This review discusses the role of oxidative stress in the development and progression of IPF and its underlying mechanisms as well as the evidence of oxidative stress in human IPF. Finally, we analyze the mechanism of action, the efficacy and the current status of different drugs developed to inhibit the oxidative stress as anti-fibrotic therapy in IPF.Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by an abnormal reepithelialisation, an excessive tissue remodelling and a progressive fibrosis within the alveolar wall that are not due to infection or cancer. Oxidative stress has been proposed as a key molecular process in pulmonary fibrosis development and different components of the redox system are altered in the cellular actors participating in lung fibrosis. To this respect, several activators of the antioxidant machinery and inhibitors of the oxidant species and pathways have been assayed in preclinical  Among all the idiopathic interstitial pneumonias, the most common form is idiopathic pulmonary fibrosis (IPF), whose incidence is estimated to be ranged between 2.8 and 9.3 per 100,000 people per year in North America and Europe . IPF occAs the disease progresses, some pathological changes appear, including fibrotic lesions and accumulation of fibroblast in focal zones called “fibroblast foci,” which causes the characteristic “honeycomb” appearance. The etiologic stimulus that initiates the disease and the underlying mechanism of pulmonary fibrosis are still unknown or poorly understood. Current studies suggest that fibrosis may result from the presence of continuous stimuli (both endogenous and exogenous) or injury followed by an aberrant wound healing process and a dysregulated repair/remodelling of the lung .Lung fibrosis is associated with accumulation of fibroblasts, myofibroblast activation or differentiation, alveolar reepithelization, extracellular matrix (ECM) dysregulation, oxidative stress, and inflammation . Thus, fThis review addresses the importance of the balance of oxidants/antioxidants in the pathogenesis of pulmonary fibrosis as well as the evidence of oxidative stress in human IPF with emphasis on the pharmacological approach targeting oxidative stress.2•−), hydroxyl radical (HO•), and hydrogen peroxide (H2O2). RNS are molecules derived from the reaction between nitric oxide (NO) and O2 and derivates, one example is peroxynitrite. RNS can generate oxidative stress but also the named nitrosative stress  and reactive nitrogen species (RNS) production and antioxidant defence that leads to cellular dysfunction and tissue damage . ROS aree stress . Lungs, e stress .β (TGF-β). This growth factor is known to be modulated by ROS, indeed, experimental studies have evidenced that ROS can increase the secretion of TGF-β from epithelial cells and directly activate it , fibronectin and procollagen, which are the most characteristic profibrotic molecules , myeloperoxidase (MPO), xanthine oxidase, nitric oxide synthase (NOS), and the mitochondrial electron transport chain . From tholecules . Furtherolecules . It is wolecules  and thisolecules . Nox4 exolecules  and ROS olecules . Hyperplolecules  and Nox4olecules . Other solecules . In addiolecules . A studyolecules . It has olecules . Nox4 exolecules . Vasculaolecules , ROS genolecules .Whereas Nox4 is mainly expressed in fibroblasts and epithelial cells, Nox2, is primarily expressed by neutrophils and macrophages and, to a lesser extent, in structural cells  . In IPF • and NO-derived species may interact with different molecules and modify their function , neuronal (nNOS) and inducible (iNOS) . RNS arefunction . In IPF,function .Different studies have demonstrated that NO signal pathway may enhance TGF-β expression in lung fibroblasts and increase the expression of collagen type I and heat-shock protein (HSP) 47 . FurtherAs we have mentioned, mitochondria is a major source of ROS production due to the uncoupling of the electron transport chain  and thisThe lung counteracts the damage induced by ROS with a wide variety of antioxidant defences. This endogenous antioxidant system includes small-molecular-weight antioxidants , classic antioxidant enzymes , other antioxidant enzymes , phase II detoxifying enzymes , stress-response proteins , mucins (MUC), and metal binding proteins  . The nucIn lungs, these antioxidant enzymes are expressed by the bronchial and alveolar epithelial cells and macrophages  and diff2O2 and, therefore, inhibits H2O2-mediated fibroblast activation in IPF lungs , are highly expressed in the lungs. In addition, they play a critical role in induced pulmonary fibrosis models by preventing oxidative stress . It has Reduced GSH, a low-molecular weight antioxidant, is synthesized by bronchial epithelial cells and alveolar macrophages. Different studies supported that TGF-β1 suppresses gene expression of glutamate cysteine ligases (GCL), an enzyme implicated in the biosynthesis of GSH, in alveolar epithelial cells . OverexpGiven the accepted role of oxidative stress in IPF, it is essential to investigate the presence of oxidative stress biomarkers. These biomarkers could provide clues about the disease progression and prognosis as well as be useful in the clinical assessment of the patients. It was in 1987 when the presence of oxidative stress biomarkers was first described  in IPF pGSH is one of the antioxidant small molecule par excellence and one of the most measured biomarkers. Levels of this antioxidant molecule and its oxidized form, GSSG, have been measured as indicators of oxidative stress in multiple diseases. Regarding IPF, most of the studies reported lower levels of total GHS (reduced (GSH) + oxidized (GSSG), tGSH) and reduced GSH in IPF patients than in controls , just twin vivo and, thus, are biomarkers of oxidative stress , and among all