The oral mucosa, as part of human mucosa, is an essential part of the oral cavity. It is the first natural barrier against the intrusion of newcomers and a habitat for the oral microbiome. As such, it is receiving ever-increasing interest in clinical and translational research. However, it is in the field of cancer treatment and its toxicity wherein oral mucosa has a prominent role, as oral mucositis is one of the most debilitating cancer treatment complications and a notorious source of worry for oncologists and poor quality of life for cancer patients. This narrative review focuses on the entangled implications of human oral mucosa in cancer and, specifically, in the development of cancer-related oral mucositis support strategies.The oral mucosa is a key player in cancer patients and during cancer treatment. The increasing prevalence of cancer and cancer-therapy-associated side effects are behind the major role that oral mucosa plays in oncological patients. Oral mucositis is a debilitating severe complication caused by the early toxicity of chemo and/or radiotherapy that can restrict treatment outcome possibilities, even challenging a patient’s survival. It has been referred to as the most feared cancer treatment complication. Predictive variables as to who will be affected, and to what extent, are still unclear. Additionally, oral mucositis is one of the sources of the increasing economic burden of cancer, not only for patients and their families but also for institutions and governments. All efforts should be implemented in the search for new approaches to minimize the apparently ineluctable outburst of oral mucositis during cancer treatment. New perspectives derived from different approaches to explaining the interrelation between oral mucositis and the oral microbiome or the similarities with genitourinary mucosa may help elucidate the biomolecular pathways and mechanisms behind oral mucosa cancer-therapy-related toxicity, and what is more important is its management in order to minimize treatment side effects and provide enhanced cancer support. The mucosa, also called the mucous membrane, is one of the most extensive organs in the human body, which is found mainly in the oral cavity, gastrointestinal tract, urogenital tract, respiratory tract, and, to a lesser extent, in organs such as the eyes. It behaves as a defensive barrier, resists physical stimuli and friction, and, therefore, has a high rate of cell turnover. It also has absorptive functions and carries a rich microbiota, which gives it unique properties in health and well-being.The oral mucosa is the specialized part of the mucosa that covers the entire oral cavity up to the oropharynx. Histologically, it consists of a stratified squamous epithelium and an underlying connective tissue or lamina propria, which is keratinized at sites of friction. In the area where it meets the teeth, it differentiates into a masticatory mucosa that is tightly adherent to the underlying bone, known as attached gingiva. Furthermore, the function that has received the most attention recently is its immunological role, in addition to serving as a preferential habitat for the oral microbiome, as mentioned previously .One of the main roles of the mucosa is its barrier function. An ample diversity of challenges can disrupt the epithelial barrier of the mucosa. Among them are end metabolites and allergens derived from food, alcohol, therapeutic agents, inadequate oral hygiene, bacteria, virus, and fungi. Dysregulation or unbalance in the epithelial barrier has been described as the origin of a leaky epithelium that generates dysbiosis through a double mechanism, first, reducing commensal microbes and second, enhancing opportunistic pathogens. Said damage to the mucosal barrier can be exerted at different levels in the epithelium, such as the zonula occludens 1, 2, and 3, claudins, E-cadherins, desmosomes, and junctional adhesion molecules [The role of the oral mucosa barrier in both the pathogenesis of and resilience to COVID-19 infection is still under study. The preferential invasion of the virus through the oral mucosa is explained by the fact that it is a receptacle for a high number of ACE2 receptors throughout the oral mucosal epithelium that are used as couplings by viral particles, allowing the release of key parts of the virus into the cell cytoplasm for replication . The eleLesions and manifestations of SARS-CoV-2 in the oral mucosa include dryness of the mucosa, mucosal irritation, and inflammation and pain caused by the release of tumor necrosis factors and cytokines associated with the acute inflammatory episode characteristic of this viral infection .Taste and smell reside primarily in the oral mucosa, in the taste receptors on the dorsum of the tongue (taste buds), in the tonsils and oropharynx, and in the olfactory receptors located in the nasopharynx. Both can be altered or markedly diminished in COVID-19. The loss of taste and smell (dysgeusia and anosmia) is often sudden and abrupt. Mucosal congestion or edema and mucosal dryness may explain the loss of smell , while tThe oral mucosa is a main actor in cancer. The toxicity of cancer treatment rapidly and preferentially affects the oral mucosa, causing oral mucositis. Oncological-treatment-induced oro-gastro-intestinal mucositis, otherwise recognized as oral mucositis, or mucositis, is the most visible clinical complication of cancer therapy and one of the most feared by oncologists . It has Regarding the type of agent, it has been described that, specifically, H&N patients treated with cisplatin plus radiotherapy will develop oral mucositis . TaxanesNew treatment regimens, such as the mammalian target of rapamycin (Mtor-inhibitor), exert high mucosal toxicities with different characteristics from typical oral mucositis. It can be recognized via a necrotic area surrounded by erythema, which produces very significant pain that frequently obliges the remodulation of the therapy ,21,22. EOral mucositis lesions vary from erythema to ulceration in the mucosa developing with different grades of pain, swallowing, eating, and speaking impairment, compromised nutrition, weight loss, and dehydration, with treatment delays and even interruptions and hospitalizations. Mucosa ulcerations and inflammation can be accompanied by bleeding and pain and may impair specific functions depending on the sites affected. Mucosal barrier disruption leads to pathogen penetration and potentially systemic bacteriemia and sepsis that may be fatal. Oral mucositis has a significant impact on the patient’s quality of life and may negatively impact the survival of the cancer patient . The welThe interest in the responsibility of bacteria in the pathogenesis of oral mucositis has resulted in numerous papers ,29,30,31Thanks to the combination of metagenomics science with computational models, the physiopathologic understanding of oral mucositis has seen an evolution from the classical five-step model described by Sonis. The actual school of thought hypothesizes that there is a gene pathway implication of oral microbiome dysbiosis in the genesis of mucosal ulceration in oral mucositis and delayed and/or impaired wound healing in oral mucositis ,34. In oCancer treatment strategies are designed to target rapidly dividing cancerous cells. Subsequently, tissues characterized by a high cell turnover such as the oral mucosa and gastrointestinal and vaginal mucosa are also subjected to chemotherapeutic agents through the cytotoxic effects of cancer therapy. The oro-gastro-intestinal mucosa is moist and elastic and exposed to friction (masticatory function and food transit) and therefore exhibits intense and constant cell turnover with high mitotic activity in cells and cell shedding every 14–21 days. This active cell turnover and metabolism is higher in the mobile mucosa and lower in the masticatory mucosa . This paThe oral microbiome that is attached to mucosa cells, as well as the microbiome-related host defense and the crosstalk between the oral mucosa and the oral microbiome, is affected during oral mucositis. The novel discovery of the roles of major virulence factors from members of the oral microbiome in the development of oral mucositis, the duration of ulcerations, and the delay of tissue healing need to be further explored in order to better understand the relationship between oral mucositis and the oral microbiome, including the microbiota ,36. WhetDysbiosis has been reported to exist whenever disruption of the epithelial barrier occurs ,40.Patients immersed in cancer treatment suffer from this newly coined cancer dysbiosis . Cancer-P. gingivalis can inhibit wound healing and is able to escape the host immunity [Cancer treatment changes the oral microbiome. At present, the hypothesis that the microbiota exerts a fundamental role not only in the cancer onset but also in the cancer treatment response is explained by the fact that certain species are behind in delayed and reduced wound healing . For insimmunity . Rothia species in oral cancer [neisseria and reduced streptococcus in pancreatic cancer [Oral microbiome sampling displays specific signatures associated with different types of cancer, for example, a reduction in the Streptococcus and l cancer , reducedl cancer , reducedc cancer , and an c cancer .P. gingivalis and periodontitis are at higher risk of pancreatic cancer [P gingivalis has been appointed as a protagonist in oral dysbiosis in manifold papers. Its role in cancer and in oral mucositis is currently thought to be more of a principal role than one of a passive kibitzer.It has been demonstrated that subjects with c cancer . P gingiFusobacterium nucleatum, Clostridia, and Treponema species that are typically found in periodontitis and inflammatory conditions, while commensal subspecies such as Streptococcus are diminished. Dysbiosis with high counts of F. nucleatum has been associated with severe mucositis via the aggravation of epithelial injury and enhanced inflammation and apoptosis [In oral mucositis, the chemotherapy-disrupted oral microbiota is shifted to Gram-negative bacteria such as the poptosis ,51.Gram-negative species and the above-mentioned mucositis-associated microbiome perpetuate themselves in the pro-inflammatory breeding ground, so all means of reversing or modulating oral dysbiosis could prove beneficial to cancer patients.In