Skeletal muscle trauma such as fracture or crush injury can result in a life-threatening condition called acute compartment syndrome (ACS), which involves elevated compartmental pressure within a closed osteo-fascial compartment, leading to collapse of the microvasculature and resulting in necrosis of the tissue due to ischemia. Diagnosis of ACS is complex and controversial due to the lack of standardized objective methods, which results in high rates of misdiagnosis/late diagnosis, leading to permanent neuro-muscular damage. ACS pathophysiology is poorly understood at a cellular level due to the lack of physiologically relevant models. In this context, microfluidics organ-on-chip systems (OOCs) provide an exciting opportunity to investigate the cellular mechanisms of microvascular dysfunction that leads to ACS. In this article, the state-of-the-art OOCs designs and strategies used to investigate microvasculature dysfunction mechanisms is reviewed. The differential effects of hemodynamic shear stress on endothelial cell characteristics such as morphology, permeability, and inflammation, all of which are altered during microvascular dysfunction is highlighted. The article then critically reviews the importance of microfluidics to investigate closely related microvascular pathologies that cause ACS. The article concludes by discussing potential biomarkers of ACS with a special emphasis on glycocalyx and providing a future perspective.

BACKGROUND: In recent years, it has been demonstrated that when the endothelial glycocalyx, composed of proteoglycans, glycosaminoglycans and glycoproteins, is altered or modified, this property is lost, playing a fundamental role in cardiovascular pathologies. Cardiovascular risk factors can destroy the endothelial glycocalyx layer. Exercise has a positive effect on cardiovascular risk factors, but little is known about its direct effect on the integrity of the endothelial layer.
METHODS: The Cochrane Library, PubMed, Web of Science and Scopus databases were searched from their inception to June 30, 2022. The DerSimonian and Laird method was used to compute pooled effect size estimates and their respective 95% confidence intervals for the acute effect of exercise (within 24 h) on the endothelial glycocalyx and its components in healthy adults.
RESULTS: Ten studies were included in the meta-analysis, with a total of 252 healthy subjects. The types of exercise included were resistance training, interval training, resistance training and maximal incremental exercise, with a duration range of 30-60 min. Glycocalyx assessment times included ranged from 0 to 90 min post-exercise. Our findings showed that endothelial glycocalyx increases after acute effect of exercise in healthy population (.56, 95% CI: .38, .74). The acute effect of exercise on endothelial glycocalyx components were .47 (95% CIs: .27, .67) for glycosaminoglycans, .67 (95% CIs: .08, 1.26) for proteoglycans and .61 (95% CIs: .35, .86) for glycoproteins.
CONCLUSIONS: In a healthy population, various types of exercise showed an acute improvement of the endothelial glycocalyx and its individual components.

Chronic venous disease (CVD) and hemorrhoidal disease (HD) are among the most common vascular diseases in the world, with CVD affecting 22-41% of the population in Europe and HD having a point prevalence of 11-39%. The burden is substantial in terms of the effect of symptoms on patients\' health-related quality of life (HRQoL) and direct/indirect medical costs. Treatment begins with lifestyle changes, compression in CVD and topical therapies in HD, and escalates as needed through oral therapies first and eventually to surgery for severe disease. CVD and HD share etiological features and pathological changes affecting the structure and function of the tissue extracellular matrix. Mesoglycan, a natural glycosaminoglycan (GAG) preparation composed primarily of heparan sulfate and dermatan sulfate, has been demonstrated to positively impact the underlying causes of CVD and HD, regenerating the glycocalyx and restoring endothelial function, in addition to having antithrombotic, profibrinolytic, anti-inflammatory, antiedema and wound-healing effects. In clinical trials, oral mesoglycan reduced the severity of CVD signs and symptoms, improved HRQoL, and accelerated ulcer healing. In patients with HD, mesoglycan significantly reduced the severity of signs and symptoms and the risk of rectal bleeding. In patients undergoing excisional hemorrhoidectomy, adding mesoglycan to standard postoperative care reduced pain, improved HRQoL, reduced incidence of thrombosis, and facilitated an earlier return to normal activities/work, compared with standard postoperative care alone. The clinical effects of mesoglycan in patients with CVD or HD are consistent with the agent\'s known mechanisms of action.

Microvascular integrity is a critical factor in myocardial fluid homeostasis. The subtle equilibrium between capillary filtration and lymphatic fluid removal is disturbed during pathological processes leading to inflammation, but also in hypoxia or due to alterations in vascular perfusion and coagulability. The degradation of the glycocalyx as the main component of the endothelial filtration barrier as well as pericyte disintegration results in the accumulation of interstitial and intracellular water. Moreover, lymphatic dysfunction evokes an increase in metabolic waste products, cytokines and inflammatory cells in the interstitial space contributing to myocardial oedema formation. This leads to myocardial stiffness and impaired contractility, eventually resulting in cardiomyocyte apoptosis, myocardial remodelling and fibrosis. The following article reviews pathophysiological inflammatory processes leading to myocardial oedema including myocarditis, ischaemia-reperfusion injury and viral infections with a special focus on the pathomechanisms evoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition, clinical implications including potential long-term effects due to viral persistence (long COVID), as well as treatment options, are discussed.

