Strain sensors in the form of buckypaper (BP) infiltrated with various polymers are considered a viable option for strain sensor applications such as structural health monitoring and human motion detection. Graphene has outstanding properties in terms of strength, heat and current conduction, optics, and many more. However, graphene in the form of BP has not been considered earlier for strain sensing applications. In this work, graphene-based BP infiltrated with polyvinyl alcohol (PVA) was synthesized by vacuum filtration technique and polymer intercalation. First, Graphene oxide (GO) was prepared via treatment with sulphuric acid and nitric acid. Whereas, to obtain high-quality BP, GO was sonicated in ethanol for 20 min with sonication intensity of 60%. FTIR studies confirmed the oxygenated groups on the surface of GO while the dispersion characteristics were validated using zeta potential analysis. The nanocomposite was synthesized by varying BP and PVA concentrations. Mechanical and electrical properties were measured using a computerized tensile testing machine, two probe method, and hall effect, respectively. The electrical conducting properties of the nanocomposites decreased with increasing PVA content; likewise, electron mobility also decreased while electrical resistance increased. The optimization study reports the highest mechanical properties such as tensile strength, Young’s Modulus, and elongation at break of 200.55 MPa, 6.59 GPa, and 6.79%, respectively. Finally, electrochemical testing in a strain range of ε ~ 4% also testifies superior strain sensing properties of 60 wt% graphene BP/PVA with a demonstration of repeatability, accuracy, and preciseness for five loading and unloading cycles with a gauge factor of 1.33. Thus, results prove the usefulness of the nanocomposite for commercial and industrial applications. Their ability to transform mechanical deformation stimuli into electrical shift signals is largely appreciated by researchers as well as industrial guys5. At large, flexible sensors are principally divided into four categories, namely resistance type, capacitance type, triboelectric, and piezoresistive type6. Henceforth, the piezoresistive type is usually synthesized by a facile method, with low power consumption, convenient signal acquisition, and a simple readout mechanism7. Thus, various materials have been tried to obtain a highly efficient, flexible, sensitive, and stretchable strain sensor. However, nanomaterials are highly regarded for their abilities to satisfy all these criteria and provide further room for research and development.Flexible strain sensors, in contrast to metal or semiconductor-based conventional strain sensors, exhibit a superior application potential in a wide array of fields that includes monitoring of sports performance8. Most significantly, the tremendous attention it gathered among technological and scientific communities due to superior mechanical and electrical properties and high frequency which go up to THz9. Graphene is a material of immense strength with young’s modulus of 1100 Gpa, the fracture strength of 125 GPa, specific surface area of 2630 m2/g, the thermal conductivity of 5000 W/mK, the thickness of 0.345 nm, excellent transport phenomena, zero bandgaps, and mobility charge carrier of 250,000 cm2/V2s10. Among other extraordinary features of graphene, strong π-π stacking, and forces of attraction such as van der Waals among planar basal planes of graphene layers that allow them to aggregate, which results in an ability to develop a controllable self-assembled structure11. These extraordinary properties of graphene endow graphene with novel technological opportunities, in the form of promising nanofiller material for the sole purpose of reinforcement of composites, in contrast to other carbon nanomaterials. Thus graphene stands out among other materials and ideal for developing 3-dimensional structures12. Furthermore, the defects of carbon nanotubes in orientation and geometry can be compensated by graphene sheets. This unique characteristic of graphene has profound implications and thus gives the lead to the era of ultra-sensitive strain sensors. Thus graphene is described as a “miracle material” has demonstrated its sheer potential for the synthesis of graphene-based strain sensors10.Graphene is such material that proves to be a promising candidate as the flexible sensor, on account of its outstanding flexibility, high electrical conductivity, chemical stability, and lightweight13. However, advancements have been made with the use of graphene as a modifier in polymer matrices, whereas no considerable success has been achieved due to poor compatibility between polymer matrix and pristine graphene. Though, as compared to pristine graphene, abundantly present oxygen functional group in graphene oxide not only allows better compatibility and dispersion in aqueous solution but also provides a strong connection between GO and polymer matrix through non-covalent and covalent bonds14. Thus, that makes GO a better choice to be used to prepare graphene oxide/polymer nanocomposite in the form of buckypaper (BP) and study its strain sensing properties.In the field of polymer nanocomposites, graphene proves itself to be a promising modifier due to its astonishing properties. However, the whole effort on polymer nanocomposite is in line to modify neat polymer to attain new and better properties without adding excessive weight or sacrificing processability15. However, polymeric based buckypaper has achieved much success and has been able to seek superior attention to vast sensing applications. The graphene sheets have interlayer interaction due to van der Wall forces of attraction that are relatively weak and have slippage as a result of sliding between layers of graphene. Thus, these issues have the potential to disturb the strain sensing properties of strain sensors16. The buckypaper infiltrated with polymer matrix is viewed as one with better strain transfer phenomena across the composite by providing better binding interfacial bonding. The polymer infiltration into the porous graphene network improves interfacial adhesion among graphene and polymer, which results in a strong bond between graphene and polymer and forms a helical polymer structure. The current method of synthesis has provided a solution to the intrinsic tendency of graphene sheets to agglomerate due to van der Waals forces of attraction, the high viscosity of graphene/polymer suspension, and low solubility in solvents. Whereas, the graphene oxide produced initially had essential functional groups to make strong bonds with polyvinyl alcohol and produced a buckypaper stain sensor with strong interfacial bonding among graphene sheets and polymer matrix17. Han, et al.18 synthesized Carbon nanotube-based buckypaper infiltrated with a polymer matrix of epoxy resin that helped to achieve significant mechanical properties such as tensile strength, Young’s modulus, and elongation-at-break of 146.1 Mpa, 13.8 GPa, and 1.3% respectively. Whereas, Yee et al.17 synthesized multiwalled carbon nanotube-based buckypaper infiltrated polyvinyl alcohol with superior mechanical properties such as tensile strength, Young’s modulus, and elongation-at-break of 156.28 MPa, 4.02 GPa, and 5.85%, respectively. The strain sensor synthesized in this work demonstrated better mechanical properties such as tensile strength, Young’s modulus, and elongation-at-break of 200.55 MPa, 6.59 GPa, and 6.79%, respectively. Another important aspect of the strain sensor is its gauge factor which the selected sample has of 1.33, which is higher than reported gauge factors of buckypaper strain sensors such as 0.4919, 0.3420, and 0.9 to 1.321. Hence, this strain sensor proves to be a significant addition to the existing range of strain sensors and may provide a wide range of applications in various fields of life.Buckypaper is a thin porous freestanding network of carbon fillers bounded by van der Waals forces of interaction and in appearance, it looks like paper-like material as its name indicates. It is fabricated through various techniques, namely the spin coating technique, evaporation induced, vacuum filtration method, self-assembly technique, and resin infiltration technique23. Regardless, polyvinyl alcohol has high applicability for strain sensing applications, is biodegradable, synthesized artificially, and readily available commercially24. Samples were evaluated through mechanical, electrical, electromechanical, and morphological techniques to determine the sample properties. The research findings were consistent with the identification of optimal conditions and concentration ratio of PVA and graphene to synthesize PVA infiltrated BP for strain sensing.In this work, a graphene-based strain sensor infiltrated with polyvinyl alcohol (PVA) is reported. The buckypaper is usually synthesized from carbon nanotubes, but here we report a graphene-based buckypaper, which is the main novelty of the work. The other process of synthesis follows a facile technique, which is reproducible and requires limited equipment for the synthesis. Whereas, the nanocomposite material has superior mechanical properties in terms of tensile strength, young’s modulus, and elongation at break as compared to other buckypaper strain sensors. Graphene as a material has promising characteristics, in terms of superior mechanical and electrical properties, flexibility, and high thermal conductivity. Thus, graphene exhibited a bright prospect for strain sensor application. A nanocomposite material consisting of graphene oxide and polyvinyl alcohol was prepared by varying concentrations of 45, 60, and 75 wt% through simple vacuum filtration and polymer intercalation. The motivation behind the use of PVA for infiltration is supported by past studies demonstrated by several researchers−1. In FTIR analysis, a strong peak at 3435 cm−1 is assigned to strong hydroxyl group O–H (O–H stretching vibrations)25. In pristine graphene same peak was observed but with lower intensity. In contrast, after surface modification, the higher intensity peak shows the degree of oxidation of pristine graphene by oxidation in a highly acidic condition26. The peaks at 2935 and 2880 cm−1 are attributed to symmetric and asymmetric stretches of C–H and the H–C=C–H group is attributed to the presence of methylene stretches. The two new peaks at 1775 and 1701 cm−1 are not observed in pristine graphene, while on graphene oxide indicates carbonyl (C=O) group, which could be related to extending vibrations due to carbonyl group (–COOH)27. Whereas, the vibrations at 1775 and 1701 cm−1 could be associated with the attachment of C–O groups giving evidence of the presence of oxygen-containing groups at the graphene surface. The peak observed at 1620 cm−1 on both pristine and oxidized graphene could be attributed to alkene (C=C), termed as the backbone of the graphene structure. The strong peak at 1110 cm−1 also indicates (C–O–C) the presence of strong oxygen-containing functional groups28. The surface modification of graphene by a strong acidic mixture of sulphuric and nitric acid has significantly modified the structure of graphene and shows a high degree of covalent functionalization29.In order to confirm the functionalization of GO, FTIR analysis of pristine graphene and GO was conducted. FTIR analysis is shown in Fig. 30.A high degree of dispersion and stability of graphene oxide in aqueous suspension is highly desired to obtain an outstanding GO film in the form of buckypaper with good mechanical and electrical properties. In this research, the