view of the current evidence showing the implications of certain microbiota hubs, such as the gut microbiota, in the response to radiotherapy-induced mucositis, it seems at least sensible, if not wise, to seek the reintegration of a balanced oral microbiome and an oral microbiome boost in order to try to modulate the host local response to cancer therapy toxicity, namely, a lesser degree of oral mucositis .In 2020, global cancer statistics estimated 932,000 new cases of head and neck cancer (H&N) and 467,000 deaths globally . The maiThe current reality for H&N patients is one of younger subjects with higher cure rates, increasing numbers of survivors, increasing numbers of years as survivors, and multimodality management including chemotherapy and/or radiotherapy and/or surgery.Acute (during treatment): oral mucositis.Chronic (after the end of treatment): xerostomia, dysphagia, pain, and persistent/chronic oral mucositis.The most prominent cancer-therapy-related toxic effects according to the time of onset are the following:Patients may experience pain, social and physical limitations, psychological effects related to these, as well as self-appearance issues that altogether may lead to anxiety, depression, and lack of motivation to enjoy life. Unfortunately, these complications may be present “per se” in an acute, chronic, and long-lasting manner . The quaA patient facing a cancer diagnosis will undergo numerous and important medical costs that will have an effect that has recently been referred to as financial toxicity . HousehoThe costs derived from oral mucositis in hematopoietic stem cell transplantation can range from USD 112,447 to USD 29,921,414 per patient . The hosFinding safe measures for oral mucositis looks like a necessity not only for cancer patients but also for the rest of the actors involved, including health systems.When it comes to oral mucositis, divergences between generally lower-severity pictures perceived by oncologists and what patients experience have been reported . These dIt is important that PROMs questionnaires implemented for the assessment of oncology patients include signs of the existence or not of the cohort of emotional and physical symptoms that are highly prevalent, namely, sadness, anxiety, emotional distress, or social withdrawal. It is also advisable that the patients be able to report signs and symptoms such as the existence and degree of dysphagia, xerostomia, trismus, dysgeusia, appetite changes, sleep quality, as well as difficulty in speaking and communicating ,65,66. HIt has been reported that symptoms of cancer treatment toxicity subjectively perceived by a patient are at risk of being underestimated by the clinician in the range of 40–70%. This occurs even in data collection during randomized studies, which is why the incorporation of ideally validated PROMs is emphasized in clinical studies .Approaching patient needs and preferences from a shared patient–physician decision-making approach is now greatly promoted  and has It has been reported that patients experiencing oral pain show a lower salivary flow compared with controls . Oral moA clinical trial performed in H&N cancer radiated patients, with the primary outcome being a decrease in symptoms after the use of the previously described composition, demonstrated a significant improvement in long-term symptoms, physical, social, and personal, and pain, as well as in the quality-of-life parameters analyzed, limitation in eating, limitation in enjoying food, limitation in speaking, and limitation due to dryness. Patients reported fewer interruptions during sleep . No sideAlthough oral mucositis was not included as an outcome, patients experienced a statistically significant pain reduction even though only 40% of the patients showed increased salivary flow, while 60% did not. Therefore, another mechanism for pain amelioration must be implicit. https://clinicaltrials.gov/ct2/show/NCT05635929 (26 May 2023)) in 50 H&N cancer patients with a mucositis severity outcome during the first 6 weeks of treatment and follow-up after 6 months have pain as an outcome and oral mucositis severity. The use of PROMs in conjunction with a mucosal topical non-acidic lipophilic composition enriched with a potent natural antioxidant, under the name saliactive®, seems to be in line with the accumulating evidence of reactive oxygen species (ROS) pathways and their mediation of the inflammatory cascade that may be behind a good part of the complex pathobiology of chemo/radiotherapy-induced oral mucositis [Partial unpublished data from an ongoing interventional study registered at ClinicalTrials.gov ) as part of the Stop Dysbiosis Project, has shown statistically significant superior clinical outcomes in oral clinical parameters in patients with oral dysbiosis with the use of a microbiome-boosting toothpaste containing extra virgin olive oil (EVOO), xylitol, and betaine. While the control and placebo groups resulted in significant decreases in pH levels, the tested group kept pH levels at the physiologic value, contributing to oral eubiosis [The role of the oral microbiome in the onset of oral dysbiosis because of cancer therapy and its relation to the cancer therapy response has been described before. The potential benefit of improving oral dysbiosis in this group of patients needs to be undertaken with support measures as dental interventions are restricted during the duration of cancer treatment. In this respect, a fresh-from-the-press controlled, double-blind, and multicenter randomized clinical trial, declared at ClinicalTrials.gov ) will help to elucidate the potential of a synergistic and symbiotic interaction with the host at the genital mucosa level once it has lost estrogen protection. All attempts to minimize cancer-therapy-related effects on the genitourinary mucosa in breast cancer survivors that should be promoted as therapeutic strategies are limited in this group of patients, as the applications of estrogens and/or selective estrogen receptor modulators are either non-indicated or highly restricted [An ongoing randomized blind comparative experimental clinical trial in patients with a history of malignant breast cancer declared at ClinicalTrials.gov  updated its guidelines in 2021 by means of a systematic review through which they were able to identify the interventions with the highest evidence of being the most effective .Surprisingly, chewing gum is not recommended for oral mucositis in the above mucositis guidelines. Several expert opinions complement these guidelines with the following recommendations: dental evaluation and professional treatment prior to cancer therapy with the desire to reduce the risks of local or systemic infections of odontogenic origin, and patient education on the benefits of basic oral care to improve self-care and adherence to oral care protocols. Special attention should be implemented prior to and during treatment, including rinsing with saline and sodium bicarbonate, which, despite being inert, improve overall cleaning, help maintain oral hygiene, and improve patients’ well-being. The implementation of oral care protocols is beneficial for the prevention of oral mucositis during QT, head and neck RT, and hematopoietic stem cell transplantation (HSCT). It is worth mentioning that it is suggested not to use chlorhexidine in patients treated with radiotherapy in the head and neck area. Furthermore, in a case-control study on risk factors regarding the onset of osteoradionecrosis of the jaw in radiated head and neck patients, the use of chlorhexidine multiplied the risk 1.28-fold and root scaling performed within the previous 2 weeks 2.43-fold .®, and glutamine as part of the emerging evidence of the potential of natural topical approaches for counteracting the toxicity in human mucosa [Careful timing of interventions is advisable as well as the preferential use of natural ingredients such as honey, saliactiven mucosa ,108,109.Attention should be paid to the pro-metastatic evidence that some lipids, different from the oleic or linoleic acid in extra virgin olive oil, such as palm or palmitic oil have shown. This is of special relevance in patients suffering from oral cancers, as the authors showed that short dietary exposure to palmitic acid from palm oil in mice with oral carcinomas led to long-term stimulation of metastasis. A description of the pro-metastatic pathway of palm oil, when part of a diet even in small amounts, is a source of worry due to the potentially negative complex interactions between palm oil low-quality lipids and H&N cancer patients .Efforts are being made to identify valid biomarkers such as pro-inflammatory cytokines for the early detection of patients that are especially susceptible to oral mucositis. The complexity of microorganism metabolomics, as well as the fluctuating behavior of cytokines, pro and against inflammation, hinders the prospect of a pure microbiome dysbiosis pattern being claimed as the initiator of oral mucositis, even though a more resilient microbiome with a lower inflammatory potential seems to protect from developing oral mucositis .Oral mucositis is a complication that appears during chemo and/or radiotherapy treatment and involves the breakdown of the mucosal barrier, risk of systemic infection, and substantial pain, which can lead to the premature termination or remodeling of treatment and the interruption of treatment and eventually may affect a patient’s survival. Chronic side effects related to cancer and cancer therapy and chronic pain associated with oral mucosa also affect the quality of life of cancer survivors and challenge their health caretakers.The increasing prevalence of cancer with more patients with access to cancer therapies, and more cancer survivors for more years, make it necessary to minimize the side effects of cancer treatment toxicity on the oral mucosa.New approaches with synergistic efforts between basic science, clinicians from different disciplines, and translational research are needed to limit the toxicity of cancer treatments to reduce the incidence and severity of oral mucositis and provide better cancer support. New topical antioxidant microbiome-boosting strategies to minimize cancer therapy adverse effects in the oral mucosa seem to offer a window of opportunity for patients during oncological treatment in the context of oral mucositis.