the lipid oxidation products the most studied is the malondialdehyde (MDA). These biomarkers were found to be higher in IPF patients when compared to healthy controls . Jack ete stress . Concente stress . In addie stress .2O2 and in some cases, concentrations of this marker are higher in IPF patients, and a negative correlation between H2O2 and diffusing capacity of the lungs for carbon monoxide (DLCO) was observed  is a potent inhibitor of NOX, which specifically and irreversibly binds to flavin, the membranous component of the NOX. It is the most commonly used and well-studied Nox inhibitor; however, its irreversible binding, lack of specific, poor solubility and toxicity c option   through a high-throughput screening approach to discover small-molecule inhibitors targeting NOX enzymes . Both sm studies  .In 2010, GKT137831 was granted orphan drug status for the treatment of IPF by the European Commission and is currently in clinical trials for IPF. A phase 2 clinical trial of GKT137831 [GKT137831 in IPF Patients With Idiopathic Pulmonary Fibrosis (GKT137831)] has recently started and it is a placebo-controlled, multicentre, randomized trial to test GKT137831 in ambulatory patients with IPF. The primary outcome is the reduction of the circulating concentrations of o,o’-dityrosine, an oxidative stress biomarker. Changes in concentrations of the collagen degradation and FVC are some of the secondary outcomes  is an pression . These ppression .in vitro assays have demonstrated that NAC prevents GSH depletion in various cell types such as macrophages, epithelial cells, and fibroblasts , interleukin-8 (IL-8) and matrix metalloproteinase-9 (MMP-9) in epithelial cells, macrophages, and lymphocytes from patients with IPF .via the decrease of the amounts of hydroxyproline, fibrosis and several cytokines’ levels .The first clinical trial that assesses the effectiveness of NAC in IPF therapy was the IFIGENIA, which purpose was to determine whether NAC added to prednisone and azathioprine was more effective than the standard therapy with prednisone plus azathioprine. This study showed the three-drug therapy preserved VC and DLCO in IPF patients better than standard therapy  .In the IFIGENIA trial, all patients received the combination of the three drugs but none, NAC alone. Thus, in order to study the effectiveness of NAC monotherapy for the treatment of IPF, it was conducted the PANTHER trial. Initially, subjects who have IPF were randomly assigned to receive: 1) three-drug regimen , 2) NAC and placebo, or 3) placebo. After performing a midpoint analysis of the study, the three-drug regimen was stopped due to safety concerns. For this reason, the entire study was interrupted for 3 months but later continued. The primary outcome was the change in FVC over 60 weeks. Results showed that acetylcysteine offered no significant benefit concerning the preservation of FVC in patients with IPF when compared with placebo  .Following this line, a phase III clinical trial evaluating the efficacy and safety of combined therapy with pirfenidone and inhaled NAC for IPF was conducted in Japan. The primary outcome was a change in FVC. Data showed there was no difference between the two groups in the change in FVC. Therefore, combination therapy did not bring any clinical benefit  Univers (ClinicaTOLLIP) and MUC5B genes modified the efficacy of NAC. These genes have been associated with IPF susceptibility and survival. TOLLIP encodes toll-interacting protein (TOLLIP), which is inhibitory of toll-like receptors, which are, in turn, responsible for the activation of inflammatory, oxidative and immune response pathways. This post hoc study showed that NAC might improve prognosis in genetically predisposed individuals, specifically, those carrying an rs3750920 (TOLLIP) TT genotype .In 2015, a post hoc exploratory analysis of subjects enrolled in the PANTHER-IPF clinical trial was conducted to determine whether specific polymorphisms in toll-interacting protein .Furthermore, a further phase I/II open label pilot study has been recently proposed to investigate the safety and tolerability of inhaled NAC in patients with IPF. It is titled “Pilot Study to Evaluate Inhaled N-Acetylcysteine in Pulmonary Fibrosis.” The primary outcomes are changes in pulmonary function: FVC and DLCO. This study faced different challenges during enrolment due to the COVID-19 epidemic and it is withdrawn at this moment. It is estimated to start at the beginning of 2022 and finish at the end of 2023  is a polyphenolic plant flavonoid ubiquitously present in vegetables and fruit as well as tea and red wine . It is aX1, etc. . HoweverX1, etc.   and the diminish of total cells and macrophage counts in BALF. Moreover, treatment with liposomal quercetin produced a significant reduction of hydroxyproline content and apparently lessened areas of lung fibrosis and collagen deposition .As mentioned in the previous paragraphs, quercetin is able to reduce oxidative stress and fibrotic processes such as EMT in different IPF effector cells. In addition, several l trials  ” The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. This first-in-humans open-label pilot study provided initial evidence that senolytics may improve the 6-min walk distance in IPF  Summarized in Nevertheless, since e in IPF   is one most active phenolic acids extracted from pacities . It can pacities   Summarized in Nevertheless, in 2017 it was started an open label clinical trial of Chinese herbal medicine for IPF , whose aim was to determine whether treatment with the herbal formula PROLUNG could improve IPF symptoms, respiratory function and the quality of life compared with pretreatment baseline. The primary outcome was the annual rate of change in FVC. The PROLUNG formula contained, among others, Radix Epigallocatechin