optimum condition to obtain a well-dispersed solution of graphene was recorded at 60% sonication power, with sonication applied for 15 s after every 30 s for 20 min. The sonication process exploited and disintegrated graphene oxide from aggregates and bundles into freestanding graphene oxide sheets. The low power sonication after one hour clearly showed that graphene oxide has very low dispersibility in methanol and acetone and settles at the bottom of the beaker. Whereas in ethanol, graphene achieved a high degree of uniformity and dispersibility. The dispersibility of oxidized graphene is due to the highly polar nature of ethanol contributed by the presence of carboxylic groups on the graphene oxide surface that creates electrostatic repulsion and polar-polar affinity31. These results further signify that the electrical double layer consisting of a rigid layer bonded to particles and the electrostatic repulsion produced by the diffused layer, which overcomes van der Waals forces resulting in a homogenous solution of GO. As a concluding remark, relatively charged GO overcomes van der Waals attraction and plays a crucial role in solution stabilization. The zeta potential results lower than − 15 mV and higher than 15 mV are considered acceptable for good quality dispersion. However, a value higher than 40 mV is considered as high-quality dispersion32.Figure 33. The tunnelling resistance and contact resistance are less in 75 BP/PVA as compared to 60 BP/PVA as shown in Fig. 34. Thus, the filling of empty spaces forces graphene sheets apart and increases distance among them; therefore, resulting in increased tunnelling and contact resistance.The SEM image of the surfaces of BP is presented in Fig. 35. Good infiltration of the PVA matrix into graphene sheets ensure good adhesion between BP sheets and PVA matrix and contributes to better mechanical properties.Figure 3 character) at around 1338.9 cm−1 is due to the defects, disorder, impurities etc., present in the samples whiles G-band (sp2) at 1563.4 cm−1 corresponds to the characteristic peak of most of the carbon related materials due to the in-plane vibration of carbon atoms. G band shifted to a higher energy of 1611.9 cm−1 in acid treated GN. This could be due to changes and disturbance in GO sheet. The intensity ratios of D- and G-bands (ID/IG) calculated for pure GN and acid treated GO are 0.05 and 1.01 respectively. The dramatic increase of D-band Raman intensity is interpreted as the presence of defects and disorder formed in the sample after vigorous mechanical and chemical process of acid treatment37.Figure 38. The low-intensity peak shows the presence of sulphur atoms due to acid treatment for the functionalization of graphene and also sulphur is used as a growth promotor during the synthesis of graphene by a chemical vapor deposition method. EDX composition of 60 BP/PVA polymer composite C-peak 40. The last peak on PVA infiltrated BP at Energy-dispersive X-ray analysis (EDX) of GO and PVA infiltrated BP (60 BP/PVA polymer composite) was performed to know the elemental composition. Table 41. The strain-to-failure ratio represents the maximum elongation ability in contrast to the original length before its complete failure.The tensile testing was performed to determine the performance of various compositions of PVA infiltrated BP, such as 45 wt%, 60 wt% and 75% of BP, respectively. Figure 42. PVA infiltrated BPs show tensile strengths in a range of 121–200.53 MPa, Young’s modulus within 3.69–6.59 GPa, while all BPs have strain to failure ratio in a range of 4.66–6.79%. The pure 100% BP was not synthesized successfully due to the high degree of slippage between graphene layers, which does not allow layers of graphene to stay together and cannot be peeled off successfully from the substrate. Slippage can be predicted with high certainty as it is an inherent property of carbon nanotubes and graphene materials, even slippage in carbon nanotubes BP is attributed to slippage of graphene layers as graphene is the mother material of carbon nanotubes43. The slippage further can be explained as weak van der Waals interaction between layers of graphene44. The other possibility of failure to achieve freestanding graphene-based BP without any PVA infiltration is attributed to the agglomeration of graphene layers at a high loading of 100%. The forces of attraction among graphene sheets in 100 wt% BP were so weak that it broke when tried to peel off from the PTFE membrane45. Table The stress–strain curve in Fig. 15. The phenomena of Plastic deformation is permanent in nature, first necking starts to appear in structure and further material shows no resistance to the applied force, and finally breaks apart. These tests help to define the working range of a material in which it can be utilized and exceeding this limit may fail the respective component permanently29. All PVA infiltrated BPs demonstrated steeper linear slope with high tensile strength, Young’s modulus, and strain to failure ratio in a range of (ε ~ 4 to 6%). The 75-BP/PVA polymer composite showed a lowest tensile strength of 121.38 MP, Young’s modulus of 3.69 GPa, and strain to failure ratio of 4.66% as shown in Fig. 46.However, PVA infiltrated BPs composites demonstrated linear elastic deformation in the elastic region, and plastic deformation in the non-elastic region, first necking, and finally complete failure17. Additionally, the strong hydrogen bonding between functional groups containing oxygen such as C=O, –OH may also add strength by the contribution of interaction between graphene oxide carbonyl groups and PVA hydroxyl groups47. PVA contains a hydroxyl group capable of hydrogen bonding interacts with the functional group present on functionalized graphene such as carbonyl (C=O), hydroxyl (–OH), and carboxylic group. Thus, strong interaction and interfacial adhesion between various functional groups of GO and PVA matrix contribute to good dispersion throughout the BP, resulting in superior mechanical properties.The superlative mechanical properties can be a result of improved interfacial interaction between Graphene sheets and the PVA matrix. During the infiltration process, the PVA solution diffuses into BP and interacts with GO by binding GO layers together48 while less than prepared by soaking49.However, the Graphene-based BP/PVA shows variability in mechanical properties as shown in Fig. 50. Moreover, the solidification of PVA at various locations on the BP surface and the presence of insoluble hydrogels in the PVA solution further reduced or completely blocked the flow of PVA solution into BP. All these factors collectively contributed to incomplete diffusion of the PVA matrix into BP, hence retarding its mechanical properties51.Furthermore, Young’s modulus is also higher than the reported in the literature (0.25–1.37) while 60-BP/PVA polymer composite demonstrated Young’s modulus of 6.59 GPa, significantly higher than reported for BP strain sensors. The further addition of PVA into BP in 45 BP/PVA reduced the tensile strength to 155.27 GPa and Young’s modulus to 4.33 GPa. This effect can be attributed to the irregular distribution of the PVA matrix into BP; besides higher concentration of PVA solution blocks the pores of BP at the surface and stops further penetration into BPOverall, PVA infiltration into BP phenomenally improved its properties and provided necessary strength to the structure of BP so that it can be peeled off from the PTFE membrane. All the studies in the mechanical section indicate that 60-graphene based BP/PVA polymer composite is a better choice due to its superior properties, with 40% higher tensile strength from 75-graphene-based BP/PVA polymer composite while 23% higher than 45-graphene based BP/PVA polymer composite. In terms of Young’s modulus, it is 31% higher than 75-graphene-based BP/PVA polymer composite while 14% higher than 45-graphene based BP/PVA polymer composite. The better mechanical characteristics of 60-graphene based BP/PVA polymer composite is evident that good dispersion PVA matrix and infiltration into the graphene network and the existence of strong intermolecular interaction between PVA and graphene sheets. The strong interaction between the PVA matrix and graphene makes possible an effective strain signal transfer throughout the structure and makes it feasible for strain sensing application.52. A dense system of conductive graphene in BP offers a smooth flow of current via BP. In order to evaluate BP’s strain sensor electrical efficiency, BP specimen DC electric measurement was conducted through a digital multimeter based on a two-point probe method concept, ASTM D-4496-13. Figure BP possesses electrical resistance that is based on three primary elements i.e., contact resistance among graphene sheets, tunnelling resistance among the bordering graphene, and pristine resistance of graphene as an individual53.The increase in PVA loading, not only increases PVA in BP but also built a thick layer of BP surface, hence they collectively block the current path and increases BP resistance. Furthermore, this is followed by greater bulk resistivity value and lower conductivity. In contrast, uppermost bulk resistivity and lowermost conductivity noticed for 45-graphene based BP/PVA composite reflects a thicker coating of PVA surface deposit54.There was a slight increase in BP/PVA thickness from 0.43 to 0.49 mm, due to more PVA could hold on the nanocomposite surface. Furthermore, a decrease in conductivity in BP/PVA may be attributed to high electrical insulating characteristics of PVA polymer, which is attached at the composite interface hence the bulk and surface resistivity that results in poor electrical conductivity. The electrically insulating PVA penetration into the porous graphene system fills the gaps among adjacent graphene. As a result, electrically conductive paths are decreased; hence, contact and tunnelling resistance increase among adjacent graphene sheetsThe electrical properties of graphene-based BP specimens were analysed further using a four-point probe method based on Van der Paw Hall effect measurement. The results of electrical studies are illustrated in Table 18. As displayed in Table –1 cm2/Vs, and density, 7 × 1021 cm−3 Moreover, greater content of BP forms a denser system of conductivity paths, consequently lower bulk resistivity and higher conductivity. In contrast, PVA infiltration has affected electronic conductivity as depicted in Fig. 2 S/m order, which is appropriate for strain sensing application.According to Fig. 20–1021 cm−3 range55, which are considered comparatively higher than prior studies. Among all graphene-based BP/PVA samples, 60 BP/PVA composite achieved the highest mobility of 2.97 × 10–1 cm2/Vs but with the lowest carrier density of 5.5 × 1021 cm−3. This indicates that low-density electron can move more conveniently via the composite with a faster rate, leading to superior strain sensing performance. While BP samples conductivity was obtained to be proportional to electron density product, Ne, and mobility, µe, in which q refers to electric charge, as written in Eq. , as 75-graphene-based BP/PVA starts to deform its shape after (ε ~ 4%) and linear relationship between strain and relative resistance change no longer holds59. In addition to tunnelling resistance, the higher value of the gauge factor can be attributed to increased contact resistance among layers of graphene, additionally, the PVA matrix fills vacant spaces in BP. In stretch position, graphene layers become completely isolated with no conductive paths and even worse happens when graphene becomes