Mechanical ventilation (MV) is a life-saving respiratory support therapy, but MV can lead to diaphragm muscle injury (myotrauma) and induce diaphragmatic dysfunction (DD). DD is relevant because it is highly prevalent and associated with significant adverse outcomes, including prolonged ventilation, weaning failures, and mortality. The main mechanisms involved in the occurrence of myotrauma are associated with inadequate MV support in adapting to the patient’s respiratory effort (over- and under-assistance) and as a result of patient-ventilator asynchrony (PVA). The recognition of these mechanisms associated with myotrauma forced the development of myotrauma prevention strategies (MV with diaphragm protection), mainly based on titration of appropriate levels of inspiratory effort (to avoid over- and under-assistance) and to avoid PVA. Protecting the diaphragm during MV therefore requires the use of tools to monitor diaphragmatic effort and detect PVA. Diaphragm ultrasound is a non-invasive technique that can be used to monitor diaphragm function, to assess PVA, and potentially help to define diaphragmatic effort with protective ventilation. This review aims to provide clinicians with an overview of the relevance of DD and the main mechanisms underlying myotrauma, as well as the most current strategies aimed at minimizing the occurrence of myotrauma with special emphasis on the role of ultrasound in monitoring diaphragm function. Mechanical ventilation (MV) aims to ensure adequate gas exchange and to totally or partially replace the action of the respiratory muscles, which can be overloaded during acute respiratory failure. However, MV has widely recognized potentially harmful pulmonary effects ,2 leadinVIDD is conceptualized as a reduction in the diaphragmatic force-generating capacity, specifically related to the use of MV  that occThe recognition of diaphragm dysfunction (DD) is relevant in critically ill patients because it is a common event that occurs in the different stages of critical illness, since admission , during Considering the relevance of diaphragmatic dysfunction in critically ill patients, the current literature has been committed to prioritizing the care of patients under MV in order to monitor diaphragm function in the ICU and to minimize or avoid diaphragm myotrauma to prevent the development of VIDD .Knowledge about the main mechanisms involved in the occurrence of myotrauma underlies the strategies that can be used to protect the diaphragm during MV ,20.The purpose of this review is to explore evolving concepts about the use of diaphragm ultrasound as a technique not only to assess diaphragm function but also to help monitor diaphragmatic effort for protective ventilation. We present an overview of the relevance of diaphragm dysfunction in critically ill patients on MV, its main mechanisms, and strategies to prevent it, focusing on ultrasound as a tool for monitoring diaphragmatic function.Evidence of diaphragmatic muscle injury in critically ill mechanically ventilated patients has been widely appreciated and recognized  and is bmyotrauma has been adopted to refer broadly to the ventilator-associated diaphragmatic acute muscle injury [To understand diaphragmatic dysfunction in critically ill patients, efforts have been made to standardize terminology, with the aim of ensuring communication between researchers. Thus, the term e injury .Over-assistance myotrauma (disuse atrophy) represents the effect of excessive respiratory support and reduced respiratory drive/effort, resulting in disuse atrophy and weakness. It is the best documented form of myotrauma, in both experimental studies ,31 and cUnder-assistance myotrauma  is a recognized form of muscle injury that occurs when ventilatory support is insufficient or unable to reduce the load on the diaphragm during increased respiratory drive (load-induced diaphragm injury). The persistence of high levels of respiratory efforts during under-assistance results in high muscle tension during concentric contraction ,38. In eEccentric myotrauma  occurs when there is contractile activity of the diaphragm during fiber lengthening instead of shortening. Eccentric contraction is observed in the expiratory phases of ventilation: (1) when the diaphragm exerts an expiratory brake to preserve the end-expiratory lung volume ; (2) in Expiratory myotrauma—in experimental models, it was observed that the use of high PEEP reduces the final expiratory length of the diaphragm and can cause loss of sarcomeres, resulting in longitudinal atrophy with impairment of the length-tension ratio of the diaphragm .According to the most current evidence, myotrauma is presumably associated with several mechanisms linked to the inappropriate management of MV, mainly related to the inadequacy of ventilatory support to suit the patient’s respiratory effort (over- and under-assistance) and as a result of AVP. The evidence for these mechanisms is summarized below :Over-assConsidering the main mechanisms involved in myotrauma, more recently, the literature has been dedicated to the recognition and early monitoring of diaphragmatic dysfunction, allowing the appreciation and development of rational strategies with the potential to minimize or prevent VIDD  Figure .Any strategy aimed at protecting the diaphragm must examine its functional aspects, with a particular emphasis on monitoring the diaphragm’s effort . The mosVarious tools can be employed to monitor the function/activity of the diaphragm. However, the various peculiarities of these techniques make them more or less appropriate in critically ill patients ,19,44. TDiaphragmatic ultrasonography has been shown to be a relevant tool for assessing diaphragm function that reached significance in critically ill patients due to its numerous advantages ,46,47: (The devices used to perform DUS have experienced advances (probes with better resolutions). In addition, the improvement and standardization of the technique allowed for the acquisition of reliable images of the diaphragm function ,48,49.The diaphragm is a dome-shaped, musculo-fibrous membrane. It is the main inspiratory muscle. Evaluation of the diaphragm with ultrasound is based on its anatomy and function. During inspiration, when the diaphragm contracts, the muscle fibers shorten, thicken, and stiffen, displacing the entire musculotendinous structure of the diaphragm, lowering its dome, moving the abdominal contents caudally and expanding the lower thoracic cavity .-In the subcostal region, the diaphragm is seen as a deep curved structure that separates the thorax from the abdomen;-In the mid-axillary intercostal region, in the zone of apposition (ZA), the diaphragm is identified as a three-layer structure; a hypoechoic inner muscle layer surrounded by two hyperechoic outer membranes (the peritoneum and pleura).Using the ultrasound, the diaphragm may be explored through two acoustic windows ,47,50 F:-In the Thus, during diaphragm inspiratory contraction, the ultrasound may observe: (a) the inspiratory caudal displacement (excursion) of the diaphragm in the subcostal region; (b) the end-expiratory thickness of the muscle (at rest) and the thickening and stiffening of the diaphragm during inspiration, in the ZA.In critically ill patients, a unilateral assessment of the right diaphragm is acceptable unless unilateral dysfunction is suspected  .Recently, a meeting of experts sought to outline a consensus focusing mainly on various technical/methodological aspects of ultrasound of the diaphragm. This consensus is therefore an important reference to standardize and universalize the performance of diaphragm ultrasound and should be regularly consulted in the application of the method.Excursion assessment: a low-frequency probe (3.5–5 MHz) was positioned below the right costal margin, between the midclavicular and anterior axillary line, directing medial-cranially and dorsally, tracking the posterior third of the right hemidiaphragm in a two-dimensional (2D) mode. Next, the M-mode exploration line was positioned as perpendicular as possible in relation to the diaphragm domus, in order to measure the movement of anatomical structures over time, and therefore, measure diaphragm mobility by placing calipers at the bottom and top of the diaphragmatic inspiratory slope ,51,52.During inspiration, the diaphragm descended in the craniocaudal direction, towards the probe ,47,50. TIn patients on ventilatory support, a brief disconnection of the ventilator (T-tube) or maintaining minimal levels of CPAP was necessary to assess diaphragmatic movement and thus eliminate passive inflation bias by ventilator pressure . The dowExcursion can be measured during tidal breathing and during maximal inspiratory effort in cooperative patients (best excursion) in order to assess diaphragm dysfunction .Diaphragm thickness assessment: a high frequency linear probe (>7–10 MHz) was positioned perpendicular to the lateral chest wall, between the midaxillary and anterior axillary line, between the 9th and 10th intercostal space (apposition zone–ZA). The diaphragm is seen usually at a depth of two to four centimeters from the skin, as a hypoechoic inner muscle layer surrounded by the peritoneum and pleura membranes. Diaphragmatic thickness was measured at the end of expiration  and inspiration  as the distance between the diaphragmatic pleura and the peritoneum using the 2D or M-mode ,56,57. ADiaphragm thickness (Tdi) may depict atrophy, while the thickening fraction (TF) represents diaphragm inspiratory activity (effort) ,60,61. Reference values for diaphragmatic excursion, thickness and thickening in healthy individuals are described in the The following is an overview of the recent evidence on diaphragmatic and intercostal (IC) ultrasound assessment, focusing on clinical applications aimed at promoting diaphragmatic protective MV strategies .Diaphragm dysfunction can be identified with DUS. Diaphragm dysfunction is characterized on DUS as an abnormality on diaphragmatic excursion indicated by reduced mobility , absent, or paradoxical (mainly seen in deep breathing and sniff maneuvers) . In critUltrasound-diagnosed DD is associated with adverse outcomes . Abnormal diaphragmatic thickening fraction, defined as a diaphragmatic thickening fraction of <20%, has also been used to diagnose DD . AccordiDiaphragm atrophy is a component of VIDD, and has been shown in experimental ,76,77 anSeveral studies have used the measurement of diaphragmatic thickness at the end of expiration (Tdi) as a non-invasive surrogate of diaphragmatic muscle mass, thus allowing the assessment of diaphragmatic atrophy in critically ill patients, especially those on MV ,78. In aThe wide range of values to determine the lower limit of Tdi (between 1.6 and 2.3 mm) both in healthy individuals and in critically ill patients on MV in different studies ,58,78,79Goligher et al.  studied Subsequently, other studies observed the relationship between atrophy and MV ,36. ScheVivier et al.  studied Regarding a single measurement of Tdi to assess atrophy, Dot et al.  investigHowever, even a single Tdi measurement at the early stages of critical illness can provide relevant information. Recently, Sklar et al.  demonstrOur understanding of the mechanisms of ventilator-induced diaphragmatic dysfunction (VIDD) has increased in recent years. Research now focuses on methods to monitor diaphragm function in parallel with efforts to prevent VIDD. The institution of assisted ventilation (“spontaneous breathing”) as early as possible seems to meet the efforts to prevent VIDD, but poses challenges to also comply with MV with “lung protection”. Also, as already demonstrated in previous studies, diaphragmatic atrophy due to disuse can occur even in assisted ventilation ,67,77 inAt this moment, the titration of the inspiratory effort and the synchronization in the patient-ventilator interaction seem to provide the best evidence in the simultaneous protection of the lung and the diaphragm, although the efficacy of such strategies is mainly supported by physiological and epidemiological data ,41,42,442O). This strategy, based on patient breathing effort, increased the time that patients had this predefined “diaphragm-protective” effort without compromising tidal volumes and transpulmonary pressures. Recent studies are now in course to assess the feasibility of strategies on titrating ventilation and sedation, in order to optimize the respiratory effort to achieve lung and diaphragm protective ventilation . In a reAlthough in these previous studies the respiratory effort titration was based on the monitoring of respiratory pressures, some authors proposed that the DUS can be useful in assessing the contractile activity of the diaphragm, and therefore also in assessing the respiratory effort ,20,22,44Assessment of the diaphragm thickening fraction (TF) as a surrogate of contractile activity of the diaphragm (the level of respiratory effort) is a reasonable approach ,49. AdjuAlthough the optimal level of diaphragmatic activity is uncertain, Goligher et al.  showed tThese findings along with studies that observed the existence of a correlation between TF and diaphragm effort ,68 serveHowever, it should be emphasized that the use of ultrasonography of the diaphragm, particularly the inspiratory thickening fraction (TF), as a surrogate for diaphragmatic effort, is still debated in the literature.Transdiaphragmatic pressure (Pdi) represents the specific muscle strength of the diaphragm, and its measurement has been considered the gold standard for diaphragm function, particularly after the bilateral magnetic stimulation of phrenic nerves . However2O). The authors found a significant correlation between TF and PTPdi, indicating that changes in diaphragm thickening correlate with the diaphragmatic work of breathing.However, there are controversial findings regarding the ability of TF to estimate diaphragmatic effort. Vivier et al.  investig2O). The authors observed that with increasing PS levels, parallel reductions were found between diaphragm TF, PTPes and PTPdi during tidal breathing. Diaphragm TF significantly correlated with PTPes and PTPdi. There was no correlation of any index with the excursion of the diaphragm.Umbrello et al.  investigGoligher et al.  investigIn order to estimate reliable measures for assessing respiratory effort, Umbrello et al.  investigUnlike these previous studies ,54,68,73Oppersma et al.  investigPoulard et al.  investigRecently, Steinberger et al.  investigThese controversial findings may arise from many points. (1) Heterogeneity of the population studied: Goligher and Oppersma ,86 invesAlthough these controversies indicate that caution should be taken in interpreting TF as a substitute for respiratory effort, we believe that Goligher’s findings that correlate changes in diaphragm configuration (estimated by Tdi) with diaphragmatic contractile activity (estimated by thickening fraction) may indicate that TF offers a plausible alternative for estimating respiratory effort, whose monitoring is essential for the prevention of diaphragmatic myotrauma ,23.Patient–ventilator asynchrony (PVA) can be defined as a mismatch between patient effort/demand and ventilator-delivered breaths  .PVA is not uncommon and may occur in up to a quarter of mechanically ventilated patients ,90,91, bPVA is associated with adverse effects such as dyspnea, increased work of breathing, auto-PEEP, worsening of pulmonary gas exchange, decreased quantity, and quality of sleep, leading to worse outcomes  and the end of the inspiratory phase (premature or delayed cycling), in addition to an imbalance in the inspiratory flow (insufficient or excessive) .PVA potentially impacts on diaphragm function and has been proposed as one of the mechanisms linking MV to diaphragm weakness, i.e., myotrauma . Optimal patient-ventilator interaction, without asynchrony, would theoretically be ideal for the diaphragm . More reAs previously described, the main mechanisms associated with myotrauma are: over-assistance leading to respiratory effort suppression and disuse atrophy, under-assistance associated with high effort and load-injury during the inspiratory concentric contraction, eccentric contraction during the expiratory phase, and the longitudinal atrophy. PVA-associated muscle injury is mainly related to eccentric contraction . In certAlthough the visual inspection of the airflow, volume, and pressure signals on the mechanical ventilator display may point to asynchrony, PVAs may go unnoticed in this method ,12.The gold standard for detecting PVA is esophageal pressure monitoring (Pes), providing an accurate inspection of the patient’s inspiratory muscle effort and corresponding ventilatory supply. However, monitoring of Pes remains limited because it is commonly unavailable and has technical pitfalls  ,98.Diaphragmatic electrical activity (EAdi) is another tool indicated for monitoring PVA, and is also considered a reference technique , but witConsidering that the inspiratory diaphragmatic activity (contraction) determines the changes in pleural pressure, it has been argued that DUS may be used to simultaneously monitor the function of the diaphragm and the breathing pattern in order to detect PVA ,49.Soilemezi et al.  employedSimultaneous observation of TF and Paw may indicate an auto-trigger PVA, when an assisted breathing cycle is observed without detection of inspiratory thickening ,49.Vivier et al. investigated the performance and accuracy of a new method based on the ultrasound analysis of diaphragm excursion (DE) or thickening combined with airway pressure to detect PVA. They found that this method  was more accurate than flow and pressure waveform analysis alone, and had better feasibility than diaphragm EMG for detecting patient-ventilator asynchronies .It should be noted that although DUS might be a reasonable alternative to detect most types of PVA , furtherWeaning from MV is a process of gradual reduction of ventilatory support, configuring a challenge to the respiratory muscles, notably the diaphragm. Unsuccessful weaning from MV have worse outcomes increasing morbidity and mortality ,103.The main cause of weaning failure is an imbalance between the load and capacity of the respiratory system . IdentifDiaphragm function assessed on ultrasound has been used as a predictor of weaning, primarily as a diagnostic test to predict extubation success ,105.Numerous studies have used the DUS to assess the prediction of weaning, and there are even meta-analyses and systematic reviews on the subject in the literature ,106,107.The earliest studies suggested that a successful extubation or weaning failure was likely with diaphragm excursion cut-off values of 11–14 mm .However, recently Vivier et al.  assessedRegarding the value of DUS to predict weaning from MV, it must be assumed that the results are controversial, and general conclusions are not allowed at this moment.This controversy seems to be mainly related to the heterogeneity regarding the population and study design, and on the characterization of the variables under test. There are marked variations in:(1) the timing of the ultrasound assessment in relation to the spontaneous breathing test (SBT), patient position during the SBT,(2) the standardization of the diaphragm evaluation technique with ultrasound in patients on ventilatory support ,(3) varying definitions of SBT failure, weaning failure, or extubation failure, which were not standardized across studies, making comparison between outcome measures difficult.Furthermore, a substantial proportion of patients with diaphragmatic dysfunction seen on DUS could be successfully weaned from the ventilator  suggesti-To identify patients at high risk of weaning failure, DUS is performed before SBT.