Wnt signaling is of high relevance in the development, homeostasis, and regeneration of oral tissues. Therefore, Wnt signaling is considered to be a potential target for therapeutic strategies. The action of Wnt is tightly controlled by the inhibitors sclerostin (SOST) and Dickkopf (DKK)-1. Given the impact of SOST and DKK-1 in hard tissue formation, related diseases and healing, it is of high relevance to understand their role in oral tissues. The clinical relevance of this knowledge is further underlined by systemic and local approaches which are currently in development for treating a variety of diseases such as osteoporosis and inflammatory hard tissue resorption. In this narrative review, we summarize the current knowledge and understanding on the Wnt signaling inhibitors SOST and DKK-1, and their role in physiology, pathology, and regeneration in oral tissues. We present this role from the perspective of the different specialties in dentistry, including endodontics, orthodontics, periodontics, and oral surgery. Research and development of novel treatment strategies for regenerative dentistry has become crucial to improve oral health due to the growing numbers of dental and maxillofacial problems which require treatment. Therefore, cell-therapy modalities, biologicals, and gene therapy approaches are in development with the aim to provide novel tools for the clinical demands  and dickkopf-1 (DKK-1) are the primary inhibitors controlling the Wnt signaling pathways . These iin vitro andin vivo studies on the regulation of SOST (The glycoprotein SOST is mainly secreted by osteocytes, the mechanosensor cells of the bone, and has a major effect on bone and dental tissue (According to the findings of 10 years analysis of publications regarding SOST and DKK-1 in medical fields , it becoResearch and developments in endodontics lead to the continuous improvement of the field, as the introduction of new techniques and biomaterials drive profound progress in endodontic clinical practice. In particular regenerative endodontics is an exciting dental specialty. Treatment protocols of infected root canals in immature teeth were established which allow continued apical closure and root maturation (Clinically applied regenerative protocols, such as revascularization, utilize the regenerative capacity of endogenous stem cells. During treatment, over instrumentation into the periapical tissues causes stem cells to migrate and enter into the canal system via the blood clot. This process leads to the treatment of immature teeth with pulp necrosis by replacing dentin, root structures and pulp-dentin complex cells (et al. indicate that Wnt/β-catenin signaling is required for odontoblastic differentiation and also promotes proliferation of pre-odontoblasts and odontogenesis during root development (Results of ZhangAfter tooth development odontoblasts secrete dentin and the pulp chamber system narrows with age  In respoExpression of DKK-1 is up-regulated in a rodent model of induced periapical lesions, suggesting that DKK-1 is involved in the inflammatory processes and bone resorption in periapical lesions (Given the importance of hypoxia-induced signaling in the early phase of pulp healing we investigated the production of SOST and DKK-1 in dental pulp cells upon treatment with hypoxia or the hypoxia mimetic agent L-mimosine in monolayer, spheroid, and tooth slice cultures. Our results show that the response with regard to SOST and DKK-1 production depends on the culture model.Taken together, the literature highlights a major role of SOST and DKK-1 in tooth development and as a potential target for regenerative strategies.Orthodontic tooth movement is a result of external force applications to the teeth, an intervention which involves remodeling in dental and surrounding oral tissues, such as periodontal ligament, alveolar bone, and gingiva . The appMechanical forces can regulate the expression of SOST by osteocytes; for instance the expression of SOST is reduced when loading is increased, and increased when loading is decreased leading to an increase in bone formation or bone loss, respectively (During orthodontic tooth movement, one of the essential processes is remodeling of the periodontal ligament. Periostin is one of the factors which increased in the periodontal ligament during initial stages of orthodontic tooth movement (Cementoblasts are highly differentiated cells from the mesenchymal lineage which generate cementum . DiseasePeriodontitis is an inflammatory disease of the teeth supporting tissues, has a multifactorial etiology. The inflammation created by specific microorganisms extends deep into the tissues and causes the destruction of the tooth supporting connective tissue and alveolar bone. This progressive process leads to the pathological impairment of collagen fibres, loss of periodontal ligament and alveolar bone recession (In vitro models of oral soft tissue augmentation suggest that DKK-1 is also increased in oral soft tissue wound healing (There are hints from animal studies that inflammation can not only trigger bone resorption, but also decrease bone formation. This anti-anabolic effects seem to be mediated by increased levels of DKK-1 (The blocking of Wnt signaling impairs the periodontal ligament and alveolar bone (Dental cementum is a mineralized hard tissue on the surface of root dentin and present either in acellular or cellular form. Defective cementum results in periodontal breakdown, tooth dysfunction, and finally leads to tooth loss. Cementogenesis is a key element in the process of periodontal tissue regeneration . SOST waThe here presented literature supports the significant effects of SOST and DKK-1 in the periodontium system and periodontal diseases. As a result, they could be the main targets in future periodontics regenerative therapies.The alveolar bone supports the tooth in the maxilla and mandible and is characterized by continuous and rapid remodeling in response to mechanical forces . FollowiIn bone, SOST is mainly secreted by osteocytes and represents a key modulator of bone homeostasis (The response of bone to mechanical loading is highly important in implantology. Since SOST is a key player in the regulation of bone formation in the response to mechanical loading it is important to understand its role in the alveolar bone. Upon loading, osteocytes reduce the expression of SOST permitting Wnts to bind their receptors. (DKK-1 can decrease Wnt/β catenin signalling and reduced the production of type II collagen in chondrocytes under mechanical loading (From a clinical standpoint, osteoporosis is a risk factor in implantology. Inspired by the fact that inhibition of SOST can effectively improve bone formation in osteoporotic patients strategies which harness this capacity to improve bone formation around implants have been evaluated. (Taken together these data show the relevance of the Wnt signalling inhibitors of SOST and DKK-1 for implantology and bone augmentation, as well as for tumor development and cancer therapy. Future studies will show how effective targeting of SOST and DKK-1 can be applied to stimulate regeneration and for tumor therapy.The here presented review highlights the relevance of Wnt signaling, the inhibitors SOST and DKK-1, and its key role in oral tissue homeostasis throughout life (No data is associated with this article. This manuscript is a review paper on sclerostin and dickkopf-1 impacts on dentistry. The authors made good publication search work, and reviewed the expressions and biological functions of sclerostin and DKK-1 in each parts of tooth and surrounding tissues. Furthermore, the authors explored the correlation between SOST and DKK-1 and various pathologies. More importantly, the treatment pathways to target SOST and DKK-1 were discussed profoundly. The only flaw is the lack of SOST and DKK-1 in enamel formation, which does not affect the merits of this paper.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The manuscript fits into the aim of the journal. The manuscript is well written and the results presented interesting. I would like to know the search strategy. Inclusion/exclusion criteria. Minor aspects: Endodontic perspective: "Given the importance of hypoxia-induced signaling in the early phase of pulp healing we investigated the production of SOST and DKK-1 in dental pulp cells upon treatment with hypoxia or the hypoxia mimetic agent L-mimosine in monolayer, spheroid, and tooth slice cultures". Citation? Periodontic Perspective: " Dental cementum is a mineralized hard tissue on the surface of root dentin and present either in acellular or cellular form. Defective cementum results in periodontal breakdown, tooth dysfunction, and finally leads to tooth loss." I recommend adding a reference. Finally, I recommend re-writing the conclusion without citationsI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Variances in polymers processed by single-screw extrusion are investigated. While vortical flows are well known in the fluids community and fountain flows are well known to be caused by the frozen layers in injection molding, our empirical evidence and process modeling suggests the presence of vortical fountain flows in the melt channels of plasticating screws adjacent to a slower-moving solids bed. The empirical evidence includes screw freezing experiments with cross-sections of processed high-impact polystyrene (HIPS) blended with varying colorants. Non-isothermal, non-Newtonian process simulations indicate that the underlying causality is increased flow conductance in the melt pool caused by higher temperatures and shear rates in the recirculating melt pool. The results indicate the development of persistent, coiled sheet morphologies in both general purpose and barrier screw designs. The behavior differs significantly from prior melting and plastication models with the net effect of broader residence time distributions. The process models guide potential strategies for the remediation of the processing variances as well as potential opportunities to achieve improved dispersion as well as complex micro and nanostructures in polymer processing. The global plastics industry exceeds one billion kg in production output per day, with practically all of this material processed by one or more plasticating screws. While extrusion is a steady-state process, it is highly transient in the reference frame