physically apart.Table 60. The loading and unloading cycles were demonstrated in the strain range of (ε ~ 4%) which is within the elastic region. The relationship between tensile strain and relative resistance change vs time of 60-graphene-based BP/PVA polymer composite is shown in Fig. Furthermore, to fully reveal electrochemical characteristics of BP/PVA polymer composite for strain sensor application. Cyclic uniaxial tensile testing was performed to demonstrate and investigate the piezoresistive behaviour of graphene-based BP/PVA polymer matrix during multiple unloading and loading cyclesFigure 61, suggesting two possible phenomena that might be responsible, the first is the hysteresis that the sample does not return to its original value after each cycle and the second reason can be attributed to internal structure destruction of PVA infiltrated BP that results in permanent deformation of the sample. The cyclic loading and unloading of the sample increased its original length that increased the gap between layers of graphene, which consequently increased contact and tunnelling resistance, thus higher relative resistance change is observed in the second, third, fourth, and fifth cycle62. In the end, it can be concluded that 60-graphene-based BP/PVA demonstrated better characteristics of a strain sensor, showed reproducibility and hysteresis free operation.However, on the other hand, 75 BP/PVA did not give satisfactory results. Initially, after the first cycle strain did not return to zero and stopped at 0.1%, indicating the deformation in the shape of the sample. A slight incremental change is also observed in relative resistance change after each cycle63. Overall, all PVA infiltrated graphene-based BPs demonstrated a good piezoresistive response in the strain range of (ε ~ 4%), but 60 graphene-based BP/PVA demonstrated the highest test results under five loading and unloading cycles and showed recovery in characteristics after each loading and unloading cycle64. All these parameters validate the applicability of graphene-based BP infiltrated with PVA for strain sensing applications.In general, the sensing ability of PVA infiltrated BP, mainly depends on three aspects, increase or decrease in contact resistance between graphene sheets, piezo resistivity of individual graphene sheets under strained conditions, and change in tunnelling resistance between graphene sheets due to increase in the gapIn summary, a high-quality flexible, and stretchable strain sensor was fabricated by vacuum filtration technique and PVA intercalation. 60 percent concentration of BP with infiltration of PVA showed the best strain sensing characteristics. The sensor demonstrated mechanical strength, Young’s and elongation at break of 200.55 MPa, 6.59 GPa, and 6.79%, respectively, in comparison to buckypaper based strain sensors found in the literature. The sensor showed electric conductance characteristics due to the conducting properties of graphene, while conductivity decreased with increasing PVA content. The 60 BP/PVA infiltration demonstrated a gauge factor of 1.33 and the piezoresistive response was repeatable with no hysteresis for 5 cycles. These characteristics of 60 BP/PVA polymer composite proves to be the best choice among others with improved strain transfer, linearity, repeatability, highly reproducible results, and recoverable structure within strain range. It has commercial applicability to measure critical human health parameters and predict symptoms of chronic diseases, structural health monitoring, wearable technology, and industrial pressure sensors.A solution of sulphuric acid (98%) and Nitric acid (70%) in a proportion of 3:1 (v/v) was prepared and graphene was immersed in it. Immersion resulted in an exothermic reaction and introduced oxygenated groups on the graphene structure through covalent functionalization. The solution with graphene was bath sonicated for 3 h at room temperature. The combination of acid treatment, along with bath sonication helps to create bond cleavage in carbon lattice via electrophilic attack. It also provides an opportunity to carbonyl group for attachment and at the same time, removes residual metallic catalysts. The solution was poured into large beakers with deionized water to dilute the solution and bring down pH near to neutral. The solution was left overnight to let the graphene oxide settle down. The supernatant was discarded, and the precipitate was collected and washed with copious amount of the deionized water. The process of washing with deionized water was repeated until the pH above 5 was achieved. Finally, the solution was poured through the PTFE filter membrane and the graphene oxide was put into a Freezer at − 80 ºC for 24 h, followed by freeze-drying for 24 h to remove the remaining water content.Three samples of oxidized graphene, each weighing 100 mg were immersed in three 50 ml solvents, namely acetone, methanol, and ethanol. All three samples were sonicated in low power ultrasonic bath cleaner for an hour. The ethanol sample was found to be one with better dispersion of graphene oxide visually. All three samples were further sonicated by high power probe sonication  for 15 s with a 30-s break for a total duration of 20 min at an ultrasonic amplitude of 60% . After zeta potential analysis, ethanol was found to one with the best solubility and dispersion. Later the solution of graphene oxide with ethanol was filtered through Polytetrafluoroethylene (PTFE) membrane filtration using a vacuum pump (ULVAC-41B).2H4O)n. PVA is used widely in textile, coating, and papermaking. In BP synthesis, it serves the purpose by developing strong interfacial interaction between graphene and polymer matrix due to functional groups. A 2 wt% solution of PVA in water was prepared such that the solution is not too viscous and there is no residue left. The solution, according to the required weight for infiltration was poured on to the BP formed on the PTFE membrane and was allowed to infiltrate into BP. Samples with different weight fractions of PVA were dried in a vacuum oven at 40 °C for 24 h. The weight fraction of graphene in infiltrated samples was found by subtracting the amount of graphene used initially to cast a BP.The choice of polymer is critical as it plays a major role in determining the BP properties. PVA is a biodegradable, low-cost synthetic polymer with a chemical formula of . Analytical grade concentrated sulphuric acid −1. Further, the zeta potential of dispersed graphene oxide in various solvents was collected using Zetasizer Nano ZS  to identify the solvent with the highest solubility and dispersibility. Whereas the morphology of the BP was observed using a scanning electron microscope (FEI Quanta 400 SEM). EDX analysis was done using EDX spectroscopy (Oxford-Instruments INCA 400 equipped with X-Max Detector). The graphene and graphene oxide samples was determined by using Raman spectroscopy model Renishaw inVia, USA at a wavelength of 5142 nm with green laser excitation. While for mechanical characterization, the strips of rectangular-shaped BP (20 mm × 5 mm) were prepared following standard ASTM D-882 The samples were analysed for tensile loading using a computerized tensile testing machine (Lloyd LR10K Plus). A constant tensile load at a rate of 0.1 mm/min was applied until the sample fractured. Further, for electrical characterization, two aluminum foil strips were attached to opposite ends of samples using silver adhesive to reduce contact resistance and reinforce the connection binding. Direct current electrical resistance was measured using a digital multimeter (Sanwa Japan CD800a), following two probe method according to the ASTM D4496-13 standard. The bulk resistivity  to find out functional groups attached to graphene and graphene oxide. The IR spectra were obtained between wavenumber 650 and 4000 cmThe thickness of BP was measured by using a digital micrometer (Mitutoyo Japan). Whereas, electrical conductivity was measured using Eq. .4\documeFurther, electrical properties  were measured by the Four probe technique using the van der Pauw Hall measurement system (Ecopia HMS 3000 Korea), at a temperature of 300 K under magnetic field. The source of direct current between 1 to 15 mA was passed through outer probes and the resultant voltage drop was measured, however, Ohm’s law  under applied strain. The gauge factor was measured in the linear elastic range of (


We report on the synthesis and enhanced thermal conductivity of stable Ag-decorated 2-D graphene nanocomposite in ethylene glycol based nanofluid by laser liquid solid interaction. A surfactant free nanofluid of Ag nanoparticles anchored onto the 2-D graphene sheets were synthesized using a two-step laser liquid solid interaction approach. In order to understand a pulsed Nd:YAG laser at the fundamental frequency  to ablate Ag and graphite composite target submerged in ethylene glycol (EG) to form AgNPs decorated 2-D GNs-EG based nanofluid. From a heat transfer point of view, it was observed that the thermal conductivity of this stable Ag-graphene/EG is significantly enhanced by a factor of about 32.3%; this is highest reported value for a graphene based nanofluid. Graphene is a flat monolayer of carbon atoms or a thin layer of pure carbon tightly packed into two-dimensional (2D) honeycomb lattice. Early investigations of graphene demonstrated that this material exhibits extraordinary physical and chemical properties such as significantly higher values of thermal conductivity, electrical conductivity, high room temperature carrier mobility and lateral quantum confinement amongst others. These properties confer graphene and graphene based nanocomposites numerous potential technological applications such as super capacitors, organic solar cells, photovoltaics, fuel cells, and inter alia7. In terms of heat transfer, the thermal conductivity of graphene is demonstrated to be within the range of 3,000–5,000 Wm−1 K−1 at room temperature which is an exceptional figure when compared to the thermal conductivity of pyrolytic graphite (2000 W m−1 K−1 at room temperature), and surpasses even the highest value of natural diamond  as well as that of standard Cu (384.1 Wm−1 K−1). Hence, graphene would be an ideal candidate for use in nanofluids applications12, especially when decorated with additional metallic nanoparticles as will be demonstrated in this contribution.Following the discovery of graphene by Geim and Novoselov2O, oil or ethylene glycol (EG) amongst others. Figure −1 K−1 at room temperature whilst that of metals and their corresponding oxides are two to three orders of magnitudes higher. Hence, the mixture of such metallic or their oxides nanoparticles in standard coolant host fluid in a form of a nano-suspension would induce a significant enhancement in the thermal conductivity of the nanofluid. Such an enhancement has been predicted theoretically by Batchelor and O’Brien in 1977 and Hamilton, Grosser et al., as early as 196210. The thermal conductivity of a nanofluid was predicted to be10.eff/kf is the enhancement of the thermal conductivity of the nanofluid, kf, kp are the thermal conductivity of the host fluid and the nanoparticles respectively, η being the volume concentration and φ is the sphericity reflecting the shape anisotropy of the nanoparticles. Following the pioneering experimental work of Choi et al.,11, such an enhancement in thermal conductivity in various nanofluids was confirmed although prepared by different methodologies28 including direct evaporation, submerged arc nanoparticle synthesis, laser ablation, microwave irradiation, polyol