However, DMTs did not alter CSF GAP-43. Interestingly, in RRMS CSF GAP-43 levels were higher in patients with signs of active inflammatory disease than in patients in remission (p = 0.042). According to CSF GAP-43 concentrations, regeneration seems reduced in progressive MS, increased during disease activity in RRMS but is unaffected by treatment of highly active DMTs.Neurodegeneration in multiple sclerosis (MS) correlates with disease progression and reparative processes may be triggered. Growth-associated protein 43 (GAP-43) exhibits induced expression during axonal growth and reduced expression during MS progression. We aimed to evaluate if GAP-43 can serve as a biomarker of regeneration in relapsing-remitting MS (RRMS) and whether disease-modifying therapies (DMTs) influence GAP-43 concentration in cerebrospinal fluid (CSF). GAP-43 was measured using an enzyme-linked immunosorbent assay in 105 MS patients  and 23 healthy controls (HCs). In 35 of the patients, lumbar puncture, clinical assessment, and magnetic resonance imaging was performed before initiation of therapeutic intervention, and at follow-up. CSF GAP-43 concentration was significantly lower in progressive MS compared with HCs ( However, regenerative mechanisms promote the repair of tissue damage, including remyelination in order to restore conduction. These pathogenic processes may be reflected by alterations in biomarker concentrations in cerebrospinal fluid (CSF), such as (i) neurofilament light (NFL), a biomarker of axonal damage5, (ii) glial fibrillary acidic protein (GFAP), a biomarker of astrogliosis6, and (iii) neurogranin, a marker of synaptic integrity7.Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that exhibits neurodegenerative features. The immune attack causes multiple demyelinating lesions with axonal loss but, with time, degeneration takes over with astrogliosis and atrophy8 and a major component of the motile growth cones of elongating axons and immature synaptic terminals9. GAP-43 is widely used as a marker of neuronal growth and regeneration, as it is highly expressed during synaptogenesis and axonal outgrowth11. Upon axotomy and in experimental models of ischemia, traumatic brain injury, and MS, GAP-43 protein expression is temporarily induced adjacent to the lesions18. Altered GAP-43 expression has also been reported in MS brains post-mortem20, including decreased expression in the vicinity of white matter lesions and increased or unaltered expression adjacent to remyelinated lesions20. CSF GAP-43 concentration correlates negatively with the Expanded Disability Status Scale (EDSS)20, and lower levels of CSF GAP-43 have been found in secondary progressive MS (SPMS) compared to early stages of MS, controls, and other neurological diseases21. Using a novel enzyme-linked immunosorbent assay (ELISA), we recently measured CSF GAP-43 in clinically isolated syndrome, early MS patients, and controls; though no differences were found between these major groups, patients who progressed had lower CSF GAP-43 concentrations22. In the present study, we investigated whether disease-modifying therapies (DMTs) alter CSF GAP-43 concentrations in MS, which would suggest an impact on regeneration.Growth-associated protein 43 (GAP-43), also known as B-50 or neuromodulin, is a membrane-associated proteinp = 0.004], but not in relapsing-remitting MS (RRMS) , compared with healthy controls (HCs) [2340 (1580–3230) pg/mL] , and p = 0.003, and p = 0.002, respectively compared with RRMS. The diagnostic accuracy of CSF GAP-43 in diagnosing progressive MS, calculated with a ROC curve, gave an area under the curve (AUC) of 0.73 (p = 0.012).Significantly lower CSF GAP-43 concentrations were found in progressive MS  Fig. . The difs = −0.339, p < 0.001), disease duration , and EDSS . When dividing the MS population into RRMS, PPMS and SPMS patients, EDSS correlation was significant only in PPMS . After adjustment for age in the PPMS group the correlation was still significant (p = 0.009). No significant differences were found between CSF GAP-43 concentrations in females and males, and baseline GAP-43 concentration did not correlate with the albumin ratio.While no correlation was found between CSF GAP-43 concentrations and age in HCs, it correlated negatively with age , and the latter had a longer disease duration , after adjusted analysis for age and disease duration, disease duration was still significant (p = 0.02). Although, CSF GAP-43 concentrations at baseline were higher in patients with gadolinum-enhancing magnetic resonance imaging (MRI) lesions [2560 (1720–2840) pg/mL] compared with those without lesions [2030 (1470–2470) pg/mL], this difference was not statistically significant  pg/mL], compared with CSF obtained in remission  was highly dependent on baseline concentrations   switching from treatment naïve (n = 1), first-line (n = 15) or second-line (n = 19) to fingolimod (n = 20) or alemtuzumab (n = 15), and those who did not . At follow-up, we neither found a significant difference in CSF GAP-43 concentrations between patients with NEDA-3  and those with no NEDA-3 . In the group of RRMS patients that switched to fingolimod or alemtuzumab there was a slight trend that those with higher baseline CSF GAP-43 concentration more often achieved clinical disability improvement , but not significant . Examining treatment effects on CSF GAP-43 concentrations in strata of patients who either started on first-line treatment and changed to second-line treatment or changed from one type of second-line treatment to another second-line treatment, did not reveal any significant changes in CSF GAP-43 concentration .At baseline, CSF GAP-43 concentrations were not different in patients on DMTs  were recently recruited from consecutive patients at the MS Centre, Sahlgrenska University Hospital, Gothenburg, Sweden, to explore the influence of alemtuzumab therapy on CSF biomarker concentrations. At baseline, 24 patients received first-line treatment , 20 received second-line treatment  and 61 were treatment naïve. Descriptive clinical and demographic characteristics are presented in Table We included 23 HCs and 105 MS patients, including 73 with RRMS, 20 with SPMS, and 12 PPMS, fulfilling the revised McDonald criteria from 201029 was used to score neurological deficits and impairment. A relapse was defined as an episode of neurological disturbance lasting for at least 24 h that could not be better explained by another cause30. Lumbar puncture was performed at baseline (n = 127), and in the fingolimod (n = 20) and alemtuzumab (n = 15) treatment groups, CSF was obtained again after a median of 7 (range 3–13) and 24 (range 24–26) months, respectively. One patient had only a follow-up lumbar puncture sample. The CSF samples were handled according to the consensus protocol of the BioMS-EU network for CSF biomarker research in MS31. MRI of the brain was performed on 66 patients at baseline and in close association with the clinical neurological examinations and lumbar puncture . A standard MRI protocol for MS including intravenous gadolinium contrast was performed on a 1.5 or 3 Tesla MRI scanner and included T1, T2, and fluid attenuation inversion recovery (FLAIR) sequences, according to the Swedish guidelines32.All patients were assessed clinically at baseline by MS-specialized neurologists. The EDSS22, with minor modifications. Briefly, plates were coated with NM4 monoclonal antibody  in carbonate buffer (pH 9.6), and incubated over night at 4 °C. After three washes with phosphate-buffered saline with tween (PBST), wells were blocked with a solution of PBST-milk  for 1 hour on a shaker at room temperature and placed at −20 °C for at least 12 hours to enable higher throughput during sample runs. After thawing and three more washes, the detection antibody , 50 μL of twofold prediluted samples, and calibrators (recombinant GAP-43) in PBST-milk were co-incubated overnight at 4 °C. Plates were washed three times and secondary antibody  diluted in 1% bovine serum albumin (BSA)/PBST at 1:20000 added and incubated on the bench for 2 hours at room temperature. Wells were washed and 100 μL of 3,3′,5,5′-tetramethyl-benzidine  added. Plates were incubated in the dark for 30 min before adding 100 μL of 0.2 M H2SO4 and measuring the absorbance at 450 nm immediately, with a 650 nm reference, on a SunriseTM microplate absorbance reader . The analysis was carried out using the same batch of reagents and the analyst was blind to disease condition. Quality control samples were run for estimation of intra- and inter-plate variations. The intra-assay CV for a sample with a mean concentration of 3597 pg/mL was 5.4% with an inter-assay CV of 8.9%, and for sample with a mean concentration of 571 pg/mL the intra- and inter-assay CVs were 10.7% and 11.1% respectively. The lower limit of quantification (LLoQ), determined as the lowest concentration at which GAP-43 could be detected reliably, was 475 pg/mL after adjusting for a twofold sample dilution. Further assay evaluation of precision, dilution linearity, spike recovery in matrix, and sample stability has been described previously25.The GAP-43 protein concentration in CSF was determined by an in-house ELISA as described previouslyAlb was calculated as the ratio of CSF albumin (mg/L) to serum albumin (g/L)33.Serum and CSF albumin concentrations were measured by immunonephelometry on a Beckman Immage Immunochemistry system . Qp < 0.05.Data were not normally distributed; therefore, non-parametric tests were used. Differences across patient groups, clinical measures, and treatments were evaluated as continuous variables using Kruskal-Wallis or Mann-Whitney U tests. The Wilcoxon signed ranks test for paired samples was used to evaluate changes in CSF GAP-43 over time in patients switching from other treatments to fingolimod or alemtuzumab. Possible correlations between biomarker concentrations and clinical measures were evaluated using Spearman correlation. The chi-squared test was used for categorical variables. Multiple regression analysis was performed to test the influence of age, disease duration, and EDSS on CSF GAP-43 concentration. SPSS version 23.00  and GraphPad Prism 5.0  were used for statistical analyses. All tests were two-sided with a significance threshold of 34. For patient material from previous studies, reference is made to the respective publication28 for their ethical approval. For the remaining patients and for HCs, participating in the assessment of alemtuzumab, the study was approved by the Regional Ethics Review Board in Gothenburg, Sweden (Reference number 460–13).All patients and HCs voluntarily participated in the study, and informed consent was obtained from all subjects. Measures were taken to minimize pain and discomfort for all participants in the study, and all methods were performed in accordance with the relevant ethical guidelines and regulations. The study conforms with The Code of Ethics of the World Medical Association (Declaration of Helsinki)


