Due to its excellent mechanical properties and high aspect ratio, graphene can significantly improve the water and chloride ion permeability resistance of cementitious materials. However, few studies have investigated the effect of graphene size on the water and chloride ion permeability resistance of cementitious materials. The main issues are as follows: How do different sizes of graphene affect the water and chloride ion permeability resistance of cement-based materials, and by what means do they affect these properties? To address these issues, in this paper, two different sizes of graphene were used to prepare graphene dispersion, which was then mixed with cement to make graphene-reinforced cement-based materials. The permeability and microstructure of samples were investigated. Results show that the addition of graphene effectively improved both the water and chloride ion permeability resistance of cement-based materials significantly. The SEM (scanning electron microscope) images and XRD (X-ray diffraction) analysis show that the introduction of either type of graphene could effectively regulate the crystal size and morphology of hydration products and reduce the crystal size and the number of needle-like and rod-like hydration products. The main types of hydrated products are calcium hydroxide, ettringite, etc. The template effect of large-size graphene was more obvious, and a large number of regular flower-like cluster hydration products were formed, which made the structure of cement paste more compact and thus significantly improved the resistance to the penetration of water and chloride ions into the matrix of the concrete. Cement-based materials are the most widely used materials for construction projects. With the rapid development of the economy and the vigorous progression of urbanization, higher requirements are presented for cement-based materials, such as their mechanical performance and durability ,2,3,4,5.Graphene, as the thinnest two-dimensional nanomaterial known in the world, boasts a two-dimensional network lattice structure formed by single-layer carbon atoms with a sp2 hybridized orbital. It has excellent mechanical, thermal, electrical, and barrier properties and a large specific surface area ,15,16,17Existing studies have shown that there are generally two methods for using graphene or graphene oxide to improve the durability of cement-based materials. One is to add graphene or graphene oxide to cement-based materials as an admixture, and the other is to combine it with other substances to prepare nanocomposite materials as coatings on the surface of cement-based materials. So far, research has been focused on the preparation methods of graphene and the effects of the oxygen content of graphene on improving the durability of cement-based materials. Very few researchers have explored the influence of graphene on the durability of cement-based materials from the perspective of its size. The existing research generally believes that graphene can regulate the growth form of cement hydration products and has a template effect ,29. For Based on previous research, the effects of graphene with different sizes on the water and chloride ion permeabilities of cement-based materials were studied in this research by the water permeability height method and the rapid chloride ion migration method, respectively. Combined with XRD, SEM, EDS (energy-dispersive X-ray spectroscopy) and other characterisation methods, the changes in hydration product morphology and hydration rate in cement-based materials with graphene and graphene oxide were analyzed. To observe the interaction between graphene and cement-based materials more intuitively, cement paste/graphene/cement particle samples were prepared by a new method. The sample prepared by the new method allows cement to directly adhere to the surface of graphene instead of simply mixing graphene with cement. Therefore, the growth morphology and aggregation mode of cement hydration products on the graphene surface can be clearly observed by SEM, and the mechanism of graphene improving both water and chloride ion permeability resistance was studied. Cement: P.II42.5 Portland cement produced by Guangxi Yufeng Group Co., Ltd. , conforming to Chinese Standard GB175-2007, was used for preparing the samples. The main properties of the cement used are shown in Polycarboxylic acid water reducers (PCs), produced by Fuclear Technology Suzhou Co., Ltd. , with a water reduction efficiency of 30%, were used as a superplasticizer for preparing cement samples.Graphene dispersion: Two types of peeling graphene (PG1 and PG2) slurry prepared by Guangxi Qinglu Technology Company  were used for preparing graphene-reinforced cement composites in this study. The solid contents of the two types of graphene dispersion were 5% and 4% by weight, respectively. The graphene in the dispersion was in the agglomeration state as it was supplied. After treatment, a graphene slurry was prepared.Standard sand: the standard sand used for making cement mortars in this study was the ISO standard sand produced by Xiamen ISO Standard Sand Co., Ltd. Water: distilled water was used for all cement samples.According to previous findings , the besTo observe the dispersion effect, UV-vis spectrophotometry tests were carried out on the two groups of PG dispersion before and after mechanical stirring and ultrasonic dispersion treatment. The mechanical stirring and ultrasonic dispersion processes together lasted 15 min and the test wavelength was 187~700 nm. To eliminate the influence of PCs in the dispersion on the absorbance of graphene dispersion, the spectrophotometry test was carried out on PC solutions with the same concentration. Results show that the absorbance of the PC solution tended to approach zero after 600 nm (as shown in According to (1)−1, and the number of graphene layers was calculated. The results are shown in Two types of graphene were characterized with the XploRA plus Raman spectrometer with a scanning range of 500~3500 cmThe average number of layers of the two types of graphene can be calculated by the empirical Formula (1) based on their Raman spectrum shown in GI represents graphene peak G;Of which: ID2 represents graphene peak 2D, andGI/ID2 indicates the structural and crystalline integrity of graphene, the higher the value of GI/ID2, the more defects the graphene will have; otherwise, the more complete the structure of graphene, the better the crystallinity. In GI/ID2 values of PG1 and PG2 are 0.13 and 0.57, respectively, indicating that PG1 has fewer defects and higher crystallinity than PG2.The sheet diameter of graphene was measured by an LA-960 particle size analyzer . Figure (2)The chemical bonds and types of functional groups were measured with a PerkinElmer Frontier FTIR spectrometer. The results are shown in −1 corresponded to the -OH vibration absorption peak, 2928 cm−1 to the C-H vibration absorption peak, 1647 cm−1 to the C=C absorption peak, 1388 cm−1 to the HBrinterference peak, and 1065 cm−1 to the C-O-C stretching vibration absorption peak.It can be seen that the two types of graphene had similar absorption peaks, in which 3430 cmThe XRD curves of the two types of graphene were measured by D8AA25 XRD. Since the XRD curves of the two types of graphene were almost identical, only one curve is presented, as shown in It can be seen that an obvious characteristic carbon peak appeared at 26.2° (2θ). According to the Bragg Equation (2), the layer spacing of the two types of graphene can be obtained.d represents the crystal spacing;Of which n represents the reflection series, taking 1 in this study; andAccording to Equation (2), the layer spacing of the two types of graphene can be obtained at 0.314 nm.(3)The micromorphology of graphene was observed by the Phenom XL G2 scanning electron microscope. From (1)A water permeability test was conducted according to the water permeability height method recommended by Chinese Standard GB/T 50082-2009 Standard Test Method for Long-term Performance and Durability of Ordinary Concrete.(2)The chloride ion permeability test was carried out following the RCM method recommended by Chinese Standard GB/T 50082-2009 Standard Test Method for Long-term Performance and Durability of Ordinary Concrete.According to the authors’ previous research results, the content of graphene in the cement paste is 0.02% by weight of cement, while the content of PCs is 0.1% by weight of cement. The mix proportion of cement samples for the water permeability test is shown in The mix proportion of cement samples for the chloride ion permeability test is shown in The sample for the permeability test is in a round platform shape with an upper diameter of 175 mm, a lower diameter of 185 mm, and a height of 150 mm. After the samples were removed from their molds after 24 h of initial curing, the excessive cement slurry was brushed away from both ends and tops of the samples with a steel wire brush, and then the samples were cured in the standard maintenance room for 28 d. The samples were sealed in the permeability test mold before the test. The sealing process was as follows: First, the sealing material made of paraffin and rosin at a 5:1 ratio by weight was put into the oven to melt, followed by being daubed with a layer of 1–2 mm thick on the side of the samples with a brush. Afterwards, the samples were pressed into the preheated test molds at a slow speed until the sample reached the bottom of the test mold. The temperature of the test mold was determined just to be able to melt the sealing material slowly but not cause it to flow.Six samples were installed on a concrete water permeability instrument, as shown in After the water permeability test was completed, the samples were split into two parts along the longitudinal direction by a press machine. Then the water mark of the samples after splitting was traced with a waterproof pen, and a sample was divided into 10 equal parts along the water mark with a steel ruler. The water permeability height was then measured, and the average of the 10 measured values was taken as the water permeability height. The reading was accurate to 0.1 mm. The calculation process is shown in Equation (3) . The aveOf which The water permeability height of the three samples  subjected to water permeability after splitting is shown in It can be seen from −12 m2/s);The depth of chloride permeability of cement paste samples and related RCM test data are presented in U represents the absolute value of voltage used (V);T represents the average of the initial temperature and end temperature of the anode solution (°C);L represents the thickness of the sample (mm) (as accurate down to 0.1 mm);Xd represents the average chloride ion permeability depth (mm) (as accurate as 0.1 mm); andt represents test duration (h).