of the polymer. In this article, we seek to investigate and model the plastication behavior in the widely used general purpose and barrier screw designs. Our research is guided by modeling and simulation, which support the understanding of the interaction between the machine design, material properties, and processing condition. We are specifically interested in understanding the polymers’ states as a function of position and time within the extrusion screws during plastication.Maddock  performeThe five-zone melting model  shown inL:D) ratios. The reason for this trend is that longer screw lengths provide greater residence times and associated heat transfer by viscous dissipation to ensure plastication at higher material flow rates. Screw design guidelines have been established [The historical trend has been to increase processing throughput using longer screws and higher length:diameter  single-screw extruder with a bore diameter of 38 mm (1.5 in) was instrumented with an auxiliary process controller  that incorporates real-time computing capabilities with 23 wired analog inputs and 11 wired digital inputs. The instrumentation includes a melt pressure transducer , die pressure transducer , infrared thermocouple , intrusive melt thermocouple , laser micrometer , puller velocity , system power meter , absolute rotary encoder , water bath thermocouple, and others.An extrusion grade of high-impact polystyrene  was processed with the melt properties described in The black, blue and violet blends’ master batches were all polystyrene-based  to ensure compatibility with the HIPS. To investigate the viscosity behavior of the neat HIPS and colored blends, a Dynisco LCR7000 capillary rheometer  was used in compliance with ASTM D3835–08 . The viscosity at different shear rates and three different temperatures  was measured, and is plotted in The extruder was operated at 40 RPM during the addition of the three charges each having 5% of the black, blue, and violet blends. Each charge was added when the prior material being processed fully cleared the feed channel in the first two turns of the screw. Screw freezing experiments (similar to Maddock’s ) were thu as a function of time t and space in three dimensions x by solving the momentum equation [T is predicted according to the energy equation including heat conduction, heat convection, and internal viscous heating given the predicted shear stresses and shear rates PC and thermal conductivity k are modeled as a function of position x and temperature T according to the linear interpolation of the data in A process simulation was developed to investigate the melting and flow behavior of the polymer during plastication with the general purpose screw. The simulation predicts the flow velocity field equation :(1)ρDuDtLF model ,16 with dH/dL at the end of the feed section. Inspecting rows six through eight of 1. Feed Section Packing: Comparing the external images of the general purpose screw of The results suggest that the feed section in the general purpose screw could be shortened by at least two turns, or the rate of taper in the transition section increased so as to more efficiently utilize the full length of the screw.2. Axial Velocity Variation in General Purpose Screw: The varying downstream velocities of the different regions of the channel section are clearly evident from the outer surfaces in 3. Axial Velocity Variations in the Barrier Screw: Similar velocity variation is also observed in the barrier screw, for example with violet material flowing ahead of the blue material at turn 12, as well as blue material flowing ahead of the black material at turn 20. Indeed, there is even more rapid propagation of the melt stream due to the barrier flight, with the blue blended polymer racing far ahead of the black polymer. The sections of dH/dL. However, overall, the melting rate in the solids bed of the barrier screw is very impressive compared with that of the general purpose screw.4. Tadmor and Shapiro Melting Models Inappropriate for Barrier Screw: Viewing the cross-sections of vortical morphology [5. Flow Conductance in Recirculation Zone: The recirculation zones are clearly evident within the general purpose screw, as shown by concentric ovals within the melt pool at the right of the channel (adjacent the active flank) for the cross-sections of turns 14 to 26 in rphology ,19. Simirphology .Regarding the arc length development of the vortex, the tangential velocity of the recirculation zone is much less than the circumferential velocity of the screw relative to the barrel. The cross-section at turn 16 of fountain flow effect [Considering the flow in these recirculation zones, it is recognized that these are areas of relatively high shear, and thus, further viscous heating. The flow conductance is thus higher in the melt channels than the adjacent solids bed, even though they are adjacent in the channel, which explains the previously described axial velocity variation. This axial velocity variation provides a w effect ,22 where6. Significant Variances in the Processed Polymer: The varying polymer structures observed in the sections of the general purpose screw may be problematic for at least two reasons. First, there is a very broad residence time distribution since the polymers in the different regions of the channel are flowing at different rates. The black material stagnating early in the screw channel  will tend to increase the vortical fountain flow due to less time for heat conduction concurrent with greater shear heating. We now believe that this vortical fountain flow is a predominant cause of the “surging” phenomenon in extrusion and loss of control at higher screw speeds.Incorporate additional mixing sections within screw designs. Since the vortical fountain flow is caused by persistently growing melt recirculations in the melt pool adjacent the active flank, intermittently breaking up the melt channel will cause the vortical fountain flows to disperse. All the results, both experimental and theoretical, suggest that the use of early, coarse mixing channels would be highly effective.The evidence suggests that vortical fountain flows have significant effects in polymer plastication. We believe that the developed coiled sheet morphology could be predicted and exploited to achieve improved dispersion or create micro or nanostructured morphologies within the screw channel. However, higher fidelity material constitutive and processing models are needed to guide researchers and practicing engineers to improve processing capabilities and fully exploit the potential of the processed polymeric systems and composites. For now, variances in temperature and flow rate and pressure will adversely impact most polymer processing applications. To minimize the vortical fountain flow and its adverse effects, practitioners should:


The striatum is a key hub in the basal ganglia for processing neural information from the sensory, motor, and limbic cortices. The massive and diverse cortical inputs entering the striatum allow the basal ganglia to perform a repertoire of neurological functions ranging from basic level of motor control to high level of cognition. The heterogeneity of the corticostriatal circuits, however, also renders the system susceptible to a repertoire of neurological diseases. Clinical and animal model studies have indicated that defective development of the corticostriatal circuits is linked to various neuropsychiatric disorders, including attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, obsessive-compulsive disorder (OCD), autism spectrum disorder (ASD), and schizophrenia. Importantly, many neuropsychiatric disease-risk genes have been found to form the molecular building blocks of the circuit wiring at the synaptic level. It is therefore imperative to understand how corticostriatal connectivity is established during development. Here, we review the construction during development of these corticostriatal circuits at the synaptic level, which should provide important insights into the pathogenesis of neuropsychiatric disorders related to the basal ganglia and help the development of appropriate therapies for these diseases. Cortico-basal ganglia circuits control a range of neurobiological functions, ranging from motor control and reward to cognition. The functional diversity of cortico-basal ganglia circuits rests on their diverse inputs from the cerebral cortex. It is likely that the highly heterogeneous nature of corticostriatal inputs makes the corticostriatal circuits vulnerable to a broad range of neurologic and psychiatric disorders. Here, we highlight the developmental progression and maturation of the morphology and physiology of corticostriatal pathways using neonatal and postnatal rodent brains. We also review the pathogenesis of various neurodevelopmental disorders that are related to dysfunctions of corticostriatal circuits. Exploring synaptic wiring of corticostriatal circuits should create a research window for the development of therapeutic approaches for treating basal ganglia-related neurologic disorders.An essential function of neural networks is the processing of sensory inputs and the generation of motor outputs. The cortico-basal ganglia circuitry is in a key hub that is involved in the integration of sensory and motor information by the brain. The striatum of the basal ganglia receives a large number of cortical inputs from the motor, sensory, association and limbic cortices . The corMany psychiatric disorders are rooted in developmental dysfunctions that affect neural circuits within the brain. Thus, it is imperative to understand how neural circuits are formed during development. In this review, we have focused on the construction at the cellular and molecular level during development of the corticostriatal circuits. We have summarized the developmental maturation timeline of corticostriatal innervations in Genetic studies using mouse models have shown that many genes important to the development of neural circuits are involved in the pathogenesis of neurologic and psychiatric disorders. The significance and biological functions of these building blocks of neural circuits are, in fact, best illustrated by pathologic studies of neuropsychiatric diseases. We have therefore also reviewed the pathophysiology of neuropsychiatric disorders where it is known that dysfunction of corticostriatal