The experimental results prove that under the optimized heating temperature of about 70 °C the heaters successfully help implement complete desorption of residual NH3 showing a good sensitivity and cyclic stability.Ammonia gas sensors are very essential in many industries and everyday life. However, their complicated fabrication process, severe environmental fabrication requirements and desorption of residual ammonia molecules result in high cost and hinder their market acceptance. Here, laser direct writing is used to fabricate three parallel porous 3D graphene lines on a polyimide (PI) tape to simply construct an ammonia gas sensor. The middle one works as an ammonia sensing element and the other two on both sides work as heaters to improve the desorption performance of the sensing element to ammonia gas molecules. The graphene lines were characterized by scanning electron microscopy and Raman spectroscopy. The response and recovery time of the sensor without heating are 214 s and 222 s with a sensitivity of 0.087% ppm Ammonia gas plays a vital role in numerous fields, including nitric acid manufacturing, petrochemical industries, plastics, explosives, textiles, as a refrigerating fluid and in gallium nitride, etc ,2, but e3 sensors with different features such as materials, structures and fabrication methods and great advances have been achieved [m-aminobenzene sulfonic acid) (PABS), poly(3-hexylthiophene)) [2, SnO2, ZnO, V2O5, In2O3, WO3, CeO2, Carbon nanotubes, graphene) [2, PANI/ZnO, PABS/SWCNT) with synergistic effects [3 sensor with an infrared source. The effect was attributed to the absorption of infrared light by graphene to generate a charge carrier [In the past several decades, many researchers have endeavored to develop numerous differerent NHachieved . Variousophene)) ,6,7, inoraphene) ,11,12,13 effects ,15,16,17 effects ,19. Howe effects . The fab effects . The met effects , synthes effects , chemica effects  and elec effects  etc. are effects . Several effects . Gautam  carrier . Most ot carrier . While t2 acts as an electron acceptor and NH3 acts as an electron donor on graphene), which leads to the transfer of electrons. The transfer between graphene and adsorbed gas molecules changes the resistance and carrier density of graphene. According to this principle, graphene is considered to be useful for detecting a variety of molecules. However, its low productivity, severe manufacturing requirements and possible transfer process result in costly barriers to its commercial application. Recent literatures reported that graphene-based materials can also can be made from commercial polyimide (PI) film by laser direct writing [3 molecules on the sensing element. Then after being heated at an optimized temperature of 70 °C, the absorption and desorption behaviors of the sensor are investigated and the results shows that it exhibits complete desorption of ammonia molecules and good stability.Graphene, a two-dimensional material, has outstanding potential as a gas sensor . Graphen writing , making  writing  and soun writing . Here we2 laser system with wavelength of 10.6 μm , an XY moving stage and a target substrate. The focused beam spot size is reduced to about 0.1 mm when the focal distance is set to be 5 cm by adjusting the mirror s and focus lens. PI film tape  was attached to the target substrate on the XY moving stage. When the focused thin laser beam was focussed on the PI film with help of the moving stage, converting PI into graphene with the designed patterns. The principle is that a laser could produce extremely high local temperatures of more than 2500 °C and high local pressure, which facilitates carbonization and graphitization of the polyimide surface. Under ambient conditions, the oxygen and water molecules around the direct writing area will react with graphitic carbon to release some CO and CO2 gases and then porous structures are formed. Furthermore, the heterogeneous distribution of oxygen, moistures and unpredictable rapid heat flow result in a complicate 3D porous morphology [As illustrated in rphology . 2, 1.6 mm/s and 357 μs respectively. A laser irradiated zigzag pattern is illustrated in According to our previous work , we haveThe patterned lines were firstly characterized by SEM. Raman spectra was recorded by a CRM200 Raman System  and the excitation wavelength is 532 nm with spot size of ∼ 500 nm and 2.5 mw at the source. Their thermal effect on the sensor was characterized by an infrared thermal imager .3 (test gas) and atmosphere across the two terminals.As illustrated in −1, a G peak at ~1581 cm−1, and a 2D peak at ~2663 cm−1. The positions of these three characteristic peaks are substantially consistent with that of graphene [2/g, which is slightly larger than that of the coated polyaniline gas sensor previously reported [The morphologies and properties of the laser direct-write PI were characterized by SEM and Raman spectroscopy. From graphene . The D preported . In addi3 molecules because its ultra large surface area will bring more opportunities for ammonia molecules, acting as donators, to attach to graphene surface [3 molecules provide electrons to compound with the hole in the graphene conduction belt resulting in electronic resistance increase of the sensing element. The laser direct-written graphene lines provide numerous 3D porous micro/nano structures, which facilitate adsorption of ammonia gas molecules and their sensitivity will become higher.Electron transport in graphene is very sensitive to NH surface ,43. A go surface . When amThe sensing response is defined as ΔR/R, where 3 concentration could be observed, and the sensitivity of the sensor was about 0.087% ppm−1. Therefore it can be concluded that the change rate of the electrical resistance has a positive linear relationship with the concentration of ammonia gas, but the relationship between response/recovery time and gas concentration is on the contrary.In order to evaluate the function of the two heaters, the voltage applied on the heaters was set to be zero at first to study the performance of the sensor alone. 3 gas with concentration about 235 ppm. Subsequently, real-time cycling response test of the sensor was performed in ten cycles of periodic presence of NHT. The normalized resistance difference changes ΔRT/R with temperature are nearly linear. When the thermal radiation temperature was 90 °C, the ΔRT/R of gas sensing element was about 13.07%. This may be due to the change in the intercalation of graphene by thermal instability, which in turn changes its resistance. The inset of The effect of heating temperature on the electronic resistance of the gas sensing element was investigated at first by performing heating–cooling cyclic tests within 30–90–30 °C. 3. Secondly, the resistance further rose to another stable value due to the thermal effect when the sensor was heated to the set temperature by applying a DC voltage onto the heaters. Thirdly, the ammonia gas in the test chamber was pumped outside and we can see that the resistance decreased gradually to a fixed value because NH3 was desorbed at the set temperature. Finally, the power is turned off and the resistance further decreased to its initial value state as the temperature retrieved to room temperature. The inset image is the horizontal contrast of 3 during desorption and the resistance can recover to its initial value. It can be concluded that the sensor demonstrated good resolution, excellent sensitivity, good thermal stability and appreciable response/recovery time because the graphene heaters helped to implement complete desorption of ammonia gas when the temperature is more than 70 °C.In order to confirm an appropriate heating temperature around the sensing element and improve heating efficiency, we investigated the heating temperatures on response performance of the sensor by changing the temperature to be 50, 70 and 90 °C under an ammonia gas concentration about 235 ppm. A series of voltages of 3.5V, 4.7V, and 6.2V was applied to the heaters to maintain the temperature around the middle graphene gas sensor at 50 °C, 70 °C, and 90 °C, respectively. Firstly, the resistance of the sensing element increased and kept at about 15% increment when the graphene sensor was exposed to 235 ppm NH2 laser beam was utilized to scribe PI tape to successfully fabricate three parallel graphene lines for an ammonia gas sensor, in which the middle one acted as a sensing element and the other two acted as heaters to implement complete desorption of the ammonia molecules absorbed on graphene surface. SEM and Raman spectra proved that the irradiated micropatterns were changed into graphene with 3D porous structures. Without a heating process, its response/recovery time were 214/222 s, respectively, with the sensitivity of ca. 0.087% ppm−1. With the optimized 70 °C heating temperature around the sensing element, residual ammonia molecules were completely detached from the graphene surface, and the sensitivity and cyclic stability were greatly improved. Thus, such method might be a possible candidate to fabricate graphene-based ammonia gas sensors, which will be widely used in future applications including environmental detectors and wearable nose-sensors.A CO


In this work, we investigated three types of graphene  with different size and morphology, as additives to a lithium iron phosphate (LFP) cathode for the lithium-ion battery. Both the LFP and the two types of graphene (G V4 and G V20) were sourced from industrial, large-volume manufacturers, enabling cathode production at low cost. The use of wrinkled and/or large pieces of a graphene matrix shows promising electrochemical performance when used as an additive to the LFP, which indicates that the features of large and curved graphene pieces enable construction of a more effective conducting network to realize the full potential of the active materials. Specifically, compared to pristine LFP, the LFP/G, LFP/G V20, and LFP/G V4 show up to a 9.2%, 6.9%, and 4.6% increase, respectively, in a capacity at 1 C. Furthermore, the LFP combined with graphene exhibits a better rate performance than tested with two different charge/discharge modes. Moreover, from the economic and electrochemical performance view point, we also demonstrated that 1% of graphene content is optimized no matter the capacity calculated, based on the LFP/graphene composite or pure LFP. Current strategies to enhance the electrochemical performance of LFP include carbon addition in LFP [Driven by serious global environmental issues, coupled with increasing fossil fuel costs, research and investment in the development of sustainable energies, such as wind, solar, hydroelectricity, biology, and geothermal energies, have been emerging among the global trends. Due to the intermittent and regional characteristics, these sustainable energies, need to be efficiently stored for various practical applications like backup power tools, electronic devices, and hybrid electric vehicles (HEVs). Energy-storage technology with good properties has been developed quite rapidly over the last decade. Currently, the lithium-ion battery (LIB) is one of the most promising energy storage systems because of its outstanding electrochemical performance and high capacity ,2. Furthh safety ,7,8. Nevn in LFP ,11,12,13n in LFP ,15,16,17n in LFP ,19,20. Cn in LFP . Conventn in LFP . Recentln in LFP ,26,27,28Therefore, the addition of graphene in an LFP composite significantly improves the electrochemical performance of LIBs. However, the impact of the graphene size and morphology on the electrochemical performance of LFP has been rarely reported. Herein, we reported the detailed investigation of the effects of size and morphology of graphene on electrochemical performance of LFP. In this research, the graphene materials