−12 and 4.4 × 10−12 m2/s, respectively, representing a decrease of 33.9% and 21.4%, respectively, compared to that of the control sample.The chloride migration coefficients of the three groups of cement paste samples are shown in 3 solution after the permeability test, and the silver-white area that developed at the lower part of the samples was the part where chloride ions penetrated. It can be clearly seen that in the control sample, a large silvery-white area developed. However, the boundary was uneven, indicating that the internal structure of the control sample was uneven. While the silvery white area developed in the cement paste samples with PG1 and PG2 was slightly reduced compared with that in the control sample, the boundary was almost in a straight line, representing that the addition of graphene made the structure of the matrix more compact and uniform.After adding graphene to cement samples, the water permeability resistance and chloride ion permeability resistance of cement paste samples increased significantly, which is because the two-dimensional sheet structure and the impermeable property of graphene played a bridging role in the cement matrix, thus preventing the connection of internal cracks to deflect the interconnected pores in the cement paste and prolonging the migration channel of chloride ions . Due to In addition, graphene with a nanoflake structure produced a spatial crack prevention effect in the cement matrix, which can reduce and delay the generation of internal cracks in the cement matrix and thus improve the compactness of cement stones. The larger the size of graphene in a certain range, the more obvious the spatial crack prevention effect. The large-size PG1 graphene had fewer defects on the surface and more nucleation sites, whose template and bridging effects are more obvious than those with PG2. The large-size graphene is easy to curl and form a “semi-enclosed” structure. When water molecules and chloride ions penetrate the structure, they are difficult to penetrate into other parts of the cement matrix. Therefore, the hydration product structure inside the PG1 cement paste samples was denser, and both its water and chloride ion permeability resistances were higher.3S and C2S diffraction for PG1 and PG2 cement paste samples are also lower than those of the control sample, indicating that the addition of PG1 and PG2 accelerates cement hydration reactions.It can be seen that adding graphene did not change the position of the crystal diffraction peak in hydration products, suggesting that the addition of graphene did not change the type of cement hydration products but had an impact on the content and crystallinity of hydration products. Through peak intensity analysis, it is found that whether it was 3 d or 28 d, the diffraction peak of CH crystal near 18° (2θ) of the PG1 cement paste sample was significantly improved, indicating that the addition of PG1 can effectively improve the crystallization degree of CH crystal and accelerate the formation of CH crystal. This is because there are a large number of oxygen-containing functional groups on the surface and edge of PG1, providing reaction sites for the formation of CH crystals to accelerate their hydration reactions and regulate their size. This phenomenon can be explained by the classical heterogeneous nucleation theory . The pea(1)Graphene-reinforced cement-based material samples prepared by a conventional methodTo observe the microstructure of the cement slurry sample after the incorporation of graphene, the graphene-reinforced samples and control samples without graphene were examined by SEM. The mix proportion of the samples was the same as that of the samples for the chloride ion permeability test see , with 3 According to the types and data of elements in points 4 to 8 in One of the reasons for these phenomena is that graphene plays a bridging role  in the c(2)Cement paste/graphene/ cement particle samples prepared by a new methodIn the above tests, graphene was distributed in a cement paste sample in a three-dimensional disordered form. It was not easy to accurately observe the interaction between cement hydration products and graphene. To further observe the hydration of cement on the surface of graphene and analyze the regulation effect of PG1 and PG2 on cement hydration products, a new method was adopted in this paper: first, two cement paste samples with a diameter of 10 mm and a thickness of about 2–3 mm were made, and after their initial setting, several drops of PG1 and PG2 graphene dispersion made by mechanical stirring and ultrasonic were respectively absorbed with a rubber head dropper and evenly coated on the surface of cement paste. The amount of graphene dispersion should just cover the surface of the cement paste samples without overflowing to make graphene nanosheets distributed on the surface of the cement paste sample. Finally, a small number of cement particles (3~5 g) were evenly sprinkled by a cement sieve with an aperture of 80 um to prepare samples of cement paste/graphene/cement particles, which were moved to an environment chamber for standard curing. The cement paste/graphene/cement particle samples prepared by this new method ensured that graphene and cement hydration products on the surface of graphene could be observed on the surface of cement paste. Its structural diagram is exhibited in The SEM images of cement paste/graphene/cement particle specimens prepared by the above new method are shown in As shown in From 2, and a small amount of AFt were mainly at measurement points 9, 11, 13, and 15. At the same time, the content of C at those measurement points was higher than that of general cement hydration products, indicating that the cement hydration product was attached to the surface of graphene.According to the EDS element composition analysis results presented in (1)Due to the unique nano two-dimensional sheet-like structure of graphene, which plays a bridging role and template effect in the cement matrix, it prevents the connection of internal cracks, refines the size of hydration products, improves the density of cement-based materials, and makes graphene cement-based materials more resistant to water permeability and chloride ion penetration than the blank group.(2)XRD analysis shows that the addition of graphene does not change the type of cement hydration products but can improve the rate of the hydration reaction and accelerate the formation of CH crystals.(3)Through scanning electron microscopy observations of graphene cement mortar specimens, it is found that during the early stage of hydration, a large number of small granular hydration products are formed on the surface of graphene, and later, regular reef-like hydration products are generated, and the structure of the cement becomes denser.(4)By observing the newly prepared cement mortar-graphene-cement particle specimens through scanning electron microscopy, it can be directly observed that a large number of regular and dense flower clusters and needle clusters of hydration products are formed on the graphene surface. This indicates that graphene has a template effect, and its oxygen-containing groups on the surface provide reaction sites for cement hydration, regulating the morphology and size of the hydration products. As the hydration reaction proceeds, the hydration products increase, which makes the cement matrix more compact, thus improving the water permeability resistance and chloride ion permeability resistance of cement-based materials. Due to the larger average area diameter and fewer defects of PG1 than PG2, and the more complete structure, its template effect is more pronounced.(5)2, and a small amount of AFt, among others.Analysis of EDS elemental composition shows that the flaky substance inside the cement specimen is graphene, and the hydration products grow and cover the surface of graphene; the flower-cluster-shaped hydration products are mainly composed of C-S-H, Ca(OH)Studying the water and chloride ion permeability of cement-based materials is of great significance to assess the durability of concrete and propose measures to reduce building maintenance costs and improve building service life associated with concrete durability. Different from other studies, this paper investigated the influence of graphene on the water and chloride ion permeability of cement-based materials from the perspective of graphene size. Based on the results, the addition of either of the two types of graphene can reduce both the water and chloride ion permeability of cement-based materials. When graphene was well dispersed, large-size graphene had fewer defects and more oxygen-containing groups. Both the water and chloride ion permeability resistances of cement-based materials were improved more obviously. In this study, the cement slurry-graphene cement particle sample was prepared by a new method for the first time, and the growth law and morphology of the hydration products on the surface of graphene were observed by SEM, which further revealed the mechanism of graphene in improving the water and chloride ion permeability of cement-based materials. The specific conclusions are drawn as follows:Because the production technology of large-diameter graphene was simpler and the cost became lower, the research methods and results proposed in this study can not only enrich the existing research on graphene cement-based materials but also provide a theoretical basis and application reference for graphene to improve the durability of cement-based materials. However, there are still some limitations. There is a lack of research on the water permeability and chloride ion permeability of graphene for cement concrete materials because, compared with cement paste, the internal structure of concrete is more complex, and the effects of different sizes of graphene on the water and chloride ion permeabilities of concrete may be different. Therefore, further research is needed in this area.


Diagnosing pulmonary sarcoidosis raises challenges due to both the absence of a specific diagnostic criterion and the varied presentations capable of mimicking many other conditions. The aim of this review is to help non-sarcoidosis experts establish optimal differential-diagnosis strategies tailored to each situation. Alternative granulomatous diseases that must be ruled out include infections , chronic beryllium disease, hypersensitivity pneumonitis, granulomatous talcosis, drug-induced granulomatosis , immune deficiencies, genetic disorders (Blau syndrome), Crohn’s disease, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and malignancy-associated granulomatosis. Ruling out lymphoproliferative disorders may also be very challenging before obtaining typical biopsy specimen. The first step is an assessment of epidemiological factors, notably the incidence of sarcoidosis and of alternative diagnoses; exposure to risk factors ; and exposure to drugs taken for therapeutic or recreational purposes. The clinical history, physical examination and, above all, chest computed tomography indicate which differential diagnoses are most likely, thereby guiding the choice of subsequent investigations . The goal is to rule out all diagnoses other than sarcoidosis that are consistent with the clinical situation. Chest computed tomography findings, from common to rare and from typical to atypical, are described for sarcoidosis and the alternatives. The pathology of granulomas and associated lesions is discussed and diagnostically helpful stains specified. In some patients, the definite diagnosis may require the continuous gathering of information during follow-up. Diseases that often closely mimic sarcoidosis include chronic beryllium disease and drug-induced granulomatosis. Tuberculosis rarely resembles sarcoidosis but is a leading differential diagnosis in regions of high tuberculosis endemicity. How often have I said to you that when you have