial cells are damaged and denatured under the action of poison, which forms a fibrous network in lymphatic vessels to block lymph flow . Other fDifferent mechanisms may lead to lymphatic thrombosis or occlusion in cancer patients, including external compression from tumor masses, neoplastic occlusion of lymphatic vessels by metastatic cells or lymphatic dysfunction afterlymphadenectomy . CoagulaPatients with chronic venous insufficiency, deep vein thrombosis, venous valve damage may develop persistent inflammation and chronic damage to the lymphatic vessel, leading to loss of lymphatic vessel contraction function, reduced lymphatic drainage, and severe lymphatic thrombosis . The conAlthough lymphatic thrombosis occurs in a variety of diseases, it has rarely been reported. For cancer lymphatic thrombosis, the leading causes include external tumor compression, neoplastic obliteration by metastatic cells, or lymphatic injury after lymph node dissection. Patients with fungal, bacterial and viral infections in tissues near lymphatic vessels may have lymphatic thrombosis and progressive lymphatic destruction. Lymphatic thrombosis was also found in sporadic cases of complications of central venous thrombosis or injury during cardiothoracic surgery, chronic venous insufficiency and thoracic outlet syndrome, which accompanied with lymphatic venous valve injury or obstruction of thoracic catheter drainage. If the lymphatics thrombosis causes accumulation of interstitial fluid, the lymphatico-venous anastomosis is expected to reduce the inner pressure of the lymphatic vessel and reconstruct lymph flow. For patients with severe, unexplained edema, clinicians may consider the possibility of the lymphatic thrombosis. Indocyanine green lymphography and radionuclide lymphoscintigraphy may locate lymphatic obstruction, while laboratory tests are still limited. Many cases of lymphatics thrombosis were found in lymphatic biopsy. Further studies are needed to understand the mechanisms of lymphatic thrombosis and develop novel diagnostic and therapeutic strategies.JLiu conceived and designed the review. JLiu, WZ, and JT wrote the first draft. JLi, JLia, and XQ participated in writing of the manuscript. All authors contributed to the article and approved the submitted version.This study was supported by the National Nature Science Foundation of China (81873473 and 91939110), Academic Promotion Program of Shandong First Medical University (2019QL014) and Shandong Taishan Scholarship (JLiu).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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S configuration of substituent at C5, the acylaminomethyl group linked to C5 and the N-aryl substituent. The synthesis of oxazolidinones has gained increasing interest due to their unique mechanism of action that assures high antibiotic efficiency and low susceptibility to resistance mechanisms. Here, the main features of oxazolidinone antibiotics licensed or under development, such as Linezolid, Sutezolid, Eperezolid, Radezolid, Contezolid, Posizolid, Tedizolid, Delpazolid and TBI-223, are discussed. As they are protein synthesis inhibitors active against a wide spectrum of multidrug-resistant Gram-positive bacteria, their biological activity is carefully analyzed, together with the drug delivery systems recently developed to overcome the poor oxazolidinone water solubility. Finally, the most employed analytical techniques for oxazolidinone determination in different matrices, such as biological fluids, tissues, drugs and natural waters, are reviewed. Most are based on HPLC (High Performance Liquid Chromatography) coupled with UV-Vis or mass spectrometer detectors, but, to a lesser extent are also based on spectrofluorimetry or voltammetry.This review covers the main aspects concerning the chemistry, the biological activity and the analytical determination of oxazolidinones, the only new class of synthetic antibiotics advanced in clinical use over the past 50 years. They are characterized by a chemical structure including the oxazolidone ring with the  The word antibiotic was first introduced in 1941 by Selman Waksman to indicate any small molecule produced by a microbe capable of counteracting the growth of other microbes . In the According to the WHO  definition, antimicrobial resistance refers to change in microorganisms  which make the drugs used to treat the infections they have caused ineffective . Such reThe European Antimicrobial Resistance Surveillance Network (EARS-Net) provides data on antimicrobial resistance in the EU and European Economic Area (EEA), estimating that there were 671,689 cases of infections with selected antibiotic-resistant bacteria in 2015. This resulted in 33,110 attributable deaths, corresponding to an incidence of 131 infections and a mortality rate of 6.44 deaths per 100,000 inhabitants [By 2014, data on multidrug-resistant tuberculosis (MDR-TB) were made available from 153 countries, accounting for 96% of the world population and cases of incident tuberculosis (TB) . WorldwiResearch in this field is primarily aimed at the development of new technologies , understanding the ways in which antibiotic-resistant microorganisms emerge and spread, formulating strategies for the responsible use of antibiotics and reducing the risk of infections in healthcare ,9. ThereGram-negative bacteria (GNB), such as Enterobacter and Escherichia coli, are responsible for severe infections, such as pneumonias, surgical infections, urinary tract infections and meningitis. Recently there has also been a worrying increase in MDR across several species of GNB and strains resistant to many of the available antibiotics . As outlMoreover, the PK/PD features of oxazolidinones can be improved by exploiting appropriate drug delivery systems that allow us, by drug incorporation or covalent conjugation, to overcome the main hindrances related to the clinical use of oxazolidinones, including poor water solubility and adverse systemic effects.A