-To predict the weaning outcome or to diagnose the cause of weaning failure, DUS is best performed after initiation and/or completion of an SBT.Although diaphragmatic ultrasound is a promising diagnostic tool, to determine its role in predicting weaning, additional studies are needed to standardize  some relTissue Doppler Imaging (TDI) is an ultrasound technique that detects the change in the frequency of ultrasound signals reflected by moving structures, already widely used to assess cardiac function but only more recently applied to assess the diaphragm in adults  and neonn = 20) with the aim of describing the pattern, reporting normal values, and assessing the reproducibility of diaphragmatic TDI waveform velocities during contraction (including peak contraction velocities (PCV) and relaxation ). Also in this study, the authors recorded the pattern and values of diaphragmatic TDI in ICU intubated patients (n = 106) elected for a spontaneous breathing test, comparing cases of successful and unsuccessful weaning, and, in a subgroup of these patients (n = 24), they correlated TDI measurements with parameters derived from transdiaphragmatic pressure (Pdi). The results indicated the patterns of contraction and relaxation of the TDI diaphragm in normal subjects and in patients with successful and unsuccessful weaning. It was a notable finding that weaning failure patients exhibited significantly higher PCV and TDI-MRR velocities compared to healthy participants and weaning success patients, such that the higher the values of PCV and TDI-MRR during weaning, the greater the likelihood of weaning failure. In addition, in the subgroup of patients evaluated with Pdi, high correlation coefficients of TDI PCV with peak Pdi and PTPdi, and Pdi-MRR and TDI-MRR were demonstrated. These findings offer insights into the physiological behavior of patients with weaning failure using a non-invasive technique.Although scarcely studied, recently Soilemezi et al.  presenteCammarotta et al.  investigAlthough the preliminary results are very significant, it is important to point out that much progress is still needed in the standardization of the method that includes the determination of the diaphragmatic movement point of interest (ROI); influence of other factors, such as compliance of the rib cage and activation of accessory inspiratory and expiratory muscles .Traditional methods to assess diaphragmatic function on ultrasound, such as measuring diaphragmatic excursion, diaphragm thickness and thickening fraction (TF), although consolidated, are limited to measuring the deformation of diaphragmatic muscle tissue in the transverse axis and therefore do not assess the ‘longitudinal’ muscle shortening, that is, the movement in the direction of the contracting muscle fibers.Speckle tracking ultrasound (STUS) is a new method of analysis, already widely used in echocardiography , which aA speckle represents a region of muscle tissue whose gray pattern on ultrasound remains relatively constant. The analysis of the STUS software is based on following (to track) a group of speckles during the contractile cycle, measuring their displacement and deformation (movement of the speckles in relation to each other). The degree of deformation is known as ‘strain’ while “strain rate” measures the deformation velocity. Because STUS tracks specific regions of interest it is considered relatively angle independent and tracking can help differentiate passive movement from active contraction.The applicability of using STUS to investigate diaphragm movement was tested in different scenarios. n = 13) submitted to NIV in CPAP  or unsupported (spontaneous breathing) and compared with inspiratory thickening fraction (TF). They found that both TF and transverse strain significantly increased under CPAP and PSV and that transverse strain correlated well with TF. Hatam et al.  analyzedn = 13) submitted to an inspiratory overload protocol (randomized from 0 to 50% of the maximum inspiratory pressure). Diaphragm electrical activity (EAdi), transdiaphragmatic pressures (Pdi) and thickening fraction were also recorded. They found that strain and strain rate, but not TF, increased with progressive loading of the diaphragm. Both strain and strain rate were highly correlated with Pdi and EAdi, but not TF. In this study, STUS was superior to conventional ultrasound techniques (TF) for estimating diaphragmatic contractility under inspiratory threshold loading.Oppersma et al.  evaluaten = 50) in comparison with the evaluation of diaphragm thickness, thickening fraction (TF) and excursion . They found a moderate correlation between right diaphragmatic longitudinal strain and TF, and a weak correlation between strain and excursion. Inter- and intra-rater variability was satisfactory for TF, excursion and strain.Orde et al.  evaluateXu Q et al.  evaluateFritsch et al.  evaluateAlthough there are promising results, STUS lacks validation in a large study. In addition, the software for STUS analysis was designed to determine myocardial deformation, and they are “closed boxes” that need to be broken. Many studies performed offline analyses, demanding considerable time, and making applicability in a clinical situation difficult. Additional studies involving STUS in subjects with abnormal diaphragmatic function and/or critical illness, and comparison with electromyography or transdiaphragmatic pressure measurements may be needed.Shear wave elastography (SWE) is a new technique recently applied to assess the diaphragm, which consists of creating a source of vibration (focused acoustic impulse beam generated by the ultrasound probe), resulting in tissue deformation and generating a shear wave that can be quantified .The SM expresses tissue biomechanical information and, therefore, is innovative for translating qualitative information about the properties of the diaphragm muscle. A higher SM indicates greater tissue stiffness.In two previous studies of healthy subjects, SWE reproduced the diaphragmatic contractile activity.Chino et al.  studied n = 102, of which 88 were mechanically ventilated) and mechanically ventilated piglets (in which transdiaphragmatic pressure and diaphragmatic biopsies were collected). The study observed a heterogeneous pattern of diaphragm configuration changes. A decrease or increase of more than 10% from the baseline was common in patients for thickness (86%) and SM (92%). Specifically, the SM remained unchanged in 8%, increased in 51%, and decreased in 41% of patients. Changes in the SM were inversely correlated with changes in diaphragm thickness in critically ill patients. A notable finding was that in the experimental model, the reduction in the SM was associated with diaphragm atrophy, lipid accumulation, and reduced strength. Aarab et al.  evaluateAlthough Aarab’s  findingsAlthough ultrasonography has advantages when compared to other methods of assessing diaphragm function, its limitations must be considered for proper interpretation. Patient positioning  and the -Histological findings of the muscle,-Interaction with other respiratory muscles,-Reference tools for PVA detection, and-Baseline measures of respiratory effort  and fatigue (such as TTI and relaxation rate).Although ultrasonography has evolved significantly in recent times, there is still a long way to go for its wide use in clinical practice. Regarding critical illness, it is expected that potential improvements in transducers and in machine presets can improve the visualization and measurement of variables. In addition, it is essential that we have more studies that contrast sonographic findings of the diaphragm with:Also, a technical improvement that allows automated image acquisition can make it a genuine monitoring tool.Diaphragm dysfunction is frequent and is related to many adverse outcomes in critically ill patients on MV. Diaphragm protection is a recent concept based on strategies aimed at preventing myotrauma. Monitoring diaphragmatic function and identifying diaphragmatic dysfunction are fundamentals of this protection strategy. Diaphragm ultrasonography may represent a possible complementary, promising tool which could be useful for monitoring diaphragm function at the bedside, potentially allowing you to adapt ventilator settings to provide protective diaphragm ventilation. Homogeneous prospective studies are needed in terms of study design, standardization of the method, in the number and selection of patients, and which all are compared with a reference gold standard method.