eliminated the impossible, whatever remains, however improbable, must be the truth?The Sign of Four, 1890).Sir Arthur Conan Doyle  diagnostic guidelines involved using a Delphi methodology to classify several manifestations as indicating a highly probable or probable diagnosis of sarcoidosis, based on the World Association of Sarcoidosis and Other Granulomatosis (WASOG) Sarcoidosis Organ Assessment Instrument , 5. MoreThis review focuses on the differential diagnosis of pulmonary sarcoidosis. Our aim was to provide practical diagnostic help to physicians who have limited experience with sarcoidosis. The first section presents useful diagnostic tools  and provides examples of imaging and pathology findings. In the second section, we describe specific settings in which alternative diagnoses must be considered and discuss the best tools for differentiating these diagnoses from sarcoidosis.2.We performed a comprehensive literature search for publications relevant to the differential diagnosis of sarcoidosis. To this end, we searched PubMed using the terms “sarcoidosis” OR “pulmonary granulomatosis” OR “tuberculosis” OR “histoplasmosis AND “epidemiology” OR “thoracic imaging” OR pathology” OR “microbiology” OR “occupational-induced” OR “environmental-induced” OR “drug-induced” OR “immunodeficiency” OR “genetic” OR “vasculitis” OR “Crohn’s disease.” We considered original articles and reviews published in English between January 2010 and January 2023, as well as other articles that did not meet these criteria but were of specific interest.3.3.1.3.1.1.The ratio of the incidence of sarcoidosis over the incidence of each alternative diagnosis varies significantly across geographic areas and across sub-populations in a given area. These variations dramatically impact the probabilities of different diagnoses, according to Bayes’ theorem. A comparison of the incidences of sarcoidosis and tuberculosis illustrates this point. In some countries, tuberculosis is the main differential diagnosis of sarcoidosis , 9. SwedContrary to tuberculosis, pulmonary histoplasmosis is not ubiquitous but instead occurs in well-delineated areas such as the Ohio River and Mississippi River valleys in the USA and specific regions of Central and South America, Africa, Asia, and Australia. This disease is very rare in Europe, with the exception of Italy . PatientChronic beryllium disease and other occupational mineral-induced granulomatous diseases, hypersensitivity pneumonitis, and drug-induced granulomatosis occur in specific settings. Blau syndrome, which very rarely involves the lungs, is usually diagnosed at a younger age compared to pediatric sarcoidosis .3.1.2.Symptoms and signs, particularly those observed in extra-pulmonary manifestations which may be observed in up to 50% of sarcoidosis patients, may be useful to differentiate sarcoidosis from alternative diseases. For example, some manifestations were classified supportive of sarcoidosis diagnosis with a high probability  or with probability  according to official American Thoracic Society Clinical Practice Guidelines  Recently3.1.3.The likelihood of specific findings  differs between sarcoidosis and the alternative diagnoses.3.1.3.1.3.1.3.1.1.In 70% of patients with sarcoidosis, chest radiographs show typical lymphadenopathy, with or without pulmonary infiltrates. Parenchymal disease is evident in only 45% of patients at the time of maximal lymphadenopathy. In patients without parenchymal infiltrates, the lymphadenopathy is hilar and bilateral (98%). In a study of 62 patients, the most common mediastinal locations were the aortopulmonary (76%) and right paratracheal (71%) regions and the most common combination was bilateral hilar, right paratracheal, and aortopulmonary (37%) . Symmetrcf infra) in which the node enlargement is usually moderate, and drug-induced granulomatosis , and small nodules (<3 mm) are usually seen (80% of patients) .Large lymphadenopathy in the anterosuperior mediastinum suggests lymphoma  20)..20).3.1.3.1.3.Eggshell calcifications can be seen in sarcoidosis , some fu3.1.3.2.3.1.3.2.1.The typical radiographic manifestation of parenchymal lung involvement by sarcoidosis consists in diffuse micronodules predominating in the upper and middle parts of the lungs .By chest CT, perilymphatic micronodules are the most common abnormality in pulmonary sarcoidosis (77% of cases) . These oA limited number of sarcoidosis-like granulomatous diseases can closely mimic sarcoidosis, including chronic beryllium disease and drug-induced granulomatous diseases , 33. In Granulomatosis induced by checkpoint-inhibitor cancer immunotherapy is becoming increasingly common due to the expanding indications for these drugs . The imaBy contrast, in tuberculosis, the most typical lesions in the event of airway dissemination are nodules, centrilobular nodules (notably tree-in-bud nodules), and clustered nodules predominating in the upper lobes, right middle lobe, lingula, and superior segment of the lower lobes ; and conThe most common radiographic abnormality in acute symptomatic histoplasmosis consists of multiple nodular opacities usually smaller than 3 mm in diameter, generally in a diffuse distribution . PleuralIn hypersensitivity pneumonitis, profuse, minute, diffuse micronodules in a centrilobular distribution sparing the subpleural parenchyma are frequently described .Several nongranulomatous lung diseases may mimic sarcoidosis, such as silicosis and coal miner’s pneumoconiosis, in which micronodules predominate in the upper lungs (78%), in a centrilobular and subpleural, bilateral, and symmetrical distribution, sometimes with confluence and posterior predominance 38%)  37, 38), 3837, 3%  37, 38In lymphangitis carcinomatosa, the nodules share with sarcoidosis a predominance in the peribronchovascular regions (11 of 18 cases) . HoweverPulmonary amyloidosis may produce misleading imaging-study findings such as diffuse micronodules in a predominantly perilymphatic distribution , 43, 44.3.1.3.2.2.These patterns are illustrated in In about 10% of patients with sarcoidosis, the predominant chest CT finding consists in ground-glass opacities  or alveoPredominant ground-glass opacities in patients without immunodepression occur chiefly in connective tissue diseases, drug-induced pneumonitis, alveolar proteinosis, nonspecific interstitial pneumonia  . Alterna3.1.3.2.4.True primary pulmonary sarcoid cavitation, in which the walls of the cavities are formed by characteristic noncaseating lesions, has been reported in 2.2% of patients with sarcoidosis . HoweverOther interstitial lung diseases can cause cavities. Thus, thin-walled cystic air-filled spaces can develop in lymphocytic interstitial pneumonia  and thic3.1.3.3.3.1.3.3.1.Progressive massive fibrosis often manifests as mass-like lesions, usually in a bilateral upper-lobe distribution, not only in sarcoidosis ,K but al3.1.3.3.2.A common chest CT finding in sarcoidosis is interlobular septal thickening, which is often irregular or associated with marked distortion of the lung structures . Linear Several signs of fibrosis strongly suggest sarcoidosis. In a study of 27 patients with sarcoidosis, nine patients exhibited varying degrees of parenchymal distortion consistent with fibrosis  and in a3.1.3.3.3.Fibrosing pulmonary sarcoidosis can produce honeycomb cavities . Honeyco3.1.3.4.In pulmonary hypertension, signs of lobular distortion , fibrosi3.1.4.A careful examination of biopsy specimens can help with the differential diagnosis, since several microscopic features differ between sarcoidosis and the alternative diseases. We highlight the most typical and most atypical findings in sarcoidosis and in most alternative diseases which are summarized in 3.1.4.1.Pulmonary sarcoidosis is defined as a systemic disease manifesting chiefly as granulomatous interstitial pneumonia. Consequently, the identification of characteristic noncaseating epithelioid granulomas is essential to the diagnosis.bronchial mucosal biopsies, whose number strongly affects the diagnostic yield  or large masses (macronodules), with relative sparing of the intervening lung. The nodules predominate along the lymphatics . This topographic distribution is a very strong argument for pulmonary sarcoidosis. It suggests a critical role for lymphatics in nodule development and, consequently, supports the involvement of airborne particles in the pathogenesis of pulmonary sarcoidosis. In addition, given the presence of granulomas near the small airways, peribronchiolitis with bronchiole-lumen narrowing is common. Furthermore, the blood vessels are often involved in areas of granulomatous inflammation. Granulomatous vasculitis may affect all levels from the large elastic pulmonary arteries to the venules, although the lesions are more marked in the veins than in the arteries. Necrotizing sarcoid granulomatosis, first reported in 1973, is characterized by extensive noncaseating granulomatous inflammation with foci of parenchymal necrosis, combined with marked vasculitis affecting both the arteries and the veins , closely associated with CD4+ T lymphocytes. The peripheral component contains CD8 lymphocytes, CD4+ FOXP3 + Treg cells, Th17 cells, B lymphocytes, and IgA-producing plasma cells  Figure . A featuic yield . The broic yield , 58. A kanulomas . At the anulomas  53). Ne. Nebroncanulomas , 60. In he veins . The gra3.1.4.2.per se is not specific of sarcoidosis, as shown in Mycobacterium tuberculosis  may be misdiagnosed (Schistosoma mansoni) may produce arterial granulomas responsible for pulmonary arterial hypertension . . per se rtension . Exposurrtension . In addi3.1.4.3.Aspergillus antigens , lymphadenopathy, other infected tissues, or pleural fluid. The microbiology laboratory must perform microscopic examinations and cultures according to standardized procedures  the auramine O fluorescent stain, usually chosen for screening, with a reading at X25 or X40 magnification and (ii) the Ziehl-Neelsen stain, used to confirm a positive auramine O test, with a reading at X100 magnification. Culturing is the reference test, since it identifies a bacterial strain belonging to the M. tuberculosis complex detection based on polymerase-chain-reaction (PCR) gene amplification of samples (PCR-TB test) is a routine investigation recommended for diagnosing tuberculosis  its sensitivity is lower compared to cultures, as the results are positive only with loads above 5,000 to 10,000 bacilli/mL of sample compared to 1 bacillus/mL, in theory, for cultures. Smear examination can rapidly detect those patients with the highest bacillus loads and account for about 50–60% of patients with culture-positive pulmonary tuberculosis (The microscopic examination of stained smears has two main limitations: (i) it does not reliably distinguish between rculosis . Sensitirculosis .Culturing is the reference standard test for diagnosing tuberculosis. The samples are first decontaminated and centrifuged to kill nontuberculous bacteria , which grow faster than do mycobacteria and can contaminate cultures . The samAn alternative method relies on matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), which provides a characteristic mass spectral fingerprint of whole inactivated mycobacterial cells. This method is accurate for identifying bacteria. Its simplicity, speed, and affordability make it suitable as a routine technique for identifying mycobacteria , 95.M. tuberculosis complex within a few hours   to identify mycobacteria of the ication) , 96–99.  