circuits is involved. A summary of the various animal model studies that have shown links to corticostriatal abnormalities and neuropsychiatric diseases is presented in Corticofugal pathways form the major afferent inputs to the basal ganglia. In the developing mouse brain, corticofugal projection neurons are classified into two cell types: pyramidal tract (PT)-type cortical projection neurons and intratelencephalic (IT) projection neurons , 2010. PCorticostriatal projections are topographically organized in such a manner as to convey neural information from various different cortical regions into the striatum where this diverse information is integrated. The dorsolateral/sensorimotor striatum, which is known to be involved in motor sequencing and habit-related functions, mainly receives its cortical inputs from the motor and somatosensory cortex. The dorsomedial/associative and ventral/limbic striata, which are related to goal-directed motor learning and reward, respectively, receive cortical inputs from the frontal cortex, mesocortex and allocortex . The decConsidering the axonal terminal fields in the striatum, it has been shown that corticostriatal axons from different cortical regions innervate the striosomal and matrix compartments with different weights. The striosomal compartment receives substantial cortical inputs from evolutionarily conserved areas of the cortex, including the prelimbic, anterior cingulate, orbitofrontal, and insular cortices. The surrounding matrix compartment receives cortical inputs from the neocortex, including the motor, somatosensory and visual cortices .When the laminar distribution of the corticostriatal neurons is explored, the early-born PT-type corticostriatal projection neurons in the rat brain have been found to be primarily located in lower Layer V (Layer Vb), from where they project their axons into the striosomes. By way of contrast, the late-born IT-type corticostriatal neurons are located in Layer III and upper Layer V (Layer Va), from where they predominantly project their axons into the matrix compartment . InteresEvidence based on retrograde axonal tracing and electron microscopy have shown that more corticostriatal axons of the IT-type compared to the PT-type are linked to neurons of the direct striatonigral pathway (dSPNs). In contrast, more PT-type than IT-type corticostriatal axons are linked to neurons of the indirect striatopallidal pathway iSPNs; . When thA coculture study has demonstrated the specificity of corticostriatal innervation by prenatal and postnatal cortical afferents. During cortical and striatal coculture, neurites derived from the prenatal cortex homogeneously grow into co-cultured striatal tissue, while, on the other hand, neurites derived from perinatal stages specifically grow into the striosomal compartment of co-cultured striatum irrespective of the age of the striatal tissue. Only a small amount of neurite innervations can be found in striatal tissue when it is co-cultured with postnatal cortex . These rCorticostriatal synaptogenesis occurs postnatally after corticostriatal axonal innervation has been established. A cell culture study has shown that cortical synaptic inputs into the striatum are important for maturation of the dendritic arborization of the SPNs . SPNs reDuring the early postnatal stages, developmental maturation of the electrophysiological properties of the SPNs involves immature SPNs that are characterized by a depolarized resting membrane potential together with hyperexcitability and a lack of inward rectification . When deCortical synaptic inputs not only drive synaptic activity in SPNs, but are also able to indirectly inhibit SPN activity via fast-spiking interneuron-mediated feed-forward inhibition . ElectroIn the dorsolateral striatum, corticostriatal long-term potentiation (LTP) is inducible as early as P9–P10, whereas LTD cannot be induced until P15 . This deA previous study has suggested that recurrent activity in the closed loops of cortico-basal ganglia circuits is able to regulate the synaptogenesis of SPNs . Synaptis-coupled G-protein receptors in SPNs by a D1 agonist is able to increase corticostriatal activity and the number of dendritic spines  gene family. Shank1, Shank2, and Shank3 are members of a postsynaptic scaffolding SH3 and multiple ankyrin repeat domains protein family. Mutations of the Shank family proteins are associated with autism and a number of other neuropsychiatric disorders  as a hub gene that is involved in the development of cortical projection neurons. Patients with deletion mutation of the TSHZ3 gene exhibit ASD symptoms, and an animal model study has shown that there is an increase in corticostriatal LTP in Tshz3 heterozygous mice  is another gene associated with ASD susceptibility , an ASD-risk gene, is known to increase the neuronal excitability of iSPNs during P18  and members of the Slitrk gene family. SAPAP3 is an excitatory postsynaptic scaffold protein. Mutations of SAPAP3 have been found in patients with OCD . An abnormal increase in SLC1A1 expression with a parallel decrease in EAAT3 activity, have been found in the brains of patients with OCD , another schizophrenia-risk gene, has been shown to decrease neurite arborization and the number of dendritic spines in SPNs  gene. Patients carrying SLITRK1 variant alleles have known to exhibit Tourette syndrome (SLITRK1 in the cerebral cortex and striatum of the human brain is similar to that found in the monkey brain and the mouse brain (Tourette syndrome is a childhood-onset neurodevelopmental disease that is characterized by involuntary vocal and motor tics. Tourette syndrome is categorized as one of the three tic disorders in DSM-V . Tourettsyndrome . Slitrk1se brain . Previouse brain . Given tA broad repertoire of genetic components participates in the synaptic wiring of the corticostriatal circuits during development. Activity-dependent machinery is also adopted to fine tune synaptogenesis to develop precise functionality within the cortico-basal ganglia network. Characterization of the development and functioning of corticostriatal circuits may not only help us to understand the developmental basis of motor control, skill development and habit learning as well as complex cognitive functions such as speech and language, but may also provide insights into the pathophysiology of corticostriatal circuits-related neurologic and psychiatric disorders. This, in turn, may lead to the identification of potential therapeutic approaches to the treatment of these important diseases.


Several experimental techniques and modern surface characterization tools have been developed to evaluate and characterized the performance of corrosion inhibitors for metals and alloys  and toxicology, but its use in the field of corrosion research is not widespread . The data obtained from this study indicated that amino acids with a COO– side-chain group (Asp and Glu), together with Lys are the best candidates for the design of small peptides with potential to perform as corrosion inhibitors.Recently, an excellent review has been published on the use of natural amino acids as corrosion inhibitors . Data obtained from the study indicate a strong correlation between experimental and theoretical results and showed that the molecular size of the caprylate salts is the determining factor in the inhibition efficiency. The models used and experimental results indicated that dicyclohexylamine caprylate is the most efficient inhibitor.The discovery of volatile corrosion inhibitors (VCI) are often carried out by trial and error and tedious experimental approaches. However, a team led by Assis V. Benedetti from three prestigious Brazillian research institute in Brazil, investigated the possibility of using caprylate salts based on amines as volatile corrosion inhibitors for metallic zinc using both experimental and computational chemistry approaches (Mehmeti and Berisha). The research was conducted in the Department of Chemistry, Faculty of Natural and Mathematic Sciences, University of Prishtina, Pristina, Serbia. The goal of the study was to use theoretical calculations to better understand the inhibition. Experimental and theoretical results showed that 2-mercaptonicotinic acid exhibited the best inhibition efficiency due to the presence of the pyridine nitrogen, carboxyl, and the sulfur atom in the thiol group interacting in a planar geometry with the surface.In another contribution, the corrosion study of mild steel in aqueous sulfuric acid solution using 4-Methyl-4H-1,2,4-Triazole-3-Thiol and 2-Mercaptonicotinic Acid were investigated using experimental and Computational Chemistry approaches . The objective of their work was to assess the anti-corrosive performances of studied molecules by applying quantum chemical calculations (DFT), molecular dynamics simulation, principle component analysis (PCA) as well as agglomerative hierarchical cluster analysis (AHCA). DFT, molecular dynamic simulation, PCA, and AHCA results showed that corrosion inhibition efficiency ranking of studied molecules were as follows InhA > InhB > InhC. The theoretical results were in agreement with experimentally determined inhibition efficiencies of the molecules previously reported.Three thiophene derivatives abbreviated as InhA, InhB, and InhC were chosen to theoretically analyze their anticorrosive efficiencies. The work was conducted jointly by a group led by Guo from three different Universities namely in China, Palestine, and in Turkey . The results provided useful information for developing novel HPPD inhibitors, leading to further understanding of the interaction mechanism of HPPD inhibitors. This present contribution although not focused on corrosion, presented an important contribution of computational chemistry in the area of drug discovery.Finally, a very interesting paper on the combination of virtual screening protocol by in silico toward the discovery of novel 4-Hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors was contributed by a team from China. In the work, an integrated virtual screening protocol combining 3D-pharmacophore model, molecular docking and molecular dynamics (MD) simulation was established to find novel HPPD inhibitors from four commercial databases (IO wrote the introduction, EE summarizes the papers and DD summarizes and edited the final draft.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.