Graphene, with its excellent properties and unique structure, has been extensively studied in the context of modifiable cement-based materials. However, a systematic summary of the status of numerous experimental results and applications is lacking. Therefore, this paper reviews the graphene materials that improve the properties of cement-based materials, including workability, mechanical properties, and durability. The influence of graphene material properties, mass ratio, and curing time on the mechanical properties and durability of concrete is discussed. Furthermore, graphene’s applications in improving interfacial adhesion, enhancing electrical and thermal conductivity of concrete, absorbing heavy metal ions, and collecting building energy are introduced. Finally, the existing issues in current study are analyzed, and the future development trends are foreseen. Cement-based materials are widely used in infrastructure construction due to their high production efficiency, abundant raw material sources and good workability. As a result, they are the most commonly used construction materials in the world . HoweverWith the rapid development of nanomaterial science, researchers have used nanomaterials combined with industrial solid waste materials  in When fly ash concrete is mixed with GO of 0.25% mass and 24.3% oxygen, its chloride ion penetration resistance is the strongest , and wheGenerally, the factors affecting concrete carbonization can be divided into three aspects: material factors, environmental factors , and construction factors. Regarding material factors, graphene materials inhibit the carbonation rate of concrete by enhancing its compactness (microscopic pore structure) and alkalinity. Devi  exposed In terms of bending fatigue, Cho  proposedResearchers have also explored the application of graphene materials in concrete abrasion resistance, antibacterial properties, and crack reinforcement. Liu  found thResearchers have used protective coatings or carbon fiber-reinforced composites (CFRP) to enhance the durability and strength of concrete. The introduction of graphene can enhance the bonding between concrete and coating materials, steel bars, and CFRP, thus enhancing the protection and strengthening effect. The following section reviews the application of graphene materials in improving the interfacial bonding between concrete and coating materials, steel reinforcement, and CFRP.To improve the bonding effect between concrete and CFRP, Al-Saadi  used oxiAs shown in In order to improve the adhesion between the concrete and the protective coating, the scholars found that the use of GO to enhance the adhesion is a reliable new approach. Bahraq  believedGraphene can enhance the electrical and thermal conductivity of cement-based materials, and the modified materials play an essential role in areas such as road snow and ice melting, structural health monitoring, and building energy harvesting, bringing benefits such as reducing energy consumption, improving structural safety, and protecting the environment.In response to road snow and ice melting, researchers have designed the optimal mixing quantities of graphene materials considering concrete’s mechanical strength and resistivity. Wang et al. ,96 belieCombined with the improved electrical conductivity of the concrete, the researchers also studied the health monitoring of concrete structures. As shown in In recent years, the problems of cities’ ecological environment have become worse. With the continuous implementation of the goal of “double carbon” and the continuous promotion of “sponge city” construction, recycled concrete and thermoelectric composite concrete have become a global research hotspot. It is found that graphene-permeable concrete can meet the requirements of light-load road pavement in sponge cities and has good adsorption function for common heavy metal ions (such as lead ions) in water. Zhang Yubin et al.  preparedIn addition, graphene cement-based composite materials can convert the abundant solar energy in concrete structures into electrical energy for energy harvesting in urban buildings. Its principle is shown in Although graphene and its derivatives have broad research prospects in improving the properties of cement-based materials, some issues and challenges still need to be overcome before they can be generalized to practical engineering applications.(1) The production cost of graphene materials is high, and it is still challenging to accurately control the size, thickness, number of layers, and oxygen content during the preparation process.(2) The dispersion of graphene materials is terrible, and the chemical reactivity between cement-based materials and graphene is limited, resulting in a small amount of graphene and its derivatives (the amount of addition in the research paper is no more than 0.3%), which makes it difficult to give full play to its strengthening effect. In addition, the high cost and low efficiency of the commonly used ultrasonic dispersion methods limit their wide application in practical engineering.(3) The strengthening mechanism of graphene’s different sizes, thicknesses, layers, and oxygen content on cement-based composites is not precise. Researchers have different opinions on the optimal dosage of graphene materials, and no consensus has been reached.(4) Under the influence of temperature, humidity, alkaline environment, stress, and other factors, the long-term performance stability of graphene and its derivatives in cement has not been fully verified.In this paper, we have summarized and systematically analyzed the research status of graphene and its derivatives in improving the cement base’s operational performance, mechanical properties, durability, and other applications of cement substrates. The conclusions are as follows:(1) The graphene material adsorbs the free water in the mix, reducing the cement-based material’s fluidity and slowing the concrete’s shrinkage and creep. At the same time, the good thermal conductivity of the graphene materials also promotes hygroscopic rate and heat diffusion in cement-based materials.(2) There are three main reasons for using graphene to improve the overall mechanical properties of cementitious materials: the structural characteristics of graphene materials give high strength, the ability to promote the hydration reaction of cement, and the ability to fill the cavity gaps. In addition, the oxygen content, diameter, thickness, specific surface area of graphene materials, and the curing time of concrete will indirectly affect the intrinsic mechanical properties and reasonable material dispersion is a prerequisite for improving the overall mechanical properties.(3) Introducing graphene improves concrete’s impermeability, chloride ion penetration resistance, freeze–thaw resistance, and inhibits fatigue cracks’ expansion. In addition, the antimicrobial, hydrophobic, electrically and thermally conductive properties of graphene materials provide new ideas for the durable protection of marine building structures.(4) Graphene materials have great potential in improving the bond between cement-based materials, melting snow on a concrete surface, monitoring concrete stress state, absorbing heavy metal ions, and collecting building energy, etc. Continued exploration in these areas will promote the development of concrete structures in the direction of high durability, functionality, intelligence, environmental protection, and energy conservation.To further advance the engineering application of graphene materials for improving concrete properties, this paper provides the following outlook on the development direction of this field.(1) Future research should further explore the interaction mechanism between graphene and cement-based materials and develop more diverse graphene derivative materials. Meanwhile, it is necessary to find low-cost and efficient graphene dispersion methods to realize the engineering applications of graphene materials.(2) To determine the optimal mix range of graphene materials under multiple factors, it is also necessary to conduct systematic tests and simulations to explore the strengthening mechanism of graphene size, thickness, layer number, and oxygen content on cement-based composites.(3) Further research on the toxicity, environmental impact, and long-term stability of graphene concrete is a vital prerequisite for promoting the widespread use of graphene materials.(4) Relevant research institutions or departments can also standardize the preparation technology of graphene materials and formulate classification standards for the properties of different graphene materials, which can improve its application effect in cement-based materials and help promote the comparative analysis of different subsequent research results.


Tooth loss due to fracture and the failure of endodontic treatment (ET) are common situations in teeth with extensive tissue destruction. This is due to the fragility of the remaining dental structure and the difficulty in sealing cavities, which is sometimes associated with the violation of the supracrestal insertion tissue. The previous restoration of marginal ridges or cusps with composite resin (CR) restores their fracture resistance, due to the adhesive characteristics of the restorative material, while also protecting the quality of endodontic treatment through better sealing. However, the protocol adopted in teeth requiring endodontic treatment involves performing the restorative procedure only after the endodontic procedures. The objective of this study was to report a case in which restoration of marginal ridges and/or cusps was performed prior to endodontic treatment, focusing on maintaining the tooth in function without dental fracture. The restoration was performed with an inverted operative sequence before the endodontic treatment. There was a violation of the supracrestal insertion tissue, requiring crown lengthening surgery (CLS) prior to the restorative procedure. Clinical and radiographic evaluations were performed postoperatively at seven days, three, six, and nine months, and five years. Tooth function was maintained without dental fractures or restoration loss. Periradicular space healing occurred with the disappearance of the lesion. Performing the restorative procedure prior to endodontic treatment in teeth with extensive coronal destruction is an alternative technique that facilitates clinical procedures, reduces the likelihood of dental loss due to fracture, and promotes endodontic treatment success. The reduction of dental structure caused by caries, fractures, and access cavity preparations, and the consequent decrease in fracture resistance, have a negative influence on remaining teeth, highlighting the importance of the amount of remaining walls at the time of endodontic access .Endodontically treated teeth have significantly different biomechanical properties compared to vital teeth . ConfiguPre-endodontic restorations refer to dental restorations that are placed before root canal therapy is performed. These restorations are essential to maintaining the structural integrity of the tooth and reducing the risk of tooth fractures .When a tooth is affected by caries or trauma, it can lead to a weakening of the tooth structure. Pre-endodontic restorations, such as fillings or dental crowns, are used to restore the damaged structure of the tooth and provide additional support to the tooth. This helps prevent further damage and maintains the natural tooth for a longer period .The conventional operative sequence, in which the restorative treatment (RT) occurs after the endodontic treatment (ET), favors the persistence of tooth fragility for a longer period , which may increase the prevalence of dental fractures before, during, and after endodontic treatment . In the Restorations of endodontically treated teeth (RETT) can recover up to 72% of the fracture resistance of teeth compared to those with intact dental crowns . Thus, pAn important factor to consider before performing pre-endodontic restorations is the evaluation of the periodontal condition. The RT should always aim for the health of the periodontal tissues and respect the re-establishment of the biological space, designated by the latest classification (2018) of the American Academy of Periodontology (AAP) as the supracrestal insertion tissue . SubgingThe aim of this study was to report a case in which restoration was performed by recovering the supracrestal