samples . Specifi samples , 86, 100With extrapulmonary samples, the larger the volume the greater the likelihood of identifying the bacteria. For example, for possibly tuberculous lymph nodes, needle aspiration alone has a limited diagnostic yield, except in countries where tuberculosis is uncommon or when a PCR test is performed on the aspirate . However3.1.5.2.Histoplasma capsulatum is a dimorphic fungus. Urine can be tested for Histoplasma antigen.Histoplasmosis is diagnosed either by identification of the organism upon microscopic examination and culturing of sputum or tissue samples or by PCR testing of whole blood. M. tuberculosis, these bacteria do not require any special precautions in the laboratory. If the standard cultures are negative, PCR tests for the 16S rRNA gene can be performed as they may, in some cases, identify the causative bacterial agent.Several bacteria other than mycobacteria may cause symptoms suggestive of sarcoidosis and should be sought using standard bacteriological tests before considering tests for organisms that are more challenging to identify. Most of these bacteria are easily recovered by culturing then identified by routinely available MALDI-TOF mass spectrometry. Unlike Syphilis and leprosy do not typically damage the lung parenchyma. A single case of syphilitic granuloma in the lung parenchyma has been reported . The diaTo look for viruses such as the human immunodeficiency virus, varicella-zoster virus, and cytomegalovirus, specific tests must be ordered. The diagnosis is usually achieved by specific PCR or serological tests, which are selected based on the clinical presentation, country of residence, and local epidemiology.Metagenomic next-generation sequencing may, in the future, prove a useful and rapid tool for detecting bacteria, fungi, or viruses in granulomatous tissue. Advantages of this technique include the simultaneous identification of multiple pathogens, detection of microorganisms that are present in small amounts or difficult to grow, and feasibility on formalin-fixed and paraffin-embedded tissue.3.1.6.Increased serum angiotensin converting enzyme level and abnormal calcium and vitamin D metabolism are often observed in sarcoidosis. However, both abnormalities are neither sensitive nor specific. They can be abnormal in several other granulomatous conditions particularly tuberculosis and CBD and even in non-granulomatous conditions like lymphomas.18FFluodeoxyglucose (FDG) positron emission tomography (PET) CT (PET/CT) is the most sensitive test to assess activity in involved organs in sarcoidosis and no study has been done to assess its usefulness for diagnosis. There are not dedicated studies comparing PET/CT in sarcoidosis and other granulomatous or non-granulomatous diseases like for example lymphomas. Moreover, its use has not been recommended at diagnosis except in rare cases where a cardiac sarcoidosis is suspected  The prompt and accurate diagnosis of pulmonary tuberculosis is essential.3.2.1.1.1.Sarcoidosis is particularly difficult to diagnose in patients with rare and atypical radiological presentations such as unilateral hilar or mediastinal lymphadenopathy, necrotic lymphadenopathy, predominantly bronchiolar micronodular infiltration or miliary, lung cavitations, or pleural effusion. These presentations should suggest tuberculosis, particularly in endemic regions (section 3.1.1.). The absence of caseating granulomas does not rule out tuberculosis . In all 3.2.1.1.2.Tuberculosis is easily ruled out when the following criteria are combined: country with a low incidence of tuberculosis, no contact with tuberculosis patients, radiological findings typical for sarcoidosis (section 3.1.3.), absence of clinical or imaging-study findings suggestive of tuberculosis, and negative microbiological tests on respiratory samples  or tissue specimens .M. tuberculosis, including PCR tests, can produce false-negative results , tuberculosis is more difficult to definitively rule out at presentation, as shown by a recent study of the Sarcoidosis Diagnostic Scores . Sarcoid results . Moreove results . In doubInterestingly, in one study, the risk of developing sarcoidosis was significantly increased in patients with tuberculosis, particularly involving extrapulmonary sites . Moreove3.2.1.2.Mycobacterium kansasii and Mycobacterium malmoense, whereas bronchiolar micronodules with a tree-in-bud appearance and bronchiectasis more often indicate Mycobacterium avium complex (MAC) infection. Isolated or multiple nodules can be found in M. avium complex and Mycobacterium xenopi infections.The clinical presentation and imaging-study findings closely resemble those seen in tuberculosis. Several specific features that vary across mycobacterial species deserve note. Fibrocavitary lesions in the lung apices are more common with To rule out nontuberculous mycobacterial infections, microbiological studies should be performed, as they usually allow the isolation and identification of mycobacteria. However, the diagnosis may be difficult in patients with multiple pulmonary nodules by chest CT, since investigations for mycobacteria in respiratory secretions or BAL fluid may be falsely negative. In this situation, the only definitive test is a surgical biopsy examined using specific microbiological techniques (section 3.1.5.1.).3.2.1.3.Histoplasmosis may be a differential diagnosis of sarcoidosis in several circumstances.3.2.1.3.1.When the presentation is acute, imaging studies may be misleading if they show both lymphadenopathy, which may be bilateral, and diffuse lung micronodules. However, the clinical presentation more closely resembles that of community-acquired pneumonia, and the epidemiological setting is suggestive (section 3.1.1.).In everyday practice, the differential diagnosis with sarcoidosis is most difficult in patients with (i) multiple chronic pulmonary nodules or (ii) pulmonary hypertension revealing previously unrecognized late-stage mediastinal fibrosis.3.2.1.3.2.Histoplasmosis occurs in specific epidemiological settings (section 3.1.1.) The diagnosis relies on the identification of the causal organism by microscopic examination of sputum or tissue and by culturing or PCR testing of whole blood.3.2.1.4.Tropheryma whipplei. Patients usually present with weight loss (93%), diarrhea (81%), and arthralgia (73%). Pulmonary involvement is extremely rare and produces diffuse pulmonary ground-glass opacities predominating in the lower subpleural areas, pleural involvement, and noncaseating pulmonary granulomas  are associated with an increased risk of both beryllium hypersensitivity and chronic beryllium disease, with odds ratios greater than 10 . However3.2.2.2.Positive lymphocyte transformation tests to metals other than beryllium have been reported in patients with sarcoidosis-like presentations and workplace exposures to metals . The metals/minerals were aluminum, nickel, titanium, chromium, palladium, silica, mercury, and zirconium. Thus, some patients given a diagnosis of sarcoidosis may have metal-induced sarcoidosis-like granulomatous disease , 125.3.2.2.3.Hypersensitivity pneumonitis, notably in its nonfibrotic form, is caused by exposure to airborne environmental or occupational antigens and can share features with sarcoidosis. However, differentiation from sarcoidosis is generally easy, as shown by a study of the Sarcoidosis Diagnostic Scores . The ons3.2.2.4.M. avium or Mycobacterium phocaicum)  . Chest C3.2.2.5.Pulmonary granulomatous talcosis can produce radiological abnormalities resembling those seen in sarcoidosis (section 3.1.3.) . A histo3.2.3.A recent WHO pharmacovigilance review reported 2,425 cases of drug-induced sarcoidosis and strong associations with TNF-a antagonists, interferon, pegylated interferon, and immune checkpoint inhibitors , 131.3.2.3.1.Despite data supporting the use of TNF-a antagonists to treat sarcoidosis, these drugs have been reported to induce sarcoid-like reactions , 132. Et3.2.3.2.Some of the most recent anticancer drugs including immunotherapeutic agents and targeted therapies have been incriminated in the development of granulomas. The recent WHO pharmacovigilance report recognizes PD-1, CTLA4 (103 cases), and BRAF and MEK inhibitors (37 cases) as causes of sarcoid-like granulomatosis .3.2.3.2.1.p = 0.002) in this retrospective study . Sarcoid-like reactions can mimic cancer progression. Of 45 patients given adjuvant combined nivolumab-ipilimumab therapy for melanoma, 10 (22%) were diagnosed with sarcoid-like reactions manifesting most often as hilar and mediastinal lymphadenopathy and in some patients as skin and bone involvement . An unre3.2.3.2.2.Other anticancer treatments that can induce sarcoid-like reactions include BRAF and MEK inhibitors. Cases have been reported with the BRAF inhibitor vemurafenib used alone  or with 3.2.3.2.3.Intravesical BCG therapy for bladder cancer can cause systemic granulomatosis , 158. GrThe chest radiograph may be normal or show a miliary pattern mimicking disseminated tuberculosis, a fungal infection, or hematogenous metastases .3.2.3.3.New treatments for hepatitis have largely superseded interferon-a, except for patients with hepatitis delta. Interferon-induced pulmonary granulomatous disease has therefore become rare.3.2.3.4.A sarcoidosis-like disease can develop in HIV-positive patients who have responded to antiretroviral therapy by a rise in CD4 T-cell counts and a fall in viral loads. In 10 retrospectively identified HIV-positive patients with a newly diagnosed, sarcoidosis-like disease, the chest CT findings resembled those produced by sarcoidosis in HIV-negative patients: they consisted of lymphadenopathy, nodules, thickened interlobular septa, focal consolidation, reticular opacities, ground-glass opacities, and cyst-like or other cavities . In HIV-3.2.3.5.The monoclonal antibodies rituximab, omalizumab, ustekinumab, vedolizumab, and natalizumab are suspected causes of pulmonary granulomatosis , 163. Me3.2.4.3.2.4.1.This disease often results in recurrent bacterial respiratory infections (65% of cases), bronchiectasis, and autoimmune manifestations (40% of cases) and may co-exist with lymphoproliferative disorders . However3.2.4.2.Aspergillus fumigatus. A biopsy of persistent pulmonary nodules or consolidations is often required and frequently shows noncaseating granulomas. Radiological presentations mimicking sarcoidosis are very rare , marked blood eosinophilia, serum C-reactive protein elevation, and positive assays for perinuclear antineutrophil cytoplasmic antibodies.3.2.6.3.