To investigate the knowledge of multi-professional staff members about theearly mobilization of critically ill adult patients and identify attitudesand perceived barriers to its application.A cross-sectional study was conducted during the second semester of 2016 withphysicians, nursing professionals and physical therapists from six intensivecare units at two teaching hospitals. Questions were answered on a 5-pointLikert scale and analyzed as proportions of professionals who agreed ordisagreed with statements. The chi-square and Fisher's exact tests were usedto investigate differences in the responses according toeducational/training level, previous experience with early mobilization andyears of experience in intensive care units.delirium, risk of musculoskeletal self-injury andexcessive stress at work.The questionnaire was answered by 98 out of 514 professionals (response rate:19%). The acknowledged benefits of early mobilization were maintenance ofmuscle strength (53%) and shortened length of mechanical ventilation (83%).Favorable attitudes toward early mobilization included recognition that itsbenefits for patients under mechanical ventilation exceed the risks for bothpatients and staff, that early mobilization should be routinely performedvia nursing and physical therapy protocols, and readiness to change theparameters of mechanical ventilation and reduce sedation to facilitate theearly mobilization of patients. The main barriers mentioned were theunavailability of professionals and time to mobilize patients, excessivesedation, delirium, risk of musculoskeletal self-injury andexcessive stress at work.The participants were aware of the benefits of early mobilization andmanifested attitudes favorable to its application. However, the actualperformance of early mobilization was perceived as a challenge, mainly dueto the lack of professionals and time, excessive sedation, Internationalmulticenter studies on EM in the ICU evidence a low prevalence of out-of-bedmobilization, especially among patients under MV. The same situation wasrecently described in Brazilian ICUs, where only 10% of patients under MV weremobilized out of bed.(11)A growing body of evidence supports the safety, feasibility and long-term functionalbenefits of early physical therapy, i.e., starting within the first 48 hours ofmechanical ventilation (MV) and being maintained throughout the stay in theintensive care unit (ICU).(12-14) These studies identified personal and patientsafety and lack of clinical comprehension as potentially relevant hindrances to theperformance of EM. Recent studies(15-17) found that the need of a larger number ofprofessionals, insufficient working hours and the staff's culture regardingmobilization, including a lack of resources, prioritization and leadership, areamong the main interdisciplinary barriers to the performance of EM.Few studies have sought to explain why EM is not effectively performed in ICUclinical practice. Some studies on improvement of the quality of care deliveryinvestigated whether the attitudes and education of professionals relative to EM arebarriers to actual performance.(11)A multicenter prevalence study found that the EM of patients under MV is uncommon,especially in regard to patients ventilated through endotracheal tubes, with muscleweakness, cardiovascular instability and sedation being the most commonly perceivedbarriers to mobilizing patients at a higher level. These difficulties might beovercome, which is relevant to increasing mobilization in BrazilianICU.The aim of the present study was to investigate the knowledge of a multi-professionalteam on the EM of critically ill adult patients and identify their attitudes andperceived barriers to effective performance.Hospital de Clínicas de PortoAlegre  and Irmandade da Santa Casa deMisericórdia de Porto Alegre . Informedconsent was obtained through electronic means before the electronic questionnairewas answered.The present cross-sectional study consisted of a survey of professionals who delivercare at six ICUs in two teaching hospitals in Brazil. The study was conducted in thesecond semester of 2016 and was approved by the research ethics committees of theparticipating hospitals, All the professionals at the ICU of both hospitals were invited to participate in thestudy through e-mails sent by the study coordinator to service chairs, who thenresent them to the professionals. Physicians, including routine and assistingphysicians and medical residents, were named by the medical team chair of each ICU.Nurses, nursing technicians and physical therapists allocated to these units werenamed by the nursing team chair of each service and the chair of the department ofphysical therapy of each hospital.®, and the results wereobtained in real-time through coupling to Statistical Package for the SocialSciences (SPSS) software.The link to access the questionnaire was sent by e-mail to the service chairstogether with the invitation to participate in the study. The service chairs resentthe e-mails to the members of their teams, on which the study coordinator wascopied. To make responding to the questionnaire and data collection easier, it wasdeveloped using the software SurveyMonkey(15) which was applied to the full intensive care team.The questionnaire included items to investigate the respondents' knowledge about thepotential benefits of EM in the ICU, their attitudes regarding the application ofthis technique in the ICU and perceived barriers to the performance of EM. The itemswere answered on a 5-point Likert scale with the following options: "I fully agree","I agree", "I neither agree nor disagree", "I disagree" and "I fully disagree".The questionnaire was adapted from the one employed in a recentstudy,Early mobilization was defined as any activity performed beyond the range of motionwithin 48 hours of the onset of MV. Experience with EM and availability of an EMprotocol in the ICU were defined as present when the respective responses to thefollowing questions were "yes": (1) "Have you had training in, have you worked at ordo you work at an institution where patients under MV are actively mobilized?"; and(2) "Has an EM protocol been implemented at the ICU where you work?"The right answers to the questions investigating knowledge about EM were definedbefore the onset of the survey. The answers "I disagree" and "I fully disagree" wereconsidered the right ones for the question "Does range of motion suffice to maintainmuscle strength in the ICU?" The answers "I agree" and "I fully agree" wereconsidered the right ones for the item on whether EM is associated with a shorterduration of MV. For the remainder of the items, positive responses were "I agree" or"I fully agree" and negative answers were "I neither agree nor disagree", "Idisagree" or "I fully disagree".delirium, (8) access to specialized equipment, (9) personalsafety, (10) patient safety, (11) cost and (12) therapy is not performed although itis recommended. The questionnaires for nurses and physical therapists also includeda list, with the following items: (1) risk of musculoskeletal self-injury, (2)fatigue, (3) excessive stress at work, (4) need to work overtime, (5) other(specify). In both questionnaires, the professionals could mark any number ofoptions they considered appropriate and add other items they held to representpotential hindrances to EM in the ICU.The questionnaire for physicians included a non-hierarchical list of potentialbarriers to mobilization in the ICU, including the option "other (specify)", asfollows: (1) duration of nursing procedures, (2) duration of respiratory physicaltherapy, (3) availability of physical therapists, (4) patient undergoing procedures,(5) excessive sedation, (6) mobility is irrelevant in the ICU, (7)The participants were given 1 month to respond to the questionnaire from the momentit was sent. An e-mail reminding the participants to respond to the questionnairewas sent one week before the deadline. To ensure that no participant would beincluded in the survey twice, e-mail addresses were checked against the list ofparticipants' e-mail addresses. The questionnaires were answered anonymously and ona voluntary basis.Descriptive statistics were performed to characterize the sample. The responses givenon the Likert scale ware expressed as absolute frequencies and proportions. Thechi-square test was used to investigate whether the physicians' responses differedas a function of their educational level . Fisher's exact test was used to investigate significantdifferences in the nursing staff's responses as a function of their educationallevel (nursing technicians versus nurses), previous experience with EM forphysicians, nursing professionals and physical therapists (yes versus no), and yearsof experience (< 5 years versus ≥ 5 years) for nursing professionals andphysical therapists. The significance level was set at p < 0.05. The data werestored and analyzed using SPSS software for Windows, version 18.0.Both participating institutions were university-affiliated hospitals, and the ICUtypes were as follows: clinical-surgical (n = 3), pneumological (n = 1), oncological(n = 1) and transplant (n = 1). A total of 514 professionals were invited toparticipate, including 154 physicians, 293 nursing professionals and 67 physicaltherapists.Twenty-two physicians responded to the questionnaire, corresponding to a responserate of 14% (22/154). All the physicians were intensivists, and medicalresidency was the most prevalent educational level . Most phTwenty-one (95%) physicians agreed that the benefits of EM exceed the risks forpatients under MV . MostphSixty-one members of the nursing team responded to the questionnaire,corresponding to a response rate of 21% (61/293). Of these, 29 (47%) werenursing technicians. Most nursing professionals reported having more than 5years of experience in the ICU, and most nurses had a specialization inintensive care . Twenty-seven (44%) respondents reported noprevious experience with EM in the ICU . Half ofMost nursing professionals agreed that the benefits of EM exceed the