series of new compounds, including bis-oxazolidinones, have been synthesized and tested in vitro for antibacterial activities as potential antitubercular agents . Due to S configuration of substituent at C5 and the acylaminomethyl group linked to C5 and the N-aryl substituent (ring B). The meta-fluoro substitution on B ring increases the biological activity, whereas the para-substitution expands the antibacterial spectrum [Oxazolidinones are a fully synthetic class of bacteriostatic agents that find no congeners in natural product compounds and were the first synthesized at E.I. du Pont de Nemours & Co. in the mid-1980s and successively implemented by Pharmacia . Their historical development has been discussed in different literature reviews ,23. The spectrum . The mecspectrum ,26. Oxazolidinones inhibit protein synthesis by interaction with the A-site pocket of the 50S subunit at the peptidyl transferase center (PTC). This interaction affects the binding and/or positioning of the initiator-tRNA and prevents the binding of tRNA at the A site, thereby preventing the translation sequence. Both LNZ and Eperezolid emerged from preclinical tests as potential drug candidates showing almost identical MIC (lowest concentration of a compound/antibiotic at which no growth is observed) values, antibacterial spectrum and pharmacokinetic parameters. LNZ was selected for further development for its prolonged half-life in humans; these data emerged after LNZ and Eperezolid Phase I clinical studies. The chemical strategy for the large-scale synthesis of LNZ is described in Therapeutic treatments based on LNZ improved the outcomes of several drug-resistant infections, including TB; however, long-term side effects such as reversible myelosuppression, potentially irreversible optic neuropathy and peripheral neuropathy are often correlated to its prolonged administration . To overThe phenomenon of bacterial resistance to antibiotics is constantly increasing in the world and requires methods for their determination in various types of matrices, not only drugs, biological fluids or tissues, but also foods and natural waters. In fact, antibiotics were recently recognized as contaminants of emerging concern (CECs) owing to their wide distribution and persistence in the environment, mostly in wastewaters and in natural water systems. Among the oxazolidinones, LNZ is certainly the one that has attracted the most attention and liquid chromatography, mass spectrometry and electrochemical or spectrophotometric/fluorimetric methods have been developed for its analytical determination.The most used analytical techniques are certainly based on HPLC (High Performance Liquid Chromatography) methods, mostly coupled with UV-Vis spectrometric detectors. HPLC methods concerning the determination and quantification of LNZ in different matrices , since the time of its discovery until 2019, were carefully summarized in a recent review . As poinIn recent years, the increasing use of the mass spectrometer as an HPLC detector has led to the development of analytical methods that take advantage of the greater sensitivity and selectivity of this detector in respect to the UV one. One review  summarizIn addition to HPLC methods, other techniques have been used to determine oxazolidinones. Spectrofluorimetric methods were used  for LNZ Other methods concern electrochemical techniques, which are interesting for their rapidity, affordability and selectivity. In this area, LNZ was also the oxazolidinone object of most studies ,45,46,47Oxazolidinones are protein synthesis inhibitors active against multidrug-resistant GPB, including MRSA, penicillin-resistant streptococci and vancomycin-resistant enterococci. This peculiar spectrum of action suggests that these compounds inhibit bacterial growth by interfering with protein synthesis with a unique mechanism of action. The identification of the binding site and the most likely mode of action took considerable efforts  and, in Oxazolidinones bind to and inhibit both bacterial and archaeal ribosomes, but do not interact with human cytoplasmic ribosomes. The mechanism of action differs from all existing protein synthesis inhibitors as the inhibition occurs at a very early stage and involves the binding of N-formylmethionyl-tRNA (tRNAfMet) to the ribosome. The competition with chloramphenicol and lincomycin for binding the 50S subunit indicates that oxazolidinones have close binding sites, even though they do not inhibit peptidyl transferase. They bind to the bacterial 50S ribosomal subunit, at the 23S portion, without interacting with the 30S subunit. Specifically, the main action of oxazolidinones is the binding of the A-site pocket of the 50S subunit at the PTC of the ribosome with consequent inhibition of the initiation complex and translocation of peptidyl-tRNA from A site to P site. In detail, LNZ binds to a pocket formed by eight RNA residues, one of which (U2585Ec) is stabilized in a distinct conformation, nonproductive for peptide bond formation. In this way, LNZ affects the binding and/or positioning of the initiator-tRNA and prevents the binding of tRNA at the A site, thereby halting the translation process .Oxazolidinones are used for the treatment of skin and soft tissue infections. Due to the unique mode of action, they have, in principle, a low chance to develop drug resistance. However, owing to the worldwide spread of acquired resistance genes , three different oxazolidinone-resistance mechanisms have been characterized so far: the point mutation G2576T in the domain V of 23S rRNA genes (single nucleotide polymorphism); the acquisition of the ribosomal methyltransferase gene designated as “cfr gene”; and mutations in rplD and rplC genes encoding 50S ribosomal proteins L4 and L3, respectively ,50.The pharmacokinetic profile of LNZ makes this antibiotic a good choice for the treatment of orthopedic infections such as chronic osteomyelitis, which requires a prolonged administration time. Its oral formulation