“Necrotizing sarcoid granulomatosis” is still a provisional diagnostic term, given the uncertainty about whether it represents necrotizing angiitis with a sarcoid reaction or true sarcoidosis with a distinctive pathological pattern . The epi3.2.6.4.Interstitial lung disease, sometimes with granulomatous pulmonary lesions, may develop in patients with sicca due to Sjögren’s syndrome. Very infrequently, this condition may require differentiation from sarcoidosis with pulmonary fibrosis producing linear opacities extending from the hilum to the subpleural area . However3.2.7.per se the cause of pulmonary granulomatosis. At the trachea, in contrast, macroscopic abnormalities can be visible by endoscopy, a finding never observed in sarcoidosis . These cells may be sparse and associated with nonnecrotizing granulomatous inflammation .4.Alternative diagnoses must be ruled out before a diagnosis of sarcoidosis can be given. To this end, a rigorous diagnostic strategy must be applied. First, epidemiological factors must be clarified, including local infectious diseases, regions of travel, occupational and environmental exposures, drug abuse, exposure to medications, and family history. A detailed medical history and thorough physical examination are also crucial, as they may, for instance, suggest an immunodeficiency or identify extrapulmonary abnormalities that may be characteristic of specific diseases. Chest CT is very helpful, particularly when read by a highly experienced radiologist who can characterize the findings as typical or atypical for sarcoidosis and for the alternative diagnoses. All other investigations are guided by this information. A study reported nearly three decades ago used Bayes’ theorem to diagnose chronic interstitial lung diseases based only on clinical and radiological findings . High coDV and FJ conceptualized the review. DV prepared the first draft of the manuscript with MB (for imaging), J-FB (for pathology), EC (for microbiology), and BD (for drug-induced granulomatosis). MB provided the radiological figures and legends. J-FB provided the histological table and figures and legends. DV, MB, J-FB, EC, BD, CR, IB, AM, HN, J-MN, and FJ critically revised and edited the manuscript and agreed to the submitted version. All authors contributed to the article and approved the submitted version.The authors declare that this review was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We find that chalcogen defectsand the graphene interface radically alter the optical propertiesof the transition-metal dichalcogenide in the heterobilayer, due toa combination of dielectric screening and the many-body nature ofdefect-induced intralayer and interlayer optical transitions. By analyzingthe intrinsic radiative rates of the subgap excitonic features, weshow that while defects introduce low-lying optical transitions, resultingin excitons with non-negligible oscillator strength, they decreasethe optical response of the pristine-like transition-metal dichalcogenideintralayer excitons. Our findings relate excitonic features with interfacedesign for defect engineering in photovoltaic and transport applications.Associating atomic vacancies to excited-state transportphenomenain two-dimensional semiconductors demands a detailed understandingof the exciton transitions involved. We study the effect of such defectson the electronic and optical properties of WS Therefore,and due to the defect’s ubiquitous nature, a microscopic understandingof the emergent electronic and excitonic properties of TMDC–graphene(Gr) heterobilayers in the presence of vacancies is interesting fordynamic modeling of optoelectronic devices and applications.The electronic and optical properties of layered TMDCs andtheirheterostructures are sensitive to the potential created by defects.2–Gr and MoS2–Gr heterobilayerswith monatomic chalcogen vacancies. We employ a GW-BSE approach56 to compute the many-body electronic properties and optical characteristicsand find that due to the combination of screening and strong opticalhybridization, absorption resonances of well-known pristine TMDC excitonsare strongly quenched in the heterostructure, resulting in substantiallyaltered absorbance properties compared to the pristine TMDC–Grheterobilayer or defected TMDC without graphene. These pristine-likeTMDC “A” and “B” peaks are largely reduceddue to the mixing of the optical transitions with both graphene anddefect electronic states, and the electron–hole transitionsdetermining their excitonic composition are fundamentally altered.This manifests also in a strong reduction of the excitonic bindingenergy for the excitons composing those absorption peaks. In addition,Fermi-level alignment of the defect transition levels and the magnitudeof the spin–orbit interaction, determined by the choice ofTMDC, lead to substantial changes in the heterostructure optical properties.We obtain the intrinsic radiative rates for excitons with the largestbinding energy, which create strongly mixed subgap resonances andshow that the associated inverse rates are comparable to those calculatedfor pristine TMDC monolayers.In this work, we investigate the electronic and optical propertiesof WS2 (respectively MoS2) and 5 × 5 graphene elementarycells; see Supporting Information (SI).We consider a vacancy concentration of ∼3%, corresponding toan isolated monoatomic sulfur vacancy per supercell, located at theopposite side of the graphene layer with sufficiently small interactionsbetween defect sites at neighboring periodic replicas of the supercell.17 We first perform a geometry optimization ofthe supercell atomic positions, keeping the supercell volume constant(see ref (SI). This optimization reduces the nearest-neighborbonds close to the vacancy (which shrinks and strains the TMDC lattice)as well as the interlayer distance between the TMDC and the graphenelayer. Using DFT as a starting point , we perform a one-shot GW (G0W0) calculation for each TMDC–Gr heterobilayer . 59 GW quasi-particle corrections increase the gap inboth systems, qualitatively, conserving the DFT picture for theseheterobilayers.17 There are four spin–orbitsplit defect states shifted upon the GW calculation to higher energywith respect to the Fermi level. Far from the Fermi level, we findthe valence band splitting due to spin–orbit interaction tobe ∼460 meV for WS2–Gr and 150 meV for MoS2–Gr, which is consistent with 425 ± 18 and 170± 2 meV obtained from high-resolution ARPES measurements.26 The dielectric screening also shifts the pairof occupied defect states to lower energies (by ∼400–450meV for WS2–Gr and ∼400 meV for MoS2–Gr). Simultaneously, the pristine-like band gap of WS2 increases from 1.69 eV at the DFT level to 2.20 eV at theGW level. Similarly, the pristine-like band gap of MoS2–Gr changes from 1.73 to 2.19 eV. These values reflect a significantrenormalization of the TMDC band gaps compared to the monolayer case,as expected due to the quasi-metallic character of graphene with GWcorrections including image charge effects.59 Our GW results are in agreement with previous calculations witha reported band gap reduction of ∼300–350 meV60 compared to each pristine counterpart.58 They are also consistent with the experimental values of the quasi-particleband gap found in MoS2–Gr heterostructures, reportedto be ∼2.0–2.2 eV,62 and in WS2–Gr, which is in the range ∼2.0–2.3 eV.64We employ a commensurate supercellcomposed of 4 × 4 WS2–Gr and MoS2–Gr heterobilayersusing theBethe–Salpeter equation55 within the Tamm–Dancoffapproximation (see the SI). We show in 2–Gr as well as its decompositioninto intralayer graphene, intralayer TMDC, and interlayer contributions(see the SI for the case of MoS2–Gr). At low optical energies, intralayer graphene electron–holeexcitonic features are found to be the most prominent. Graphene electronicintraband transitions  are known to dominate this regime,65 which is marked by a dashed gray rectangle.The resonant peaks are a consequence of the finite k-gridsampling of the graphene Dirac cone, and therefore, the absorptionin this region is actually continuous in the dense grid limit. Inthe high infrared spectral range, excitonic peaks corresponding tointerlayer graphene–defect and graphene–pristine opticaltransitions appear at higher energies while graphene intralayer contributionsbecome less relevant. At optical energies ≳2.0 eV, intralayerTMDC contributions  become the dominantfeatures of the spectrum over the interlayer contributions. Out ofall optical transitions sampled for the examined k-gridand energy range, 0.4% belong to intralayer graphene, while 62% correspondto intralayer TMDC transitions, with the remaining 37% representinga large degree of interlayer mixing.Next, we examine the excitonic properties of defectedWS71 This limit is represented by a dashed horizontal line in 2 in the absence of graphene.28 To furthervalidate our findings, we compare the absorbance spectra of WS2–Gr with and without vacancies. We observe that, unlikethe defected heterostructure, the absorbance of the pristine heterobilayeroscillates around the graphene limit in that energy range, supportingour previous conclusion. In the visible range , experiments on WS2 have reported a red shift and asignificant reduction of the exciton peak area upon graphene stacking.72 These effects are typically attributed to both changes in the dielectricenvironment upon the heterostructure formation and possible interfacialcharge transfer.73 Our results demonstratethat within the exciton basis set, optical transitions at both layersmix already upon light absorption. In defected WS2–Grheterobilayers, we observe a reduction of the strength of the pristine-likeTMDC resonances in addition to the substantial interlayer mixing inthe subgap optical region dominated by transitions to the defect states.This effect is attributed to the strong optical mixing of TMDC andgraphene, which results in additional interlayer optical transitions.These occur within the pristine gap at many different k-points due to the dispersive nature of the Dirac cone and yielda redistribution of the oscillator strength from the original pristinetransitions to the defects. These combined effects of the grapheneand vacancies quench the pristine-like “A” and “B”resonances75 and also broaden them.41 As a consequence, they are no longer as dominantin the spectrum. Moreover, the composition of the absorption peaks,clearly defined at ∼2.2, ∼2.4, and ∼2.7 eV, alsochanges drastically compared to the expectation for the pristine ordefected TMDC monolayers (see the SI).The spectral absorbance of graphene for infraredlight is almostconstant at 2.4%.76). Each excitonic state, |ΨS⟩, defined by its wave function amplitude ASvck and energy ΩS, isrepresented by a column of dots whose area is proportional to ∑vk |AvckS|2, for each electronband (c), and ∑ck|AvckS|2, for each hole band (v). The colorof the dot represents the layer from which c or fromwhich v the transitions occur. We observe intralayergraphene optical transitions in the low energy region (≲0.5eV), while excitonic resonances with interlayer character appear onlyabove 0.5 eV. The dispersive nature of graphene can be seen from theincrease in the conduction band number of graphene with energy. Asexpected, the quenched high-energy resonances show significant contributionof mixed TMDC and graphene optical transitions; thus, although theyappear in similar positions, they no longer possess true “A”and “B” characters (see the SI). We note that while the increase of the dielectric screening bythe surrounding media and the reduction of the absorbance is expected,64 here the effect is further pronounced due tothe electron–hole defect and nondefect mixing in the subgapregion.To further understand this effect, we show in 2 and 0.3–0.7 eV forWS2 pristine “A” excitons.78 Theoretical predictions give 0.6 eV for MoS2 and 0.2 eV for WS2 pristine “B” excitons.75 In 2–Gr (see the SI for MoS2–Gr). The binding energy is computedfrom the energy difference between the free and bound electron-holepairs composing each exciton (see SI). For excitons in the opticalregion where