risks forpatients under MV . Nursing staff with more than 5 years ofexperience in the ICU were more likely to agree that the benefits of EM exceedthe risks for patients under MV (p = 0.049) . Most reThe barriers to EM most frequently indicated by the nursing professionals aredescribed in Fifteen physical therapists responded to the questionnaire, corresponding to aresponse rate of 22% (15/67). Most respondents (73%) reported having more than 5years of experience in the ICU and previous experience with EM , being tAlmost all the physical therapists agreed that the benefits of EM exceed therisks for patients under MV , and that the benefits of EM forpatients under MV exceed the risks to the team's personal and professionalsafety . Most respondents  stated that they had enoughtime to help mobilize patients under MV . The resThe barriers to EM most frequently indicated by the physical therapists aredescribed in (15) that analyzed the knowledge and attitudes ofmulti-professional health team members involved in care delivery to critically illpatients.Among the main findings of the present study conducted in the ICU of two Brazilianteaching hospitals, we highlight that most members of the multi-professional teamhad knowledge about the potential benefits of EM, including the maintenance ofmuscle strength and a shorter duration of MV, and that most participants agreed thatthe benefits of EM exceed the risks to patients under MV. Similar results werereported in a previous study(15) Approximately two-thirds of the physical therapistsand nursing professionals stated they had sufficient time to help mobilize patientsunder MV once per day. Most physical therapists and nursing professionals agreedthat the benefits of EM for patients under MV exceed the risks to the team'spersonal and professional safety. Nursing technicians were less likely to agree thatthey had sufficient time to help mobilize patients under MV once per day compared tonurses. The barriers to EM most frequently cited by physicians were theunavailability of professionals on the team and of sufficient time to routinelymobilize patients, excessive sedation anddelirium. Risk of musculoskeletal self-injury and excessivestress at work were also mentioned by nurses and physical therapists as barriers toEM.Most physicians agreed on the EM of patients under MV; however, only half of themagreed on indicating EM for patients receiving vasoactive drugs. The physiciansstated they would change the MV parameters and reduce sedation to enable the EM ofpatients. The multi-professional participants in the presentstudy exhibited knowledge about the potential benefits of and a favorable attitudetoward EM in the ICU but identified several barriers to its actual application inclinical practice. The barriers to EM are patient-related, such as patient symptomsand conditions; structural, such as human and technical resources; related to theICU culture, including habits and the particular attitudes at each institution; andprocess-related, from lack of coordination to lack of rules for the distribution oftasks and responsibilities.(20) These multiple barriers were also detected inthe present study.The findings of the present study confirm the hypothesis that there is a gap betweenevidence-based knowledge and its application in clinical practice. Several authorsadmit that while knowledge continues to advance, practice remains one stepbehind. However, the workload of the ICU nursing teamis admittedly high, which might impact safety and the quality of caredelivered. These facts confirm the results of the presentstudy, as only 62% of the nurses agreed that they had sufficient time to helpmobilize patients under MV once per day.More than 80% of the physicians stated that EM should be routinely performed vianursing and physical therapy protocols, unless explicitly contraindicated. Inaddition, they stated they would agree to change MV parameters and reduce sedationto enable the EM of patients. Nurse-oriented mobility protocols point to increasedmobility and functional benefits for patients.(20)Although most nursing professionals and physical therapists agreed that they hadsufficient time to help mobilize patients under MV once per day, the need to workovertime was one of the main barriers to EM that they mentioned. The unavailabilityof physical therapists was the main barrier to EM mentioned by the participatingphysicians. These findings confirm the ICU culture- and process-related barriersalready established in the literature.(15) and Canada.(17) Time and the professionals required tomobilize critically ill patients might be considerable hindrances to EM in the ICU.In addition, they represent a frequently reported concern in regard to theimprovement of the quality of care needed to facilitate the acceptance ofmobilization.(12-15) A solution developed at some centers was to shiftthe perception and revise priorities in the daily care delivery routine to includemobilization. Creation and implementation of a dedicated ICUmobility team might also represent an option to increase the mobility of patientsand was proven safe and viable. This approach allowed the mobilized patients to getout of bed on 2.5 more days, without any adverse events, resulting in betterclinical outcomes and functional independence, in addition to reducing hospitalcosts.(27)Several barriers were mentioned by all the groups of participants, including theunavailability of professionals and insufficient time to perform EM with criticallyill patients. These barriers were also reported by members of multi-professionalteams in the United States(15) Although EM was shown to be safe and feasible forpatients, there is no information in regard to the staff safety, which mightconstitute a considerable barrier to EM in the ICU.(28)Concerns about musculoskeletal self-injury, stress and overtime work were barriersmentioned by the nursing professionals and physical therapists who participated inthe present study; these findings corroborate the reports in theliterature.Our study has potential limitations. First, the results are subjected to selectionbias as a function of the low response rate. Second, the fact that we did notcalculate the sample size needed to ensure that the number of participants wassufficient to detect significant differences might have resulted in a type II errorin the data analysis. Finally, the responses to the questions investigating"knowledge" might have been influenced by the fact that the literature on EM isscarce and reduced the potential for the generalization of clinical trials on EM. Asstrengths, the present was the first study that investigated the full staff thatprovides care to critically ill patients at academic institutions, including nursingtechnicians, to better understand interdisciplinary concerns about EM.delirium, risk ofmusculoskeletal self-injury and excessive stress at work. We detected considerablebarriers to the early mobilization of critically ill adult patients admitted to theintensive care unit. This information might serve to initiate the training ofprofessionals involved in this procedure and in the implementation of institutionalprotocols.Most participants had information about the benefits and significance of earlymobilization for critically ill patients and exhibited a favorable attitude towardthe performance of early mobilization in the intensive care unit. However, theymentioned countless barriers related to the work routine, staff interaction, unitoperation and clinical conditions of patients. Early mobilization in the intensivecare unit was perceived as a challenge, mainly due to the lack of professionals,insufficient time, excessive sedation,


The use of advanced biomaterials as a structural and functional support for stem cells-based therapeutic implants has boosted the development of tissue engineering applications in multiple clinical fields. In relation to neurological disorders, we are still far from the clinical reality of restoring normal brain function in neurodegenerative diseases and cerebrovascular disorders. Hydrogel polymers show unique mechanical stiffness properties in the range of living soft tissues such as nervous tissue. Furthermore, the use of these polymers drastically enhances the engraftment of stem cells as well as their capacity to produce and deliver neuroprotective and neuroregenerative factors in the host tissue. Along this article, we review past and current trends in experimental and translational research to understand the opportunities, benefits, and types of tentative hydrogel-based applications for the treatment of cerebral disorders. Although the use of hydrogels for brain disorders has been restricted to the experimental area, the current level of knowledge anticipates an intense development of this field to reach clinics in forthcoming years. In recent decades, considerable progress has been made in the development of experimental therapies to treat different brain disorders. Among the different approaches examined, cell therapy has been configured as a viable option for restoring the damaged brain. Tissue recovery after damage has been associated with the mobilization and integration of new cerebral cells derived from exogenous sources. Alternatively, endogenous brain repair mechanisms may also be stimulated by the transplantation of different cell populations with the ability to secrete factors that mobilize endogenous neurogenesis. Cell transplantation through a systemic intravascular route has been regularly tested in animal models and brain injury patients. Intra-venous and intra-arterial administrations are considered relatively feasible to perform and are less invasive than cerebral implantation. However, the systemic route is handicapped by the inefficient mobilization of therapeutic cells from the blood towards the brain tissue given that most cells are retained in the pulmonary capillaries, spleen, liver, and kidneys ,2, thereHowever, even the cerebral route is not free of difficulties. Among them, we should mention the reduced temporality of the graft due to the poor