process and phase-transfer. Various nanofluids consisting of nano-scaled Ag, CuO, Al2O3, TiO2 and SiO2 in various host fluids28 have further validated this enhanced thermal conductivity reaching values varying from 10 to 70%. However, the highest enhancements, generally, were observed in shape anisotropy nanosystems such as Ag nanorods28.As shown in Fig. 31. The Ag nanoparticles (Ag NPs) decorating the 2D GNs carpets would act as a facilitating heat medium transfer between the host liquid (EG) and the graphene nanosheets (GNs). In addition, the agglomeration of the (Ag NPs) is likely to be minimized if they are anchored onto the GNs. Hence, in view of validating such a concept, a ternary nanofluid was engineered by pulsed laser ablation in two steps phases: (i) producing graphene sheets first, and then (ii) producing silver nanoparticles. Both are fabricated in the same ethylene glycol host fluid. The measured thermal conductivity of AgNPs-GNs-EG has been found to be to be superior than that exhibited by pure Ag NPs-EG or pure GNs-EG nanofluids37.The originality of this contribution lies in investigating for the first time the thermal transfer enhancement of a nanocomposite of silver nanoparticles (Ag NPs) decorated 2-D graphene nanosheets (GNs) dispersed in ethylene glycol (EG). In the rest of the manuscript, a ternary-composite nanofluid is labeled as AgNPs-GNs-EG. The rationale behind such an approach is that the 2-D nature of graphene sheets would assist in ensuring the percolation threshold at lower volume concentrations in addition to their elevated intrinsic thermal transfer property combined with their homogeneous dispersion in polar host liquids40. This nanoparticles’ synthesis technique is based on laser—solid interaction with the target immersed in a liquid or covered by a protective liquid layer . As shown in Fig. 2H6O2) could take place.As mentioned above, the synthesis of the AgNPs/GNs/EG nanofluid was performed in 2 steps utilizing the so-called Laser Liquid Solid interaction (LLSI) also known as pulsed laser ablation in liquids (PLAL). Indeed, in parallel with the standard well-established vacuum pulsed laser deposition (PLD) technology dedicated to the synthesis of nano-structured and nanophased materials in the form of thin film coatings, LLSI/PLAL is a hybrid chemical–physical laser based approach, promoted for the synthesis of metallic and oxide nanoparticles in a form of colloidal nanosuspensionsyer Fig. . The adv40. As a result, a vapor phase in the form of bubbles is formed. As in the case of H2O, acoustic excitations are then induced by the dynamics of the vapor plume as well as by the locally overheated metallic target40. The effect of the two acoustic excitations provokes the implosion of gas bubbles inducing ablation at the surface of the melted metallic target at the “focus point of the incident laser beam” in the case of Ag target and causing a removal of graphene sheets in the case of graphite target. As the ablated particles are in the nano-size range, this suggests that the bubbles are succumb to a positive external pressure before the implosion. Excluding the laser beam parameters, one should expect that the size of the synthesized nanoparticles by this laser liquid interaction, would depend on the bubbles nucleation rate and their implosion cycles40. Taking into account the different mechanisms mentioned above, one is led to conclude that LLSI/PLAL is likely to be governed by a photo-acoustic energy transfer phenomenon. The corresponding maximum energy fluence of the Nd-YAG was limited to ~ 85 mJ/pulse. The ablation time varied from 5 to 30 min in order to control the volume concentration of the nanoparticles within the ethylene glycol based nanofluid. The temperature of the EG coating fluid layer/ target interface is certainly above the ethylene glycol boiling point of 197.3 °C (470.4 K). The estimated induced temperature at the point where the laser pulse impinges on the target submerged in the EG is estimated to be around Tint = (hc/kBλ) ~ 14.2 × 104 K, significantly above the melting  and vaporization  temperatures of the Ag and graphite targets. Accordingly, and in view of the above considerations, one could expect that while the Ag NPs follow the standard ablation mechanisms to form silver particle clusters as a result of agglomeration, the graphene sheets would, likely, form via acoustic effects mechanisms. More precisely, single or multiple sheets of graphene should be pulled out of the graphite target.The real mechanisms of ablation are not discussed in detail as these, major physical phases are well established. As depicted in Fig. From experimental point of view, graphite and silver targets (both 99.9% purity as well as the ethylene glycol (EG anhydrous 99.8%) used in this study were of chemical grade supplied by Sigma-Aldrich. In phase One, a graphite target with , pulse duration of 12 ns, repetition rate of 10 Hz and an output energy of ~ 85 mJ/pulse was focused through a convex lens with a focal length of f ~ 300 mm to produce graphene nanosheets nanofluid in EG with the processing time of 5–30 min. In phase two, the graphite target was replaced by the silver target(< Ø >  ~ 5 mm diameter and 1 mm thick). The ablation time was fixed at 20 min. After ablating Ag, the Ag target was removed and the AgNPs/GNs/EG nanofluid was collected for further analysis. For comparison purposes and as reference sample, pure graphene-EG and Ag-EG nanofluids were prepared in similar conditions. Hence pure Ag, pure graphene, and Ag-graphene nanofluids will be referenced as AgNPs-EG, GNs-EG, and Ag-GNs-EG, respectively.1 radiation (λ = 1.5406 Å) with a scanning angular step of 0.2° s−1 over angular range 2θ of 20°–90°. The morphology of AgNPs/GNs/EG nanofluid was studied by using a Leo-Stereo high-resolution scanning electron microscope (HRSEM). Identification and characterization of the functional groups on the nanoparticles of the nanofluid was carried out using a Perkin Elmer ATR-FTIR spectrometer within the spectral range of 500–4,000 cm−1. The Raman studies were carried out using a WITEC Alpha 300 Confocal Raman system operating with the second harmonic of a Nd:YAG laser (λExc = 532 nm) as the excitation source. The size and morphology of the nanoparticles in suspension within the nanofluid were determined using a JEOL JEM 2010F microscope. The thermal conductivity of the fabricated AgNPS/GNs/EG nanofluid was investigated by a simplified transient hot-wire technique.The crystalline structure of AgNPs/GNs/EG nanofluid coated on a glass substrate was investigated by X-ray diffraction (XRD) using a SmartLab (Rigaku) diffractometer with a CuKαAg = kBT /6πη〈Ø/2〉 at room temperature is about 16.710–16 m/s2 and 3.2310–16 m/s2, respectively, (ηEG = 14 (mPa.s)). Such low diffusion coefficients, relative to the above estimated border to border separation distances of 〈ξ〉 ≈ 3 nm and 〈ξ〉 ≈ 12 nm seem to indicate that the AgNPs are unlikely to agglomerate at room temperature. From crystallographic point of view, the selected area electron diffraction (SAED pattern) of Fig. In Fig. .41, Vi and Lue et al.42, as well as Zhang et al.43. It is observed that such an anchoring process of the Ag NPs onto the GNs carpets is stable with time, confirming the homogeneous dispersion and the stability with time of such an anchoring. We also investigated the nature of such Ag NPs liaison onto GNs in order to understand its physical/chemical nature. The high-resolution transmission electron microscopy observations Fig. Figure Figure −1. One can distinguish clearly the D  and G  bands as well as the 2D and the 2G bands representative of a few layered graphene. As established, the D peak originates from TO phonon mode near K points in the Brillouin zone. This peak is only activated by structural defects as well as second order Raman scattering process through the intervalley double resonance and demonstrates the crystallinity of the sample44 in congruence the previous observations. The Raman spectra also show the first order Raman peak located at 1,580 cm−1 denoted by G band originating from the doubly degenerate zone center phonon E2g mode which corresponds to the C–C stretching modes43. The peak appearing at 2,680 cm−1 is the second order Raman peak, denoted by 2D and overtones D mode44. The intensity of the D peak  intensity is higher than that of the G peak with an intensity ratio (ID/IG) of about ~ 1% pointing to a high crystallinity within the graphene nanosheet45.Figure 2H6O2 if any at least at the 10% limit of detection of XRD technique limitation. This does not provide evidence of a potential physisorption or chemisorption at the surface of the 2-D Graphene sheets of Oxygen from the surrounding host fluid C2H6O2 molecules as corroborated by the previous EDS observations.Figure 35. This wide plasmon peak implies the non-agglomeration of the Ag nanoparticles as well as their small average size. Based on Mie Scattering Theory (MST), where the width at half maximum of the plasmon peak is related to the average size via the relation: 1/2〉 = γ0 + AvF/〈Ø〉  (γ0 + AvF/〈Ø〉)), where 〈Ø〉 is the size of nanoparticle, A = 3/4 for silver, γ0 is the velocity of bulk scattering (51012 deg s−1), vF is the Fermi velocity (for silver vF = 1.39106 deg m/s), the corresponding average size is about 〈Ø〉 ≈ 21.7 nm in the size range of those observed in the previous HRTEM observations. In the spectral range of 200–300 nm, there is a strong absorbance peak centered at 230 nm with a broad shoulder in both GNs-EG and AgNPs-GNs-EG samples as shown in the Fig. 46. In addition to the wide plasmon peak of the AgNPs, and the proper GNs absorbances, there is an additional set of quasi sharp absorbances in the AgNP-GNs-EG sample. These various substructure absorption peaks within the UV spectral range of 200—350 nm, are simulated and are summarized in Table 47. Likewise, both AgNPs-GNs-EG and GNs-EG absorbances exhibit a band at 261 nm which is attributed to pure graphene, while the 273 nm absorbance indicates the restoration of extensive conjugated sp2 carbon network51. The peaks at 221 nm and 430 nm are attributed to graphene oxide as reported previously52. This graphene oxide seems to indicate a significant chemical binding between the graphene sheets and the host fluid molecules of C2H6O2 as stipulated in the previous EDS observations.Figure mentclass2pt{minim57. However, for AgNPs-GNs-EG nanofluid there was a slight increase with temperature with a slope of about 7.0 × 10−4 W/mT2. At 45 °C, the thermal conductivity reaches 0.414 W/mK. When compared with the results, reported in literature on dispersed graphene in ethylene glycol summarized as shown in Table 55 the current enhancement value of 32.3% seems to be the highest so far.Figure In this contribution, we caused a multicomponent nanofluid based on silver NPs densely decorated with 2D graphene sheets was dispersed homogeneously with ethylene glycol as host base fluid sample. Such a stable multicomponent nanofluid was synthesized by laser liquid solid interaction in a two steps approach. Such a technology approach allows a significant anchorage of the AgNPs onto the graphene 2D sheets. The thermal conductivity of such nanofluids was measured to be 0.414 W/mK corresponding to a remarkable enhancement of the order of 32.3% compared with ethyl glycol. This is the highest reported value for a graphene based nanofluid. Further studies are required in order to understand the reason for the high anchoring of the Ag NPs onto the GNs sheets as well as the possibility of engineering Ag nanorods decorated GNs-EG based nanofluids.