the pristine “A” and “B”resonances would be expected, we observe that excitons have substantiallylower binding energies compared to the pristine or encapsulated counterparts,as well as substantially smaller oscillator strengths. We attributethis to a redistribution of the oscillator strength due to the combinedeffect of substantial hybridization of the defect and nondefect electron–holetransitions with graphene, as well as the small binding propertiesof excitons in graphene resulting from its quasi-metallic nature atlow energies. Importantly, we also find excitons (with oscillatorstrength in the range 10–2–1.0 a.u.) in theoptical region 1.5–2.0 eV with a binding energy comparableto that of pristine excitons in the absence of a graphene layer. Theseexcitons result from intralayer optical transitions to defect statesand interlayer graphene–defect transitions. To gain insightinto the nature of these excitons, we show in k-space distribution fora representative case marked by a circle in k-space. The right-hand side of k-points, supporting our analysis that this exciton is formedby a combination of defect–defect (notably at K̅), graphene–valence,and graphene–defect transitions (for the k-pointnoted as k*).The binding energy of the exciton quantifies how stronglyboundthe electrons and holes participating in the excitation are. Intralayergraphene excitonic features have vanishing small binding energies 81 We considerthe inverse rate, which scales as γS–1 ≔ τS ≈ ΩS/μS. This rate accounts only forpart of the radiative line width, as other contributions, e.g. electron–phononand exciton–phonon terms, are not included, and is useful toevaluate the significance of the oscillator strength. Our analysisreveals that the inverse rates for the excitons with binding >50meVcan be as large as τS ≈ 0.1ps for both heterobilayers. However, depending on the oscillator strength,they can be shorter, even as small as τS ≈ 0.1 fs for MoS2–Gr (see the SI). Intralayer graphene excitonic features,which have significantly small binding, have substantially largerintrinsic rates due to their large optical transition dipole. Darkinterlayer excitons with large binding have larger inverse rates,as large as ∼100 ps for WS2–Gr, due to thesmaller oscillator strength. For pristine WS2–Grbright “A” and “B” excitons in the TMDClayer, τS can be even shorter, essentiallydue to the increased oscillator strength  which yields τS ≈ 10–4–10–5 fs. We note that compared to pristine TMDCs,80 graphene adsorption has a strong impact on τS, which only become comparable again to thepristine ones in the presence of defects due to the strong excitonhybridization of the graphene and the subgap vacancy-related features.Furthermore, charge transfer times of photocarriers at TMDC–grapheneinterfaces,83 where single-particle defect tunneling is understood to be the dominatingcoherent transport channel,17 can be of a similarorder of magnitude. In this scenario, defects slow down coherent chargetransfer due to relatively small interlayer tunneling. Interestingly,in the presence of graphene, defects optically enhance transitionsassociated with them, resulting in excitons with significantly higheroscillator strength, compared to the reduced oscillator strength ofthe original pristine-like “A” and “B”TMDC excitons.Finally, we relate our findings to the intrinsicradiative decayrates of zero-momentum excitons, which can be computed from the GW-BSEoscillator strength and excitation energy.2–Gr and MoS2–Gr heterobilayerswith chalcogen vacancies by employing first-principles many-body perturbationtheory. We find that strong hybridization of the defect states withgraphene gives rise to subgap features, which manifest as strong resonancesin the optical absorbance spectrum, while quenching the “A”and “B” pristine exciton peaks originally coming fromintralayer TMDC transitions. These altered absorption features maybe used to extend the functionality in the infrared of solar cells.We have analyzed the stability of the excitons and found a strongreduction of the binding energy for those TMDC excitons, while stronglyhybridized interlayer and defect-dominated excitons have binding energiesup to ∼250 meV. We computed the intrinsic radiative decay rateof these excitons and found inverse rates of up to 0.1 ps. Overall,our results demonstrate how point-like defects can be used to designoptical features in graphene-based van der Waals heterostructures,where excitons inherit properties from two well-distinct layers ina nontrivial way, pointing to the relevance of a first-principlesunderstanding of many-body effects in the description of these systemsfor transport and potential optoelectronic applications.In conclusion, we have studied the electronicand optical propertiesof WS


Caffeoylquinic (5-CQA) and feruloylquinic (5-FQA) acids, found in coffee and other plant sources, are known to exhibit diverse biological activities, including potential antioxidant effects. However, the underlying mechanisms of these phenolic compounds remain elusive. This paper investigates the capacity and mode of action of 5-CQA and 5-FQA as natural antioxidants acting as hydroperoxyl radical scavengers and xanthine oxidase (XO) inhibitors. The hydroperoxyl radical scavenging potential was investigated using thermodynamic and kinetic calculations based on the DFT method, taking into account the influence of physiological conditions. Blind docking and molecular dynamics simulations were used to investigate the inhibition capacity toward the XO enzyme. The results showed that 5-CQA and 5-FQA exhibit potent hydroperoxyl radical scavenging capacity in both polar and lipidic physiological media, with rate constants higher than those of common antioxidants, such as Trolox and BHT. 5-CQA carrying catechol moiety was found to be more potent than 5-FQA in both physiological environments. Furthermore, both compounds show good affinity with the active site of the XO enzyme and form stable complexes. The hydrogen atom transfer (HAT) mechanism was found to be exclusive in lipid media, while both HAT and SET (single electron transfer) mechanisms are possible in water. 5-CQA and 5-FQA may, therefore, be considered potent natural antioxidants with potential health benefits. Coffee is one of the most popular beverages in the world, and it is known to provide several health benefits . It cont5-Caffeoylquinic (5-CQA) and 5-feruloylquinic (5-FQA) acids are two types of phenolic compounds found in abundance in coffee and other plants, which have been shown to possess various biological activities  Figure . 5-CQA iXanthine oxidase (XO) is an enzyme found in the liver and other tissues that plays a crucial role in purine metabolism. It catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid, generating reactive oxygen species (ROS) as by-products. High levels of XO activity and ROS production have been associated with oxidative stress, inflammation, and various diseases, including cardiovascular disease and diabetes . Several•) in physiological environments and on the mechanism of XO inhibition. The HOO• radical is a moderately reactive ROS with a half-life of about a few seconds in biological cells, and it is the simplest of the peroxyl radicals that can cause significant damage to cells [In this context and in order to explore in depth the antioxidant potential of 5-CQA and 5-FQA as well as to compare their capacities, this study focused on the evaluation of the reactivity toward the hydroperoxyl radical , RAF , and SET (single electron transfer) ,28,29,30• . The Gib• . The phesol is the Gibbs free energy of the reaction in solution, R is the gas constant, and T is the temperature (298.15 K).In this work, density functional theory (DFT) computations were carried out using the Gaussian 09 version E.01 software . The M06≠ are reaction symmetry numbers, tunneling corrections, Boltzmann constant, Planck constant, and Gibbs free energy of activation, respectively [The quantum mechanics-based test for overall free radical scavenging activity (QM-ORSA) methodology was employed for the kinetic study, which was validated experimentally ,40,41. Tectively ,48,49. Tectively .i and koverall are the rate constants of a specific reaction path and the sum of the rate constants of all reaction paths, respectively.The ratio of the probability of a specific pathway to the total probability of all possible pathways, branching ratio (Γ), was determined using the equations below:The Gibbs free energy of activation  were corrected using the Collins‒Kimball theory to account for diffusion limitation [Finally, the apparent rate constants (kmitation .https://www.rcsb.org/structure/3nvy accessed on 15 September 2021). The PDB file obtained was processed using Maestro tools: Protein Preparation Wizard and System Builder. The ligand was processed with LigPrep, the tool of Maestro designed to prepare small molecules. The format of the structure obtained was mol2. All the mol2 files generated by Maestro used the force field OPLS3e [We applied the blind docking (BD) consensus approach to study the interactions between both ligands and XO. BD is a method that scans the whole protein surface finding potential hotspots for a specific ligand . First, d OPLS3e . Proteinhttps://github.com/bio-hpc/metascreener) The scoring function of AD and LF considered the following parameters: Lennard-Jones interactions term (LJ), hydrogen bonds (H-bonds), electrostatic interactions, hydrophobic stabilization, entropic penalty due to the number of rotatable bonds, and internal energy of the ligand. Maestro software  was also used to calculate the interactions between ligand and protein residues.BD calculations were performed using AutoDock Vina  and LeadThe most relevant pose of each ligand obtained in the BD was selected to run molecular dynamic simulations (MD). Three MDs were carried out using Maestro-Desmond software version 2020-4 . Both complexes created were immersed in a box filled with water molecules using the simple point charge (SPC) scheme. The measurements of the box were 10 × 10 × 10 Å. Sodium ions were added to neutralize charges. Ions of chlorine and sodium were added to obtain a final NaCl concentration of 0.150 M. Periodic boundary conditions were used, and a cutoff of 9 Å was established for van der Waals interactions. The particle mesh Ewald (PWE) method with a tolerance of 10-9 was used in the electrostatic part. The energy minimization was carried out by 2000 steps using the steepest descent method with a threshold of 1.0 kcal/mol/Å. The NPT simulations were realized at 300 K with the Nose-Hoover algorithm , and theUnderstanding the behavior of phenolic groups at physiological pH is critical in studying free radical scavenging properties in water. While the pKa values of 5-CQA are available in the literature , the sam• radical in both aqueous and lipid media. In water, the HAT reaction of the non-aromatic OH groups was found to be energetically unfavorable, as indicated by positive ΔG values . This suggests that these OH groups are not effective for antiradical action. Similarly, the RAF reaction at both C8 and C9 positions also showed positive ΔG values, making this mechanism less likely to occur. However, the RAF reaction at the C8 position was almost isergonic , indicating that this process can take place. As a result, the kinetic study also considered the RAF mechanism at C8.On the other hand, the aromatic OH groups had negative ΔG values for both 5-CQA and 5-FQA , suggesting that they are the most likely sites for the HAT process. In terms of the SET mechanism, both forms showed positive ΔG values. However, the dianionic form exhibited the lowest ΔG values , indicating that this mechanism could also be possible for this form.When considering pentyl ethanoate, where only the neutral form exists, the HAT reaction was found to be thermodynamically favorable for the phenolic OH groups . In contrast, the RAF reaction was an endogenous process for both compounds . Despite this, the kinetic study also examined the RAF reaction at the C8 position.Overall, the results indicate that the HAT mechanism is more likely to occur in the aromatic OH groups, while the RAF mechanism is less favorable. However, the RAF reaction at the C8 position is also possible. The SET mechanism was found to be less likely but could still be active for the dianionic form.