survival ratio of the cells as well as their dispersion towards regions far away from the area of interest, thus diluting any therapeutic effect. It is assumed that in response to injury the brain tissue is converted into a hostile microenvironment not only for the brain itself, but also for the grafting of different cell populations that generally do not survive beyond a few weeks after implantation ,6,8. TheIn regenerative neuroscience, the combined implantation of cells and different biomaterials to increase the viability of cellular grafts constitutes a very promising approach in full expansion . In thisCerebrovascular diseases encompass a set of syndromes of different etiology and severity that lead to transient or permanent disorders of brain function. Pathologically, cerebrovascular diseases may be a consequence of: (i) alterations in cerebral blood flow; (ii) disturbances in blood circulation that modify blood flow and pressure; and (iii) disorders of cardiac function. Stroke represents a sudden onset of cerebrovascular disease and occurs in most cases through a vascular obstructive process  or by the rupture of one or more brain blood vessels and extravasation of blood (effusion) into the extravascular space , both leading to a reduction or total abolition of blood supply to the brain. Epidemiologically, stroke is a leading cause of adult disability and cognitive impairment and is the second-leading global cause of death behind ischemic heart disease ,15. It iMitigation of stroke-originated brain damages strongly depends on the recognition of signs and symptoms in the hospital emergency area and the consequent rapidity of medical intervention. Hemiparesis, loss of sensation, impaired speech, vertigo, and gait disturbances represent the initial clinical signs ,20. In iPatients who survive a stroke and do not receive adequate treatment within this narrow therapeutic window or when its reception is ineffective often show disabilities with different degrees of affectation . For theCell therapy has been proposed as a strong and convenient strategy for the reconstruction of the damaged brain tissue or guide cerebral plasticity in perilesional areas enhancing functional recovery. Transplanted cells should modulate recovery mechanisms similar to those acting in spontaneously healing or rehabilitation improvements. The first objective of cell therapy is to provide a source of transplanted exogenous cells that can differentiate into the main components of nervous tissue . Additionally, transplanted cells should stimulate endogenous self-repairing mechanisms and produce biomolecules to promote neurogenesis and angiogenesis. A variety of stem cells, progenitors and differentiated cells have been engrafted in different models of brain damage. Since the first studies using cells from neural or hematopoietic origin to promote recovery in ischemic animals ,35,36,37The use of cell therapies for the treatment of human diseases dates back to the 1950s, specifically in the area of hemopathies. In those years, two independent groups reported how the intravenous administration of hematopoietic stem cells and progenitors from spleen or bone marrow favored the hematopoietic regeneration of mice previously subjected to myeloablation by lethal irradiation ,49. ThomIn the area of cerebral disorders and specifically in stroke, during the last two decades, numerous studies with animals have validated the efficiency of different cell populations (mainly stem cells and progenitors of diverse tissue sources) in promoting functional recovery after brain injury. In addition, considerable progress has been made in the study of the molecular and cellular substrates responsible for this recovery. Knowledge obtained in last few years about the action mechanisms of the different SCs as well as about their therapeutic limitations moved this field into a new scenario, the combined implantation of SCs with different biomaterials of natural or artificial origin. Generally, different stem cells and progenitors (SCs/P) are capable to differentiate into progressively more mature cell phenotypes  as well as to secrete different trophic factors ,58. BothWhen a cerebral infarction occurs the injured area is anatomically and functionally categorized in a central nucleus where blood flow has been totally interrupted and brain tissue evolves towards infarcted condition (infarct core) and a perilesional area where the blood flow has be reduced but not abolished containing structurally intact but functionally inactive neural networks (ischemic penumbra) . If the Over the last two decades, different type of cells (mostly multi- and pluripotent stem cells) have been used as therapeutic tools to enhance nervous tissue regeneration and brain plasticity phenomena . After tAmong the various types of stem cells, neural stem cells (nSCs) and neural precursors (nPCs) were initially established as the ideal cell populations for the repair of central nervous system. During embryonic development, neurogenesis through natural and pre-existing nSCs and nPCs principally occurs in two main brain regions: the subventricular zone (SVZ) and the ventral and lateral ganglionic eminences (VGE and LGE). The first region (SVZ) is the origin of the largest population of neocortical neurons while the ganglionic eminences give rise to the neurons of the basal ganglia and the neocortical interneurons . In contThe implantation of nSCs has been considered a therapeutic option to favor the production and integration of terminal neural cells in either the core or the perilesional regions ,71,72. AIn stroke mice, the intracerebral co-transplantation of human nSCs and the protease 3K3A-APC to stimulate the in vivo proliferation of transplanted nSCs reestablished the neural circuitry favoring post-stroke functional recovery . HoweverEmbryonic stem cells (eSCs) constitute an alternative type of SCs that have been commonly used in a wide variety of studies. They are pluripotent cells capable of self-renewing and differentiating into any cellular phenotype of the organism including the neural lineage. The ability of eSCs to promote post-ischemic functional recovery has been demonstrated in several studies ,80. HoweMesenchymal stem cells (mSCs), bone marrow mononuclear cells (BMmCs), and induced pluripotent stem cells (iPSCs) represent an alternative to nSCs and eSCs since they can be isolated, generated and expanded with no excessive difficulty. These cell populations have shown neuroprotective and neuro-regenerative effects in different animal models. They can be isolated or generated from the patients themselves therefore allowing autologous transplantation and avoiding graft rejection. Among the potential benefits of mSCs, iPSCs, and BMmCs it is worth mentioning the modulation of the brain tissue microenvironment through the secretion of several growth factors that regulate the immune response, limit astrogliosis and microgliosis, stimulate endogenous neurogenesis and angiogenesis or reduce apoptosis by decreasing the oxidative stress ,84,85.The iPSCs hold many of the functional properties found in eSCs, exhibiting similar morphology, the endogenous expression of pluripotency genes and their ability to self-renew or differentiate into progenitors, precursors, and mature cells of different germinal origin including neural cells . DiffereThe BMmCs constitute a heterogeneous group of mature hematopoietic cells  and a small proportion of stem cells and hematopoietic progenitors, which together with stem cells and progenitors of mesenchymal origin (mSCs) represent a promising approach for the treatment of cerebrovascular disorders. BMmCs increase neurogenesis ,96 and cmSCs are by far one of the most commonly employed cell populations. mSCs constitute a heterogeneous non-hematopoietic cell population which were first characterized by Friedenstein et al. in 1970 . Althoug+ cells in areas surrounding the infarct core as well as with vascularization in the damaged area accompanied by a reduction of glial scar [mSCs may reduce inflammatory response and apoptosis by decreasing the levels of pro-inflammatory molecules such as interleukins IL-1β and IL-6A, or TNF-α ,115,116.ial scar ,129. Axoial scar .Most of the above mentioned neurotherapeutic mechanisms are related to the factors released by the mSCs, which might have a certain parallelism with the secretome activity present in other types of stem cells with known neuroprotective and neuroregenerative potential. While many of these factors can be secreted by exocytosis which constitutes a main mechanism for releasing extracellular proteins or neurotransmitters in neurons, recent studies suggest that part of the paracrine action of mSCs may be accomplished by cell-derived vesicles also called exosomes that could transport mRNAs, miRNAs and proteins with tissue repairing potential ,132. In Although stem cell implantation in experimental models of stroke has been performed even several weeks after cerebral damage ,135 signThe optimal route for cell implantation has still to be defined, although cerebral administration reports better benefits than that of intra-venous and intra-arterial infusion . SurprisCerebral implants are more invasive than other transplantation routes. In general, the implantation of cells in the rodent brain has not been translated into important side effects. However, the human brain is extremely sensible to surgical manipulation and minor damages could create profound functional deficits beyond previous stroke-originated dysfunctions . HoweverThe safety and tolerability of the implantation of SCs in patients with cerebral damage has been widely demonstrated for different types of SCs and for all administrative routes ,45,46,47The use of biomaterials to assist cell therapy after brain injury is merely restricted to the experimental arena, which raises important concerns on whether we are really seeding a reasoned technology for future use in patients, or if we are facing an unreachable scenario. Preclinical data have supported the efficacy of the co-transplantation