Disorder‐induced Griffiths singularity of quantum phase transition (QPT) is a crucial issue in 2D superconductors (2DSC). In a superconducting system, the strength of disorder is found to be associated with the vortex pinning energy, which is closely related to the quantum Griffiths singularity; however, a direct study to elucidate the role of vortex pinning energy on the quantum Griffiths singularity in 2DSC remains to be undertaken. Here, an artificial 2DSC system is designed by randomly depositing superconducting nanoislands on 2Delectron gas (2DEG). Quantum Griffiths singularity is present in a graphene/Pb‐islands‐array hybrid, where the superconducting behavior transits to weakly localized metallic behavior induced by the vertical magnetic field and exhibits critical behavior with a diverging dynamical critical exponent approaching zero temperature. Compared to the study of graphene/Sn‐islands‐array hybrid where the sharp QPT is observed, the vortex pinning energy acquired from the Arrhenius plot analysis is greater in graphene/Pb‐islands‐array hybrid, which may contribute to the presence of the quantum Griffiths singularity. This work may provide a comprehensive interpretation of the QPT in 2DSC. The disorder‐induced Griffiths type quantum phase transition is observed in 2D graphene/Pb‐islands‐array hybrid at ultralow temperature. Compared to the similar graphene/Sn‐islands‐array hybrid with sharp quantum phase transition, the larger vortex pinning energy of graphene/Pb‐islands‐array hybrid is believed to be responsible for the observed quantum Griffiths singularity. The QPT can dominate the thermodynamics up to a relatively high temperature and in fact, the appearance of many unusual superconducting properties results from the proximity of quantum critical points (QCPs), which can be distinguished by a finite‐size scaling (FSS) behavior. Quenched disorder (static in time) has a profound influence on the QPT of 2DSC and high‐temperature cuprate superconductors that are intrinsically disordered.The thermodynamics of 2D superconductors (2DSC) is usually governed by quantum phase transition (QPT) because of the enhanced quantum fluctuation induced by finite‐size effects in a low‐dimensional electron system.10 Sup The conventional perpendicular magnetic field turned SIT/SMT is usually sharp with a fixed QPT at zero temperature, which has been previously observed in the amorphous and granular 2D superconductors, interface superconductor LaTiO3/SrTiO3, under‐doped La2−xSrxCuO4 and graphene/Sn‐islands‐array hybrids. While recent experiments instead show a smeared SMT with a divergent dynamical critical exponent (known as the quantum Griffiths singularity) as observed in crystalline superconducting Ga thin film, the LaAlO3/SrTiO3(110) interface, monolayer NbSe2, and ion‐gated ZrNCl film. The presence of quantum Griffiths singularity is believed to be caused by a disorder effect in inducing superconducting rare regions (puddles). In a superconducting system, the dynamics of vortices can determine the electromagnetic properties of superconductors where the quenched disorder strongly influences the dynamics of systems in pinning the vortex. Consequently, the strength of disorder is characterized by the vortex pinning energy that is obtained from analysis of the Arrhenius plot. However, previous observations of quantum Griffiths singularity were reported in quite different 2DSC systems, and the relevant vortex pinning energies cannot be compared in parallel between various 2DSC systems. Therefore, a systematic study to elucidate the role of vortex pinning energy on the quantum Griffiths singularity in 2DSC remains to be undertaken. According to our previous work, the superconducting puddles‐2DEG hybrid is an artificial 2D superconducting system, providing a general platform to explore 2D superconductivity with different vortex pinning energies.The disorder can suppress global superconductivity in 2DSC by either applying magnetic fields to generate vortices or degrading sample quality.19 The where a double quantum critical behavior with a sharp QPT can be realized. Compared to that in graphene/Sn‐islands‐array hybrids, the vortex pinning energy in the graphene/Pb‐islands‐array hybrid is greater, and is responsible for the quantum Griffiths singularity. These results may improve current understanding of the profound influence of the vortex pinning effect on the QPT in 2DSC.In the present study, we deposit Pb nanoislands on single‐crystalline graphene to form a 2D superconducting system consisting of graphene/Pb‐islands‐array hybrid. By applying a vertical magnetic field, the system shows a quantum Griffiths‐type superconductor to metal transition (SMT) in contrast with our previous observation in graphene/Sn‐islands‐array hybrids with different vortex pinning energy,8 wher2 Then, 20‐nm‐thick Pb was deposited on single‐crystalline graphene by electron beam evaporation . Owing to the poor wettability of graphene and the low melting point of Pb, the deposited Pb is prone to being randomly distributed into irregular disconnected nanoislands, as suggested by cross‐sectional transmission electron microscopy  substrate becomes totally insulating below 10 K , the top single‐crystalline graphene provides an ideal 2DEG platform that enables 2D coupling between the superconducting Pb nanoislands. Like the superconductor‐metal‐superconductor system acting as a basic Josephson junction, the Pb nanoislands and the adjacent single‐crystalline graphene constitute Josephson junction arrays.Single‐crystalline graphene was synthesized by chemical vapor deposition on an intrinsic Ge (110) substrate .28 TheRs(T) at zero magnetic field  curve exhibits semiconductor‐like behavior . Since the shunt effect from the intrinsic Ge (110) substrate is absent at temperatures below 10 K, the observed semiconductor‐like behavior is due to the weak localization behavior proposed in 2D metals. Then, the system undergoes a two‐step superconducting transition process. First, a small decrease in resistance is observed near the critical temperature of bulk Pb . As when cooling from TcPb, the second transition appears due to the Josephson coupling effect and the sheet resistance decreases rapidly in a slide‐like shape to the zero‐resistance transition temperature Tczero≈0.55K (Region III), where Rs(T) falls below the resolution limit of our instrument . Region IV corresponds to the true superconducting region with zero resistance. Compared to a graphene/Sn‐islands‐array hybrid, the superconducting transition temperature range of a graphene/Pb‐islands‐array hybrid is found to be relatively broad, which may be ascribed to the reduced Josephson coupling effect due to large average spacing of Pb‐islands. The Josephson coupling effect through the 2DEG provided by single‐crystalline graphene is confirmed by comparison experiment in that the graphene/Pb‐islands‐array hybrid becomes insulating when oxygen plasma is utilized to remove the graphene between adjacent Pb nanoislands . The observed insulating behavior also demonstrates that Pb nanoislands deposited on single‐crystalline graphene are completely disconnected from each other. For a 2D superconducting system, a Berezinskii–Kosterlitz–Thouless (BKT) type transition is expected, which interprets the process such that the bound vortex–antivortex pairing breaks into the unbound vortex–antivortex at elevated temperature. The BKT transition temperature (TBKT) is derived from the V–I measurements at V∝I3. In the log–log scale V–I plot in Figure V∝Iα behavior is observed, and TBKT is 5.3 K where α = 3, as indicated by the dash‐dot line in the inset to Figure The temperature‐dependent sheet resistance  The characteristic of SMT in graphene/Pb‐islands‐array hybrid can be revealed by detailed transport measurements near the QCP. Figure Rs(T) curves at different magnetic fields , showing SMT behavior. The Rs(T) curves at each field first behave as a weakly localized metal (dR/dT < 0) and then transit to a superconducting state (dR/dT > 0) at superconducting onset temperature Tconset(B) (indicated by black arrows) as the temperature decreases. And, the system exhibits a complete weak localization behavior once the applied magnetic field exceeds 3800 Oe. Tconset(B) shifts monotonically to lower temperatures with increasing magnetic field. To further investigate the SMT behavior near the QCP, magnetoresistances at temperatures from 50 mK to 4 K are measured, as shown in Figure  with two separated crossing points, the appearance of multiple crossing points in graphene/Pb‐islands‐array hybrids is reminiscent of the quantum Griffiths singularity of SMT in Ga film. Figure B–T phase diagram consisting of Bcross(T)  (blue dots). The tendency of Bcross(T) dots is in line with that of Tconset(B) dots and both yield the boundary between the superconducting state (dR/dT > 0) and the weakly localized metallic state (dR/dT < 0): however, the superconducting boundary exhibits an unusual upturn deviating from the Werthamer–Helfand–Hohenberg (WHH) theory (fitted by the blue dashed line), providing a prediction of mean‐field upper critical field (Bc2) in conventional type‐II superconductors under classical phase transition. At zero temperature, the WHH fitting gives a predicted Bc2 value of about 3300 Oe, which is far below the real critical field Bc∗ (by extrapolation) of about 3800 Oe. This special upturn is believed to be a consequence of the smeared quantum phase transition (QPT) corresponding to quantum Griffiths singularity.The magnetic‐field‐tuned SMT is essential for 2DSC, and SMT occurs at zero temperature but governs the thermodynamics up to finite temperatures.20 Thezv → ∞. To verify the nature of the multiple crossing points, FSS analysis is performed. In the FSS analysis, at least three curves are required. So, for the purpose of effective analysis, only the critical transition region formed by more than three adjacent Rs(B) curves can be approximated by one quantum “critical” point. Finally, a total of eleven respective “critical” points is obtained in the left‐hand panels of Figures S7–S9 (Supporting Information). According to the FSS law, the resistance near the critical point  takes the scaling form expressed thus: Rs = RcF(|B − Bc|Tzv−1/), where B is the magnetic field, Bc is the “critical” field, Rc is the “critical” resistance and F(x) represents an arbitrary function of B and T with F(0) = 1. The parameter v is the correlation length exponent, z represents the dynamical scaling exponent, and δ = |B − Bc| is the absolute value of distance from the transition. The FSS analysis for each “critical” point is shown in the right‐hand panels of Figures S7–S9 (Supporting Information). The derived zv values for each “critical” point are plotted as a function of magnetic field .Quantum Griffiths singularity is recognized for its multicrossing behavior and a divergent effective critical exponent zv → ∞.5, 6d Figure : it is s When approaching zero temperature, rare regions of inhomogeneous superconducting islands gradually emerge and interact via long‐range Josephson coupling to manifest global superconductivity. Recent studies show the quantum Griffiths singularity on highly‐crystalline superconductors with weak pinning and disorder. In principle, any static disorder will contribute to the increase of pinning in a superconducting system, therefore, the strength of disorder is characterized by the vortex pinning energy, which is obtained from analysis of the Arrhenius plot. The Arrhenius plot is often used to study the thermal activated flux flow (TAFF) behavior, where sheet resistance behaves in the form of R∝exp ( − U(B)/kBT), here, kB is the Boltzmann's constant and U(B) is the thermal activation energy, which is the slope of the linear fit in the Arrhenius plot.The quantum Griffiths singularity in 2D superconductors was first observed in Ga thin film, as a consequence of the formation of rare regions at ultralow temperature due to quenched disorder.1 WhenFigure U(B) = U0ln(B0/B), indicating the highly 2D nature of the long range vortex–vortex interaction in the graphene/superconductor‐islands‐array hybrid. The slope U0 of the U(log B) curve in Figure  For the graphene/Pb‐islands‐array hybrid analyzed in the present work, the vortex pinning energy is U0Pb=2.2kB: this is more than three times that of the graphene/Sn‐islands‐array hybrid . Note that the average vortex pinning energy is U02∝γξ2, where ξ is the superconducting coherence length and γ is the disorder parameter. Due to the fact that both graphene/Pb‐islands‐array hybrid and graphene/Sn‐islands‐array hybrid possess a similar superconducting coherence length , the greater pinning energy may mainly originate from a stronger quenched disorder, which indicates that strong disorder dominates the dynamic properties of the superconducting system, thus leading to the quantum Griffiths singularity in the graphene/Pb‐islands‐array hybrid. In fact, the assumed stronger disorder in the graphene/Pb‐islands‐array hybrid is verified by the comparison of the surface topographies of Pb and Sn nanoislands on graphene . According to SEM measurements, the spatial and size distributions of Pb nanoislands are more disordered in the graphene/Pb‐islands‐array hybrid, and there are considerable amounts of tiny scattering islands with only a few nanometers surrounding the core islands, which are rare in the graphene/Sn‐islands‐array hybrid. The presence of tiny scattered