has an almost 100% bioavailability; moreover, intravenous administration is also available. LNZ is indicated for nosocomial skin infections and it has been included in the WHO’s list of drugs for treating drug-resistant strains of Mtb . The adverse effects related to LNZ administration consist of bone marrow suppression in the case of prolonged administration of the antibiotic (more than 2–3 weeks), with related thrombocytopenia, anemia and decreased hemoglobin concentration. However, all blood abnormalities were reversible and returned to baseline values 10–14 days after the end of the treatment. An irreversible peripheral neuropathy may occur in the case of prolonged treatment (more than 6 months) . Drug solubility is a critical factor for the clinical development of antibiotics, since the dissolution rate greatly influences their absorption, blood concentration and bioavailability. Since oxazolidinones are poorly water-soluble compounds, the recent advancements in the bio- and nanotechnologies represent a good chance for the development of drug delivery systems (DDS) able to overcome the hindrances related to hydrophobicity. To the best of our knowledge, few classes of nanomaterials have been investigated as carriers for oxazolidinones, including cyclodextrins and biopolymers. Recently, a Tedizolid-hydroxypropyl-cyclodextrin (TZD/HP-CD) inclusion complex was proposed by Cielecka-Piontek and coworkers . The dis®), also significantly influenced the solubility of TZD, increasing and prolonging its release. Nevertheless, the decrease in the permeability hindered further development of the proposed Pluronic-based delivery system [The same authors demonstrated that hydrophilic polymers, such as hydroxypropyl methylcellulose (HPMC) and triblock copolymers based on poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO)  acid (PLGA), poly(lactic) acid (PLA) and polycaprolactone (PCL), have been proposed for the localized delivery of LNZ to overcome the adverse effects associated with its systemic use.PLGA and PLGA/PCL electrospun fibers loaded with LNZ were recently evaluated for the treatment of MRSA associated with bone infections, prosthetic infections and soft tissues . The nanThe use of PLA as local drug delivery system for LNZ was investigated for the direct administration of the drug at the orthopedic implant site, with the aim to reduce the bacterial attachment on wires. The medical implants, namely orthopedic Kirschner wires, were coated by the solvent casting technique with the desired antibiotic–polymer solution, using LNZ at three different concentrations  to create a local DDS able to efficiently prevent the adhesion of MRSA . LNZ-loaded lipid–polymer hybrid nanoparticles (LIN-LPNs) were prepared by nanoprecipitation using lecithin, DSPE-mPEG(2000), cholesterol (as lipidic components) and PLGA (as polymeric core) at a 1:5.7 polymer-to-lipid ratio. The activity of the hybrid nanosystem was evaluated in vitro against intracellular and biofilm-embedded MRSA. LIN-LPNs showed high drug loading (12%) and a sustained release profile . Enhanced intracellular and anti-biofilm activities were observed with respect to the free drug against these less accessible, antibiotic-resistant pathogens that often cause osteomyelitis chronicity and recurrence . LNZ-loaded gelatin nanoparticles were surface-functionalized with mannose (LNZ-Mn-GNPs) for selective targeting to alveolar macrophages as an effective strategy to fight Mtb infection. The primary host of Mtb is the alveolar macrophages where they grow, replicate and then spread through the body; hence, targeting mannose receptors on macrophages can be a useful strategy to treat the disease. The authors reported the in vitro physicochemical characterization and ex vivo hemolytic toxicity evaluation, pointing out the safety and reliability of the formulation . 2 to diffuse through the cellular membranes. The antibiotic was connected to the bis-catecholate-based siderophore via the peptide WSPKYM to obtain a cleavable SAC. The inhibition of bacterial growth required the enzymatic cleavage of the linker by proteases, whereas the intact conjugate was inactive [As an alternative to traditional nanocarriers, antibiotics can be delivered by siderophores, small-molecule chelators that are produced by bacteria to sequester Fe(III), an essential nutrient required for bacterial growth and virulence. Specifically, the outer membrane proteins of GNB, binding ferric siderophores, provide opportunities for active transport and delivery of antibiotics into the cytoplasm. In this regard, the siderophore-mediated antibiotic delivery was fruitfully exploited to promote the transport of oxazolidinones through the bacterial outer membrane. Inspired by the Trojan horse approach, Seiple and coworkers recently proposed a siderophore−antibiotic conjugate (SAC) to overcome the inability of Eperezolid-NHinactive . Moreover, the conjugation of Eperezolid with a siderophore linked to a cephalosporin was exploited to obtain a dual drug conjugate able to guarantee efficient passage of these drugs through the bacterial outer membrane . The proThe treatment of bacterial infections due to Gram-positive and Gram-negative strains is still challenging, especially with regard to resistant strains. The abuse of antibiotics has resulted in the increase of widespread antimicrobial resistance to commonly prescribed drugs, requiring the development of new active compounds able to manage severe microbial infection, reducing morbidity and mortality. The scenario described in this review shows the leading position of oxazolidinone antibiotics against multidrug-resistant GPB and drug-resistant Mtb, although until now only LNZ and TZL have been licensed for human use. Several oxazolidinone derivatives failed in the Phase I or Phase II clinical stages due to inherent toxicity and side effects. Moreover, the spectrum of activity of LNZ is relatively narrow and mainly covers GPB. The development of new oxazolidinone