• radical in water at physiological pH. The results are presented in 8 M−1s−1 and 2.28 × 107 M−1s−1, respectively. However, the reaction of 5-CQA is about 10 times faster than that of 5-FQA. Analysis of the data in 7 M−1s−1). This suggests that the deprotonated catechol moiety in water is highly reactive toward radical species. Similar findings were also observed for other catechol derivatives, such as 5-O-methylnorbergenin [Using the QM-ORSA protocol , and basbergenin , quercetbergenin , caftaribergenin , and antbergenin .7 M−1 s−1) [8 M−1 s−1) [5 M−1s−1) [5 M−1s−1) [6 M−1s−1) [6 M−1s−1) [Moreover, it is worth noting that the overall rate constants of 5-CQA and 5-FQA are comparable to that of the reference antioxidant ascorbic acid (k = 9.97 × 10M−1 s−1)  and the M−1 s−1)  but high M−1s−1) , BHT (2. M−1s−1) , carnosi M−1s−1) , and can M−1s−1) . This in• radical in pentyl ethanoate are presented in 6 and 4.10 × 104 M−1s−1, respectively, reflecting the potent free radical scavenging activity of these compounds compared with typical antioxidants, such as Trolox (1.00 × 105 M−1s−1) [4 M−1s−1) [3 M−1 s−1) [3 M−1s−1) [3 M−1s−1) [Since the SET process is not feasible in nonpolar media, it was not considered in the lipid environment, thus the study focused only on the RAF and HAT mechanisms. The results obtained from the reaction of 5-CQA and 5-FQA with the HOO M−1s−1)  and BHT  M−1s−1) . These vM−1 s−1) , carnosi M−1s−1) , and can M−1s−1) , indicat• radical in physiological media at high-rate constants, with 5-CQA reacting faster than 5-FQA. Mechanistically, 5-CQA reacts primarily via the HAT mechanism in polar and lipidic media, whereas 5-FQA appears to be more active in water via the SET mechanism rather than the HAT mechanism. The overall rate constants of both compounds are comparable to or greater than those of reference antioxidants, suggesting that these compounds are promising candidates for further study as potential antiradical agents in physiological media.In summary, the findings revealed that both 5-CQA and 5-FQA react with the HOOThe results of the BD calculation  show howThe results of the MD show how the protein reached a stable conformation in both complexes. The maximum RMSD value of the protein was 2.7 Å in both complexes. Regarding the MD with the protein without ligand, the maximum RMSD value was 1.8 Å. Moreover, the ligand stayed in a stable pose in the active site: 5-CQA had a maximum RMSD value of 4.5 Å, and 5-FQA had a value of 3.6 Å .The main interactions of the 5-CQA along the trajectory were as follows: ionic interactions—Glu1261; hydrophobic interactions—Phe914, Phe1009, Val1011, and Ala1078; and polar interactions—Gln767, Thr1010, Gln1040, Ala1078, Ser1080, and Ser1082 . The mai• radical following the main antiradical mechanism under physiological conditions. The three mechanisms—HAT, RAF, and SET—were considered for all possible positions of the molecules, taking into account the influence of physiological pH. The results revealed that 5-CQA and 5-FQA were potent antioxidants with a greater capacity to scavenge hydroperoxyl radicals in polar and lipidic media than common antioxidants, such as Trolox and BHT. 5-CQA with the catechol moiety was found to be more active than 5-FQA. Furthermore, 5-CQA and 5-FQA exist mainly in dissociated form at physiological pH, which is important for their antioxidant activity. It was also revealed that the mechanism of 5-CQA action was mainly the HAT in both physiological environments, while the mechanism of 5-FQA was environment-dependent, with the SET mechanism becoming more important in polar environments.The free radical scavenging activity and mechanism as well as the XO inhibition potential of 5-CQA and 5-FQA were fully investigated. The radical scavenging activity was assessed by modeling the reactivity of 5-CQA and 5-FQA toward the HOOOn the other hand, the inhibition potential of XO was evaluated using BD and MD simulations. The BD results showed that the active site of the enzyme was the first hotspot with the best docking score for 5-CQA and 5-FQA. The 100 ns MD simulation confirmed the stability of the complexes and revealed that both compounds interact mainly with the same residues as quercetin.These results suggest that 5-CQA and 5-FQA are potent free radical scavengers and XO inhibitors and may have potential applications as natural antioxidants in various fields, including the food and medicinal industries.


The results show that graphene-based materials can effectively adsorb polar small molecules in vegetable oil, and that the modification of graphene materials with carboxyl and hydroxyl groups improves their adsorption ability for polar small molecules, which is attributed to the conversion of physical adsorption to chemical adsorption by the modification of oxygen-containing groups. This study provides a theoretical basis for the design and preparation of graphene materials with high adsorption properties.As a new engineering dielectric, vegetable insulating oil is widely used in electrical equipment. Small polar molecules such as alcohol and acid will be produced during the oil-immersed electrical equipment operation, which seriously affects the safety of equipment. The polar molecule can be removed by using functional fossil graphene materials. However, the structural design and group modification of graphene materials lack a theoretical basis. Therefore, in this paper, molecular dynamics (MD) and quantum mechanics theory (Dmol As a liquid dielectric, insulating oil plays an essential role in cooling and insulation, and is the key material used to ensure the safe and stable operation of a transformer . MineralAs a material with a large specific surface area, graphene provides more adsorption sites and can directly contact a variety of small molecules . At the In this paper, the molecular simulation method is employed to study the adsorption of polar molecules in functionalized modified graphene oil, mainly focusing on the diffusion characteristics of small molecules in oil and the dynamic process of diffusion to the interface of functionalized modified graphene, and the interaction characteristics of functionalized modified graphene and polar small molecules. The adsorption sites, adsorption energy, as well as the density of state changes are studied by the quantum mechanics method.The model construction is all based on the Materials Studio (MS) software. The calculation process includes molecular dynamics and quantum mechanics in order to analyze the influence of the porous structure and different groups. A micro-computing model is constructed, which consists of water, formic acid, acetic acid, formaldehyde, acetaldehyde, and other polar molecules produced by the aging and cracking of graphene, triglyceride (the main component of vegetable oil), and insulating oil. Four configurations of graphene (GE), porous graphene (PGE), porous hydroxy graphene (HPGE), and porous graphene modified by hydroxyl and carboxyl groups (COOH-HPGE) were selected in this paper, as shown in 3 module based on quantum mechanics is selected to build a small molecular model of graphene adsorption polarity. Eads is the adsorption energy; Etotal is the total energy of polar small molecules adsorbed on graphene; EGE is the energy of graphene; Epolar is the energy of small polar molecules.The DmolThe motion process of polar small molecules can be more easily seen from the microscopic scale. NEIO/HPGE  and ENEIO/COOH-HPGE  are 18.69% and 97.40% higher than ENEIO/GE , and EPSM/HPGE  and EPSM/COOH-HPGE  are 892.08% and 2302.17% higher than EPSM/GE , respectively. This means that the modification of oxygen-containing groups can simultaneously increase the adsorption capacity of graphene-based materials to vegetable oil and polar small molecules, but the GE rich in oxygen-containing groups is polar, so its adsorption selectivity to polar small molecules is significantly enhanced, especially under the action of hydroxyl and carboxyl groups.The interaction energy of graphene-based materials and vegetable oil, and graphene-based materials and polar small molecules in the four models were calculated see , respectHydrogen bonds are an important factor enhancing the interaction between substances . It can Quantum mechanics can better explain the role of oxygen-containing groups in the adsorption process. In this paper, we used the Dmol3 module based on quantum mechanics to calculate the adsorption energy of single polar small molecules in vegetable oil on graphene, and to observe their optimized structures. From the optimized structure , it can The energy level interactions between the polar small molecules and graphene-based materials during the adsorption process can be described by comparing the density of states (DOS) before and after adsorption. This article uses molecular dynamics (MD) and quantum mechanical theory (Dmol3) simulation methods to compare the dynamic snapshots, interaction energy, hydrogen bonds, adsorption energy, differential charge, and density of states (DOS) of four materials, namely graphene (GE), porous graphene (PGE), porous hydroxylated graphene (HPGE), and hydroxyl and carboxyl co-modified porous graphene (COOH-HPGE), for polar small molecules (PSMs) in vegetable oil (NEIO). Based on MD analysis, compared with the GE and PGE models, PSMs tend to aggregate on the surface of oxygen-containing functionalized graphene due to the increased number of hydrogen bonds. Meanwhile, HPGE and COOH-HPGE exhibit significantly enhanced interaction energy with PSMs, with EPSM/HPGE , and EPSM/COOH-HPGE , respectively, increasing by 892.08% and 2302.17% compared with EPSM/GE . Based on Dmol3 analysis, the adsorption energy of graphene-based materials on PSMs gradually increases with the complexity of modification. The adsorption of PSMs on GE and PGE is confirmed to be physical adsorption only, while the adsorption of PSMs on HPGE and COOH-HPGE is confirmed to be chemical adsorption, indicated by the adsorption energy, adsorption distance, and differential charge transfer. Finally, the DOS analysis further confirms that the structure of graphene-based materials modified with oxygen-containing functional groups is more stable, and electron transition is easier when adsorbing polar molecules. This study provides a theoretical analysis method for designing functionalized graphene materials with the ability to remove PSMs from vegetable oil.