gallate (EGCG) is a polyphenol, the ester from epigallocatechin and gallic acid, and the major biological component of green tea, even though it can be also found in some other vegetables such as onions, hazelnuts and plums . EGCG hain vitro inducing fibroblast cell lines with TGF-β1. Simultaneous treatment with EGCG inhibited the increased fibroblast proliferation, reduced hydroxyproline levels and decreased expression of MMP-2 and -9, p-Smad, α-SMA and type I collagen. Thus, EGCG inhibited fibroblast activation and collagen accumulation by inhibiting TGF-β1 signalling   .Further studies demonstrated that EGCG administration alleviates the oxidative stress generated during bleomycin-induced pulmonary fibrosis in rat models. Furthermore, administration of this compound improved body weight and enzymic and non-enzymic antioxidants. It also decreased levels of ROS, lipid peroxidation, hydroxyproline, and the activity of myeloperoxidase. On the other hand, it increased cell counts. EGCG treatment also decreased the increased expression of nuclear factor-kB, TNF-α, IL-1b, MMP-2, and 9, TGF-β1, Smads, and α-SMA; restored the activities of antioxidant enzymes such as GST and NQO1; and induced Nrf2 .A study from 2014 showed that EGCG treatment provides antioxidant, anti-inflammatory, and anti-proliferative effects that protect against irradiation-induced pulmonary fibrosis in rats. Treatment with EGCG reduced mortality rates and lung index scores; improved histological changes in the lung; reduced collagen depositions and MDA content; enhanced SOD activity; inhibited (myo) fibroblast proliferation; protected alveolar epithelial type II (AE2) cells; and regulated serum levels of TGF-β1, IL-6, IL-10, and TNF-α. Treatment with EGCG also activated Nrf2 and its downstream antioxidant enzymes HO-1 and NQO-1 .in vitro studies that treatment with EGCG inhibits fibroblast proliferation, among others fibrotic processes, and, mainly, inflammatory processes. In several in vivo assays, it has been reported that EGCG provides antioxidant, anti-inflammatory and antifibrotic protection in different IPF models mainly via activation of the Nrf2 pathway.It has been demonstrated, as we have reviewed above, in ClinicalTrials.gov Identifier: NCT03928847) Summarized in Based on of these preclinical studies, in 2018, started an open label trial to test the effects of oral EGCG treatment on lung tissues and serum samples obtained from 20 patients with IPF and it is titled “Fibroblast Specific Inhibition of LOXL2 and TGFbeta1 Signaling in Patients With Pulmonary Fibrosis.” Half of the patients were given orally EGCG before they underwent biopsy, and the other half did not receive the treatment. EGCG treatment reversed profibrotic biomarkers in their diagnostic biopsies: type I collagen, snail family transcriptional repressor and phosphorylated SMAD3 levels were significantly lower in treated patients. This study is in an early phase; therefore, future results are expected in coming years   is an active compound in tivities . Due to tivities . It has tivities   axis in rats. Later, other studies demonstrated that TanIIA mitigates bleomycin-induced pulmonary fibrosis, myofibroblast activation, collagen deposition, inflammatory cell infiltration and pro-inflammatory cytokine release in murine models  is a nonflavonoid polyphenolic compound found in multiple plant species, including grapes and peanuts. Resveratrol has been reported to exert a vast number of health benefits, such as antioxidant, anti-inflammatory, antifibrotic, antiviral, and anticancer activities, through many different mechanisms of action . SeveralResveratrol was demonstrated to inhibit both fibroblast proliferation and differentiation into myofibroblast. In addition, different results demonstrated that resveratrol represses TGF-β1-induced collagen production, lung fibroblast proliferation  and attenuates α-SMA expression . He et aResveratrol has been shown to produce antifibrotic effects in murine models of various diseases such as renal, cardiac, and hepatic fibrosis . In the in vitro and in vivo assays, as we have explained above. Nevertheless, it seems the obtained results have not provided sufficient preclinical evidence to consider resveratrol a good candidate for human trials. Indeed, none of the clinical trials on resveratrol registered in https://clinicaltrials.gov regards lung diseases.It has been demonstrated resveratrol is able to inhibit several fibrotic processes through suppression of oxidative stress in via the Nrf2-mediated induction of phase II detoxifying enzymes (Sulforaphane (SFN) is an organosulfur compound, mainly found in cruciferous vegetables, with indirect antioxidant activity  enzymes  .As we have mentioned above, several Melatonin (N-acetyl-5-methoxytryptamine) is the main secretory product of the pineal gland and, along with its metabolites, is a potent antioxidant with lipophilic and hydrophilic characteristics . Melatonvia activation of the Nrf2 signalling pathway in mouse lung epithelial cells  is a polyphenol compound, contained in the spice turmeric and isolated from the rhizome of the plant Curcuma longa. Curcumin has been found to have a multitude of pharmacological properties such as anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects appear to involve the regulation of various molecular targets, including transcription factors, growth factors, inflammatory cytokines, protein kinases and other enzymes. Curcumin exerts its antioxidant activities directly, by scavenging superoxide anion and hydroxyl radicals, and indirectly by, among others, activating the Nrf2 pathway and inducing the expression of different antioxidant enzymes such as HO-1  Figure .2O2 and to block the radiation-induced generation of ROS by upregulating the expression of Nrf2 and HO-1  is an