antibiotics with potent activity, a wide spectrum of activity and minimal adverse effects should be considered a priority, especially for the treatment of drug-resistant Mtb, since severe toxic effects are associated with its long-term treatment protocol. Currently, approximately 2 billion people are infected with TB and the arsenal against TB, the second most deadly infectious disease on the planet, is limited . Nanotechnology tools could be decisive for the development of new oxazolidinone therapeutics since different antimicrobial agents could be co-entrapped and delivered by engineered nanoplatforms achieving a synergistic action, a broadening of the antibacterial spectrum and improved safety profiles compared to free drugs. While nanomedicine strategies are in use for the design of vaccine carriers , nanotecThe interactions among oxazolidinone antibiotics and metal ions are a completely unexplored topic. Metal complexation is known to affect the action of many drugs ,71 and iThe analytical determinations of oxazolidinone antibiotics in the biological matrices or as pollution analytes have been marginally investigated in the past and no critical discussion has been reported. Certainly, many aspects still need to be investigated regarding the analytical methods. First of all, the development of methodologies  for oxazolidinones other than LNZ. The second aspect concerns the matrix, since most of the studies were directed at the determination of LNZ in biological fluids or pharmaceutical preparations. Only recently did de Barros and coworkers  report a


Acupuncture has been widely used as an alternative and complementary therapy for migraine. With the development of neuroimaging techniques, the central mechanism of acupuncture for migraine has gained increasing attention. This review aimed to analyze the study design and main findings of neuroimaging studies of acupuncture for migraine to provide the reference for future research. The original studies were collected and screened in three English databases  and four Chinese databases . As a result, a total of 28 articles were included. Functional magnetic resonance imaging was the most used neuroimaging technique to explore the cerebral activities of acupuncture for migraine. This review manifested that acupuncture could elicit cerebral responses on patients with migraine, different from sham acupuncture. The results indicated that the pain systems, including the medial pain pathway, lateral pain pathway, and descending pain modulatory system, participated in the modulation of the cerebral activities of migraine by acupuncture. Migraine is a chronic neurological disease characterized by recurrent headaches and neurological symptoms . As the Since the first neuroimaging study about acupuncture for migraine was published in 2008, nearly 30 studies have been emerged to improve the understanding of acupuncture for migraine with real-time visualized evidence. However, the designs and results of these studies showed significant differences. For example, some research studies concentrated on study designs from different perspectives, such as different manipulation modalities of acupuncture and different subtypes of migraine; several studies applied different neuroimaging scanning techniques or used different analytical methods. The various study designs may partly contribute to different results which affect the clinical application to some degree. Therefore, this review aimed to analyze the study design and summarize the main results of the published neuroimaging studies in acupuncture for migraine to deepen the understanding of the cerebral mechanism of acupuncture for migraine and provide reference and guidance for future research.Data collections were conducted in three English language databases  and four Chinese language databases  from database inception up to 31st Dec 2020, with the combination of the main keywords: neuroimaging, acupuncture, and pain; studies about migraine were selected. The retrospective searching was performed on reference lists of included articles. Details of search terms were depicted and modified for each database in Supplementary Table 1.The article was included if [1] the studies were original articles, [2] the patients were diagnosed with migraine, [3] acupuncture was the intervention method, and [4] neuroimaging techniques were used to investigate the cerebral changes elicited by acupuncture (Supplementary Table 1).The article was excluded if [1] it was a duplicate article or [2] it was the irrelevant article, review, case report, protocol, only abstract, editorial letter, retracted article, and animal experiment. Studies not fulfilling each of the above criteria were excluded (Supplementary Table 1).Supplementary Figure 1 shows the flow diagram of the literature search and screening process.The published year, the institution of corresponding authors , study design , types of control, and clinical scales of migraine) (Supplementary Table 3), and the related neuroimaging information  (Supplementary Table 4) were extracted.Twenty-eight original articles were included in this review.The first acupuncture-neuroimaging study for migraine was published in 2008. All the twenty-eight studies were published by Chinese researchers. The top three corresponding affiliations were Chengdu University of TCM (11 studies) –16, DongTwenty studies (71%) enrolled migraine patients without aura , 14–29. Twenty studies (71%) focused on the long-term efficacy of acupuncture for migraine , 27–33; Twenty-one (75%) studies were designed to concentrate on the central mechanisms of acupuncture for migraine. Among them, nine studies (32%) were designed as the self-control model (pre vs. posttreatment) , 28, 29,Seventeen studies used the visual analogue scale (VAS) to assess the pain intensity of migraine –29, 33. Twenty studies selected magnetic resonance imaging (MRI) to explore the cerebral responses of acupuncture for migraine  , 15–29; Functional