as additives were added into LFP powder to form a cathode by simply physical mixing. The results also revealed the optimal ratio of graphene in the cathode and improved performance of various charge/discharge modes. In addition, most of the results came from the graphene materials synthesized at the research lab, which are not suitable for mass production, and the cost of the product is extremely high, hindering the commercialization of graphene materials. Herein, the LFP powder used in this work was from YANTAI ZHUONENG-BATTERY MATERIAL CO., LTD., while two types of commercial graphene materials  from NanoXplore Inc. were investigated and compared with home-made graphene. Importantly, these three types of graphene present different sizes and morphology, and therefore, they provide a platform to investigate the effects of the size and morphology of graphene on the electrochemical performance of LFP. The results show that the features of large and curved graphene pieces enable construct a more effective conducting network to realize the full potential of the active materials. Moreover, from an economic and electrochemical performance view point, the optimized graphene content is proposed.https://www.nanoxplore.ca). The third type of graphene consisted of home-made graphene nanosheets (G), which were prepared with graphite oxidation, thermal exfoliation, and chemical reduction with natural flake graphite as the starting material [In this work, three types of graphene were involved in the preparation of LFP/graphene composites. Two grades of low-cost graphene , namely,material . In addiThe crystal structure of the prepared samples was characterized by X-ray diffraction  . The morphological structures were observed by scanning electron microscopy   and transmission electron microscopy  . Energy dispersive X-ray spectroscopy (EDX)  is a chemical microanalysis technique used in conjunction with SEM.−7 torr at room temperature. The beamline slits’ sizes were 50 μm × 50 μm with an instrumental resolution of E/ΔE > 10,000. The data were normalized by the I0 current, which was simultaneously measured with the FLY, by monitoring the drain current emitted from a Nickel mesh (90% transmission) placed in front of the sample.The X-ray absorption near edge structure (XANES) measurements were performed at the Canadian Light Source (CLS), located at the University of Saskatchewan. The Li K-edge and P L-edge XANES were measured on the Variable Line Spacing Plane Grating Monochromator (VLS-PGM)  beamline. The XANES spectra were collected in both total electron yield (TEY) and fluorescent yield (FLY) mode (only FLY is presented in this work) with a chamber pressure above 1 × 1011 photons/s at 100 mA with a resolution higher than 10,000 (E/ΔE). The spectra were normalized with respect to the edge height after subtracting the pre-edge and post-edge backgrounds using Athena software.The Fe K-edge XANES was obtained at the soft X-ray micro characterization beamline (SXRMB). It can provide 106 in a mixture of ethylene carbonate (EC) and dimethyl carbonate (DMC)  was used as an electrolyte and the separator was Celgard 2400. The galvanostatic charge/discharge measurements were performed using a Neware battery tester (BTS-4000)  at different current densities with a cut-off voltage window of 2.2–4.2 V vs. Li/Li+. All electrochemical measurements were performed at room temperature.The button-type cells were assembled in an argon-filled glove box , where water and oxygen concentrations were kept at less than 5 ppm. The working electrodes were fabricated by mixing 80 wt % of active materials, 5 wt % of acetylene black, 5 wt % of graphite, and 10 wt % of polymer binder  , which were then pasted on aluminum foil, followed by drying under a vacuum at 110 °C for 12 h. The active material loading in each electrode disc (about 12 mm in diameter) was typically 3.0–3.5 mg. The lithium disc served as both counter electrode and reference electrode; 1 M LiPFThe microstructures of the LFP/graphene composites were investigated by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) at different magnifications, and the results are presented in A high-resolution TEM image . −1). Naturally, they exhibit negligible capacity loss after 150 cycles, indicating excellent cycling stability. That aside, the potential differences between the voltage plateaus of charge and discharge profiles of all the samples can be described as: LFP/G ˂ LFP/G V20 ˂ LFP/G V4 ˂ LFP. The larger gap between the charge and discharge plateaus is probably caused by the inferior conductivity of the electrode material. Compared with bare LFP electrodes, the polarizations of the LFP/graphene electrodes upon cycling are smaller, benefiting from the superior electrical conductivity by the addition of graphene to LFP.In order to evaluate the electrochemical performance of the prepared samples, −1, respectively, which are all higher than 130 mAh g−1 of pristine LFP and represent an increase of up to about 4.6–9.2%. The initial Coulombic efficiencies (CE) of LFP/G, LFP/G V20, and LFP/G V4 are 70.9%, 68.6%, and 63.2%, respectively, which are higher than 62.1% of LFP. After the first cycles, the CEs are stable and approach 100% upon cycling. The cycling performance of samples at 5 C is also shown in The rate performances were tested with different modes, namely, Mode 1 and Mode 2. Mode 1 means that the cells are charging at 0.5 C when the discharging rate increases from 0.5 C to 10 C, i.e., slow charge; while Mode 2 means that the cells are discharging at 0.5 C when the charging rate increases from 0.5 C to 10 C, i.e., fast charge, which is also an important index of battery performance for practical applications. With the fast growing demands to shorten the charging time of practical applications in our daily life, such as portable electronics and electric vehicles, achieving fast charging in energy storage systems, especially the widely used LIBs, has been strongly considered as the most important criterion for practical applications ,34. As fOverall, from the above-demonstrated electrochemical performance, the LFP with different sizes and morphology of graphene displays a varied performance in LIBs, which shows that the graphene shape also plays an important role in capacity output. To figure out the effect of different types of graphene on the electrochemical performance of LFP, TEM images of these three graphene were obtained in 3,2-edges (below 60 eV) and the Li K-edge (above 60 eV), respectively. 4H2PO4, and P2O5. The features of a P L2,3-edge spectrum are generally described by a doublet resonance. These two peaks are due to transitions from spin–orbit split 2p electrons (the 2p3/2 and 2p1/2 levels) into the first unoccupied 3s, like an antibonding state. The intensity of peak B and peak A (IB/IA) in these lithium phosphates arises from the distortion of the phosphate tetrahedron [4H2PO4 indicates that there is more charge redistribution between the phosphate ion and Fe in LFP. By carefully comparing, we found that the IB/IA of LFP was slightly lower than the other graphene-modified LFP, which demonstrates that the graphene slightly raised the degree of disorder of the phosphate tetrahedron in LFP. The Fe K-edge XANES spectra ) were investigated, using button-type coin cells. Except for the home-made G, all of the LFP, G V4, and G V20 were sourced from industrial manufacturers, which is favorable for commercialization. Comparing the physical characterizations and electrochemical performance, we observed that with the additional graphene, the LFP/graphene exhibited much more stable cyclic performance, higher capacity, and better rate performance than their counterparts without graphene, suggesting the additional graphene could improve the electrochemical performance of LFP for batteries. Meanwhile, the addition of graphene did not affect the olivine structure of LFP. Therefore, LFP/graphene composites hold potential interest as cathode materials in high-performance lithium-ion batteries for EVs and HEVs. Electrochemical performance of commercial grade graphene also showed promise in next-generation low-cost LFP/graphene cathodes for industrial use. Moreover, by comparing the electrochemical performance of LFP with different types of graphene, it was found that the intrinsic features of graphene could be able to significantly affect performance, and that the wrinkled and large graphene nanosheet is superior to the flat and small graphene. Capacity calculated based on different methods has varying results. In this work, we also demonstrated that from the perspective of economic and electrochemical performance, 1% of graphene content is optimized no matter the capacity calculated, based on the LFP/graphene composite or pure LFP.


Here, recent work in this area is highlighted. Motivating factors for enhancing exfoliation efficiency and product quality in SCFs, mechanisms for exfoliation and dispersion in SCFs, as well as general metrics applied to assess quality and processability of exfoliated 2D materials are critically discussed. Further, advances in formation and application of 2D material–based composites with assistance from SCFs are presented. These discussions address chemical transformations accompanying SCF processing such as doping, covalent surface modification, and heterostructure formation. Promising features, challenges, and routes to expanding SCF processing techniques are described.Since the first intercalation of layered silicates by using supercritical CO We briefly discuss their compositional diversity and approaches being taken for their syntheses and processing. Supercritical fluids (SCFs) are introduced, and their properties are reviewed. Various applications of SCFs to exfoliation are presented with emphasis on opportunities to process without chemically modifying 2D materials, as well as examples where a chemical change  is a natural outcome of using particular SCFs.Following this introduction, we focus on briefly articulating the predominant SCF‐based or ‐assisted processing methods with accompanying applications made to nanosheet materials. Many of these methods have already found application in various industries for microparticle and nanoparticle processing. Next, we examine exfoliation using SCFs and specific types of nanosheet processing methods that mostly have to do with graphene (G) and graphene oxide (GO) processing. We also introduce early simulations of SCF‐based exfoliation processing to present a primary example of sophisticated molecular potential barriers emanating from Israelachvili's solvation force work from the last century. Our most lengthy section addresses diverse applications of SCF‐based nanosheet processing that impact many industrially essential topics. We conclude with a summary and try to describe some challenges materials scientists and engineers face in expanding SCF processing of layered materials.1.12D materials are referred to as nanosheets with atomic thickness and significantly larger lateral sizes. Thinning of layered materials down to a single layer or few layers can lead to enhanced or unusual electronic, optical, and mechanical properties as well as large specific surface area and chemical reactivity due to electron confinement in two dimensions.2, where M consists of one or two transition metals from groups 4–10 , X comprises one or two chalcogens ; trichalcogenides ; ii) group III  and IV  monochalcogenides, and iii) others (SnS2); 3) metal oxides, such as PbO, MnO2, α‐MoO3, V2O5, and perovskites ; 4) metal hydroxides, such as β‐Ni(OH)2, layered double hydroxides (LDHs); 5) transition metal halides, such as PbI2, BiBr2; 6) nitrides, such as hexagonal boron nitride (h‐BN or white graphene), graphitic carbon nitride (g‐C3N4), and metal nitrides; 7) transition metal carbides; 8) transition metal hydrides; 9) transition metal phosphides ; 10) transition metal phosphates and phosphonates; 11) ternary bismuth tellurohalides BiTeX ; 12) MXenes derived from carbides and nitrides ; 13) covalent organic frameworks.The past decade has witnessed a rapid development of 2D compounds in terms of variety and number of materials following the discovery of graphene in 2004. To date, a wide variety of 2D layered materials have been reported, which include: 1) monoelements: i) group III (borophene), ii) group IV , and iii) group V  elements; 2) metal chalcogenides: i) dichalcogenides with the formula MXThese emerging 2D crystals range from insulators to semiconductors to semimetals and further to superconductors, thus providing utility for diverse applications. Note that there are still a large number of possible 2D materials (about 1700 compounds) that remain to be examined.1.2Two methodologies can produce 2D materials: 1) bottom‐up (atom by atom growth); and 2) top‐down (isolation from bulk) strategies. The former mainly include physical vapor deposition, (modified) chemical vapor deposition, molecular beam epitaxy, atomic layer epitaxy, growth on SiC (to make graphene), and wet chemical syntheses.