of hydrogels and cells to repair the damaged brain ,155,156 The concept of hydrogels for biomedical applications comes from the 1960s by using copolymers of glycolmethacrylates ,158 to dCrosslinking is generally produced by physical non-covalent hydrophobic-ionic interactions and/or covalent bonds between chemical groups. The crosslinking-density and the relative amount of free and bound water is a main determinant of pore size and tridimensional structure. Natural and artificial hydrogels can be used alone or in combination. Naturally derived biomaterials are usually non-toxic; however, it is difficult to control their biodegradability and there are batch-to-batch variations in the production of the material that represent a source of variability in relation to their physical properties. Poor control of degradation in some natural polymers might be justified by the presence of degradation motifs such as hydrolysable ester groups and enzyme-mediated hydrolytic amide elements. An advantage of natural polymers is that they usually contain native binding sites to favor cell interaction and anchoring. Synthetic polymers in contrast have relatively well-controlled structures and their microstructure and properties including: pore size, degradation, functionalization, shape, sterilizability, and stiffness are adjustable. In comparison with natural materials, synthetic polymers might be created to mimic more efficiently the physical and mechanical properties of brain tissue. Synthetic polymers are usually non-inmunogenic, but may contain toxic products related to the fabrication and purification processes . GeneralOne of the first studies using biomaterials for in vivo applications was performed in the 1980s . Yannas The first biomaterials for applications related to CNS disorders were assayed nearly three decades ago by Woerly et al., who intracerebrally implanted several materials with a base of collagen to enhance cellular attachment and provide pathways of migration for regenerating axons, transplanting a mix of polymers based on poly(glyceryl methacrylate) (pGMA) and poly(2-hydroxyethyl methacrylate)-collagen (pHEMA) in the cortex of adult rats. In their studies, astrocytes from the brain colonized the interior of the hydrogels. Although not immunophenotypically characterized, this cellular invasion responded to astrogliosis against the injection of the material in a formed hydrogel state and the nature of the materials used ,194. LesIn this regard, one of the basic design parameters of the hydrogel is the density of functional groups  in the polymer backbone. The density of functional groups may influence the space between cross-links during polymerization, so that a higher density leads to hydrogels with a tighter mesh structure. Different strategies to induce hydrogel gelification have been developed for in vitro and in vivo applications ,216,217.d-glucuronic acid and β-1,3-N-acetyl-d-glucosamine -Hydroxyproline (Hyp)-Glycine (Gly) constitute the most common triplets (10.5%) in collagen  and spinal cord (8.0 kPa) . Once inN-isopropylacrylamide) and poly(ethyleneglycol) has been used to satisfactorily engraft mSCs into the mouse brain. This thermosensitive hydrogel with a sol/gel transition temperature of ~20 °C and storage modulus in the range of 0.5–1.0 kPa was implanted as a fully formed hydrogel over the brain cortex surface. Although no significant post-stroke recovery was observed after treatment in the interval of eight weeks of analysis, no significant inflammatory response induced by this specific copolymer was detected either [N-isopropylacrylamide) in combination with mesenchymal progenitor stromal cells [As a result of the promising outlook of the therapeutic approach, an increasing number of biomaterials in different formats have been assayed and extended in a wide variety of experimental brain damage models in the last decade . Some ofd either . In contal cells . In anotal cells . An inteal cells   of post-stroke damaged areas; the formation of new vessels (angiogenesis) in the infarcted and peri-infarcted regions; or in the neuro-restitution and plasticity phenomena. In the case of angiogenesis, it is extensively accepted that vascular formation stimulates endogenous recovery mechanisms, creating an adequate microenvironment for endogenous proliferation migration and differentiation, thus supporting neural restitution, synaptogenesis, axonal growth, and neuro-plasticity . These ml-ornithine [A deep reflection on the possible clinical applicability of the synthetic and/or natural biomaterials that are being used in the current brain damage models is necessary given that, with most biomaterials, the short- and long-term adverse effects derived from the implant into the brain are unknown. Many studies have focused on examining the therapeutic effects of a particular biomaterial alone or in combination with different cell populations without considering the analysis of additional cytotoxicity and inflammation induced by the material itself. In many cases, the compatibility of the biomaterials with brain-derived neural cell populations has been tested exclusively in vitro. However, in vitro studies offer a reductionist view of the tolerability of biomaterials with respect to in vivo approaches where it is possible to examine how the biomaterial can be integrated with the brain analyzing the host bioresponse towards the graft. For example, HA, one of the most frequently used biomaterials for experimental brain repair, does not produce significant astrogliosis, microgliosis, or increase neuronal death in the normal brain . In factrnithine . In othernithine . We do nrnithine . In mostrnithine .Cures for stroke and other CNS injuries through engineered biomaterials will have a major positive impact in heavy and long-term burdens on patients and healthcare systems. The development of advanced biomaterials for cerebral damage responds to a major clinical need to provide patients with an efficient technological solution. Across the last two decades of experimental research, it has been possible to partially restore functionality loss after brain injury by using biomaterials of different composition and format to favor the engraftment of cells with neuro-therapeutic abilities. Despite the valuable contribution of behavioral studies in examining the improvement of functional outcomes in animals, in many cases, the molecular and cellular substrates underlying recovery are unknown, making it necessary to further investigate these mechanisms to rationally identify those targets whose modulation through cells and biomaterials might lead to greater therapeutic benefit. In addition, it would also be ideal to advance the screening of those more promising biomaterials such as those that are poorly inmmunogenic and less cytotoxic with controlled stiffness properties to facilitate their integration with the brain tissue through minimally invasive procedures. Tolerability of hydrogels should be examined using a multidimensional approach that could initially include preliminary in vitro studies, and the subsequent implantation in animals to analyze the in vivo bio-response at both the structural and functional level. It is also essential to examine concerns regarding the best temporal point of intervention and site of implantation to achieve an efficient post-brain-damage therapeutic response.Although cerebral implantation of biomaterials-based hydrogels has not been applied in human subjects after brain injury, the antecedents presented in the preclinical  and clinical (stem cells) scenarios outline a magnificent opportunity for the treatment of CNS disorders using distinct biomaterials. In recent years, the fast evolution of this field predisposes the continuation of the search, characterization, and improvement of advanced hydrogels to clinical translation.


This work contributes the knowledge to the area regarding significant prognostic value of tissue-infiltrating immune cells in oral cancer. The authors concluded that CD163+ M2 macrophages and CD57+ natural killer cells may be the most promising predictors of survival in oral cancer patients. We appreciate the authors’ thorough analysis, which is a clinically valuable study. However, several important methodological issues should be noted, which may influence the strength of their conclusion in this review.We read with great interest the recently published systematic review and meta-analysis by Olsen et al.2First, the authors limited their search to Medline and Embase, and did not explore other international databases with broad subject areas, including Cochrane Library, ClinicalTrials.gov and Web of Science databases. Selection of a restricted subset of databases for conducting the literature search can lead to biased results, even incorrect conclusions.1 did not provide the relevant methodology on how they assessed the publication bias in this review. Lack of publication bias assessment may exaggerate the correlation between predictors and survival of oral cancer patients.2 The necessity of evaluating publication bias and its role in providing the best evidence has been established in meta-analysis.3Second, Olsen et al.4 or the Newcastle-Ottawa Scale (NOS).5 In addition, it would be better if the authors could provide a quality grading of the evidence in this review.Finally, although the authors assessed the quality of the included studies using the REMARK guidelines, we could not tell that the risk of bias of the included studies was high, medium or low. Other methods for assessment of publication quality and risk of bias may be more suitable, such as the Quality in Prognostic Studies (QUIPS) toolOverall, the authors analysed a valuable issue regarding the prognostic markers in oral squamous cell carcinoma, but the results of this review should be interpreted with caution due to the limitations mentioned above. We believe that these methodological concerns of this meta-analysis are likely to raise questions about interpretation of the authors’ findings and their clinical relevance.