integration analysis  9 studies) were the common analytical methods applied in the fMRI , 28, 29  studies The cerebral responses to acupuncture for migraine are given in Supplementary Table 4. The high-frequency reported brain regions are shown in Since neuroimaging techniques were used to explore the mechanisms of acupuncture, the central mechanism of acupuncture for migraine has gradually drawn the attention of investigators. Since the first study explored the central mechanism of acupuncture for migraine, 28 studies have been published during the past 15 years. From the beginning, these articles simply concentrated on the self-control design of the cerebral activities, gradually developed to explore the different cerebral activities of the acupuncture efficacy (such as VA and SA), and now paid attention to the different cerebral activities of acupuncture for subtypes or stages of the migraine. These articles significantly improved the understanding of acupuncture for migraine with real-time visualized evidence.The design of the acupuncture-neuroimaging study for migraine could be divided into four categories according to the contents.First, at the early stage, these studies , 28, 29 Second, people gradually tended to investigate whether the cerebral changes elicited by acupuncture were different from those by SA, to explore the different cerebral activities between the acupuncture efficacy and placebo efficacy. The majority of these studies selected functional connectivity (FC) to analyze the neuroimaging data. FC has developed to the popular direction of the neuroimaging analytical method in recent years. However, few kinds of research concentrated on the depth, the intensities of acupuncture stimulation, or other factors that influenced the efficacy of acupuncture for migraine.The application of FC based on the specific ROI of the brain, rather than the whole brain, is a substantial limitation of these studies. Thus, it is valuable to explore the central mechanism of acupuncture for migraine from different perspectives including the influencing factors and large-scale whole brain networks.Third, some studies investigated the central mechanism of acupuncture therapy for some subtypes . That means investigators mostly focused on the central mechanisms of acupuncture for specific subtypes of migraine. It has been proved that the cerebral activities of the ictal or interictal phase of the migraine existed differently –36. The Fourth, with the application of the machine learning (ML) algorithm in neuroimaging studies, people gradually began to predict the efficacy of acupuncture for migraine with neuroimaging data by the multivariate pattern analysis method. In this review, four studies applied ML to explore the structural and functional properties of the brain whether it can contribute significant information to predict the efficacy of acupuncture for migraine at the individual level , 22, 24.Of the included studies, VAS was the most used scale for pain assessment for migraine. Besides, the clinical efficacy of migraine mostly focused on symptoms such as the frequency, intensity, and attack duration of migraine. Only five studies applied emotional scales and two studies applied disease-specific scales, MSQ, to assess the emotion and QoL of migraine patients. The pain experience is multifaceted and complex, encompassing multiple dimensions including psychological, cognitive, perception, affective, and behavior . Except In this review, the neuroimaging techniques including MRI, PET, and H-MRS were applied. fMRI was the most commonly used technique to explore the cerebral activities of acupuncture for migraine. fMRI indirectly measures brain activity based on the blood oxygenation level-dependent effect , PET-CT Therefore, future studies can combine the multimodal neuroimaging techniques to detect the dynamic brain activity of acupuncture for migraine to make the results complementary and cross-validation. For example, combine molecular imaging such as H-MRS with fMRI to detect cerebral activities from the molecular and functional levels. H-MRS can be a complementary neuroimaging technique to fMRI, which can identify static as well as dynamic levels of specific brain neurotransmitters that likely relate to the fMRI signal involved in pain processing and modulation of acupuncture for migraine . BesidesThe neuroimaging studies about acupuncture for migraine demonstrated that acupuncture modulates a widely distributed network of brain areas including the frontal lobe, temporal lobe, occipital lobe, parietal lobe, diencephalon, brainstem, and cerebellum . AccordiIn this review, the included studies have suggested that the regions of the medial pain system, including the anterior cingulate cortex (ACC), insula, and middle frontal gyrus (MFG), are participating in the cerebral responses to acupuncture for migraine (The thalamus cortex is known to be a relay center for the processing of nociceptive inputs, and the thalamus can be divided into medial and ventrobasal parts . PathwayBesides, the results indicated that the key regions of default DMN  (Figure Disruption of the balance of descending pain modulation associated with chronic pain has been confirmed , 74. TheFurther analysis of the relation between the study designs and results indicated that the medial pain pathway was the core altered region during VA vs. SA control modality about the long-term effect , 27, 33.This review mainly overviewed the study design and main findings of acupuncture for migraine by neuroimaging techniques. This review manifested that acupuncture could elicit cerebral responses on patients with migraine and different from SA. Current studies began to use the ML to predict the efficacy of acupuncture for migraine. In the future, researchers can promote the integration of clinical and neuroimaging data with a bigger sample size to predict the efficacy of acupuncture for migraine and provide specific clinical guidance at the individual level.