−2.+) followed by forced hydration (to release H2)Top‐down approaches involve micromechanical cleavage (such as Scotch tape methods),N‐methylpyrrolidone (NMP), and most solvent molecules). Hydroxyl radicals, HO·, tend to form in both oxygenated and deoxygenated water.sp2 hybridization to sp3 hybridization, with a slight out‐of‐plane puckering.2 exfoliation.Ultrasonication‐assisted exfoliation is a simple method with proven scalability. However, unintended surface modification of nanosheets is introduced due to radicals formed by sonolysis in various solvents  and pressure (Pc), which was first recognized by Baron Charles Cagniard de la Tour in 1822. FigureTc and Pc define the supercritical region. SCFs have both vapor‐ and liquid‐like physicochemical properties, such as near zero surface tension, low viscosity, high diffusion coefficients, excellent wetting of surfaces, and strong solvating power , though such thicknesses still offer advantageous applications. This limitation in exfoliation is probably due to CO2's nonpolar nature and reversible and rapid escape after insertion into bulk layers on depressurization. Despite this limitation, flake thicknesses can be reduced further by cycling into and out of supercritical states.2 mixed with various solvents.ScCO2  is another SCF in which exfoliation of grapheneScN3  has been used for exfoliation of natural graphite.3 also provides simultaneous nitrogen doping of graphene layers during exfoliation, which suggests an intrinsic chemical modification.ScNH2 2‐CH2Cl2 (dichloromethane)2 and offer several advantages when designing scCO2‐based processing procedures.ScCHClF2H4, C2H6, and C3H8. These SCFs need to be investigated further for their efficacy in intercalating and exfoliating 2D materials.Other solvents that are SCFs at mild conditions include CTc ≈ 450.9 °C, Pc ≈ 4.8 MPa  are ‘‘sufficiently low'' of only 0.03 for stabilized graphene by poly‐block‐poly(4‐vinylpyridine) in scCO2  processes were used for producing particles as a result of precipitation of dissolved materials at a very high rate of supersaturation due to sudden expansion upon depressurization. This process was also applied to exfoliate layered materials Figure3A.49 T2‐processing technique for intercalating and exfoliating layered silicates2, WS2, MoSe2, etc.),4MPO4 ,2O5,3,3O4,2/2H‐MoS2,2 heterostructures,Gulari and coworkers first reported an scCOblock‐poly(4‐vinylpyridine)To promote SCF intercalation and exfoliation, methods such as stirring,2.22‐in‐water emulsions and microemulsions stabilized by PFPE, a perfluoropolyether, are formed at a relatively low CO2 pressure (8 MPa), while reverse emulsions and microemulsions of water‐in‐CO2 are induced at elevated CO2 pressure (>12 MPa) as shown in Figure 2 serves as a “switch” to tune surfactant molecular aggregation, which is reversible and can be realized by pressurization and depressurization. ScCO2 pressure variations tune such microemulsion–reverse microemulsion continuous phase transitions.CO2 mixed solvent solutions.A microemulsion‐based process has been claimed to facilitate exfoliation of layered materials.2 microemulsions in scCO2 also provide unique media for uniform decoration of 2D materials with polymer,2) and act as nanoreactors to compartmentalize precipitation.2 and water can also be used to synthesize hollow oxides .Water‐in‐CO2.32 films on CNTs.Supercritical fluid chemical deposition (SFCD) techniques allow one to deposit particles and films Figure C,88, 89,2.2 and enhance dissolution of precursors in scCO2.These SFCD processes can overcome obstacles of high interfacial tension and viscosity in graphene oxide colloids, which are challenging for most existing methods. Porous graphene decorated with multimetallic nanoparticles (NPs) with small size and tunable loading has been fabricated in scCO2.42 in which a solute is soluble, this mixture becomes supersaturated.This supercritical technique involves a mixed solvent system with a solute compound dissolved in an organic solvent but insoluble in the SCF or with solute dissolved in an SCF but insoluble in an organic solvent, where the organic solvent and SCF are miscible. When a solvent, acting as an antisolvent, is combined with scCO2 is introduced into a solvent dispersion containing few‐layer nanosheets and a solute compound soluble in this solvent, solute solubility decreases if it is not soluble in scCO2, causing supersaturation and particle condensation.Conversely, as scCOBoth of these approaches use an SCF to drive exfoliation during and after precipitation of particles. However, while both approaches have been used to make particles for various applications, they have not yet been applied to make particle composites with 2D materials.2.5Supercritical drying provides advantages for processing of 2D materials and hybrids, such as drying of graphene‐based aerogels.2.62) for some periods. After rapid pressure reduction, CO2 solubility in a composite decreases, causing nucleation and growth of oversaturated CO2 to generate bubbles. As a result, 2D nanosheets coated with a porous polymer network are formed. Such porous structures encompass closed cell pores, open‐cell pores (interconnected cells), macropores, and mesopores. Foam inner morphology relies on SCF saturation level that is associated with several parameters such as SCF pressure and temperature, dynamics of nucleation and bubble growth /G composites.Polymer foams or scaffolds can be obtained by using SCF as a physical blowing agent, provided there exists a sufficient pressure‐dependent solubility of the blowing agent in the polymeric prefoam Figure F. This s2 was used as a blowing agent and SCF to produce foams having a high permittivity and low dielectric loss.2 was injected into the first extruder and dissolved under thermal and pressure conditions therein. When exiting a second extruder, a drop in pressure and temperature resulted in foaming to produce a nanocomposite with a permittivity, ε′, of about 77.5 and a dielectric loss, ε″, of about 0.233 at 105 Hz.−3 that is very difficult to achieve when formulating high dielectric inorganic nanoparticles  in polymer matrices is another positive attribute of this advanced dielectric material.Graphene nanoplatelets (GNP) were mixed with high‐density polyethylene (HDPE) in a tandem extruder assembly at about 1.1% by volume. CO2.2‐based blowing to create foam materials at various temperatures and depressurization rates.2 at 100 °C and 15 MPa followed by decreasing the pressure at 5 MPa s−1. GO contents of 0%, 0.1%, 0.5%, and 2.5% showed that pore diameter decreased and compressive strength increased with increasing GO content to 0.5%; the 2.5% GO content showed no improvement over the 0.5% GO level.Polyvinyl alcohol/GO nanocomposite foams have been evaluated using scCO2 to induce exfoliation and foaming in graphene mixtures with HDPE.−1 K−1 according to a Maxwell–Eucken model.−1 K−1 (4.5 vol%) to 3.75 W m−1 K−1 (18 vol%). Further increases in foaming decreased bulk conductivity.Another useful material was obtained by using scN3We discuss features of critical solvent parameters and other orthogonal processes that affect exfoliation, which appear essential for using SCF‐based and SCF‐assisted processes. It is always appropriate to consider how additives, co‐solvents, and mechanicochemical treatments may impact nanosheet surface chemistries.3.1TableBefore initiating exfoliation, SCFs are considered to first intercalate into galleries or nanosheet interlayers to expand interlayer separation and swell these materials. Increasing pressure can promote such SCF intercalation and expansion of spaces between interlayers.2 that X‐ray powder diffraction peaks at 2θ values over 26° to 27° were significantly attenuated and broadened as a result of such intercalation and expansion. Similarly, intersheet spacings in layered silica (Na+ Cloisite) were shown to substantially expand on scCO2 treatment with galactose‐based stabilizers.A fundamental aspect of SCF‐assisted exfoliation is that 1) intercalation of SCFs and often other solvents, polymers, and stabilizers occurs under supercritical conditions, and 2) when high pressure is released, expansion of SCF within interlayers drives sheets apart to yield exfoliation that is stabilized or not, depending on the conditions and environment of pressure release. Gulari and SerjatkuluWhile most reports of SCF‐driven exfoliation have not included corroborating X‐ray diffraction evidence that intercalation by SCFs and stabilizers when present occurs, past SCF expansion data unequivocally demonstrate that exfoliation has occurred. Exfoliation in the absence of intercalation can only occur if an external adhesive force is applied, or a sufficiently high shear force is applied. It can, therefore, be concluded that intercalation driven by SCF is a starting point for exfoliation, at least in processes without high shear fields or ultrasonication. It would be useful to quantify intercalation by specific SCFs, particularly in situ if possible. In view of diverse applications of powder X‐ray diffraction to particle and materials syntheses in SCFs,3.1.12D > γsol + γ2D/sol, where γ2D is the Gibbs surface energy of a 2D material, γsol is the surface energy (surface tension) of a solvent (a Gibbs free energy that can be readily measured), and γ2D/sol is the interfacial energy of the solvent/2D material interface (that can be estimated from contact angle measurement).Efforts have been made to study interactions between solvent molecules and 2D materials, in searching for appropriate solvents for effective exfoliation. Exfoliation appears to occur when van der Waals forces that are sufficiently small between adjacent nanosheets are overcome.4MPO4·H2O ,2,2,2 heterostructure.