oral broad-spectrum drug and is one of the two pharmacological treatments recommended for the treatment of IPF. Although no specific mode of action has been identified, PFD possesses antifibrotic, anti-inflammatory, and antioxidant properties  Figure .Regarding its antifibrotic potential, cell culture experiments on human lung fibroblasts and alveolar epithelial cells have revealed that PFD is able to inhibit fibroblast proliferation, myofibroblast differentiation, collagen synthesis, fibronectin production, deposition of ECM components, and α-SMA and HSP47 expression . VariousRegarding its antioxidant properties, PFD has been reported to reduce ROS production, as it is a scavenger of hydroxyl and superoxide anion free radicals . It has Several studies have demonstrated the antifibrotic and anti-inflammatory effects of PFD in experimental animal models, especially in bleomycin-induced pulmonary fibrosis models. These studies revealed that PFD prevents the accumulation of hydroxyproline, collagen I and III, inflammatory cells and TGF-β1 in BALF, and/or lung tissue .In the 1990s, studies in hamster models of fibrosis indicated that PFD ameliorates bleomycin-induced lung fibrosis by suppressing oxidative stress mediators, such as MDA and MPO, and enhancing SOD activity . PFD hasin vitro and in vivo models of IPF, even though we have only highlighted the results regarding its antioxidant potential. The significant number of evidence made PFD a perfect candidate for human clinical trials.The antioxidant and antifibrotic potential of PFD has been extensively demonstrated both Although there are multiple trials to test the efficacy of PFD in humans for IPF treatment, only four phase III clinical studies of PFD in IPF have been completed and reported . Two opeClinicalTrials.gov Identifier: NCT00287716 and NCT00287729). Another phase III trial, ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis) study was conducted between 2011 and 2014. This trial confirmed that PFD reduces disease progression, as improved lung function, exercise tolerance, and progression-free survival  Summarized in Between 2006 and 2011 the CAPACITY  phase III trial was conducted. This programme included two similar multinational trials (studies 004 and 006). The results of the two integrated trials showed a significant improvement in the lung function, the primary outcome, but also in progression-free survival time, in the change in FVC and in the associated death   is a glutamic acid derivative that was initially prescribed as a sedative and antiemetic drug but it was removed from the market for its teratogenic effects . Thal poThal was reported to reduce IL-18, IL-8 and TNF-α release from LPS-induced alveolar macrophages . Additiop-JNK and α-SMA .Thal is currently used in the treatment of multiple myeloma, but its use in other diseases is restricted due to its teratogenic effects . NeverthClinicalTrials.gov Identifier: NCT00600028) Summarized in On the other hand, there is a phase III trial testing the efficacy of Thal in suppressing the chronic cough of IPF . The primary endpoint was the cough-specific quality of life measured by the Cough Quality of Life Questionnaire (CQLQ) and results showed that Thal improved cough and respiratory quality of life in IPF patients  fibroblasts and epithelial cells, and it contributes to the alteration of different processes such as migration, senescence, differentiation and EMT among others. It is, therefore, logical to think that Nox4 and Nox1 are promising drug targets for IPF. The specificity of these small molecules helps in avoiding off-target effects and in the determination of the effective dose, which is usually lower than in the case of broad-spectrum drugs. Preclinical assays both in vitro and in vivo models, but there is a lack of evidence for its efficacy in humans. The last NOX inhibitor mentioned in this review is metformin. In this case, in vitro and in vivo assays have shown that metformin is able to attenuate or reverse lung fibrosis processes; however, retrospective human clinical studies have reported that metformin is ineffective for the treatment of pulmonary fibrosis in diabetics patients with IPF.Apocynin had been considered as a NOX inhibitor for a long time; however, it has been recently demonstrated that it is a ROS scavenger. Therefore, like many other natural ROS scavengers, such as flavonoids, it has demonstrated beneficial effects in Antioxidant enhancers and ROS scavengers are usually more tolerated than NOX inhibitors, but, on the other hand, their efficacy is also lower.in vitro and in vivo suggested that it could be an appropriate option for treating the oxidative stress occurring in IPF. Indeed, it has been reported to be effective in the treatment of other diseases such as Chronic Obstructive Pulmonary Disease (COPD) or bronchitis. However, the successive clinical trials have not reported successful results. On the other hand, the PRECISIONS trial has opened the door to a much more personalised therapy, based on the genetic characteristics of each patient and, probably, it is the key for the treatment of such diseases as IPF, which is characterised by the existence of several phenotypes. Additionally, another recently proposed study aims to test the effectiveness of NAC administered by inhalation. The change in the administration could improve its effectiveness as the drug would act directly in the lungs, where the damage is occurring. However, given all the results, treatment with NAC alone would be very unlikely to be effective in curbing fibrosis.Among all the antioxidant enhancers, NAC is probably one of the most studied for the treatment of pulmonary fibrosis. Its promising results both in vitro and in vivo preclinical fibrotic models however their clinical utility as antifibrotic agents