Shock-induced endotheliopathy (SHINE), defined as a profound sympathoadrenal hyperactivation in shock states leading to endothelial activation, glycocalyx damage, and eventual compromise of end-organ perfusion, was first described in 2017. The aggressive resuscitation therapies utilised in treating shock states could potentially lead to further worsening endothelial activation and end-organ dysfunction.
This study aimed to systematically review the literature on resuscitation-associated and resuscitation-induced endotheliopathy.
A predetermined structured search of literature published over an 11-year and 6-month period (1 January 2011 to 31 July 2023) was performed in two indexed databases (PubMed/MEDLINE and Embase) per PRISMA guidelines. Inclusion was restricted to original studies published in English (or with English translation) reporting on endothelial dysfunction in critically ill human subjects undergoing resuscitation interventions. Reviews or studies conducted in animals were excluded. Qualitative synthesis of studies meeting the inclusion criteria was performed. Studies reporting comparable biomarkers of endothelial dysfunction post-resuscitation were included in the quantitative meta-analysis.
Thirty-two studies met the inclusion criteria and were included in the final qualitative synthesis. Most of these studies (47%) reported on a combination of mediators released from endothelial cells and biomarkers of glycocalyx breakdown, while only 22% reported on microvascular flow changes. Only ten individual studies were included in the quantitative meta-analysis based on the comparability of the parameters assessed. Eight studies measured syndecan-1, with a heterogeneity index, I2 = 75.85% (pooled effect size, mean = 0.27; 95% CI - 0.07 to 0.60; p = 0.12). Thrombomodulin was measured in four comparable studies (I2 = 78.93%; mean = 0.41; 95% CI - 0.10 to 0.92; p = 0.12). Three studies measured E-selectin (I2 = 50.29%; mean =  - 0.15; 95% CI - 0.64 to 0.33; p = 0.53), and only two were comparable for the microvascular flow index, MFI (I2 = 0%; mean =  - 0.80; 95% CI - 1.35 to - 0.26; p < 0.01).
Resuscitation-associated endotheliopathy (RAsE) refers to worsening endothelial dysfunction resulting from acute resuscitative therapies administered in shock states. In the included studies, syndecan-1 had the highest frequency of assessment in the post-resuscitation period, and changes in concentrations showed a statistically significant effect of the resuscitation. There are inadequate data available in this area, and further research and standardisation of the ideal assessment and panel of biomarkers are urgently needed.

BACKGROUND: With the emergence of coronavirus disease of 2019 (COVID-19), several blood biomarkers have been identified, including the endothelial biomarker syndecan-1, a surface proteoglycan. In the current systematic review and meta-analysis, we aimed to assess the diagnostic and prognostic role of syndecan-1 in COVID-19.
METHODS: PubMed, Embase, Scopus, and Web of Science, as international databases, were searched for relevant studies measuring blood syndecan-1 levels in COVID-19 patients, COVID-19 convalescents, and healthy control subjects, in patients with different COVID-19 severities and/or in COVID-19 patients with poor outcomes. Random-effect meta-analysis was performed using STATA to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) for the comparison between COVID-19 patients and healthy control subjects or COVID-19 convalescents and controls.
RESULTS: After screening by title/abstract and full text, 17 studies were included in the final review. Meta-analysis of syndecan-1 levels in COVID-19 compared with healthy control subjects revealed that patients with COVID-19 had significantly higher syndecan-1 levels (SMD 1.53, 95% CI 0.66 to 2.41, P < 0.01). In contrast, COVID-19 convalescent patients did not show significant difference with non-convalescents (SMD 0.08, 95% CI -0.63 to 0.78, P = 0.83). Regarding disease severity, two studies reported that more severe forms of the disease were associated with increased syndecan-1 levels. Moreover, patients who died from COVID-19 had higher syndecan-1 levels compared with survivors (SMD 1.22, 95% CI 0.10 to 2.33, P = 0.03).
CONCLUSIONS: Circulating syndecan-1 level can be used as a biomarker of endothelial dysfunction in COVID-19, as it was increased in COVID-19 patients and was higher in more severe instances of the disease. Further larger studies are needed to confirm these findings and further enlighten the role of syndecan-1 in clinical settings.