−1 were claimed. Such yields contrast with a very low (nearly zero) yield of monolayer graphene in both scCO2 and scNH3. However, both NMP and DMF unequivocally present processing challenges due to their high boiling points.Over 70 solvents have been examined for exfoliation, and some apparently good solvents have been identified for various 2D crystals.N‐octylbenzene,N‐butyl alcoholMixed solvents such as NMP/water,3.1.2In order to address issues of high cost, toxicology, and vapor pressure for some good solvents with high boiling points, using low‐boiling‐point solvents would be preferred, if sufficiently concentrated dispersions could be obtained. As an alternative, supercritical alcohols such as scEtOH ,3.1.32 due to an absence of phase boundaries, but loading with bulk layered materials provides phase boundaries. Although insoluble impurities in scCO2 might serve as sites where nucleation of cavitation bubbles can take place, resulting cavitation intensity is believed to be small and not significant in aiding exfoliation. Under such circumstances, shear stress and pressure fluctuations generated by ultrasound were conjectured to be mainly responsible for enhanced exfoliation yields in scCO2.2  and pitting effects stemming from bubble collapse provide mechanical energy (mostly in the form of tensile stress) to overcome attractive interactions between the layers, inducing exfoliation. Increasing fluid pressure was reported to decrease a cavitation threshold, thus suppressing any creation of cavitation bubbles. Nevertheless, a sufficiently large increase in applied ultrasound intensity could induce cavitation, even at high overpressures. A collapse of such transient cavities leads to a higher intensity and consequently enhanced sonolysis effects. Intensive cavitation in a pressurized reactor can substantially enhance exfoliation efficiency in RESS..2 Figure4a. Mea2 appeared to support a claim of high exfoliation yield of graphene of up to 63.2%. About 79% of the flakes were less than five layers, of which monolayer, bilayer, and trilayer represented 27%, 25%, and 14%, respectively. Combining mechanical shear with ultrasound allowed Zhao and co‐workers to increase this claim to a cumulative yield of 80%.As an alternative to ultrasound, mechanical shear also can help accelerate exfoliation of layered materials in SCFs.Such rotor–stator devices are popular in industrial fluid processing for formulating emulsions and for small‐scale manufacturing. Other high shear manufacturing methods such as homogenization are used at much higher scales in industrial manufacturing and have yet to be extensively investigated in SCF processing. Homogenization can be envisaged as sequential  pressurization to a supercritical state followed by depressurization in a flow that impinges on a mechanical barrier (plate). A very recent paper has addressed an example of this kind of processing.−1) have been reported using sonication in water.D/IG band ratios of about 0.54 were seen in the starting graphite material and in the exfoliated graphene multisheets. Therefore, pristine graphene appears not to have been available in this study. Further process development using such homogenization and related methods seem to offer promise.The results of this small batch study appear promising. Gravimetric yields, obtained by drying and weighing a particular volume of supernatant after 30 min of centrifugation at 3000 rpm, up to 15% were obtained.2 mg−1 is only 18% of the absorption coefficient of graphene measured by Nair and co‐workers,2 mg−1 in dispersion , for randomly oriented nanosheets.We believe that shear forces derived from fluidic dynamics in SCFs seem a possibly better approach than ultrasound, in light of an absence of sonochemically generated radicals and associated perturbation in nanosheets' quality.However, it is reasonable to presume there are many features that affect absorption coefficients of graphite and graphene samples obtained by different methods and from different sources. Some of these variations are manifested in edge and basal plane defects of various types, and their impact on electronic structure, particularly with respect to electronic absorption coefficients  have yet to be thoroughly evaluated theoretically and experimentally. A more universally accepted means of ascertaining “pristineness” is needed in order to extend our understanding of positive and negative aspects of nanosheet exfoliation processing.3.2SCF processing in 2D materials processing has mainly been considered in terms of high‐pressure changes that physically affect interlayer attraction. Additionally, SCFs behave as all solvents behave by modifying distributions of solutes in solution, by causing partitioning among multiple liquid phases, and in modifying chemical equilibria and reaction kinetics. In this section, we focus on reactions of this last type that involve covalent bond formation and scission.3.2.1l‐ascorbic acid,Currently, the reduction of GO with hydroxyl, carboxyl, or epoxide groups appears to be the most commonly used route to make graphene‐like materials, that is, reduced graphene oxide (rGO). These modifications can be done through thermal, chemical, electrochemical, or combined thermal–chemical treatments. Thermal methods usually involve high temperatures up to 1000 °C. Chemical reductions can be induced at relatively lower temperatures (less than 100 °C) by using reducing agents. While most strong reductants such as hydrazines and hydrides are highly toxic and explosive, some non‐toxic alternatives such as 2 has shown efficiency for such conversion provided the treatment temperature and time are no less than 200 °C and 3 h, respectively.2 at ≥200 °C displayed a significant increase in electrical conductivity, which reached almost 3 S cm−1 in the film treated at 300 °C  dramatically higher than that in the original GO films (<10−5 S cm−1).2 remains to be established. ScEtOH exhibited a larger reduction activity under similar critical conditions. Electrical conductivity was further improved up to 2.5 S cm−1 by using scEtOH  at 250 °C .SCFs have been demonstrated to be capable of converting GO into rGO, taking advantage of their unique properties (low density and viscosity and diminishing surface tension).2 g−1 ,−1).+ ion uptake, highlighting the importance of this SCF processing. The effective removal of the oxygen functionalities of GO in supercritical alcohols was attributed to a combination of thermal and chemical reduction. The former may involve decarboxylation and hydrodeoxygenation pathways. The latter may be associated with a de‐epoxidation mechanism.Of the five different alcohols  used at supercritical conditions, scEtOH was found to afford an rGO with the highest carbon‐to‐oxygen ratio of 14.4 and the largest surface area of 203 m−1 Figure5a–g.292O offers a green alternative to toxic reducing agents.2O and scH2O (473–653 K) compared to moderate temperature (373 K) treatment.2O and scH2O could be due to several pathways including hydrogen ion–initiated dehydration by inter‐ or intramolecular reactions, reduction of highly strained epoxide groups, decarboxylation, and generation of conjugated π‐network, as shown in Figure 2O was found to also enhance GO oxygen removal by up to 59%, resulting from an in situ hydrogen generation.2O gasification of glycerol to reduce GO sheets (with a C/O ratio of 2.5), outweighing those reported for hydrazine‐based methods.ScHH2O 473–63 K compa3.2.22O (400 °C). At milder conditions (310 °C), N‐doped few‐layer graphene was obtained in scACN without any addition of other N precursors.3  by using graphite as a starting material  with ammonia gas. Graphene doping types can be changed by adjusting scNH3 pressure and by introducing a second phase like CH4.N‐doping of graphene induces polarization in the carbon network due to the higher electronegativity of N (3.04) relative to C. A band gap is opened upon N‐doping, resulting in new properties for catalysis and device applications. SCFs provide unique processing media for chemically doping graphene (or GO) owing to their tunable transport properties. For example, GO was N‐doped by employing N‐containing compounds such as ethylenediamine, melamine, or hexamethylenetetramineal Figure6.37 Th2.SCFs can promote the doping of many other materials such as TiO3.2.32O.Crystallographic etching of graphene can be achieved based on 1) catalytic (preferably armchair) carbon gasification,2O, catalytic carbon oxidation with oxygen was shown to be significantly accelerated by the metallic NPs in scH2O.−1. Such enhancement of carbon oxidation in scH2O was attributed to the efficient removal of adsorbed gaseous products  from the catalyst surface and the formation of hydroxyl (OH) and hydroperoxyl (HO2) radicals. This anisotropic etching in combination with exfoliation in scH2O allows the scalable production of zigzag‐edge‐rich graphene nanosheets for electrochemical devices.As early as 1955, a variety of metal particles have been investigated for the catalytic graphite–water vapor reaction.2O treatment of anthracite coal  was observed to result in single‐layer graphene oxide quantum dots (GQDs).2O cutting down of large anthracite flakes started as early as 10 min. The depolymerization of coal was hypothesized to result from cleavage of ether and carbon−carbon (C—C) bonds induced by the nonpolar scH2O. In contrast to commonly used oxidizing agents, the scH2O oxidation was selective and did not bring about severe aromatic ring degradation. Exfoliation occurred at the same time, which led to a significant reduction in the number of layers for the GQDs upon extension of treatment.ScH3.2.42, enabling a phase change from MnO2 to Mn3O4 in short periods 2 to Mn3O4 to MnO changes show that a reduction occurs from Mn+4 to mixed Mn+3 and Mn+2 to Mn+2, respectively.Phase transformations of layered materials have been realized in SCFs. It has been reported that scDMF boosts oxygen release in layered MnO2O was found to trigger a phase transformation of H1.07Ti1.73O4·H2O into anatase above 200 °C.