For this reason, both the sector industry and academia have devoted their studies to eco-sustainable materials able to maintain the specific properties of cements. Synthetic inorganic polymers, based on aluminosilicate or phosphate, and prepared following a process known as geopolymerization, have been recognized for almost twenty years now as geopolymers. Characterized by chemical and mechanical properties comparable to those of ceramics, geopolymers present great tolerance for high temperatures and do not explode, contrary to the traditional hydraulic cements. In addition, geopolymers are non-toxic, eco-friendly, and sustainable materials considering, as testified by many papers of this Special Issue, that waste can be recycled as raw materials or inert fillers for their preparation, maintaining performances comparable to those of Portland cement.Concrete is the most commonly used construction material worldwide, and many efforts have been carried out in recent years to improve its functional properties while also trying to increase its sustainability. Concrete’s environmental impact is well known, linked both to the space it occupies in landfills and its highly energy-intensive manufacturing, thus branding the cement industry one of the largest COThis Special Issue, which consists of 22 articles (including two review articles) written by research groups of experts in the field, considers recent research on the design, preparation, and characterization of geopolymers.The first paper, published by Lee and coworkers, aims at developing a sustainable structural material for the construction industry, namely a marble-based geopolymer concrete . The via2 emissions compared to cement concrete. Alkali activators such as sodium silicate and sodium hydroxide were used in the preparation of alkali-activated cements, whose structures are observed to change via carbonation. In addition, they recorded a simultaneous decrease in the compressive strength, thus opening interesting future scenarios in the field of alkali-activated cements.Additionally, in the work of Kim et al., the focus is on the physical and chemical properties changes of alkali-activated cements prepared from blast furnace slag and fly ash , represeIn their contribution, Le and colleagues discussed the experimental data as regards the mechanical properties of the hybrid composite thin-plates of the short basalt fibers/carbon textile-reinforced geomortar . The effIn order to evaluate the effects of the reinforcement and their estimation as correctly as possible, Shi et al., developed practical prediction models of splitting tensile strength and reinforcement–concrete bond strength of low-calcium fly ash geopolymer concrete . The preMohd Basri and coworkers, in coating geopolymer with rice husk ash (RHA), tried to balance the increase in fire retardant properties with the water absorption effects due to the incorporation of RHA . Aiming By stressing the positive environmental impact of the geopolymers, both as a friendly alternative for concrete and utilization of hazardous wastes, Górski et al., focused their study on the recovery of discarded cathode ray tube glass as aggregate for the preparation of metakaolin-based geopolymer . After dEscherichia coli and Enterococcus faecalis, showing a very limited and absent inhibition zone for fine and coarse grain size ranges, respectively. The same research group, aiming to reduce the percentage of debris disposal derived from urban solid waste, suggested an upcycling process where glass debris is simply ground without any washing operation and added to an alkali-activated paste. Thus, metakaolin-based geopolymer mortar added with coarsely ground glass waste has been prepared and characterized, showing interesting antibacterial properties [This research line was also followed by Dal Poggetto et al., who reused glass waste prepared geopolymer at different percentages and grain size of glass to evaluate their antimicrobial activity . As the operties .Assuming that the addition of magnetite to concrete improves its mechanical properties and durability in terms of water and chloride ions absorption, Sgarbossa et al., proposed the design and preparation of novel magnetic geopolymers based on matrices with and without inert quartz aggregates, containing metal particles at different concentrations . By usinWith a view towards greater sustainability, Lancelotti et al., proposed an alternative cementitious binder based on industrial side streams and characterized by a low carbon footprint . A novelContinuing to follow the path of reducing the environmental impact of cementitious formulations, Algaifi and coworkers proposed alkali-activated mortar (AAM) made with binary binders involving fly ash (FA) and granulated blast-furnace slag (GBFS) as well as bottle glass waste nano-silica powder (BGWNP) . By usinAdditionally, Wang et al. were interested in the use of concrete reinforcements based on waste materials. In particular, they turned their attention to the huge amounts of waste ceramic tiles and blast furnace slag (BFS) produced by the ceramic tile factories and the iron smelting industry . They miQuiatchon and coworkers, aiming to increase the low utilization rate of the coal fly ash produced in the Philippines, proposed its use to prepare fly ash-based geopolymer for construction, thus also reaching the goal of lower greenhouse-gas emissions. They provided an impressive amount of specimens in order to optimize the geopolymer components for the replacement of Portland Cement for in situ applications . The engLee and colleagues assessed the preparation of potassium-based geopolymers (KGL) into leucite ceramics and tested their structure and mechanical properties . By takiKohout et al., prepared a metakaolinite-based geopolymer binder using calcined claystone as the main raw material and potassium as the alkaline activator, then proceed with their thermo-mechanical characterization . By balaMorenov and coworkers carried out an interesting work to develop, improve, and study compositions of weighted drilling muds with low content of solids, on the basis of organic salts of alkali metals and polymers for the construction of wells prone to rock swelling and/or cavings, as well as drilling fluids for drilling-in the formation . The devNafees et al., investigated the possible advantages related with the incorporation of silica fume (SF) as a partial substitution of cement in concrete, focusing on the development of modeling techniques in predicting the compressive strength of silica fume-based concrete . In the Reinforced and light-weight geopolymers can be employed in buildings, especially for walling, and in this framework Nguyen and coworkers exanimated the use of specific fillers for the metakaolin-based light-weight geopolymers, emphasizing properties such as high mechanical strengths, low thermal conductivity and density . In theiThe first of the two reviews contained in the Special Issue is by Ferdous et al., dealing with the purpose of reducing the amount of waste glass landfilled by transforming this waste into construction materials. It is well known that broken glass can be used in concrete either as a binder or aggregates. The outcomes of this knowledge are scattered, and it difficult to reach a firm conclusion about the effectiveness of waste glass in concrete, thus the authors critically reviewed its role and impact on microstructural and durability properties for both cement and geopolymer concrete .In the second review, Siddika and colleagues strengthened the same topic, i.e., waste glass based geopolymers, focusing on the effect of the chemical and mineralogical composition, as well as glass particle and curing condition of concrete on the dissolution behavior and chemical reactivity of waste glass . Conside