Pb islands will introduce additional disorder. Meanwhile, the mixed distribution of different sizes of Pb islands will yield inhomogeneous interisland Josephson coupling energy. Therefore, the vortex pinning energies together with the corresponding strength of disorder in the graphene/Pb‐islands‐array hybrid are much greater than that in the graphene/Sn‐islands‐array hybrid. It should be noted that, the strength of the disorder in 2DSC is very complicated, a direct comparison thereof between various 2DSC systems can only be achieved if a simple 2DSC system consisting of ordered superconducting metal nanoislands with variable spacing deposited on graphene can be constructed in the future.The magnetic field dependent activation energy  is plotted in B–T phase diagram for graphene/Pb‐islands‐array hybrid can be established  (blue dots) or Bcross(T) (pink dots). Most of the boundary can be described by WHH theory (blue dash‐dot line), as is often observed in conventional type‐II superconducting systems. Inside the WHH trace, the green dots TTAFF(B) defined as the detachment of the linear fit in the Arrhenius plot  shows the boundary of the thermally‐activated flux flow (TAFF) region below which quantum fluctuation overtakes thermal fluctuations. It is interesting to note that, in addition to the WHH trace, the boundary exhibits a special upturn, which is never observed in the similar system consisting of a graphene/Sn‐islands‐array hybrid . The special upturn region is found to emerge when the magnetic field exceeds Bc2, but disappears in a magnetic field above Bc∗. For the upturn region, the superconductivity is dominated by rare regions and the critical exponent zv diverging at zero temperature manifests the activated scaling behavior characteristic of the quantum Griffiths singularity. The obtained B–T phase diagram matches the proposed Griffiths systems, indicating that quantum Griffiths singularity truly occurs in graphene/Pb‐islands‐array hybrids as expected.With this summary of transport measurement results, a comprehensive d Figure 5. The b3B–T phase diagram shows that quantum Griffiths phase persists up to the infinite‐randomness QCP (Bc∗), which exceeds Bc2 from WHH theory. From the comparative experiments undertaken between Pb and Sn nanoislands on graphene, the observed quantum Griffiths singularity may be attributed to the enhanced vortex pinning energy in graphene/Pb‐islands‐array hybrid. The proposed artificial 2DSC system consisting of single‐crystalline graphene/superconductor‐islands‐array hybrid provides an ideal platform to investigate the influence of disorder on the QPT in 2DSC.In conclusion, the Griffiths‐type QPT has been reproduced in the artificial 2D superconducting graphene/Pb‐islands‐array hybrid. The 42 to atmospheric pressure. Afterwards, the chamber was heated to 916 °C and kept at that temperature during the growth progress with a mixture gas of CH4, Ar, and H2 for 300 min. Finally, the chamber was quickly cooled to room temperature under the protection of H2 and Ar.Monolayer single‐crystalline graphene was synthesized on the hydrogen‐terminated intrinsic Ge (110) surfaces via an atmospheric pressure chemical vapor deposition technique. The chamber was first evacuated to high vacuum and then aerated by a mixture gas of Ar and HThe Hall bar device was fabricated as follows: first, a 10 nm Ti/100 nm Au electrode pattern was deposited utilizing a Hall bar stencil mask 1. Then, the graphene (except in the channel region) was etched by oxygen plasma aligned with the stencil mask 2. Finally, a 20‐nm‐thick Pb was deposited by electron beam evaporation on the channel region of the Hall bar device using the designed stencil mask 3.3–He4 dilution refrigerator (Quantum Design) equipped with a heat capacity cable/RF filter box to eliminate stray RF currents.The temperature and magnetic field dependent resistances were measured by a physical property measurement system . Ultralow temperature was reached in an HeThe authors declare no conflict of interest.Supporting InformationClick here for additional data file.


Pulmonary granulomatous disease encompasses both infectious and non-infectious disease forms. Presently, the immunopathogenesis of granulomatous inflammation is incompletely understood. This issue of Frontiers in Immunology explores recent insights concerning the clinical and immunological aspects of pulmonary granulomatous disease.Judson summarizes current knowledge of the immunopathogenesis of sarcoidosis as well as the nature of varied environmental and occupational exposures, which could cause or affect the disease. Many infectious agents have been implicated in the disease, especially mycobacterium tuberculosis, and the review summarizes evidence for sarcoid patient immune responsiveness to such agents.Sarcoidosis is a complex multi-system disease of unknown cause which can be related to a diverse collection of environmental signals. The review by Muefong and Sutherland in their review of neutrophil activities in this deadliest of infectious diseases in humans. The authors raise the possibility that neutrophils may play a more central role in tuberculosis pathogenesis than previously thought. They propose that some neutrophil-related inflammatory mediators as potential targets for developing novel tuberculosis therapies.A different perspective on pulmonary tuberculosis, another granulomatous disease, is provided by Hena reviews the effects of race on sarcoidosis epidemiology. The author presents data that show that in the United States, black patients with sarcoidosis experience more severe pulmonary disease, more multiorgan involvement, and an overall worse prognosis. The author proposes that epidemiologic concepts can be used to modulate and even prevent sarcoidosis in black Americans at risk of life-threatening disease phenotypes.Kraaijvanger et al. address the problem of identifying useful biomarkers for sarcoidosis diagnosis and prognosis. As noted by the authors, sarcoidosis is a heterogeneous disease, making treatment decisions problematic. Exploration of signaling pathways in sarcoidosis such as JAK/STAT and mTOR may result in the discovery of more specific biomarkers that may be relevant to prognosis. The authors stress that there is an unmet need for more specific and more sensitive biomarkers in sarcoidosis care.Gerke focuses on the deficiencies of the current treatment options for sarcoidosis. Sarcoidosis treatment decisions are problematic because of the marked heterogeneity of the disease. Clinical evidence is sparse because the disease is relatively rare and few clinical trials have been performed. Goals of treatment are to protect organ function and to decrease symptoms, but most clinical sarcoidosis trials have not focused on the impact of the disease on function or quality of life. Gerke emphasizes the lack of knowledge concerning etiology and pathophysiology of the disease and the need to utilize more patient-centered approaches to treatment for exploration of immunosuppression, symptom control, and treatment of co-morbid conditions.Gerke study, Talreja et al. present original research on alveolar macrophage and blood monocyte gene profiles in response to in vitro dexamethasone treatment in sarcoidosis. Effects of glucocorticoids on alveolar macrophages or monocytes have not been well documented. These authors describe profound transcriptosomal changes in lung macrophages relative to cellular metabolism, lysosomal phagosomes and cytoskeleton function. Further studies are proposed to examine proteome profiles in additional cell types relevant to pulmonary sarcoidosis that can correlate with RNA seq data and give a more comprehensive picture of dexamethasone effects within the lung.Relevant to the Mohan et al.’s study using a multiwall carbon nanotube model of chronic granulomatous disease demonstrated many similarities to sarcoidosis including high expression levels of MMP12 . These investigators used MMP12 knock-out mice to investigate the role of MMP12 in granuloma formation and persistence and demonstrated similar acute responses (10 days); however; at day 60, there was a marked reduction in granuloma persistence suggesting that MMP12 is essential for the persistence of granulomas.Arger et al. observed that T-Bet expression on Th17.0 cells reflected the extent of clinical granuloma burden in sarcoidosis patients. These authors postulated that T-Bet Th17.0 cells represent a transition state leading to interferon-producing Th17.1 cells which are elevated in BAL fluid and mediastinal lymph nodes of sarcoidosis patients with granulomatous inflammation. These studies emphasize the importance of Th17 in sarcoidosis.Greaves et al. performed a comparative review of adaptive immunity in two pulmonary diseases: pulmonary sarcoidosis and chronic beryllium disease (CBD). The authors note that one of the defining features of both CBD and sarcoidosis is the pulmonary infiltration of activated CD4+ T lymphocytes. Interestingly, sarcoidosis lung also contains a significant population of Th17 cells which are absent in CBD. While beryllium is the antigen that can activate CBD lymphocytes, the antigenic specificity of sarcoidosis lymphocytes is not yet known.Locke et al. reviewed various in vitro and in vivo models of sarcoidosis. Each of the current model systems has strengths and weaknesses. The authors suggest that the integrated use of the various preclinical models will accelerate progress toward identifying targets and the testing of new drugs.We hope that the articles in this issue of Frontiers in Immunology will educate researchers and clinicians concerning the immunology of pulmonary granulomatous disease. Furthermore, we hope that these articles will serve as a stimulus to further exploration of the mechanisms of granuloma formation that will ultimately improve the lives of patients.All authors contributed equally. All authors contributed to the article and approved the submitted version.This study was funded by grants ES025191 to MT and CHHE P30 ES025128.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Sarcoidosis is a multisystem disorder which, in rare cases, can affect the urogenital tract. The clinical presentation of this benign inflammatory disorder can easily mimic that of testicular malignancy. Therefore, it is crucial to differentiate between these two entities, as misdiagnosis may lead to unnecessary surgical interventions, which have important implications for future fertility. While testicular cancer must always be ruled out, sarcoidosis should be considered in all patients presenting with a testicular mass. Here, we present a case of sarcoidosis with bilateral epididymal and testicular involvement. The diagnosis was made by frozen section and the patient was treated with corticosteroids. Sarcoidosis is a systemic inflammatory disorder of unknown etiology, characterized histologically by the presence of noncaseating granulomas in affected tissues. It is predominantly a disorder of the lungs but can affect most of the body with ophthalmological, dermatological, endocrine and reproductive manifestations. Urogenital involvement with sarcoidosis is rare, with only 0.2% of patients diagnosed clinically and 5% post-mortem . The kidA 32-year-old black male was presented with a one-month history of painful swelling in the right hemiscrotum not responding to initial antibiotic therapy. Past medical history was unremarkable and there was no family history of testicular cancer or systemic disease. On examination, he had bilateral epididymal enlargement and tenderness of the right hemiscrotum. Scrotal ultrasound revealed bilateral hypoechogenic nodules of approximately 1 cm in both epididymal heads, with a right-sided testicular infiltration along the rete testis. Additionally, a small parenchymal lesion of approximately 3 mm was noted in the right testis  pointed towards a diagnosis of sarcoidosis. Lastly, a biopsy of skin lesions or endoscopic ultrasound biopsy of mediastinal lymph nodes can lead to a more definitive diagnosis and can be invaluable in differentiating pulmonary sarcoidosis from metastasized testicular carcinoma.The unclear relationship between malignancy and sarcoidosis has been a cause for much debate. A study by Rayson et al. among patients seen at the Mayo Clinic showed a 100-fold increased incidence of sarcoidosis after treatment for testicular cancer . HoweverConsidering the possible etiologic relationship between testicular cancer and sarcoidosis, all patients with a testicular lesion and sarcoidosis should be strongly encouraged to undergo an inguinal exploration with biopsy. Some authors advocate orchiectomy for all patients with unilateral masses, even if sarcoidosis is present in other organs . By contTreatment of sarcoidosis is generally expectant, as most patients will see spontaneous resolution within two years . HoweverWhen testicular masses are encountered in patients, the differential diagnosis must consider testicular sarcoidosis, particularly in patients with confirmed sarcoidosis or epididymal involvement. This case demonstrates the need for histological confirmation prior to orchiectomy as - in contrast to testicular cancer - testicular sarcoidosis may be managed conservatively in patients who wish to preserve their fertility. Lastly, health care providers should be aware of the possible association between testicular cancer and sarcoidosis; long-term follow-up of these patients may be necessary.