+ that was supplied by scH2O, as illustrated in FigureCompared to scDMF which exfoliates titanate without phase change, scHProtonation often increases solubility in polar solvents, and can then expected to promote Ostwald ripening.2‐ethanol‐water mixed solvents provided benefits for the production of 2H‐WS2 nanosheets with abundant edges.3, yielding 2D WS2/WO3·H2O lateral heterostructures. High‐resolution transmission electron microscopy (HRTEM) revealed irregular holes or vacancies on the basal planes of WO3·H2O nanosheets.3O+ originating from the reaction of water and CO2 may initiate defect generation via an electrophilic attack.SCFs also offer external stimuli to facilitate the formation of 2D lateral heterostructures for enhanced photocatalysis.2 was also found to induce a phase transition of semiconducting  2H‐MoS2 to metallic  1T‐MoS2  was calculated to be more than three times stronger than that on the 2H‐MoS2 (−0.18 eV) , and at 2ρc, at three temperatures, 45, 90, and 135 °C.2‐induced component. This second component accounts for density effect and arises from the formation of molecular layers of scCO2 on the sheet surfaces.60 fullerene multilayers on clay surfaces.2 in terms of fundamental colloid science, Israelachvili's multilayer solvation force. Similar MD (molecular dynamics) studies of other supercritical solvents will be very useful, particularly if solvents exhibiting overlapping π binding to graphene's sp2 surfaces can be modeled.Wu and Yang provided some significant molecular dynamics simulation results where scCO2, PX (p‐xylene), and Py‐PEG, as well as examinations of CO2 and PX alone. The scCO2‐alone simulations corroborated some of Wu and Yang's finding2 and de facto association of graphene sheets with an interlayer separation of about 4 Å (because of an scCO2‐induced intersheet repulsive barrier at about 6.5 Å). Initial separations of 10 Å also evolved to an average separation of about 4 Å (first to about 6.5 Å and then to 4 Å) at a density of 0.912 g cm−3, above ρc and only slightly lower (2.6%) than 2ρc (0.936 g cm−3). This discrepancy was not discussed by Xu and co‐workers but may be a consequence of their nanosheet constraints. A conclusion that scCO2 cannot stabilize graphene nanosheets appears contrary to many experimental observations. The detailed discussion of Wu and Yang describes a step‐wise wedge‐opening effect followed by surface solvation by scCO2,−3 (ρc). The only PMTs provided by Xu and co‐workersy‐coordinate, normal to nanosheets) or to sliding of one sheet past the other at an imposed velocity of 2.5 Å ns−1 in the x‐coordinate direction. Values of PMF ranged from 0 to about 25.6 kJ mol−1 nm−2,−1 nm‐2 .y‐coordinate because the energies of these PMFs go to zero as “sliding distance” goes to zero. Additionally, in neither case is a ceiling to a steadily increasing barrier shown, since the maximum sliding distance illustrated is 6 Å.An initial examination of such π binding solvation under near‐critical and supercritical conditions has been described by Xu and co‐workers2 and PX and CO2, PX, and Py‐PEG. They found that PX alone was not effective in initiating exfoliation with initial layers spaced 6 Å apart, but at an initial separation of 10 Å, the sheets evolved to a 7.4 Å separation, indicating that at least a monolayer of PX separates the respective sheets. Mixed CO2/PX solutions were useful when the [CO2]/[PX] ratio was higher than 2.5. At such higher concentration ratios, the nanosheet spacing evolved to about 7.5 Å when starting from 6 Å, and to 10.5 Å when starting from a 10 Å interlayer spacing. Unfortunately, PMF was not calculated for these solvent compositions. A qualitatively significant advance was in analyzing stabilization by Py‐PEG, when mixed CO2/PX solvents initiated exfoliation. These simulations showed that the pyrene head groups provided π–π binding that survived venting of CO2.Xu and co‐workers also examined mixtures of CO3.4It appears that simple RESS processing can induce exfoliation and that cyclical repeating of such processing has an additive effect resulting in progressively increased exfoliation extents. SCFs with mild critical properties that are gases under ambient conditions offer important processing advantages. Using co‐solvents with some of these “mild” SCFs provides some apparent advantages, including formation of complex fluids . Also, coupling shear‐generating processing methods with SCF processing appears to be a very useful area for process development.Further work is needed in understanding and characterizing covalent bond formation accompanying extant solvent processing of 2D materials, and this need is also a development opportunity for many SCF processes applied to such materials. Shear‐induced bond breaking, sonolysis‐induced solvent radical formation, reactions of radicals with 2D sheets in SCF and SCF‐cosolvent mixtures, and redox reactions in SCF are examples of chemistries that would benefit from further understanding in connection with 2D material processing in SCFs.More physical and chemical modeling and simulation on different length scales are needed. CFD helps us understand microscopic fluid dynamics and how macroscopic waves and shear‐fields can be generated and transmitted in multiphase suspensions.42C/rGO material obtaining hydrocarbons from glycerides),2 nanosheets is a noteworthy advance in superhydrophobicity.2 separately yielded contact angles of 125°. This synergism is most likely due to a “lotus” effect that often accompanies a very rough surface topography,Applications of nanosheets prepared or processed with SCF assistance are mirroring those of nanosheets created by other top‐down and bottom‐up approaches. Catalysis and energy account for a large majority of these applications and analytical applications such as imaging and sensors represent another primary focus. Sasikala and co‐workersTableIn many of these applications Table4, 2D m4.13O4,2,2,2,2O3,2,2 with a selectivity of ≈90% for p‐menthene.Catalysis with 2D nanosheets has gained increasing research interest because of their remarkable properties and flexibility in surface and structure modification by diverse methods.2C NPs were synthesized using a supercritical alcohol route, which was followed by carbothermal hydrogen reduction.2C catalysts using other carbon substrates, including glassy spherical carbon, activated carbon, and mesoporous carbon. The high hydrocarbon yield for the Mo2C/rGO composite was attributed to the uniform distribution of Mo2C NPs on the 2D support as well as efficient transport of reactants imparted by the large pore size (≈9.7 nm) and slit‐like pore structure of the catalyst. The superior role of rGO as a catalyst support compared to other carbon materials  has also been observed in the catalytic dehydrogenation of LiAlH4.RGO‐supported Mo3O4 NPs of 3.2–8.8 nm were attached on the surface of GO resulting from decomposition of cobalt nitrate in scCO2‐ethanol mixtures.3O4/GO composite could catalyze the decomposition of ammonium perchlorate (AP) with lower decomposition temperature (297 °C) and enhanced exothermic heat (1591 J g−1) as compared to the values of 308 °C and 1448 J g−1, respectively, for pure Co3O4. Despite these preliminary results, mechanistic understanding of the catalytic decomposition of AP using Co3O4/GO is still unclear.Co3 was reported to facilitate the formation of N‐doped graphene, which enables a 4e− transfer oxygen reduction reaction (ORR) process in alkaline electrolyte. Such nonmetallic catalyst exhibited a more positive ORR potential (−0.3 V vs Ag/AgCl) and larger current density than the one prepared in NH4OH.3 than in NH4OH.Local electronic structures of graphene and GO are easily modified by chemical doping with heteroatoms to yield metal‐free electrocatalysts. ScNH2 technology , 11.9 fold enhancement in specific activity (1.55 mA cm−2 at 0.9 V vs RHE), and higher durability compared with commercial Pt/C catalyst  catalysts were derived using a similar SCF strategy. Improved ORR activities were obtained relative to bimetallic PtFe/GCM.2.In addition to abundance and environmentally friendly nature, graphene‐based materials possess outstanding electrical conductivity and high mechanical strength and stability, which are beneficial when used as catalyst supports in electrochemistry.gy Figure9a,b.102,2 NPs of 5–10 nm were uniformly attached to the surface of graphene by solvothermal hydrolysis of titanium isopropoxide in supercritical ethanol.2 and P25. Fe‐doped TiO2 nanowires were grown on the surface of functionalized graphene sheets with —COOH groups in scCO2.2 NPs and graphene benefited transfer of excited electrons from the Fe‐doped TiO2 anatase to graphene (with a work function around 4.2–4.5 eV). The band gap of Fe‐doped TiO2/graphene sheets (Eg = 2.25 eV at 0.6 wt% Fe doping) was reduced as compared to commercial TiO2 (Eg = 3.2 eV), which favors photocatalytic reactions in visible light. Interface synergistic effects between semiconductors and graphene (or rGO) likely contribute to separation of photogenerated carriers, thereby improving photocatalytic performance.SCF processing offers benefits for immobilization of semiconductors  was achieved by using a 2D lateral WS2‐WO3·H2O/1T‐2H MoS2 heterostructure obtained in scCO2.2/graphene hybrid catalyzed H2 evolution reaction with H2 production rate reaching 19.82 mmol g−1 per hour under visible light irradiation in the presence of TEOA as a sacrificial donor.2/WO3·H2O heterostructures were fabricated with the assistance of scCO2. The potential of WS2 at the conduction band (CB) minimum  is lower than that of WO3·H2O (1.26 eV), while the valence band (VB) maximum level of WO3·H2O (3.51 eV) is higher than that of WS2 (1.81 eV). Hence photogenerated electrons and holes accumulated at the CB of WO3·H2O and the VB of WS2, respectively. This response resulted in enhanced photocatalytic activity toward the degradation of methyl orange under irradiation with visible light.ScCO4.2Rechargeable batteries such as Li‐ion batteries (LIBs) and Na‐ion batteries (SIBs) store chemical energy with an ability to deliver electrical energy response by repeated charging–discharging processes. 2D nanosheets are showing promise in rechargeable batteries with better rate capability and higher cycling stability than bulk counterparts.−1, provided that lithium is bound on both sides of graphene to form Li2C6.−1 at 50 mA g−1),3,4−1 even after 100 cycles at a current rate of 50 mA g−1, which outperformed thermally reduced GO and scIPA reduced single‐oxidized GO electrodes.−1 after 1000 cycles at 5 and 10 A g−1, respectively. The abundance of hydrogen‐terminated groups in rGO was suggested to be beneficial for the high Li‐ion‐storage capacity. Likewise, the hydrogen‐terminated groups and defects on the carbon sheets were also proposed to contribute to enhancement in Na ion uptake.−1 at 50 mA g−1 and cycling stability up to 2000 cycles at 1–5 A g−1 were demonstrated for hydrogen‐enriched porous carbon nanosheets in Na ion batteries. Modification of graphene with 1‐pyrene sulfonic acid sodium salt (1‐PSA) in scH2O improved Li‐ion charge–discharge properties of exfoliated graphite by providing more active sites (sulfonate groups) for adsorbing lithium ions.The use of graphene as either a cathode or an anode permits fast electron and ion transport in electrodes, enabling fast charge and discharge. As an anode material for LIBs, graphene exhibits a theoretical specific capacity of 744 mAh g−1 at 420 mA g−1) and cycling stability (up to 30 cycles) as compared to pure Si NWs (about 1030 mAh g−1 during the 30th cycle).2‐rGO composites synthesized in scMeOH also provided high cycling stability (531 mA h g−1 at 0.1 A g−1 after 1000 cycles), showing potential as an anode material in LIBs.One of the major issues when using metal and metal oxide NPs as electrode materials in LIBs is the significant volume change during charge/discharge, limiting cyclability. This issue can be alleviated by combination with conductive graphene materials with high surface areas.4  nanosheets with exposed (010) surface facets were fabricated by employing a solvothermal lithiation process in SC ethanol–water solution  showed reversible discharge capacities of 163, 147, and 136 mAh g−1, corresponding to a capacity retention of 99.4%, 93.6%, and 88.3%, respectively.−1 and 90 Wh kg−1 at an 80 C rate for LiFePO4/C nanosheets)  with good cycle ability without any structural instability up to 20 cycles. V2O5 nanosheets that were prepared via an SCF route are another cathode alternative for LIBs.