The extraction of retained and completely impacted third molars is one of the most common surgical procedures performed by dental practitioners with low rates of complications.The accidental displacement during the surgeries of the maxillary third molar into adjacent anatomical spaces is one of the most critical problems that can arise.The most common sites of migration during surgical interventions are the infratemporal fossa, the pterygomandibular space, the maxillary sinus, the buccal space, and the lateral pharyngeal space.In this paper, two cases in which a maxillary third molar accidentally was displaced into the buccal space are presented, the retrieval of the tooth via intra-oral approach is explained,and the anatomical spaces implications are discussed. Post-operative complications can be observed during surgical extraction of third molars, such as uncountable bleeding, tooth root fracture, fracture of the tuberosity or the buccal bone,perforation of the sinus membrane, and prolapse of the buccal fat pad  . Few cases of accidental teeth displacement in direction of bordering anatomical areas such as the maxillary sinus  - 3, inIn this report, two cases of maxillary third molar that were moved accidentally toward the buccal space are described, and the extraction of the tooth via intraoral approach is explained.Moreover, this report reviews the anatomical spaces implications.A 25 -year- old male was referred to our oral surgery clinic after unintentional movement of the third molar in the left side of the maxilla during surgical procedure under local analgesia. The pre-operative panoramic X- ray shows the initial position of the third molar . Intra oSurgery was accomplished under local anesthesia using , tooth was reached after a submucosal incision in the buccal mucosaand was released from the surrounding tissue with a periosteal elevator Figures  and b. T® 3/0; Ethicon Johnson & Johnson, Somerville, NJ),non-steroid anti-inflammatory (Mefenamic acid 500 mg BID), analgesic (Acetaminophen 1000 mg in case of pain), and antibiotic (Amoxicillin 1g BID) drugs were prescribed for the patient.Keeping good oral hygiene (chlorhexidine digluconate 0.12 %) and the use of pack of ice were also recommended. The recovery period was without complications and he recuperated hismouth opening movements one week later , the infra-temporal side of the maxilla and the infra-temporalfossa posteriorly, the maxillary arch anteriorly, and the maxillary sinus superiorly  .The fat bad, filled by adipose tissue, is on the buccal space and extends medially between the ramus and maxillary bone limited medially by the buccinator muscle,superficially by the deep cervical fascia and muscles of facial expression laterally and anteriorly, masseter muscle, mandible and the maxillary alveolar ridge,lateral and medial pterygoid muscles and the parotid gland posteriorly  . BuccalThe position of the displaced tooth and its relation to other structures should be evaluated with a CT scan or a cone beam computed tomography (CBCT). Radiological imagesfrom CT scan or CBCT are required to localize the displaced tooth in two and three dimensions  . RadiolThe treatment decision for maxillary third molars is based on clinical and radiological information. A CBCT complete study is needed to evaluate the parameters that influence the surgical procedure  .Besides the surgical approach, the management of displaced maxillary third molar teeth is influenced by oral surgeon’s skill, experience, and adequate surgical tools.A conservative approach to remove tooth from the area ensures less post-operative complications.et al. [ et al. [ Kocaelli et al.   reporte et al.   by usinIn our two cases, it has been confirmed, both clinically and radiologically, that teeth were displaced in the buccal space after applying a rotational forces from mesial to distal direction.To avoid surgical complications, careful attention to surgical details, including, a good interpretation of the radiological images, particular management of soft tissues,and a controlled force on the teeth and the hard tissue when applying surgical instruments must be respected. At the end of the treatment, patients showed a high satisfaction of thesurgical procedures and no complications were reported. This case report was written after obtaining informed consent from the patient.Careful attention to surgical details, including, a good interpretation of the radiological images, particular management of soft tissues, and a controlled force on theteeth and the hard tissue should be regarded when applying surgical instruments to avoid such complications.The authors do not have any financial interests, either directly or indirectly, in the products or information listed in this paper.


Cancer and cardiovascular diseases are the leading causes of death and morbidity worldwide. Strikingly, cardiovascular disorders are more common and more severe in cancer patients than in the general population, increasing incidence rates. In this context, it is vital to consider the anticancer efficacy of a treatment and the devastating heart complications it could potentially cause. Oncocardiology has emerged as a promising medical and scientific field addressing these aspects from different angles. Interestingly, nanomedicine appears to have great promise in reducing the cardiotoxicity of anticancer drugs, maintaining or even enhancing their efficacy. Several studies have shown the benefits of nanocarriers, although with some flaws when considering the concept of oncocardiology. Herein, we discuss how preclinical studies should be designed as closely as possible to clinical protocols, considering various parameters intrinsic to the animal models used and the experimental protocols. The sex and age of the animals, the size and location of the tumors, the doses of the nanoformulations administered, and the acute vs. the long-term effects of treatments are essential aspects. We also discuss the perspectives offered by non-invasive imaging techniques to simultaneously assess both the anticancer effects of treatment and its potential impact on the heart. The overall objective is to accelerate the development and validation of nanoformulations through high-quality preclinical studies reproducing the clinical conditions. Recent advances in the treatment of cancers have improved patient care and cure rates. Cancer, once fatal, is now emerging as a chronic