Sarcoidosis is a heterogeneous disease in terms of presentation, duration, and severity. Due to this heterogeneity, it is difficult to align treatment decisions. Biomarkers have proved to be useful for the diagnosis and prognosis of many diseases, and over the years, many biomarkers have been proposed to facilitate diagnosis, prognosis, and treatment decisions. Unfortunately, the ideal biomarker for sarcoidosis has not yet been discovered. The most commonly used biomarkers are serum and bronchoalveolar lavage biomarkers, but these lack the necessary specificity and sensitivity. In sarcoidosis, therefore, a combination of these biomarkers is often used to establish a proper diagnosis or detect possible progression. Other potential biomarkers include imaging tools and cell signaling pathways. Fluor-18-deoxyglucose positron emission tomography and high-resolution computed tomography have been proven to be more sensitive for the diagnosis and prognosis of both pulmonary and cardiac sarcoidosis than the serum biomarkers ACE and sIL-2R. There is an upcoming role for exploration of signaling pathways in sarcoidosis pathogenesis. The JAK/STAT and mTOR pathways in particular have been investigated because of their role in granuloma formation. The activation of these signaling pathways also proved to be a specific biomarker for the prognosis of sarcoidosis. Furthermore, both imaging and cell signaling biomarkers also enable patients who might benefit from a particular type of treatment to be distinguished from those who will not. In conclusion, the diagnostic and prognostic path of sarcoidosis involves many different types of existing and new biomarker. Research addressing biomarkers and disease pathology is ongoing in order to find the ideal sensitive and specific biomarker for this disease. Sarcoidosis is a systemic inflammatory disorder of unknown cause which can lead to a variety of clinical symptoms. It commonly affects the lungs and intrathoracic lymph nodes, and is characterized by the formation of non-caseating epithelioid cell granulomas . In caseThe diagnostic trajectory of sarcoidosis is long and complicated; it requires invasive methods like bronchoalveolar lavage and evidence of granuloma in lung or other tissue through a biopsy , 7. The The discovery of a specific biomarker for this disease would help diagnose sarcoidosis. According to the National Institutes of Health Biomarker Definitions Working Group, a biomarker is “a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” . Such prThe ideal biomarker should not be related to other diseases and should be highly sensitive. Moreover, it should not be invasive, and should be reproducible. Also, the ideal biomarker should be inexpensive . A combi18F-FDG PET) and high-resolution computed tomography (HRCT) as diagnostic and prognostic tools in sarcoidosis.In this review, we address current and possible future biomarkers in sarcoidosis. Serum and bronchoalveolar lavage biomarkers are discussed in terms of antigen presentation, granuloma formation, and T-cell activation. As regards imaging, we focus on the value of chest X-ray, fluor-18-deoxyglucose positron emission tomography . sACE is an acid glycoprotein which converts angiotensin I into angiotensin II. It is mainly produced by activated alveolar macrophages and correlates with granuloma burden and radiological stages II and III . ElevateFurthermore, ACE levels in the normal range could in fact be elevated in specific patients. This is based on the influence of an insertion (I) or deletion (D) polymorphism in the ACE gene on sACE levels . In healACE could also have a role in predicting treatment outcome. High serum levels of ACE before treatment correlate significantly with lung function improvement after 6 months of methotrexate treatment . What haLysozyme is a bacteriolytic enzyme that hydrolyses glycosidic bonds in order to degrade peptidoglycans in bacterial cell walls. At the site of infection lysozyme activity limits the cause of inflammation by rapidly degrading peptidoglycans . In sarcNeopterin is a non-specific marker of inflammation produced by activated monocytes, macrophages, dendritic cells, and endothelial cells upon stimulation mainly by interferon gamma (IFN-γ) . NeopterThe human cartilage glycoprotein-39 or YKL-40 is a growth factor for fibroblasts and vascular endothelial cells and is secreted by macrophages and neutrophils. Increased serum YKL-40 levels have been found in patients with diseases characterized by inflammation, tissue remodeling and ongoing fibrosis . In sarcCD163 is a transmembrane hemoglobin-haptoglobin scavenger receptor expressed selectively on most macrophages in human tissues and on at least 10–30% of monocytes. Expression of CD163 is increased by IL-6, IL-10, glucocorticoids, and most immunomodulatory factors. Expression of CD163 decreases under the influence of tumor necrosis factor (TNF), interferon gamma (IFN-γ), and transforming growth factor beta (TGF-β). These are all cytokines involved in granuloma formation and disease activity. This may suggest a correlation between the expression of CD163 and inflammatory status in sarcoidosis patients. Shortly after activation of the toll-like receptors-2,4, and 5 (TLR), CD163 is shed into the environment as soluble CD163 (sCD163) . This quC-C motive chemokine ligand 18 (CCL18) is a CC chemokine produced primarily by antigen-presenting cells such as macrophages, dendritic cells, and peripheral blood monocytes. CCL18 is chemotactic for both naive and activated T-lymphocytes. Elevated levels of CCL18 have been detected in serum of patients with T-cell helper 2 (Th2) predominant diseases like idiopathic pulmonary fibrosis, bronchial asthma and scleroderma . CCL18 cSerum amyloid A (SAA) is produced by the liver during an acute phase reaction. In inflammatory conditions, macrophages produce high levels of SAA, which indicates that elevated levels of SAA are a clinical marker of inflammation. Elevated levels of SAA are found in several inflammatory diseases like RA and Crohn's disease . ElevateChitotriosidase (CTO) is an enzyme of the chitinase family. It degrades chitin, a polymer found in cell walls of fungi and the exoskeletons of insects and crustaceans. Pulmonary neutrophils and macrophages can secrete CTO upon stimulation of toll-like receptors (TLRs) by IFN-γ, TNF, and granulocyte/macrophage colony-stimulating factor (GM-CSF). CTO serum levels directly correlate with sACE levels . HighestAs mentioned above, macrophages are key players in granuloma formation. However, macrophages are difficult to study or use as diagnostic/prognostic biomarkers, since they are predominantly found in tissue and granuloma. Monocytes are precursors of macrophages and are found in the bloodstream, making them accessible and interesting as biomarkers in sarcoidosis. There are three subtypes of monocytes, classical monocytes (CD14++/CD16–), intermediate monocytes (CD14+/CD16+) and non-classical monocytes (CD14–/CD16++). Intermediate and non-classical monocytes are more inflammatory type monocytes, and have been found to be elevated in sarcoidosis . In addiT-cells play an important role in the development of granulomas. Antigen presenting cells like macrophages present peptides to T-helper (Th) cells via MHC class II molecules. This activates T-cells and leads to greater proliferation and recruitment of neutrophils and monocytes . Based oSerum soluble interleukin 2 receptor (sIL-2R) is the circulating form of the membrane IL-2R, a proposed marker of disease activity in sarcoidosis. Upon activation, Th1 cells upregulate the expression of IL-2R on the cell surface, and are able to shed sIL-2R into circulation . IncreassIL-2R seems to correlate with active disease and multiple organ involvement, and can possibly predict progression and relapse after discontinuation of therapy –61 FurthIt is important to state that patients with impaired renal function have elevated sIL-2R. This can result in high sIL-2R levels in the absence of active disease. Since renal impairment can occur in sarcoidosis patients, this effect has to be kept in mind when sIL-2R is used as a marker to monitor disease activity .Although the innate immune system and T-cell immunity are known to be involved in the pathogenesis of sarcoidosis, it is becoming increasingly evident that B-cells are involved in granuloma formation as well. B-cell accumulation has been shown in granuloma and pulmonary lesions, and a positive effect of B-cell depletion has been reported , 63.In vivo and in vitro studies have shown that blocking of BAFF results in reduced follicular and marginal zone B-cell numbers, while overexpression of BAFF in mice resulted in an increase in activated B-cells, activated T-cells, autoantibody production, and hypergammaglobulinemia. In sarcoidosis patients, higher levels of BAFF have been found in serum in comparison to healthy controls (B-cell activating factor (BAFF) is a cytokine of the TNF family with a critical role in B-cell development and function. controls –66. Howecontrols . In addicontrols . In a diThe B-cell ablative rituximab targets CD20, a marker expressed on the surface of naïve and memory B-cells, and has been shown to yield clinical improvement in some sarcoidosis patients , 68. ThiNot only are numbers of naïve and memory B-cells altered, but sarcoid B-cells were found to be anergic in chronic sarcoidosis. This anergy could be partly due to the reduced levels of NF-κB/p65 found in sarcoid B-cells. B-cells with reduced NF-κB have an impaired response to antigens , 71. FurRegulatory B-cells (Bregs) are IL-10 producing B-cells. This type of B-cell has been found to reduce inflammation through cytoplasmic IL-10 expression . PhenotyThis observation does appear to be in line with findings in other inflammatory diseases like SLE, RA, and multiple sclerosis. Furthermore, since IL-10 is important in the development of fibrosis, this association could justify further research into this population of B-cells , 65.In conclusion, B-cells are relatively new and somewhat unknown cells in sarcoidosis. However, since B-cells seem to be involved in several processes in sarcoidosis pathogenesis, the expectation would be that BAFF levels and memory, naïve, and regulatory B-cell counts could be used to assess disease activity and could possibly be used in the diagnosis of sarcoidosis. However, further research is required before B-cell counts and BAFF levels can be used as biomarkers in sarcoidosis.All biomarkers mentioned above as serum biomarkers appear to have the same limitations, namely, insufficient sensitivity and specificity. Since many biomarkers have shown a mutual positive correlation , 28, 73,The diagnosis of sarcoidosis is often confirmed by analyzing bronchoalveolar lavage fluid (BALF) . Various*03 genotype, which is usually found in patients with Löfgren's syndrome (LS). This biomarker therefore proved to be more useful for the diagnosis of LS, while the CD4/CD8 ratio is useful for the diagnosis of any type of sarcoidosis. On the other hand, specificity proved to be higher for CD4+ Va2.3+ T-cells compared to the CD4/CD8 ratio in BALF (97 vs. 92%), which will help with the diagnosis of sarcoidosis  has been related to the retention of intraepithelial lymphocytes (IEL) in mucosal tissue of the lung. CD103 is expressed by lymphocytes within the bronchial epithelium, some alveolar wall lymphocytes and CD4+ T-cells in the BAL. Expression of CD103 on CD4+ T-cells in BAL