−1 at 15 C and an almost 100% capacity retention after 200 cycles.Olivine‐type LiMPOon Figure10a–f.62 and depositing 1 nm SnO2 particles on graphene sheets exfoliated in scCO2 was developed for SIB anode applications.2 mixture were exceeded was made.2 solutions have been determined.2 of 0.86. The critical parameters of such a mixture of solvents are Tc = 77 °C and Pc = 12.6 MPa. These parameters were not attained in these experiments, so this processing should be termed “subcritical” or “near critical.” However, a better dispersity of nanoparticles obtained by pressurization was shown in TEM. Also, the specific capacity (mAh g−1) at “high” discharge rates up to 0 1 A g−1, was twice that measured for the “air” control as well as for CNT controls made with “ncCO2.”2‐ncEtOH, mixtures” were beneficial and should be so recognized.A recent report of preparing nanoparticulate SnO4.32 drying and H2 reduction provided a specific capacitance of 153 F g−1 and an energy density of 21.4 Wh kg−1 at a current density of 0.1 mA g−1 in an ionic liquid electrolyte (1‐ethyl‐3‐methylimidazolium bis[(trifluoromethyl)sulfonyl]imide) at 60 °C.−1 in an organic electrolyte (1 m MeEt3NBF4/PC). Graphene exfoliated in scNMP by a small scale homogenization process was used to make supercapacitors with a specific capacitance of 135 F g−1 in aqueous 6 m KOH.−1 at current densities of 5 to 50 A g−1 with good cycling stability.Supercapacitors (or ultracapacitors), including electrical double layer capacitors and pseudocapacitors, are promising short‐term high power density storage devices for applications in between those requiring electrolytic capacitors and others requiring batteries. Graphene‐based materials obtained in SCFs have been exploited as supercapacitor electrode materials. Graphene aerogels prepared by scCO−1 at 0.5 A g−1 in aqueous 1 m H2SO4.−1.−1 in aqueous 1 m H2SO4 and ionic liquid electrolyte, respectively. Note that supercritical reaction conditions and N‐precursors have a direct impact on the N‐content, N‐type doping, conductivity, and specific surface area, which profoundly affect capacitive behavior.Nitrogen‐doped graphene sheets obtained in near‐critical fluids and SCFs2,2 was shown to be capable of delivering high specific capacitances of 200 (based on cyclic voltammetry at 50 mV s−1 in 3 m KCl), 303 , 280 (at 1 A g−1 in 1 m H2SO4), and 144.6 F g−1 (based on cyclic voltammetry at 50 mV s–1 in 1 m H2SO4), respectively. High cycling stability was also claimed with a capacitance retention ratio of 98% for the ZnO/rGO composite electrode after 1000 cycles.Incorporating metal oxides, such as MnO2 has also been used to facilitate exfoliation of GO in aqueous dispersions for supercapacitor applications.−1 were obtained at 1 and 16 A g−1, respectively.ScCO4.4I–V) curves for vacuum‐dried graphene samples (at 200 °C) showed resistance in the range of 2–6 kΩ.9 A cm−2. No annealing process is required using this SCF approach, which is quite useful for the fabrication of films on various substrates. The SCF method also showed advantages for the preparation of MoS2 thin films with remarkably better electrical transport performance (≈1530 cm2 V−1·s−1) than those obtained by many other techniques.I–V characteristic was reported for MoS2 devices. Such non‐linearity was assigned to various charge transport mechanisms such as space‐charge‐limited conduction, Fowler–Nordheim tunneling, and Poole–Frenkel conduction.Direct exfoliation of graphite in SCFs obtained graphene films with high conductivity.n‐type behavior, in contrast to the p‐type field‐dependent behavior for pristine graphene.N‐doped graphene produced in scACN was demonstrated to display an 4.5A diverse band structure among various 2D materials provides for many variations in optical properties in absorption and emission. Reviews of bulk and nanoscale luminescent materials,3 nanosheets with Eu3+ and found a maximum in emission intensity at a doping level of 0.2 mol%.3)2 solvo‐thermally with Ti(OC4H9)4 in scN2 at 1 MPa and 265 °C, and doping was done by including Eu(NO3)3 in the reaction. After venting, the nanosheets were collected and calcined in air for 4 h at 800 °C. A growth process that transformed nanoparticles into nanosheets was found that was driven by Ostwald ripening. Excitation of the resulting nanosheets at 466 nm produced a red emission at 616 nm.More basic luminescence studies of nanosheets produced by SCF‐aided processing have begun but are not numerous. Yang and Hu doped CaTiO2.2 in DMF, placing this reaction mixture in an autoclave at 400 °C for 30 min, and then quenching at 5 °C. The supernatant was collected and centrifuged to obtain the MoS2 nanosheets. The scrolling of nanosheets to form scrolls (and tubes) was explained as a process driven to minimize surface free energy. This minimization is a pervasive force in nature where Gibbs surface free energy is decreased by minimization of surface area to volume ratios and is a consequence of MoS2 units being constrained to a sheet structure after exfoliation. These authors noted a strong optical absorption band at 328 nm tailing into the visible as far as 500 nm. Their reported excitation spectrum indicated a peak in excitation at 360 nm and a blue emission peak at 420 nm. It was also mentioned that increasing the wavelength of excitation resulted in more extended wavelength emission, and some of these effects are dependent on particle size.Thangasamy and Sathish examined blue luminescence from nanosheets (nanoscrolls) of MoS2 exfoliation process for MoS2 that produces stable nanosheets that are not scrolled.2 that was initially dispersed in aqueous ethanol, infused with scCO2 at 40 °C, and stirred to form Pickering emulsions of scCO2 and ethanol in an aqueous ethanol continuous phase, with scCO2 and ethanol solution droplets. These emulsion droplets are stabilized by MoS2 flakes that gradually exfoliate to stabilize more droplet interfacial area. The stability of the resulting MoS2 nanosheets, relative to the scrolls discussed above, can be rationalized by the much lower SCF temperature of this scCO2 process compared to the scDMF process. Xu and coworkers noted that such MoS2 nanosheets likely would be useful for cellular bioimaging applications, but did not report any.2 nanosheets were prepared in scCO2/PVP/ethanol aqueous solution. Small nanosheets with lateral dimensions below 120 nm were used as fluorescent labels to perform lung cancer cell labeling.Interestingly, Xu and co‐workers reported a novel scCO2O process  that was mildly oxidizing. Under certain supercritical conditions, GO nanosheets were obtained as 3 nm diameter quantum dots in high yield (55%).−1 and to provide a distinct blue fluorescence after 24‐h incubation with these cells. A separate scEtOH process  that was mildly reducing was found to produce graphenic ribbon‐like nanosheets at 6.8% yield. These ribbons produced electrically conducting films with a surface conductivity of about 0.1 mS/□. These different materials obtained with scH2O and scEtOH were obtained without using any strong acids or bases and yielded nanosheets in useful amounts.Some demonstrations of using SCF‐processed nanosheets to label cells have been reported.h‐BN.Escherichia coli and Pseudomonas aeruginosa) but not Gram‐positive (Staphylococcus aureus and Bacillus subtilis). Epifluorescence microscopy could be used to differentiate Gram‐negative and Gram‐positive organisms in the same field because of this differential staining phenomenon. These authors hypothesized that this differential staining was due to an outer wall lipid layer not present in Gram‐positive bacteria.Sathish and co‐workers also reported an scDMF process (450 °C) for creating 5 nm diameter BN QDs from 4.62D materials have been extensively developed as wet chemical and gas phase sensors, and reviews of their applications focusing on GO,2 to provide nanosheet separation and promote uniform distribution of suspended Pd NPs on these graphene nanosheets.2 removal by the adsorbed Pd NPs. Electrochemical sensing of ascorbic acid, dopamine, and uric acid was superior to graphene and “conventionally prepared” Pd/graphene electrodes using both cyclic voltammetry (CV) and differential pulse voltammetry.Only a few reports have appeared so far making use of SCFs in preparing such sensors from 2D materials. Wu and co‐workers prepared Pd nanoparticle (NP)–graphene composites using scCO2‐assisted exfoliation and NP deposition were used to also examine effects of ionic liquids (ILs).2 . Electrodes were prepared as pastes by combining respective nanocarbon materials with isopropyl alcohol/Nafion solutions and depositing onto glassy carbon electrodes. IL‐containing examples were prepared with 1‐butyl‐3‐methylimidazolium hexafluorophosphate adsorbed into Pd/nanocarbon pastes. For ascorbic acid, dopamine, and uric acid, the electrodes without added IL, the Pd‐MWCNT electrodes were slightly to significantly more sensitive than the Pd‐G electrodes. However, the added ILs significantly increased sensitivities for both nanocarbons, relative to the IL‐free electrodes, and the G electrodes outperformed the MWCNT electrodes by 2× to 3×.2 processing and augmented with IL.2 processing.2 mixture at least 20% MeOH (Tc = 239 °C) by weight. Such a mixture is 74% mole fraction CO2 (relative to CO2 and MeOH) and has critical parameters of 71 °C and 13 MPa.2. Ionic liquids have been found to be most beneficial in electrocatalysis as well.Similar Pd–graphene composites prepared by scCO4.72, discussed below, catalyze thermal decomposition.Fire resistance benefitting from incorporating nanosheet materials into polymers and composite materials has been recognized, and multiple reviews are available for graphene,co‐acrylonitrile) nanocomposites with nanoclay were prepared by melt blending in an extruder to provide nanocomposite sheets. These sheets were then subjected to scCO2 and allowed to expand at sub‐critical 110 °C to produce foamed sheets. Nanoclay‐containing nanocomposites yielded decreased peaks of heat release rate, demonstrating efficacy in flame resistance relative to polymer‐only foam controls.2 to produce graphene nanosheets and exfoliated MnO2 nanosheets.2‐epoxy materials, mixed graphene/MnO2 epoxy resins exhibited a synergistic and increased degradation with increasing heating relative to separate nanofillers. However, a mixed graphene/MnO2 epoxy resin that also contained a phosphate amine component, DAP (diphenylamido phosphate), provided synergistically improved flame retardation. This combination incorporating phosphate resulted in increased “over char” retaining larger amounts of filler at up to 700 °C.Poly2 to control interfacial friction.2 was combined with citrate and surfactant (sodium dodecyl sulfate) in ethanol and then with GO and reducing agent , and then this suspension was infused with scCO2 at 18 MPa and 100 °C. Controlled depressurization after 2 h yielded Sc‐Ni/GO nanosheets uniformly covered with nickel nanoparticles. These nanosheets were used as an additive to liquid paraffin (LP), lubricant, as were nickel nanoparticles, GO, and nickel nanoparticle–covered GO (Ni/GO) controls. The performance of the Sc‐Ni/GO as an additive resulted in a lower coefficient of friction (COF) and smaller wear scar diameters (WSDs)Graphite's long‐known efficacy as a lubricant has made examining nanosheets as lubricants a natural application for investigation. Batteas and co‐workers have reviewed using nanosheets of graphene, graphane, fluorographene, MoS2‐processed Ag nanoparticles dispersed on GO in 10W40 engine oil.A similar study by Su and co‐workers addressed lubrication by scCO4.9The Gulari and co‐workers patent