Toll-like receptors (TLRs) have a critical role in the pathogenesis and disease course of viral infections. The induced pro-inflammatory responses result in the disturbance of the endovascular surface layer and impair vascular homeostasis. The injury of the vessel wall further promotes pro-thrombotic and pro-coagulatory processes, eventually leading to micro-vessel plugging and tissue necrosis. Moreover, TLRs have a direct role in the sensing of viruses and platelet activation. TLR-mediated upregulation of von Willebrand factor release and neutrophil, as well as macrophage extra-cellular trap formation, further contribute to (micro-) thrombotic processes during inflammation. The following review focuses on TLR signaling pathways of TLRs expressed in humans provoking pro-thrombotic responses, which determine patient outcome during viral infections, especially in those with cardiovascular diseases.

The level of endothelial glycocalyx (EG) shedding is associated with morbidity and mortality, and vascular endothelial barrier dysfunction is one of the pivotal clinical problems faced by critically ill patients, so research on the protective effects of EG is of great clinical significance for the treatment of critically ill diseases. Studies have illustrated that clinical anesthesia has different degrees of effects on vascular EG. Therefore, we reviewed the effects of distinct anesthesia methods and diverse anesthetic drugs on EG, aiming to provide a brief summary of what we know now, and to discuss possible future directions for investigations in this area. So as to provide a theoretical basis for future research on potential EG-positive drugs and targets, to minimize perioperative complications and improve the prognosis of surgical patients.

Sepsis-associated encephalopathy (SAE) is characterized by a diffuse cerebral dysfunction that accompanies sepsis in the absence of direct central nervous system infection. The endothelial glycocalyx is a dynamic mesh containing heparan sulfate linked to proteoglycans and glycoproteins, including selectins and vascular/intercellular adhesion molecules (V/I-CAMs), which protects the endothelium while mediating mechano-signal transduction between the blood and vascular wall. During severe inflammatory states, components of the glycocalyx are shed into the circulation and can be detected in soluble forms. Currently, SAE remains a diagnosis of exclusion and limited information is available on the utility of glycocalyx-associated molecules as biomarkers for SAE. We set out to synthesize all available evidence on the association between circulating molecules released from the endothelial glycocalyx surface during sepsis and sepsis-associated encephalopathy.
MEDLINE (PubMed) and EMBASE were searched since inception until May 2, 2022 to identify eligible studies. Any comparative observational study: i) evaluating the association between sepsis and cognitive decline and ii) providing information on level of circulating glycocalyx-associated molecules was eligible for inclusion.
Four case-control studies with 160 patients met the inclusion criteria. Meta-analysis of biomarkers ICAM-1 (SMD 0.41; 95% CI 0.05-0.76; p = 0.03; I2 = 50%) and VCAM-1 (SMD 0.55; 95% CI 0.12-0.98; p = 0.01; I2 = 82%) revealed higher pooled mean concentration in patients with SAE compared to the patients with sepsis alone. Single studies reported elevated levels of P-selectin (MD 0.80; 95% CI -17.77-19.37), E-selectin (MD 96.40; 95% Cl 37.90-154.90), heparan sulfate NS2S (MD 19.41; 95% CI 13.37-25.46), and heparan sulfate NS+NS2S+NS6S (MD 67.00; 95% CI 31.00-103.00) in patients with SAE compared to the patients with sepsis alone.
Plasma glycocalyx-associated molecules are elevated in SAE and may be useful for early identification of cognitive decline in sepsis patients.

Perioperative fluid balance has a major impact on clinical and functional outcome, regardless of the type of interventions. In thoracic surgery, patients are more vulnerable to intravenous fluid overload and to develop acute respiratory distress syndrome and other complications. New insight has been gained on the mechanisms causing pulmonary complications and the role of the endothelial glycocalix layer to control fluid transfer from the intravascular to the interstitial spaces and to promote tissue blood flow. With the implementation of standardized processes of care, the preoperative fasting period has become shorter, surgical approaches are less invasive and patients are allowed to resume oral intake shortly after surgery. Intraoperatively, body fluid homeostasis and adequate tissue oxygen delivery can be achieved using a normovolemic therapy targeting a \"near-zero fluid balance\" or a goal-directed hemodynamic therapy to maximize stroke volume and oxygen delivery according to the Franck-Starling relationship. In both fluid strategies, the use of cardiovascular drugs is advocated to counteract the anesthetic-induced vasorelaxation and maintain arterial pressure whereas fluid intake is limited to avoid cumulative fluid balance exceeding 1 liter and body weight gain (~1-1.5 kg). Modern hemodynamic monitors provide valuable physiological parameters to assess patient volume responsiveness and circulatory flow while guiding fluid administration and cardiovascular drug therapy. Given the lack of randomized clinical trials, controversial debate still surrounds the issues of the optimal fluid strategy and the type of fluids (crystalloids versus colloids). To avoid the risk of lung hydrostatic or inflammatory edema and to enhance the postoperative recovery process, fluid administration should be prescribed as any drug, adapted to the patient\'s requirement and the context of thoracic intervention.