space prior to endodontic treatment, observing the maintenance of the treated tooth function, the longevity of the restorative procedure, the absence of dental fracture, and periradicular region healing.The study was approved by the Research Ethics Committee of the Vale do Acaraú State University (protocol #501.950/2013). The patient signed the informed consent form and was selected from the spontaneous demand of the Dental Clinic of the Federal University of Ceará (UFC), Sobral Campus.Patient with toxic shock syndrome (TSS), 27 years old, attended the institution's clinic for dental treatment. There was no complaint of pain or any type of dysfunction. Clinical examination showed the presence of an extensive caries lesion in the upper left second premolar. Extensive loss of coronal structure involving the distal marginal ridge and almost the entire occlusal surface, compromising about a third of the crown reinforcement structure. The tooth was diagnosed with chronic apical periodontitis, and endodontic treatment was necessary Figure . After cThe procedures were performed in a clinical sequence distributed over three sessions, in order to restore the reinforcing walls through the restoration with CR, leaving only the occlusal access for subsequent endodontic treatment, and definitive coronal sealing Table .In the first session, the color selection was made using the color scale , and infiltrative anesthesia with 2% mepivacaine  was used. For the CLS periodontal surgical procedure, a modified Widman flap was performed through an intra-sulcular incision using a no. 3 scalpel handle and a 15c blade . The flap was fully retracted with Free and Molt elevators , followed by the removal of granulation tissue with a Crane-Kaplan Curette . The amount of bone to be removed for the re-establishment of the supra-crestal insertion tissue was measured with a PCP-UNC 15-millimeter probe . Osteotomy was performed with Fedi and Rhodes chisels and Buck and Schluger files  until a distance of 3 mm between the end of the preparation and the marginal bone crest was re-established -3 ml, Adper Single Bond 2 adhesive -5.6 ml, and Filtek Z350 XT composite resin -4 g. The CR was performed using the matrix and matrix holder set or unimatrix clamp  and a sectioned matrix  with the aid of wooden wedges to re-establish contact points. A gutta-percha cone  with vaseline was used in the root canals to prevent the obliteration of these canals with composite resin.After the pre-endodontic restoration was completed and with the endodontic access properly preserved, root canal catheterization was performed using K-File files , irrigation (2.5% sodium hypochlorite) , intracanal medication with Tricresol Formalin in a cotton pellet , and provisional coronal sealing Figure  with ColAfter removal of the rubber dam, the detached flap was stabilized through vertical interrupted mattress suture and simple suture with 5.0 Best Care nylon thread . The occlusion of the restoration was tested, and when necessary, an occlusal adjustment was performed. Postoperative care was provided through the prescription of systemic analgesic medication Sonridor CAF  and chemical control with 0.12% chlorhexidine digluconate .The second clinical session was performed two weeks after the procedures. At that time, the suture was removed, and the healing condition was properly observed. The pre-endodontic restoration was polished using diamond tips 1190F, 1190FF, 3195F, 3195FF, 3118F, 3118FF, 3168F, 3168FF, multilaminated trunk-conical drill kit , siliconized flame-shaped tips, felt wheels, sandpaper strips, and diamond pastes .The third clinical session occurred one week later. Coronal access was performed, rubber dam isolation, removal of the cotton pellet, canal irrigation with 2.5% sodium hypochlorite , pre-enlargement with K-file files #15, #20, and #25 , and Gates Glidden 3 and 2 . Next, odontometry was performed with I-Root® electronic apex locator , canal instrumentation with Flexofile first series files  allowing apical preparation, and K-file second series files  allowing the execution of the stepped back preparation. Root canal filling was performed with gutta-percha cones  and MTA Fillapex endodontic cement .Finally, a base in glass ionomer cement was inserted before the definitive restoration in CR of the occlusal surface and final radiography Figure  to verifClinical-radiographic observations were performed after the third session using photographic documentation  and periapical radiographs. The observation periods were seven days, three months, six months, nine months, and five years.During the seven-day, three-month, six-month, and nine-month follow-ups, clinically good periodontal health, preservation of space for the supracrestal insertion tissue, absence of bleeding on probing, gingival edema, absence of marginal infiltration, absence of premature contact, adequate adaptation and integrity of the restoration, and absence of fractures or cracks in the tooth and/or restoration were observed.The 12-month follow-up, which would allow for a more secure and proper evaluation of the regression of the periradicular lesion, was not performed as the patient did not respond to calls. This was only possible five years after the completion of the procedure. At that time, the asymptomatic dental element was clinically observed to be in perfect function, the restoration was in good adaptation and conservation, and radiographically, the successful endodontic treatment was present and confirmed Figure , given tAdequate rehabilitation of the dental element after completion of endodontic therapy has always been a concern in the literature, having been referred to as one of the most important aspects in endodontic success .Clinical trials, systematic reviews, and meta-analyses that have evaluated the reverse sequence, in which RT is performed prior to ET, were not found in the literature.The reversal of the order of procedures performed in this case report is not a new technique but a proposal for alteration as a way of reconstructing lost dental tissue, minimizing the rates of tooth loss caused by a fracture in teeth to be endodontically treated . If teetIn the present case, there was a need for surgery to restore the supracrestal insertion space. Restorations placed below the gingival margin are harmful to gingival and periodontal health . In a loFor ET, a sequence of treatment planning in endodontics was established based on the diagnosis of chronic apical periodontitis, which determines the indication of ET. This treatment could be performed in just one clinical session. However, the decision to perform prior restorative treatment, with the need for recovery of the biological width, made the consultation time very long and tiring for the patient. Thus, in the first session, only the coronal access and catheterization of the root canals were performed, with the application of an intracanal medication  with appropriate volatility action for situations like this, where root canal instrumentation was not performed .In the third session, the ET was properly completed, performing instrumentation and obturation of the root canals. The pre-endodontic restoration performed in the first session allowed for the absolute isolation to be performed quite easily and safely, with the correct adaptation of the clamp and rubber dam in the cervical region of the teeth, leaving the area free of contaminating oral fluids and preventing contact of the oral mucosa with hypochlorite, without the need for additional techniques to ensure proper isolation.Reinforcing structures, such as marginal ridges and cusps, are primarily responsible for the resistance of teeth, and their reconstruction is extremely important for maintaining the integrity of the remaining teeth . In addiThe decision to restore the tooth using only a direct composite restoration is justified by the fact that it is a simplified and feasible procedure to recover the biomechanical properties of endodontically treated premolars with the structural loss , based oTeeth with conservatively endodontic cavities that preserve the integrity of the marginal ridge have greater fracture resistance, and upper premolars restored with composite resin exhibit better force distribution . These fIn clinical situations where extensive MOD cavity preparations occur in premolars, the fracture resistance of the remaining cusps is reduced to one-third when compared to healthy teeth . In anotRegarding the surfaces most prone to fracture, the palatal cusps of upper premolars tend to fracture more frequently than the vestibular cusps . This isEndodontically treated teeth are more prone to clinical failures when proximal contacts are not properly re-established with adjacent teeth . This fiIt has been observed that the main reasons for the extraction of endodontically treated teeth were periodontal disease, endodontic failure, and non-restorable tooth damage caused by fractures or caries . TherefoRestorations performed with CR have the advantage of being adhesive to the tooth structure, which can strengthen the tooth, thus offering an alternative technique to indirect restoration. A study with upper premolars found that, after restoration with composite resin, these teeth largely recovered their fracture resistance, being only less resistant when compared to intact teeth. Thus, the choice of restorative material used in the present study was adequate, since the tooth presented integrity in the restoration performed and good marginal adaptation during all follow-up evaluations, including five years .For a restoration with composite resin to have a good outcome, a strong and durable bond between the composite and dentin through the adhesive is necessary. NaOCl has no effect on dentin's inorganic part. However, it has a significant effect on the organic component of dentin . The useThe NaOCl interferes by reducing the bond strength between composites and dentin . The preCurrently, it is recommended that the newly-obturated root canal be sealed quickly and effectively by making a definitive restoration to maintain periapical health since the presence of a temporary or inadequately sealed coronal restoration can lead to reinfection of the tooth . SometimGiven this need for immediate restoration after root canal treatment, a study conducted at a Public Reference Center for Endodontics  found that 32.4% of patients undergoing treatment were not called by the public unit that referred them for definitive post-endodontic restoration, even after a minimum period of six months. This result demonstrates that the reference and counter-reference model based on the public health guidelines of this country does not favor the resolution of treatments of this nature. Teeth remain with temporary restorations and without the restoration of the coronal structure, which ends up favoring dental fracture. When not referred for extraction, they require new endodontic intervention . This fiIt is a fact that the restorations performed after the completion of endodontic treatment are important in the success of the treatment . The comThe reported case aimed to add the question of the need to include pre-endodontic restorations in this "equation." Such a procedure has been shown to be crucial for maintaining the longevity of teeth and reducing the risk of dental fractures, as they provide a solid foundation for successful root canal therapy and help ensure that the natural tooth can be preserved for as long as possible .Clinical trial studies, systematic reviews, and meta-analyses that investigate this variable within the suggested context should be conducted to assess the level of importance of this procedure in maintaining dental elements, reducing losses due to fractures, and clinical failures. It is hoped that this will confirm the positive influence of pre-endodontic restorations in reducing dental fractures and improving endodontic success.Based on the observed case result after five years, it can be concluded that the tooth presented with periodontal health, the composite resin restoration was in good adaptation and conservation, and the periradicular region was healed.Therefore, the pre-endodontic restorative treatment was resilient, contributing to the maintenance of the tooth in function without dental fracture and to the success of endodontic therapy. Clinical trials, systematic reviews, and meta-analyses should be conducted to increase the level of scientific evidence related to this issue.