is more than questionable. Natural compounds like these are usually very well tolerated with no toxic effects, but, on the other hand, they are less effective than other chemical derived drugs. Furthermore, they have no specific mode of action: they can have a multitude of targets or be ROS scavengers by themselves. The lower efficacy together with the lack of specificity makes it difficult to establish an effective dose to reach an acceptable clinical efficacy. Therefore, these drugs are more indicated for prevention than for treatment of diseases such as IPF and they could be useful in combination with other antifibrotic drugs.Many of the antioxidant compounds studied in this review are natural flavonoid or polyphenols compounds such as Quercetin, Sal B, EGCG, TanIIA and STS, resveratrol and curcumin. These compounds have shown a strong antioxidant and, in many cases, anti-inflammatory power in in vitro and in vivo assays demonstrating the benefit of using these kinds of antioxidants to treat diseases such as IPF, the reality is that the use of antioxidants in clinical trials has shown to be predominately ineffective  may be carefully studied. Chronic treatment with melatonin may have the opposite of the desired effects, so it may not be a good option for the treatment of fibrosis, since is a chronic disease. Furthermore, melatonin is heavily involved in circadian rhythms and altering its levels in the body can have detrimental effects. On the other hand, its use could be useful at specific times during the treatment of fibrosis.in vitro and in vivo studies have shown that PFD has potent antioxidant effects. However, probably, a large part of these effects is due to its main antifibrotic effect. PFD has several mechanisms of action, many of which are still unknown. Due to the difficulty in determining its specific mechanisms of action, it cannot be said PFD to be a pure antioxidant drug or to have a main antioxidant power.In this review, we have also mentioned the PFD, one of the antifibrotic drugs par excellence and one of the two currently approved drugs for the treatment of IPF. As we have reviewed here, several Another of the drugs already used in clinical practice that we have discussed in this review is Thal. In this case, Thal, in addition to its teratogenicity, which severely limits its use, has been reported ineffective in treating IPF in humans in different clinical trials. Although preclinical studies may suggest that it has anti-fibrotic effects, the reality is that the use of thalidomide for the treatment of IPF is out of the question. Thal is being tested to treat the chronic cough associated with IPF, however, four clinical studies are currently underway investigating P2X3-receptor antagonists as potential antitussives, the results are promising and they are safer than Thal . TherefoFinally, we have discussed some recently designed SOD mimetics, such as AEOL10150, AEOL 10113 and MnTBAP. These compounds, in contrast to most of the seen above, have a more specific mechanism of action, making it easier to determine the most effective concentration. Furthermore, the use of designed compounds that mimic a biological molecule avoid the complications arising from the use of the biological molecule itself, that, in this case, would be, primarily, the SOD molecule. These compounds, together with the synthetic NOX-inhibitors GKTs, are possibly the ones with the most promising future. However, more research is needed on these compounds before they can be considered suitable for clinical trials.in vitro and in vivo models and in different clinical trials. In this review, we have highlighted the role of oxidative stress in the pathology of lung fibrosis and its underlying mechanisms. However, the principal aim of this review is to analyze the mechanism of action, the efficacy, and the current status of different drugs able to protect against oxidative stress and act as antifibrotic therapy in IPF. Several more antioxidant molecules can be considered as potential therapeutics for lung diseases but have not been included in this review due to the lack of enough experimental evidence in lung fibrosis; however, they can be consulted in different reviews (Idiopathic pulmonary fibrosis is the major idiopathic interstitial pneumonia with no cause identified and it is characterized by cellular proliferation, interstitial inflammation, and a chronic and progressive fibrosis. It usually does not respond to traditional therapies such as anti-inflammatory and immunomodulatory treatments. Several studies have suggested that increased oxidative stress may play a central role in the development and progression of IPF; indeed, cellular participants in lung fibrosis show, in most cases, an imbalance between oxidants and antioxidants. In addition, the massive number of oxidative stress biomarkers described in patients with IPF have evidenced the involvement of ROS in the pathogenesis of the disease. Regarding this, several ROS scavengers and modulators of the antioxidant machinery have been tested as potential therapeutics for lung fibrosis in preclinical  reviews .Despite the evidence of the significance of oxidative stress in the progression and development of IPF, as well as the anti-fibrotic effect that many antioxidants have been reported to have, it is unlikely that antioxidant monotherapy will be able to reverse or halt IPF progression, as its efficacy is partial. However, the use of antioxidant drugs may serve to improve some aspects of the disease and may be useful in combination with anti-fibrotic drugs. This situation is not unique to IPF but also occurs with other complex diseases such as cancer , where aTherefore, antioxidant therapies in IPF should probably be focused on complementing other more efficient antifibrotic therapies.