documents discussed earlier2O was used as a reaction medium for controlling oxidation,2 was used as a medium in which to do surface functionalization with SF6, O3, and BX3.TableSeveral of these efforts disclosed using intercalation driven by agents other than SCF.5Experimental process development, introductory dynamical modeling, and several application reports show that SCF processing of 2D materials offers advantages and possibilities of overcoming some limitations that accompany subcritical shear processing. Greater exfoliation, so far, can be obtained by exfoliation in subcritical liquids, and applications such as RFID fabrication, thermal absorption, dispersion stability, and coloration likely cannot be improved by SCF processing. More highly value‐added applications that seek defect density minimization, larger sheets, and higher electrical conductivity likely will benefit from advanced SCF processing, but more process development is needed. It has become apparent that the existence of defects depends a great deal on the source and process by which a particular type of 2D material is prepared. This is particularly evident for graphene.It appears that some synergistic effects can be realized by formulating SCFs with immiscible co‐solvents to make emulsification a process component. Certain other SCFs provide useful chemical effects with some 2D materials. The importance of chemical surface modification in promoting and stabilizing exfoliation cannot be overemphasized.2, molecular dynamics simulations have provided some mechanistic understanding of scCO2 graphenic sheet interactions.Some SCFs with mild (low) critical parameters provide exfoliation without any chemical effects, and for the case of scCOIt is important to distinguish exfoliation processing of “nonreactive” SCFs from SCF processing that concomitantly uses chemomechanical activation such as ultrasonication and externally applied high shear . X‐ray powder diffraction measurements should be taken at intermediate stages in between distinct processing regimens in order to better quantify intercalation and exfoliation events.When sedimentation or centrifugation steps are included in a process, the amount of material removed should be quantified gravimetrically. This will allow more meaningful tracking of dispersion efficiency, and allow more meaningful yields to be tracked and reported. Obviously, processing that obviates any need for centrifugation separation of large fractions of 2D materials is preferred when possible and when economically accessible.5.1Supercritical fluids provide excellent mass transfer, gas‐like diffusion coefficients, and very low viscosities.2 stabilization of graphenic sheets depends on supercritical density,A general discussion about using activation volumes for mechanistic studies has been provided by Wu and co‐workers.The most crucial role for a solvent in multiphase suspensions and dispersions is not solubility per se but wetting. For many highly dispersed systems, lack of solubility is preferred because it blocks unwanted growth through Ostwald ripening. When such growth is desired, it is a simple matter to include co‐solvents that will promote solubility and ripening.Solvation of nanosheet surfaces is another significant feature, and the vanishing of surface tension above a solvent's critical point makes spontaneous wetting of all available surfaces favorable. This wetting facilitates formation of physical mixtures of nanosheets and particles. Such mixtures also experience rapid interdiffusion of components because of low viscosity and high diffusion coefficients.Using SCFs because they do not chemically transform nanosheets is motivating for their use, and SCFs that are unreactive indeed are good candidates. Some SCF processing of 2D materials, wherein critical parameters are “mild”, offer a promise of facilitating exfoliation without leaving surfactant, polymeric, or solvent residues that interfere and thwart essential transport properties such as electrical and thermal conductivities. In cases of chemically reactive SCFs that vary with SCF and nanosheet composition, specific chemistries can be induced. In these cases, chemical modifications of 2D nanosheets by some SCFs are intrinsic under critical conditions and promote ripening, redox chemistries, heterostructure formation and Ostwald ripening, and doping. Also, when sonolysis forces are present, untoward or advantageous surface modification can be induced.Multiple studies of incorporating ultrasonication into high‐pressure SCF reactors have shown synergistic results. Coupling these two processing methods is very amenable to existing chemical processing technology. Coupling shear with SCF reactors has been demonstrated so far using two different shearing approaches, and for SCFs with “mild” critical parameters have performed satisfactorily.5.2No, of species, or even (No)1/10 will be helpful in characterizing defects per gram of material. Selected sampling by AFM or by HRTEM is much less statistically significant.A continuing challenge in SCF applications to dispersing 2D nanosheets is to know analytically how much nanosheet material has been dispersed. It is more difficult to do simple UV–visible absorption measurements of supercritical2 and MeOH, CO2 and EtOH) to become subcritical at conditions thought to be critical. Process development should be done with solvent combinations where Tc and Pc have been determined as a function of mole fraction of each solvent component, so that criticality can be tuned with confidence.Mixed solvent systems are becoming more important, including pairs of immiscible solvents as well as pairs of miscible solvents. Even in cases of immiscible solvents, there is finite co‐solubility of each in the other, so care must be taken in learning how a second solvent affects a mixture's supercritical parameters. We have discussed two examples wherein significant synergisms cause mixtures of SCFs . Ultrasonication will be used to have more significant advantages in inducing designed surface modificationPressurizationThe authors declare no conflict of interest.


Previous studies investigated the prognostic role of programmed death-ligand 1 (PD-L1) expression in patients with biliary tract cancer (BTC); however, the results remained controversial. Therefore, we conducted the current meta-analysis with the aim of clarifying the association between PD-L1 expression and prognosis as well as with several important clinicopathological features of BTC. We searched PubMed, Embase, and Web of Science for relevant studies. Studies that detected PD-L1 expression in tumor cells by using immunohistochemistry (IHC) were selected. Pooled hazard ratios (HRs) and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the correlations. In total, 15 independent studies with 1,776 patients were included in this meta-analysis. The pooled data demonstrated that high PD-L1 expression was associated with poor overall survival . The correlation between PD-L1 expression and disease-free survival was not significant . In addition, no significant correlation was observed between PD-L1 expression and clinical features in patients with BTC. Our study results showed that PD-L1 expression could play a pivotal role as an effective factor of poor prognosis in patients with BTC. Biliary tract cancer (BTC) is the second most common cancer among hepatobiliary cancers, and it is a heterogeneous group of gastrointestinal tumors . BTC incFurther understanding of the tumor immune microenvironment has led to the development of immunotherapy, which has garnered much attention in recent years , 9. ProgThe process of literature selection is presented in The characteristics of the included studies are shown in I2=25.9%, p=0.167); therefore, a fixed-effects model was adopted. As shown in The data between PD-L1 expression and OS were extracted from all the 15 included studies with 1,776 patients –25. The I2=65%, p=0.016), a random-effects model was applied. The pooled HR indicated that the correlation between PD-L1 expression and DFS was not significant . Therefore, we examined each included study separately. A total of 11 included studies , 18–25 rAlthough we strictly performed this meta-analysis according to the PRISMA guidelines and selected eligible studies with uniform criteria, the study has several limitations. First, although all included studies used IHC to detect PD-L1 expression, the cut-off values defining low/high PD-L1 levels were different, which may result in heterogeneity. Second, in studies that enrolled patients with iCCA+eCCA , 22, 23,In summary, our meta-analysis demonstrated that PD-L1 overexpression was associated with worse OS but not DFS of patients with BTC. The prognostic value of PD-L1 expression was significant for OS of patients with iCCA and eCCA. However, no significant correlation was observed between PD-L1 expression and clinical features of patients with BTC. These results indicate that PD-L1 could play a pivotal role as an effective factor of poor prognosis in patients with BTC. Nevertheless, as the study had several limitations, further large-scale, well-designed studies are needed to confirm our results.This meta-analysis was performed on the basis of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines . The datThe inclusion criteria for eligible studies were as follows: (1) BTC was diagnosed on histopathological examination; (2) immunohistochemistry (IHC) analysis of PD-L1 expression was conducted; (3) association between PD-L1 expression and OS and/or disease-free survival (DFS) was presented, or sufficient information was provided to compute the hazard ratio (HR) and 95% confidence interval (CI) ; (4) theData from candidate studies were evaluated and extracted by two independent investigators (C.L. and X.P.). Any disagreements were resolved through discussion. The following information was extracted from eligible studies: the first author’s name, publication year, number of cases, country, ethnicity, study period, patient age, tumor type, detection method, cut-off value for high expression of PD-L1, treatment method, HR and the corresponding 95% CI for OS and DFS, and clinicopathological characteristics. The quality of the included studies was assessed by using the Newcastle-Ottawa Scale (NOS) . The NOSI2 values > 50% and p-values <0.10 were considered to indicate significant heterogeneity, and the random effects model was applied. Otherwise, a fixed-effect model was implemented. Subgroup analysis—stratified by tumor type, ethnicity, and sample size—was performed. Sensitivity analysis was conducted to assess the reliability of the results. Meta-aggression analysis was conducted to identify the source of heterogeneity. Publication bias was measured by using both the Begg’s test and Egger’s test. P-values <0.05 were considered statistically significant.All statistical analyses were performed using Stata version 12.0 . The HRs and 95% CIs were used to assess the prognostic role of PD-L1 expression on the survival of patients with BTC. An HR >1 with a p-value <0.05 indicated a poor prognosis in patients with PD-L1 overexpression. The odd ratios (ORs) with 95% CIs were calculated to determine the correlations between PD-L1 expression and clinicopathological parameters. Statistical heterogeneity among studies was determined using the Cochran Q-test and I-squared test , 41. I2 Supplementary Figure 1