Intervertebral disc degeneration is thought to be a major contributor to low back pain, the etiology of which is complex and not yet fully understood. To compensate for the lack of drug and surgical treatment, mesenchymal stem cells have been proposed for regenerative treatment of intervertebral discs in recent years, and encouraging results have been achieved in related trials. Mesenchymal stem cells can be derived from different parts of the body, among which mesenchymal stem cells isolated from the fetal umbilical cord have excellent performance in terms of difficulty of acquisition, differentiation potential, immunogenicity and ethical risk. This makes it possible for umbilical cord derived mesenchymal stem cells to replace the most widely used bone marrow-derived and adipose tissue derived mesenchymal stem cells as the first choice for regenerating intervertebral discs. However, the survival of umbilical cord mesenchymal stem cells within the intervertebral disc is a major factor affecting their regenerative capacity. In recent years biomaterial scaffolds in tissue engineering have aided the survival of umbilical cord mesenchymal stem cells by mimicking the natural extracellular matrix. This seems to provide a new idea for the application of umbilical cord mesenchymal stem cells. This article reviews the structure of the intervertebral disc, disc degeneration, and the strengths and weaknesses of common treatment methods. We focus on the cell source, cell characteristics, mechanism of action and related experiments to summarize the umbilical cord mesenchymal stem cells and explore the feasibility of tissue engineering technology of umbilical cord mesenchymal stem cells. Hoping to provide new ideas for the treatment of disc degeneration. With the growth of the global population and accelerated aging, low back pain (LBP) has become common public health problem worldwide . CurrentAt present, the treatment of IDD mainly includes conservative treatment and surgical treatment. Although these treatments can provide good relief to patients, they do not slow or reverse the reduction of extracellular matrix (ECM) and nucleus pulposus cells (NPCs), do not repair the patient’s disc tissue, and have unsatisfactory long-term outcomes. In contrast, regenerative therapies based on restoring the physiological structure and biomechanical function of the intervertebral disc (IVD) have gained widespread interest in recent years. Among them, the current research related to mesenchymal stem cells (MSCs) for IDD is the most extensive. MSCs are pluripotent stem cells with the ability to differentiate into a tri-spectrum of osteoblasts, chondrocytes and adipocytes . PositivIn the past, bone marrow mesenchymal stem cells (BMMSCs) were considered to be the gold standard of regenerative therapy. However, recent studies have found that umbilical cord mesenchymal stem cells (UCMSCs) are superior to BMMSCs in terms of cell source and differentiation potential. The IVD is the largest avascular tissue in the body . The surIVD is the largest avascular tissue in the body and consists of fibrocartilage tissue, which is one of the most important structures of the spine. Anatomically, IVD consists of three main components: the central highly hydrated gelatinous nucleus pulposus (NP), fibrous rings (AF) consisting of thin sheets of collagen fibers around the NP, and cartilage end plate (CEP) is a transparent cartilage structure that connects adjacent vertebrae . The aboThe specific mechanism leading to IDD is still unclear, and the prevailing view is that cell senescence, inadequate nutritional supply, repeated mechanical stress, obesity, trauma, genetics, and even smoking can lead to the development of IDD . Among tCurrently, the traditional treatment modalities for IDD include conservative treatment and surgery, and it is critical to choose the appropriate treatment for patients with different degrees of degeneration and clinical manifestations. For patients with early IDD, pharmacotherapy has a clear role in controlling pain and improving patient function and quality of life . HoweverFor patients with advanced IDD and those who have failed conservative treatment, surgery becomes the best option. Common surgical procedures include spinal decompression, spinal fusion and total disc replacement. Currently, spinal fusion is the most widely used in clinical practice and is considered the gold standard for the surgical treatment of IDD . Spinal In recent years, researchers have begun to investigate regenerative therapies aimed at regulating anabolic and catabolic metabolism within the IVD and restoring ECM and NPCs. These methods mainly include direct injection of growth factors, cell transplantation, gene therapy and tissue engineering.In cell therapy, researchers transplant cells with differentiation potential into the IVD to help restore the number of cells in the disc, promote ECM synthesis, and immune regulation. For discs with different degrees of development and degeneration, the selection of the appropriate cell type and source is critical for successful cell transplantation and disc regeneration. Common cell types include MSCs, intervertebral disc-derived stem cells (IVDSCs), and pluripotent stem cells (PSCs) . These cin vitro and then subsequently injected into the IVD. These IVD cells with the target gene will be retained in the IVD for a long time, promoting IVD regeneration and improving the patient’s symptoms. -7, BMP-2, transforming growth factor-β (TGF-β), insulin like growth factor (IGF), epidermal growth factor (EGF) and differentiation factor (GDF)-5 etc., . Howeverymptoms. . Howeverymptoms. . MoreoveMSCs were first discovered and isolated in the bone marrow of rats , and morin vitro expansion of UCMSCs are also significantly higher than that of BMMSCs , with the outermost layer wrapped around the amniotic epithelium . The WJ At present, UCMSCs mainly achieves the purpose of treating IDD through the following main ways. On the one hand, UCMSCs have the potential to proliferate and multidirectionally differentiate, replenish NPCs by differentiating to NPCs, and promote the synthesis of ECM by NPCs . UCMSCs,ex vivo studies on UCMSCs mainly focus on the effects of UCMSCs on IVD, promoting the proliferation and differentiation of UCMSCs and improving their survival rate, while the related clinical studies need to be further explored. Zhang et al.  seed cells that can regenerate IVD; 2) a biocompatible scaffold made of bioactive materials that can mimic ECM; 3) bioactive factors that promote cell proliferation and differentiation and migration . A schemin vitro under hypoxic conditions, heat treatment and the use of exogenous bioactive molecules  phosphate-buffered saline (PBS) vehicle, 2) HAMC, 3) WJ-MSCs, 4) WJ-MSCs/HAMC. The results showed that WJ-MSCs/HAMC had the strongest ability to regenerate IVD. Combined injection of WJ-MSCs and HAMC enhanced IVD regeneration through increase in cell survival, attenuation of the activation of iNOS, MMP-13, ADAMTS4 and COX-2, and significant upregulation of ECM, such as aggrecan and collagen type II. Ahn et al. (in vitro for culture. After 28 days of scaffold culture, results showed strong upregulation of cartilage-specific transcript expression. WJ-MSCs exhibited greater type II collagen synthesis than BMMSCs at both transcript and protein levels.Choi et al.  found thn et al.  found thn et al.  WJ-MSCs On the contrary, synthetic materials are relatively better than natural materials in terms of mechanical properties, while they are less biocompatible, hydrophilic and cell adhesion. In addition, degradation products of synthetic materials can induce inflammatory responses and reduce the rate of cell proliferation . SynthetIn addition, the decellularized matrix obtained by removing cells and antigens from autologous tissues through a series of methods also provides a new idea for tissue engineering of IVD . This tyin vitro expansion rate and stability, lower immunogenicity and risk of infection make UCMSCs promising as an ideal choice for the treatment of IDD. In vitro and in vivo experiments have demonstrated that UCMSCs can differentiate into NPCs, promote ECM synthesis and regulate inflammatory responses within the IVD. However, the regenerative capacity of UCMSCs has reached opposite conclusions in some trials, and relevant clinical trials are scarce.The survival of UCMSCs under the harsh IVD microenvironment and pressure load is the main factor limiting their regenerative capacity. As the field of biomaterials continues to evolve, a new way of thinking is provided by the fact that UCMSCs have been shown to better perform their regenerative role by being attached to a variety of biomaterial scaffolds with excellent properties.Currently, conventional treatment modalities for IDD provide good relief of symptoms in IDD patients, but their long-term outcomes are hardly satisfactory. A series of regenerative therapies have received much attention for their effectiveness in delaying or even reversing IDD. The higher proliferative differentiation potential, higher in vitro amplification. In recent years, cell banks for UCMSCs have been established in several countries with the aim of achieving access to large numbers of UCMSCs and helping heir clinical application. However, the number of established cell banks is currently much lower than expected. With the development and widespread use of 3D printing technology in the field of tissue engineering, 3D printed scaffolds may become a major trend. These scaffolds can be artificially adjusted to better meet the needs of UCMSCs survival and better repair the IVD. In addition, exosomes with lipid bilayers obtained by paracrine action of MSCs have been shown to promote tissue repair and regeneration. Because of their unique cell-free properties, they are significantly superior to MSCs in overcoming the microenvironment within IVD, immune rejection risk, tumorigenicity and ethical risk, which provides new ideas for further studies of UCMSCs. In the future, there are still many issues that need to be addressed for UCMSCs in regenerative treatment of IDD. More trials are needed to validate their effectiveness and safety in order to reduce the burden of IDD patients.UCMSCs, as stem cells that have only recently entered the public eye, have been little studied, and existing experiments are similarly deficient. The main reason for this situation is the immaturity of UCMSCs in terms of extraction, storage and