Moreover, sensitivity of 2.02 × 105 λ/RIU can be achieved with monolayer graphene, the thickness of gold layer is 20 nm, silver layer is 15 nm, and the hBN thickness of 492 nm. This heterogeneous infrared sensor has the advantages of high sensitivity and strong stability. The research results will provide a theoretical basis for the design of a new high-sensitivity infrared band sensor.In this paper, a bimetallic sensor based on graphene-hexagonal boron nitride (hBN) heterostructure is theoretically studied. The sensitivity of the sensor can be improved by enhancing the Goos–Hänchen (GH) shift in the infrared band. The theoretical results show that adjusting the Fermi level, the number of graphene layers and the thickness of hBN, a GH shift of 182.09  Goos–Hänchen (GH) shift refers to the slight lateral deviation of the actual reflected beam relative to the geometrical optics predicted beam when the beam is reflected at the interface between the media. Since it was demonstrated by Goos and Hänchen in 1947 , narrow 2) have excellent optoelectronic characteristics such as high electron mobility and adjustable external field [6 [2 heterostructure, under the action of two MoS2 layers and three layers of graphene at the 632.8 nm band, the maximum GH shift is obtained and the optimum sensitivity of 5.545 × 105 λ is achieved [In recent years, two-dimensional materials represented by graphene and molybdenum disulfide , the minimum reflectivity can be obtained. Thus, the phase mutation will be caused, and a large GH shift will be produced.The analysis structure of K-R is shown in λ is the incident wavelength and the unit is μm. According to the Drude-Lorentz model, the dielectric constant of the metal layer is [In this device, the dielectric constant of BK7 is given by the relationship (1)ε1=1.layer is (2)εm=1−m = 2,3. Here pλ = 1.4541 × 10−7 m and cλ = 1.7614 × 10−5 m correspond to the collision and plasma wavelengths of the Ag, respectively. For Au, pλ = 1.6826 × 10−7 m and cλ = 8.9324 × 10−6 m.Among them, hBN has two infrared different reststrahlen active optical phonon modes in the infrared band. Its dielectric constant can be expressed as (3)εu=ε∞a,b axis direction of crystal face), z axis . γ represent the high frequency dielectric constant and attenuation constant respectively. All data parameters here are taken from the literature [In the formula, terature .σ of graphene can be described in Kubo’s form. Without considering the external magnetic field, the surface conductivity σ of graphene can be expressed as the sum of in band conductivity and inter band conductivity [The surface conductivity uctivity (4)σintrT is the temperature in K and we set it to 300 K. Moreover, Here, The dielectric constant of the sensing layer can be expressed asFor multilayer structures, we can use the improved transfer matrix method to analyze the reflection phase (essed as (7)M=DBKD represents the transfer matrix at the interface, and P is the propagation matrix in the medium. Then we can get λ is the corresponding incident wavelength.Here, e method (8)DGHS=ΔDGHere, λ = 10.176 μm. Also, the corresponding parameters are gradually optimized to improve the sensitivity of the structure.Since the refractive index of the sensing layer of composite structure has a significant impact on the GH shift, the sensor based on GH shift interrogation mode can achieve the sensor performance by monitoring the GH shift signal. However, if the GH shift is too small, it may lead to errors in the monitoring results or not get better sensitivity, which will affect the application of refractive index sensor in real life. There are some important parameters of the composite structure that affect the GH shift, such as Fermi energy, the number of layers of graphene, thickness of hBN, and thickness of bimetal. The optimal sensitivity of the sensor can be obtained by finding a group of optimal structural parameters. Here, it is assumed that the incident wavelength of TM-polarized beam is FE = 0.2 eV, the reflected phase curve is the steepest. More importantly, two obvious features of GH shift can be found in FE = 0.2 eV, the normalized GH shift of 182.09 λ can be obtained near the resonance angle. These phenomena further confirm the validity of regulating GH shift by voltage. This provides an effective way to enhance the GH shift flexibly and obtain the optimum sensitivity of the structure.First of all, the influence of Fermi energy on the reflectance, reflected phase and GH shift can be plotted and the corresponding curve is drawn in N < 6, where N is the number of layers), the optical conductivity of graphene with a small number of layers can be approximately expressed as Nσ if only considering the graphene sheets of each single atomic layer are non-contact [λ is obtained. Then, as the number of graphene layers increases, the reflectance in λ in this composite structure. As mentioned above, if the sensitivity of the sensor is to be improved, the GH shift of the structure should be enhanced first, because this can make the detection of GH shift signal more accurate and convenient, and the sensitivity of the sensor can be improved correspondingly. It can be known from Note that for graphene with a small number of layers  can be obtained at θ = 64.72° by calculation. Therefore, the Au thickness of 20 nm and silver thickness of 15 nm are considered in the study of the composite structure, which is more convenient to obtain the ideal sensitivity.We know that Ag is the most suitable material for providing high sensitivity, while Au has great advantages in excellent oxidation resistance and better chemical stability. Therefore, it is