In recent years, graphene and its derivatives have gained wide attention in the biomedical field due to their good physicochemical properties, biocompatibility, and bioactivity. Its good antibacterial, osteoinductive and drug-carrying properties make it a promising application in the field of orthopedic biomaterials. This paper introduces the research progress of graphene and its derivatives in bone tissue engineering and cartilage tissue engineering and presents an outlook on the future development of graphene-based materials in orthopedics. As an emerging excellent nanobiomaterial, graphene-based materials have received great attention in major fields such as chemistry, physics, materials, and medical biology  have great applications in biomedicine  and 1,369,950 cases of total knee arthroplasty (TKA) between 2011 and 2019 . In the  biology . Boccaccmedicine . Graphenmedicine . In regamedicine . These aGraphene is a two-dimensional hexagonal planar polycyclic aromatic hydrocarbon atomic crystal with sp2 hybridized carbon atoms arranged in a honeycomb shape, whose unique atomic structure gives it special chemical, physical, mechanical, thermal, electronic and optical properties. In 2004, Geim and Novoselov isolated graphene from graphite by micromechanical forces, for which they received the Nobel Prize in Physics in 2010 .Graphene-based materials broadly refer to 2D carbon materials related to graphene, including graphene and its derivatives, such as graphene oxide (GO) and reduced graphene oxide (rGO). Meanwhile, other carbon materials, such as metal carbides and/or nitrides (MXenes) and fullerene (C60) also play an important role. Because of their physicochemical properties of high biocompatibility, low toxicity, high specific surface area, and strong adsorption ability to small molecules, graphene materials are an ideal material for tissue engineering . HoweverPostoperative periprosthetic infection is a catastrophic complication of bone implant materials. Therefore, the design of bone implant materials with good antibacterial properties and osteogenic function is extremely important in the field of bone tissue engineering. However, the traditional method of loading antibiotics into bone implant materials is increasingly limited by the problems of bacterial biofilms on the surface of the prosthesis blocking the action of drugs and the development of bacterial resistance. Here, the discovery of graphene materials has brought a chance to solve the problem.et al. found that GO has a significant antibacterial effect. It could inactivate Escherichia coli within 2 h  and more calcium deposition after alizarin red staining. The effect was similar to that of the classical pro-osteo-differentiation factor bone morphogenetic protein 2 (BMP2)  . The sti2 plates . Conside2 plates . Nayak e2 (BMP2) .Graphene has a large specific surface area and can assume a larger drug loading capacity. In addition, the noncovalent π-π bonds and hydrogen bonds in the structure allow graphene to adsorb more proteins and drugs.et al. were the first to realize the drug-carrying function of graphene. They loaded an anticancer drug camptothecin derivative (SN38) into PEG-modified GO and demonstrated the good biosafety of graphene materials as drug carriers  substrates and found that they released a significant amount of BMP-2. The GO-coated Ti substrates were found to promote osteoblast differentiation more than the pure Ti substrates. The study also found that there was more new bone formation in the Ti/GO-BMP2 group after implantation in a mouse cranial defect model. The above study showed that graphene has a large drug loading and controlled release capacity. It can also be used as an excellent drug carrier and slow release material in bone tissue engineering  is a new carbon nanomaterial with great application potential that was discovered recently. The good mechanical strength and electrical conductivity, promotion of cell proliferation and differentiation, and many other biological functions make it a hot research topic in biomedical fields such as tumor therapy and neuromuscular regeneration .et al. added chitosan at 0.5% and 3% mass ratios of GO and discovered improvements in scaffold void formation, mechanical properties, and bioactivity. In vitro experiments revealed that the material containing 3% GO was more cytocompatible and better able to promote cellular proliferation, which has potential as a 3D scaffold material for bone tissue engineering  is a widely used silicon-based organic polymer material whose biocompatibility and high solubility of oxygen make it an ideal material for cell transplantation. However, its high hydrophobicity inhibits PDMS bioactivity, limiting its use in tissue engineering. Recently, a study coated PDMS 3D scaffolds with RGO, which formed RGO/PDMS 3D scaffolds with good mechanical strength and voids ranging from 10 to 600 μm in diameter. The composite 3D scaffold was found to stimulate the differentiation of human adipose stem cells (ADSCs) to the osteoblast lineage, suggesting that the RGO/PDMS 3D scaffold may be a potential osteointegration graft  insertedAs a bioceramic material, hydroxyapatite (HA), the main component of the inorganic part of bone in the human skeleton, can be firmly bonded to natural bone and has biological activity to promote bone regeneration and thus has promising applications in bone defect repair. However, its poor tensile strength and crack resistance limit its application in bone tissue engineering. The incorporation of graphene material in the preparation of HA material can improve its mechanical strength without destroying its structure and biocompatibility. It has been reported that the hardness and Young’s modulus were significantly improved in graphene-HA composites . AnotherPoly-methyl methacrylate (PMMA) bone cement is widely used in arthroplasty and vertebroplasty as a molding material with good injectability and high mechanical strength. However, it is not biologically active and cannot form good osseointegration with adjacent bone, which may lead to prosthetic loosening after implantation. In one study, GO at a mass fraction of 0.5% was added to PMMA/HA bone cement. The addition of GO increased the growth of the calcium phosphate layer, enhanced the mechanical properties of the material, and promoted cell proliferation on its surface  Figure  insertedet al. increased the fracture toughness and tensile strength of the composite by 54% and 71%, respectively. This finding could help reduce aseptic loosening after arthroplasty (Ultrahigh molecular weight polyethylene (UHMWPE) is widely used as prosthetic liners for artificial hip and knee replacements because of its good biocompatibility, low coefficient of friction, and high impact toughness. However, its low surface hardness produces polyethylene abrasive debris in long-term use, which leads to periprosthetic osteolysis and is an important cause of aseptic loosening of the prosthesis after arthroplasty. By adding a thin layer of 0.1% graphene in the preparation of UHMPE, Lahiri roplasty .Human cartilage tissue is composed of chondrocytes, fibers, and extracellular matrix. Unlike other tissues, cartilage tissue is difficult to recover quickly on its own once damaged because of its lack of vessels and other cells. Currently, cellular therapy using MSCs can induce chondrocyte differentiation and regeneration and is now widely used to regenerate cartilage tissue. In recent years, graphene has been used as a complex scaffold for cartilage stem cell therapy by taking advantage of its ability to stimulate cell growth and differentiation and its excellent mechanical properties.In cartilage tissue engineering, graphene biomaterials play the role of a “growth factor factory”. With the high nanoscale porosity of graphene and its excellent protein-bearing capacity, aggregated proteoglycans, type II collagen, and aminoglucan are assembled with MSCs and graphene sheets to form graphene-cellular biocomposites. Meanwhile, GO can also adsorb fibronectin (FN) and TGF-β proteins through π-π and electrostatic interactions without damaging the protein structure. This composite can improve cell survival as well as chondrocyte differentiation  insertedet al. found that chondrocytes grown on this composite scaffold had an extremely high survival rate, demonstrating the biocompatibility of the GO composite scaffold. In animal models, when the CSMA/PECA/GO composite scaffold was implanted into models with cartilage tissue defects, better cartilage morphology, more continuous subchondral bone and a thicker neochondral layer were discovered compared to the normal scaffold group , synthesized from chondroitin sulfate, ethylene glycol, and GO, has been used to provide a bionic three-dimensional environment. Liao ld group , suggestin vivo , of all nanobiocatalysts, have gained great attention in clinical medicine, bioengineering, pharmaceuticals and many other fields. However, it is still difficult to control nanozymes to target and work more specifically in vivo . With gret al. discovered that nitrogen (N), boron (B), phosphorus (P) and sulfur (S)-doped graphene materials have significant peroxidase-mimicking activity. Furthermore, the dual-doped graphene of P and N shows better mimicking activity because it increases the number of activity sites and has a synergistic effect  vanadium carbide (V2C) MXene nanoenzyme (MXenzyme) showed oxidase, peroxidase, superoxide dismutase, and catalase activities similar to those of natural enzymes  showed approximate properties to superoxide dismutase , a series of two-dimensional (2D) nanomaterials, have great physicochemical properties, including high metallic conductivity, excellent hydrophilicity and a large surface area . Feng et enzymes  inserted enzymes . Likewis enzymes . Similarismutase , and theismutase .4 and H2O2, resulting in linear enhancement of SERS, resonance Rayleigh scattering (RRS), and surface plasmon resonance (SPR) absorptions. This new strategy of immunocontrolling GO catalysis has been well adapted in the detection of HCG. The above discoveries of graphene and its derivatives being utilized in both clinical treatment and laboratory tests suggest more application in nanobiocatalysis.Apart from being used as a nanozyme, GO also has surface-enhanced Raman scattering (SERS) activity  insertedThis review presented a wholesome picture of graphene and its derivatives, from their basic information to their special biological properties, including antibacterial ability, bone tissue regeneration promotability and drug delivery capacity. The application of graphene and its derivatives was then emphatically elaborated in bone and cartilage tissue engineering and nanobiocatalysis.With a variety of unique biological functions, such as drug-carrying properties, antibacterial properties and osteoblast differentiation, graphene has not only become a new direction in the field of bone and cartilage tissue engineering but is also expected to bring new breakthroughs in clinical treatment. Although graphene has received widespread attention, it is still in its infancy, especially for the interaction between graphene and various cells, tissues and organs, and there is still a lack of systematic and safe research. In the future, much basic and clinical research is still needed to break through the gap of graphene safety and degradability, making it a new application material in the field of bone and cartilage tissue engineering.


In an articleThe revised Figure 5 legend is as follow:p < 0.05. *Indicates p ≥ 0.05.FIGURE 5 Interleukin 6 (IL‐6) upregulated programmed cell death ligand 1 (PD‐L1) expression through the mitogen‐activated protein kinase (MAPK) pathway. A, In TPC‐1 and BAPCP, the total protein levels of extracellular signal–regulated kinase (ERK), C‐Jun NH(2)–terminal kinase (JNK), signal transducers and activators of transcription 3 (STAT3) and serine/threonine‐protein kinase (AKT) did not change in response to IL‐6. However, the phosphorylation levels of ERK, JNK, STAT3 were significantly increased, while the phosphorylation level of AKT was not. Considering that the cell lines and treatments corresponding to each lane were identical, the same reference protein band was accepted in both panels to better visually compare changes in the target proteins relative to the reference protein . B, After treatment with U0126 (ERK inhibitor) or SP600125 (JNK inhibitor), the IL‐6–induced total PD‐L1 protein reduced, and combination of them had a synergistic effect on PD‐L1 expression. C, Flow cytometry result showed that the membrane PD‐L1 expression increased after IL‐6 treatment but decreased after subsequent treatment with U0126 or SP600125. D, The level of PD‐L1 mRNA in the IL‐6 group was higher than that in the control group. It was inhibited after treatment with U0126 or SP600125 which worked synergistically. # Indicates The revised Figure 6A is shown below:The authors apologize for the error.