fluid is found to be different in ILD patients, depending on the type of disease . In patiWhile the CD103+CD4+/CD4+ appears to be a useful diagnostic tool in sarcoidosis caution should be taken with the interpretation of this ratio. Therefore, a CD103+CD4+/CD4+ ratio 0.2 can be seen as additional evidence pointing towards a diagnosis of sarcoidosis.For a long time, sarcoidosis was seen as a Th1-driven disease, because of the variety of type 1 specific cytokines present in BALF and serum of sarcoidosis patients, including IFN-γ, IL-12, and IL-18. However, nowadays it is accepted that sarcoidosis is driven by a combination of Th1- and Th17-associated factors . Th17 ceRegulatory T-cells or Treg cells may also play an important role in the development of sarcoidosis. Treg cells normally suppress immune responses by the host immune system against self and foreign antigens. In the case of sarcoidosis, it is hypothesized that Tregs are functionally defective or exhausted, making them unable to fully suppress the immune responses . The dysAlthough there are thus conflicting results on the presence and effect of Tregs in active sarcoidosis, what is clear is that an imbalance exists between Th17 and Tregs. Th17 cells are elevated in the blood of sarcoidosis patients, while the number of Tregs is decreased . The TreNeutrophils are important players in the innate immune system, but their role in sarcoidosis is still little understood. Neutrophils are attracted by chemokines, such as IL-8, which are released by monocytes and macrophages . PatientOther immune cells in BALF which are associated with poor outcome and an advanced radiological stage are natural killer (NK) cells . NK cellNatural killer T (NKT) cells (CD3+CD16/56+) are a regulatory T cell lineage which both express T cell (CD3) and NK (CD16/56+) receptors on their surface membranes, thereby influencing both Th1 and Th2 cytokine systems and stimulating cell-mediated immunity or suppressing autoimmune responses , 97. NK The monocyte-macrophage cell lineage is the origin of the expression of a variety of cytokines and chemokines that play many different roles in the inflammatory phenotype of sarcoidosis, including T-cell attraction and promotion of Th1/Th17 differentiation . Some inIn the case of sarcoidosis, a recent study by Arger et al.  showed tKrebs von den Lungen-6 (KL6) is a human high molecular weight MUC1 mucin protein derived from type II pneumocytes and respiratory bronchiolar epithelial cells . An incrElevated levels of KL-6 have been found in BALF and serum in patients with idiopathic pulmonary fibrosis, sarcoidosis, and other ILDs –112.The fact that it is not a disease specific marker indicates that it has no major role in diagnosing sarcoidosis. However, in sarcoidosis patients both serum and BALF levels of KL-6 correlate with higher serum ACE levels and CD4+/CD8+ ratio , 112. SuThe biomarkers mentioned above give limited information about pulmonary sarcoidosis as individual biomarkers. However, combining some of these biomarkers may be helpful in the diagnosis and prognosis of pulmonary sarcoidosis. CD4/CD8 ratio and CD103+CD4+/CD4+ ratio appear to be useful diagnostic biomarkers to support the diagnosis of sarcoidosis, while disease severity can be predicted and monitored by a correlation between KL-6 and CD4+/CD8+ ratio. Furthermore, disease progression can be monitored trough the percentage of neutrophils, NK cells, and NKT cells in BALF. In addition, Th17.1 cells and Treg cells are promising prognostic biomarkers, however, further research is required to determine the diagnostic value. The BALF chemokines CXCL9-11 in their turn may be useful biomarkers for treatment decisions.18F-FDG PET) scanning are increasingly recognized as essential imaging techniques for adequately identifying sarcoidosis localization and determining disease management  are frequently used. However, in sarcoidosis patients with extrapulmonary manifestations, such as cardiac sarcoidosis or neurosarcoidosis, other imaging modalities are warranted. For these patients, magnetic resonance imaging (MRI) and fluor-18-deoxyglucose positron emission tomography , which consists of CT extent scores for nodularity, ground-glass opacification, interlobular septal thickening and consolidation. The total CTAS was found to predict response to treatment in FVC after 1 year in their cohort of 100 patients. Furthermore, CTAS had a high degree of interobserver agreement .r = 0.543, P < 0.001). Furthermore, higher CTAS scores were seen in patients with high sACE levels  scintigraphy was the most frequently used form of nuclear imaging in sarcoidosis, but 18F-FDG PET has replaced it, as it was shown to be more accurate in depicting extrathoracic lesions . Furthermore, 18F-FDG PET was far more sensitive than ACE and sIL2R in this study  at baseline was able to predict lung function improvement after 6 months of treatment     . As anti18F-FDG PET. Furthermore, 38 patients (51%) with positive 18F-FDG PET results had normal ACE levels, suggesting an added value of 18F-FDG PET as an adjunct to serum biomarkers  of mediastinal lymphnodes on 18F-FDG PET is a predictor of relapse after discontinuation of infliximab therapy, with a hazard ratio of 4.33 (p < 0.001). This suggests that high activity on 18F-FDG PET reflects the burden of inflammation and therefore the need for prolonged therapy. A small retrospective study of 23 newly diagnosed sarcoidosis patients showed that persistent disease activity on 18F-FDG PET during the first months of corticosteroid treatment is a predictor of relapse  to quantify disease activity. Recently, a new tool for the quantification of disease activity of the pulmonary parenchyma was proposed. Volumetric 18F-FDG PET analysis of global lung inflammation was proposed by Adams et al.  measures the total activity of the pulmonary parenchyma, and although this derivative from the total lesion glycolysis in oncology studies looks promising, it was not superior to SUVmax in predicting lung function change during infliximab therapy  and extracellular water/edema (T2 mapping) . T1/T2 mP < 0.004). Moreover, a large meta-analysis including 10 studies and a total of 760 patients concluded that patients with LGE on CMR were at increased risk of events, compared to patients without LGE , even if they had preserved left ventricle systolic function  . The authors suggest that future events may be driven by the presence of myocardial fibrosis instead of inflammation  . A studyammation .18F-FDG PET has an important role as a diagnostic marker for cardiac involvement and is included in the Hearth Rhythm Society Guideline for diagnosis of cardiac sarcoidosis. “Patchy uptake on dedicated cardiac PET (in a pattern consistent with Cardiac Sarcoidosis)” in the right context can point towards the diagnosis   .18F-FDG PET in combination with CMR in the diagnostic process was studied in a cohort of 107 patients suspected of cardiac sarcoidosis. Added value was found in 45% of patients, as they were reclassified as likely to have cardiac sarcoidosis, most of them (80%) being correctly reclassified when compared with the final diagnosis  (Combining cardiac  < 0.01) .18F-FDG PET and CMR together, depicting both the pattern of injury and disease activity in a single scan   .Neurosarcoidosis (NS) refers to the involvement of the central nervous system (CNS) and is seen in approximately 5% of all sarcoidosis patients. It is a serious and devastating complication which is difficult to diagnose because of the many different ways in which this disease can present itself , 153.18F-FDG PET, and HRCT are used in different steps of the diagnostic process  pathway . This paRecently, various case reports have been published in which JAK/STAT inhibitors like tofacitinib and ruxolitinib were successfully used to treat patients with therapy-refractory sarcoidosis , 166.It may be useful in the future to further unravel this pathway and focus on which specific patients may benefit from this therapy and whether JAK/STAT activation markers can act as biomarkers.The mechanistic target of rapamycin (mTOR) signaling pathway is involved in cellular metabolism as well as proliferation and has been implicated in an increasing number of pathological conditions .It has been demonstrated in a mouse model that granuloma can be formed spontaneously when the mTORC1-inhibitor TSC2 is depleted. It was also found that sarcoid granulomas from patients with active and progressive disease showed active mTORC1 signaling . A decreIn sarcoidosis, 50–70% of the patients experience fatigue, some even experience chronic fatigue. Fatigue can still be present when sarcoidosis has clinically resolved, causing an impaired quality of life . One of The average scalp hair grows by 1 cm/month, so this method can retrospectively measure the production of these hormones over months , 172. ThHair cortisol levels could be a future long-term biomarker for the measurement of chronic stress in sarcoidosis. A great advantage of this biomarker is that it is non-invasive and easily available, and can be used in a retrospective way. Using only one or a few hair strings, it may be possible to screen for fatigue and physical distress as well as to measure it in follow-up measurements. This can be used as an alternative to the currently used questionnaires, preventing variations in scores as to when patients fill in multiple questionnaires over time .18F-FDG has been shown to be a useful PET-tracer in severe sarcoidosis. Other tracers, such as somatostatin receptors (SSTRs) like 68Ga-DOTA-NaI-octreotide (DOTANOC) or 68GA-DOTA-D-Phe-Tyr-octreotide (DOTATOC), would appear to be reliable alternatives to 18F-FDG. Multiple inflammatory cells that are found in granulomas, including epithelioid cells and macrophages, have SSTRs on their surface, while normal monocytes have not. In the case of cardiac sarcoidosis, DOTANOC is taken up by sarcoid lesions but not by normal myocardium  allows responders to infliximab therapy to be distinguished from non-responders. This imaging method is already being used in several TNF-α mediated diseases, such as RA, inflammatory bowel disease (IBD) and spondyloarthropathy . In sarcreatment . 99mTC-iSarcoidosis is a complex systemic disease reflecting immunological responses to different antigens in patients with certain genetic susceptibility , 175. OmIn sarcoidosis, multiple diagnostic and prognostic biomarkers are already being identified by using single nucleotide polymorphism (SNP) technology, RNA sequencing and pathway analysis . Strong Although numerous biomarkers have been evaluated for patients with sarcoidosis in recent decades, no gold standard has been set for their use in diagnosis or predicting disease course. Combinations of several serum biomarkers have been explored, with promising results, but the Holy Grail remains to be discovered. Future research should focus on combining serum or BALF biomarkers and further refined imaging techniques such as CT, MRI, and PET. Data on successful treatment of sarcoidosis patients with JAK/STAT and mTORC1 inhibitors suggests that these new immunological pathways should also be explored for new prognostic biomarkers in the near future.RK, MJ, and AV wrote the manuscript, contributed to the concept, and designing of the work. AV and MV revised the work critically for important intellectual content. RK and MJ set up the reference database. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.