necessary to select the thickness of each layer reasonably for obtaining higher sensitivity and stability. In FE = 0.2 eV. Here, we will consider the sensitivity regulation of Fermi energy when the composite structure is applied to the sensor. In In the previous discussion, we mentioned that Fermi energy has a great influence on GH shift and obtains a large GH shift (182.09 λ) at sn of the sensing layer will be discussed in sn of the sensing layer is plotted. When the refractive index changes between 1.2~1.35 RIU, the sensitivity curve changes drastically, and the sensitivity is higher in this range. Based on these two reasons, the variation of the refractive index of the sensing layer within this range is more convenient for detection in applications. At this time, the sensitivity can be achieved 1.76 × 104 λ/RIU, while the refractive index is 1.252. As mentioned before, the GH shift can be enhanced by increasing the hBN thickness. Therefore, the sensitivity curve is plotted in 5 λ/RIU when the refractive index is 1.306. However, in After setting the structural parameters, the dependence of the sensitivity of the GH shift on the refractive index 4 λ/RIU. Also, the sensitivity of the sensor can reach 2.02 × 105 λ/RIU when the thickness of hBN is 492 nm, but the sensor can only be used to detect samples with high refractive index. Therefore, the thickness of hBN should be determined according to the refractive index of the sample. These results can provide a theoretical basis for the design of refractive index sensor with high sensitivity and accuracy in infrared band.In summary, we propose a bimetal structure based on graphene-hBN to enhance the GH shift in the infrared band and design a sensitivity-tunable refractive index sensor based on the GH shift. The results of numerical simulation show that when the Fermi energy is 0.2 eV, a large GH shift can be obtained in monolayer graphene. In addition, when the thickness of gold layer is 20 nm, silver layer is 15 nm, and the thickness of hBN is 131 nm, the sensitivity of the sensor can reach 1.76 × 10


In this work, we have investigated the influence of the transfer process on the monocrystalline graphene in terms of quality, morphology and electrical properties by analyzing the data obtained from optical microscopy, scanning electron microscopy, Raman spectroscopy and electrical characterizations. The influence of Cu oxidation on graphene prior to the transfer is also discussed. Our results show that the controlled bubbling electrochemical delamination transfer is an easy and fast transfer technique suitable for transferring large single crystals graphene without degrading the graphene quality. Moreover, Raman spectroscopy investigation reveals that the Cu surface oxidation modifies the strain of the graphene film. We have observed that graphene laying on unoxidized Cu is subject to a biaxial strain in compression, while graphene on Cu oxide is subject to a biaxial strain in tension. However, after graphene was transferred to a host substrate, these strain effects were strongly reduced, leaving a homogeneous graphene on the substrate. The transferred single crystal graphene on silicon oxide substrate was used to fabricate transmission line method (TLM) devices. Electrical measurements show low contact resistance ~150 Ω·µm, which confirms the homogeneity and high quality of transferred graphene. The extraordinary properties of graphene has garnered much attention, and has motivated researchers to investigate its technological applications due to its high electrical and thermal conductivities, flexibility and stability ,4,5,6,7.2 substrate using an optimized electrochemical delamination method as presented in the In this study, large isolated graphene monocrystals of millimeter scale dimensions (~5 mm) have been synthesized on polycrystalline Cu foil . After tIn this section, we present the detailed analysis of the bubble-free transfer process on the morphology and on the physical and electrical properties of the synthesized monocrystal of graphene.The synthesis of millimeter size monocrystalline graphene—first reported in Ref. —begins w2 plasma etching  before being subjected to delamination.Firstly, thin layer of 5% PMMA (polymethyl methacrylate) diluted in anisole was spin-coated onto graphene on one side of the Cu foil . Next, the sample (PMMA/graphene/Cu) was cured at 90 °C for 30 min with very slow heating and cooling rates (30 min), in order to prevent cracks in graphene caused by the strain induced in PMMA resist. Because the graphene was grown on both sides of the Cu foil, the graphene on the back-side was removed by O2O causes the generation of H2 bubbles at the Cu-graphene interface:For electrochemical delamination “controlled bubbling transfer”, PMMA/graphene/Cu stacks were immersed gradually in KOH solution (40 mmol/L) and a two-electrode system held at a potential of 2.7 V. A continuous voltage was then applied between the cathode (the polymer/graphene/Cu sample) and anode (glassy carbon rod) in an electrolytic cell. KOH was used as the electrolyte solution and the decomposition of H2 bubbles help separate graphene from the Cu surface. However, the uncontrolled production of hydrogen bubbles can cause mechanical damage in the graphene film. Complete delamination occurs within a few minutes (≤20 min). The graphene/PMMA film was then thoroughly rinsed (10 times) in deionized water to ensure the removal of residual KOH.H2 substrate and dried at 90 °C for 30 min with very slow heating and cooling rates (30 min) in order to remove the water trapped underneath the graphene. The complete delamination and transfer process of graphene