disease, often at the cost of cardiovascular complications. Moreover, cardiovascular diseases (CVD) are more common and more severe in cancer patients –5. In thCardiotoxicity is a broad term that embraces toxic effects on cardiac structure, morphology, rest parameters, and the dynamic function of the heart. Cytotoxic drugs and targeted therapies used to treat cancer, including classic chemotherapeutic agents, tyrosine kinase inhibitors, antiangiogenic drugs, and immunotherapy, often impair the cardiovascular system . Of noteThe cardiotoxicity evoked by conventional chemotherapy is widely known and occur through multiple mechanisms, including overproduction of free radical species, inhibition of topoisomerase 2β causing DNA double-strand breaks and activation of apoptosis, profound changes in the transcriptome leading to the generation of reactive oxygen species, and inhibition of VEGF receptors causing endothelial dysfunction and vascular injury. In turn, the novel immunotherapeutic agents can lead to the inhibition of the Human Epithelial Receptor type 2 (HER2), impairing the cell signaling in cardiomyocytes; and the inhibition of programmed cell death proteins (PD-1) causing inflammatory infiltrates in the heart tissue –10. ThisThe objective of cardioprotection is to limit cardiac damage while maintaining antineoplastic efficacy . In the The basic concept of nanomedicine is to alter both pharmacokinetics and biodistribution of nanoencapsulated drugs, increasing their accumulation in the tumor site and decreasing their delivery to non-target organs, such as the heart. Passive and active targeting mechanisms can enable nanocarriers to reach the tumor site efficiently. The passive mechanism is based on the Enhanced Permeability and Retention (EPR) effect, which leads to the accumulation of nanostructures in the tumor site due to the characteristic leaky vasculature and absence of lymphatic drainage in the tumor microenvironment  15). In. In15). In 1995, Doxil®  was the first nanocarrier approved for clinical use , 22. Thiin vitro and in vivo. Human pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) emerge as a practical approach for the early in vitro screening of cardiotoxicity of new drugs , positron emission tomography (PET), SPECT (single photon emission tomography), and computed tomography (X - computer tomography) can simultaneously assess antitumor activity and cardiotoxicity evoked by anticancer treatments –57. ThesReal-time image acquisition, ease of data interpretation, and low cost make ultrasound imaging a promising and suitable approach, compared to other techniques, to monitor cardiotoxic events in preclinical studies –63. UltrFinally, photoacoustic imaging (PAI) is another promising ultrasound-based technique. It is a relatively new hybrid modality that combines optical imaging contrast with the spatial resolution of ultrasound , 68. PAIClinics have widely demonstrated the concept that nanomedicines improve the therapeutic index of anticancer drugs , 74. TheAll authors contributed to the writing and editing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Several technical challenges are faced by surgeons during SCS lead implantation, particularly in the confined dorsal epidural spaces in patients with spinal degenerative disease, scarring and while targeting challenging structures such as the dorsal root ganglion. Magnetic navigation systems (MNS) represent a novel technology that uses externally placed magnets to precisely steer tethered and untethered devices. This innovation offers several benefits for SCS electrode placement, including enhanced navigation control during tip placement, and the ability to position and reposition the lead in an outpatient setting. Here, we describe the challenges of SCS implant surgery and how MNS can be used to overcome these hurdles. In addition to tethered electrode steering, we discuss the navigation of untethered micro- and nanorobots for wireless and remote neuromodulation. The use of these small-scale devices can potentially change the current standard of practice by omitting the need for electrode and pulse generator implantation or replacement. Open questions include whether small-scale robots can generate an electrical field sufficient to activate neuronal tissue, as well as testing precise navigation, placement, anchoring, and biodegradation of micro- and nanorobots in the  Spinal cord stimulation (SCS) is a well-described treatment for medically refractory pain  technique, which allows for the placement of smaller electrodes. For the latter, in our experience, manual control of the lead can be challenging, especially in presence of scar tissue, and may be associated with prolonged operating room (OR) time, patient discomfort, increased cost, and potential complications. This maneuver can be impeded with complex anatomy, often seen in patients with degenerative spine disease, or for targets in which the SCS lead has to be placed within confined spaces such as the dorsal root ganglion , the implantable pulse generator (IPG), and the extension wire(s), which connect(s) the lead(s) to the IPG . SCS impThe most common complications of SCS implantation include electrode migration, hardware malfunction and fracture of electrodes, tolerance to SCS, infection, cerebrospinal fluid (CSF) leakage and pain or hematoma/seroma at the pulse generator site , decreased OR time and cost, reduced radiation exposure to the surgeon and patient and, in the light of the current Covid-19 pandemic, reduced direct contact with the patient and therefore a decreased risk for pathogen mitigation  Zemmar .ex-vivo pig brain. Such radii extend the reachable workspace and allow for greater accuracy  through a Touhy needle into the epidural space. After placing the SCS lead in the epidural space, the MNS could be utilized to navigate the SCS electrode to the desired location. A pre-operative magnetic resonance imaging (MRI) could assist in plotting a pre-defined trajectory for the MNS. Verification of the location of the SCS electrode with fluoroscopy can be obtained if desired. Verbal feedback can be given by the patient regarding the location of the induced paresthesia while being awake and in a comfortable position. This setting would enhance the comfort for the patient and the surgeon. Another major benefit of MNS is the possibility to re-adjust the SCS electrodes in an outpatient setting without the necessity of a repeated surgical procedure. This may be necessary if the lead migrates or the analgesic benefit is lost, in suboptimal postoperative coverage with the evolution of the pain syndrome to new body regions, or for testing new stimulation waveforms over time, e.g., conventional stimulation vs. burst stimulation vs. new algorithms such as Differential Target MultiplexedThe percutaneous lead placement technique necessitates fluoroscopic guidance during needle insertion and lead placement phases. MNS can reduce radiation exposure of healthcare workers  should be avoided  under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 771565).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.