Delay in vaccination from schedule has been frequently documented and varies by vaccine, dose, and setting. Vaccination delay may result in the failure to prevent deaths that would have been averted by on-schedule vaccination.We constructed a model to assess the impact of delay in vaccination with pneumococcal conjugate vaccine (PCV) on under-five mortality. The model accounted for the week of age-specific risk of pneumococcal mortality, direct effect of vaccination, and herd protection. For each model run, a cohort of children were exposed to the risk of mortality and protective effect of PCV for each week of age from birth to age five. The model was run with and without vaccination delay and difference in number of deaths averted was calculated. We applied the model to eight country-specific vaccination scenarios, reflecting variations in observed vaccination delay, PCV coverage, herd effect, mortality risk, and vaccination schedule. As PCV is currently being scaled up in India, we additionally evaluated the impact of vaccination delay in India under various delay scenarios and coverage levels.We found deaths averted by PCV with and without delay to be comparable in all of the country scenarios when accounting for herd protection. In India, the greatest relative difference in deaths averted was observed at low coverage levels and greatest absolute difference was observed around 60% vaccination coverage. Under moderate delay scenarios, vaccination delay had modest impact on deaths averted by PCV in India across levels of coverage or vaccination schedule. Without accounting for herd protection, vaccination delay resulted in much greater failure to avert deaths.Our model suggests that realistic vaccination delay has a minimal impact on the number of deaths averted by PCV when accounting for herd effect. High population coverage can largely over-ride the deleterious effect of vaccination delay through herd protection. Pneumonia is a leading global cause of child deaths. Prior to the introduction of pneumococcal conjugate vaccine (PCV) in 2000, S. pneumoniae was responsible for more 800,000 deaths in children 1–59 months annually S. pneumoniae mortality in children under five in various country-specific scenarios using a model for estimating the impact of vaccination on child mortality by fine age intervals.Delay in vaccination from recommended vaccination schedule may reduce the protective impact of vaccination on child mortality, particularly if the age period between vaccination schedule and vaccine receipt corresponds to a period of high vaccine-preventable mortality risk. Due to the peak in pneumococcal deaths in early childhood, delay in vaccination with PCV can result in additional vaccine-preventable deaths. We explored the effect of PCV vaccination delay on 2S. pneumoniae-specific mortality by week of age. We modeled vaccination coverage by week of age to calculate the direct and indirect protective effect of PCV by week of age. The model allows exposure of a cohort of children to the weekly mortality risk and protective effect of PCV to calculate the number of deaths prevented by PCV under different vaccination timing scenarios and country settings. The model was applied to eight country-specific scenarios using vaccination data from the Democratic Republic of the Congo (DRC), Ethiopia, India, Laos, Nigeria, Pakistan, Swaziland, and Zimbabwe.Assessing the effect of vaccination delay on vaccine-preventable under-five mortality requires modeling the interplay of vaccination coverage and mortality risk by fine age intervals. We generated estimates of StataCorp LLC, College Station, Texas). The model functions by exposing an annual birth cohort of children to the week of age-specific risk of mortality from pneumococcal pneumonia and meningitis, and protective effect of PCV vaccination. Each model component was defined using parameter values derived from existing literature. For each week of age, the risk of mortality is estimated based on the age-specific distribution of pneumococcal deaths and the direct protective effect of PCV is estimated based on the age-specific vaccination coverage. The herd effect of PCV is constant across all ages and calculated based on the three-dose PCV coverage among children age 24–36 months. The birth cohort is (1) exposed to the week of age-specific risk of mortality, and pneumococcal deaths in the absence of vaccination are calculated, (2) the week of age-specific direct effect of PCV based on vaccination coverage is applied, and the number of deaths averted directly by vaccination are calculated, (3) the herd effect is applied to those children not directly protected by PCV, and the number of deaths averted indirectly by population vaccination coverage are calculated, (4) residual deaths are calculated and removed from the cohort, and (5) surviving children in the cohort are exposed to the next week of age risk and protective effect  pneumoniae in the absence of Haemophilus influenzae type B (Hib) or PCV vaccination, and the modeled distribution of IPD deaths. We modeled the age distribution of deaths from S. pneumoniae based on the binned distribution of IPD deaths reported by five studies with a sample of >25 IPD deaths included in a review by Russell and colleagues k = shape of gamma distribution = 1.7Θ = scale of gamma distribution = 23x = age in weeksThere are no existing estimates of The distribution of IPD deaths within the age range of 0–59 months was then scaled to sum to 100% and the week-specific percentage of deaths was applied to distribute the estimate of total under-five pneumococcal deaths across the period by week of age.2.2The distribution of vaccination timing was defined using data from Clark and colleagues ▪▪x = Age in weeks − dose scheduleDose-specific cumulative vaccination coverage was modeled as the cumulative distribution function (CDF) of an exponential distribution fit based on the country-specific median delay from schedule in vaccine receipt. We modeled the CDF of the cumulative percentage of final vaccination coverage by age in weeks with a rate parameter defined by median vaccination delay from schedule among children vaccinated by three years using Eq. Timing of each dose was modeled independently and then combined into a single distribution, scaled by the relative dose-specific efficacy of PCV as shown in 2.3The proportion of children directly protected at each week of age was calculated based on proportion of children vaccinated and the efficacy of the vaccine. The week of age-specific direct protective effect of vaccination was calculated by applying the three-dose vaccine-type efficacy of PCV 2.4Herd effect was included in the model as an additional proportion of vaccine-susceptible pneumococcal deaths that could be prevented by population-level PCV coverage beyond those deaths prevented directly by vaccination. The total protective effect of PCV on IPD was modeled by Liu and colleagues 2.5We applied the model using eight country-specific vaccination scenarios. We selected the countries to reflect a diverse range of vaccination scenarios and a significant proportion of global child pneumonia mortality. Together, India, Pakistan, Nigeria, DRC, and Ethiopia account for almost half of all global child pneumonia deaths India was further selected to explore the impact of various vaccination timing scenarios. India is currently scaling up PCV in multiple states under a two primary dose schedule at six and 14 weeks and a booster dose at nine months. We modeled the impact of vaccination delay in India under various delay scenarios and coverage levels. We modeled the impact of vaccination delay over a range of final vaccination coverage levels ranging from 1% to 100% vaccination coverage. We developed five vaccination timing scenarios based on data from Clark and colleagues  using vaEach scenario was run with and without vaccination delay. We calculated the number of deaths averted by PCV in each scenario and number of residual deaths. For each scenario we compared the number of deaths averted with and without a vaccination delay and calculated the absolute and relative difference in deaths averted. We also ran sensitivity analyses with no herd effect to assess the role of herd protection in moderating the effect of vaccination delay.3Running the country-specific scenarios in the model, we found very little impact of vaccination delay on the absolute or relative number of deaths averted by PCV . The greApplying the current PCV vaccination schedule in India with varying levels of coverage and delay scenarios, we found a wide range of differences in absolute and relative number of deaths averted . Overall3.1The impact of delay in India under alternative vaccination schedules was explored. Under the alternative schedules, similar results were observed to the results using India’s current schedule with moderate delays . The rel3.2Without accounting for herd effect, vaccination delay has a much greater impact on the number of deaths averted by PCV . The larIn India, the relative difference was roughly constant across coverage levels by scenario and was the same as that observed below 13% coverage in the model accounting for herd protection . The abs4Our model suggests that realistic vaccination delay has a minimal impact on the number of deaths averted by PCV when accounting for herd effect. In the seven country scenarios, observed vaccination delays resulted in small absolute and relative differences in the number of deaths averted by PCV. Under various vaccination delay and coverage scenarios in India, the greatest relative differences in deaths averted were observed at low final vaccination coverage levels where no herd effect was assumed. The greatest absolute differences were observed around 60% vaccination coverage but corresponded to small relative differences in deaths averted.The model did not account for competing mortality risks, which would lead to children dropping out of the cohort because of non-pneumococcal mortality. Additionally, it did not account for in or out of country migration. The model also did not account for geographic distribution in vaccination and clustering of unvaccinated populations which could result in variable herd protection within a population. Limited data were available for some assumptions in the model, particularly around age distribution of pneumococcal deaths, herd effect of PCV at varying coverage levels, and dose-specific vaccine efficacy. The best available data were used, deferring to estimates that would yield greater effects of delay where assumptions were uncertain.Empirical data were not available to externally validation our model of vaccination delay impact on child mortality. However, our model was derived using the structure and key model parameters employed in the Lives Saved Tool (LiST). Numerous analyses have demonstrated the validity of LiST modelled estimates of the impact of health intervention coverage on child mortality The degree of vaccination delay, overall vaccination coverage, and vaccination schedule affected the impact on deaths averted. Large delays in vaccination may result in notable relative differences in deaths averted in settings with low vaccination coverage, such as during the initial introduction of PCV. However, in low coverage situations the overall impact of PCV is minimal, resulting in small absolute differences in deaths averted. High coverage results in significant herd protection minimizing the deaths due to delay even under extreme delay scenarios. Moderate absolute differences in numbers of deaths averted may occur in countries where there is a large population at risk, moderate vaccination coverage, and a moderate to long delay in vaccination. However, these large absolute differences represent a small fraction of the total deaths averted by PCV under these conditions. Vaccination delay has less of an effect in countries with later vaccination schedules as the peak in mortality occurs prior to the vaccination schedule, and as a result the delay period occurs at a time of declining mortality rates.Herd protection plays an important role in minimizing the effect of vaccination delay. In settings where there is moderate or high vaccination coverage, the herd effect protects a large proportion of unvaccinated children, including those infants that are delayed in receiving vaccination. The moderating effect of herd protection is clear in the estimates of numbers of deaths averted directly and indirectly by PCV under scenarios with and without a delay in vaccination receipt. In our models, a much greater impact of delay on deaths averted was observed when herd protection was removed from the model.Further, models that do not account for herd protection may greatly underestimate the impact of vaccination on child mortality. Gavi, the Vaccine Alliance, tracks global progress through routine estimates of vaccines’ impact on child mortality These results suggest overall vaccination coverage is a more important driver of vaccine mortality impact than vaccination timing. High population coverage can largely over-ride the deleterious effect of vaccination delay through herd protection. It is important to explore the impact of delay on child mortality for other vaccines, as the age distribution of pathogen-specific mortality and characteristics of the pathogen and vaccine tied to disease transmission and herd protection play important roles in driving the impact of delay on mortality. Efforts to increase vaccination coverage are paramount to achieving greater reductions in child mortality and thoughtful consideration should be given to how to best utilize resources.