is presented in the 2  are present in all areas except the black ones corresponding to the substrate. The blue spectrum in 2D/IG ~ 2. The red and green spectra also feature the G and 2D peaks, but have extra peaks between 900 cm−1 and 1500 cm−1 as represented in −1), a signature of structural defects in the graphene. The D peak is only observed at the edge of graphene  [The absence of the D peak away from the edge of graphene as well as the presence of G and 2D peaks in areas pointed by the red and blue circles with an intensity ratio Ind Cu2O) ,29. ThesThe electrochemical delamination method described above was used to transfer the isolated large crystal graphene samples with and without air post-growth annealing. The optical images in 2. Four samples with and without post-growth annealing were studied and the Raman spectra of one of the samples measured after graphene transfer is depicted on 2D/IG of ~3. This confirms that the graphene is a single monolayer and that it remains homogeneous after transfer. The full width at half maximum (FWHM) is ~29 cm−1, which emphasizes the high quality of the crystal.Raman spectroscopy gives quantitative information on the quality of graphene. It allows to quantify the presence of structural defects, the level of graphene doping following the transfer and the evolution of stresses in the graphene layer. The 473 nm laser was focused to a spot size of ~1 µm with a power of ~2 mW and ~0.1 mW respectively for measurement on Cu and SiOThe positions of the G and 2D peaks are compared in G and ν2D, the integrated intensities IG, I2D and the intensity ratio I2D/IG as a function of position.This study is based on a vector decomposition method developed to study the influence of strain and doping on graphene as described in references ,31. The G0 = 1582 cm−1, ν2D0 = 2707 cm−1) using an excitation laser at 473 nm. The blue line (biax. strain) represents a prediction of  for an undoped graphene under biaxial stress. The orange line (p-doped) and the pink line (n-doped) represent predictions of  for strain-free graphene under p or n charge doping respectively.We have represented the frequency of the 2D peak as a function of the frequency of the G peak as shown in The Raman analysis was performed on several graphene samples before transfer showing similar results, one of them is presented in a. The gr2) as shown in 2 is p-doped [G, ν2D) for strain-free graphene with p doping in the range 0 < p < 4 × 1012 cm−2. Moreover, it can be seen that the graphene biaxial strain is almost completely relaxed after transfer onto Si/SiO2 as shown in 2D/IG < 2 is highly doped.The Raman analysis was also done for four samples after graphene transfer  has been developed. The applied potential and controlled generation of hydrogen bubbles play an important role in this electrochemical delamination approach. This transfer method is faster than the Cu wet chemical etching method (a few minutes versus a few hours). The quality of graphene is verified by different comparative pre- and post-transfer characterization approaches, including electrical, SEM and Raman spectroscopy.sh = 797 Ω/square and a contact resistance of 150 Ω.µm with Ni/Au contacts. Thus, the electrochemical delamination transfer process paves a path to easy and fast transfer of graphene maintaining its quality and its electrical properties.We have also studied the impact of an extra post-growth annealing step on the Cu oxidation on the large single-crystal graphene. The Cu oxidation is non-uniform under the graphene crystals. The graphene on oxidized Cu is under biaxial tension, whereas the areas where graphene is laying on non-oxidized Cu exhibits biaxial compressive strain with a low doping. Moreover, after graphene was transferred to a host substrate, the strain was strongly reduced, and the graphene doping can vary depending on the host substrate. The electrical characterization of devices on a graphene single crystal shows a sheet resistance of ρ


Graphene is a promising building block material for developing novel photonic and optoelectronic devices. Here, we report a comprehensive experimental study of chemical-vapor deposited (CVD) monolayer graphene’s optical properties on three different substrates for ultraviolet, visible, and near-infrared spectral ranges (from 240 to 1000 nm). Importantly, our ellipsometric measurements are free from the assumptions of additional nanometer-thick layers of water or other media. This issue is critical for practical applications since otherwise, these additional layers must be included in the design models of various graphene photonic, plasmonic, and optoelectronic devices. We observe a slight difference (not exceeding 5%) in the optical constants of graphene on different substrates. Further, the optical constants reported here are very close to those of graphite, which hints on their applicability to multilayer graphene structures. This work provides reliable data on monolayer graphene’s optical properties, which should be useful for modeling and designing photonic devices with graphene. Graphene is one of the most attractive materials for the development of promising new photonic, plasmonic, and optoelectronic devices ,4,5,6,7.It is well-known that graphene is easily contaminated by adsorbing water and other organic and inorganic compounds ,34, but,2/Si substrates. The optical properties were investigated by highly accurate variable-angle spectroscopic ellipsometry /Si, fused quartz, and optical glass. Before measurements, graphene samples were washed and annealed in a vacuum chamber to remove polymer residuals and water. The high quality of monolayer graphene films was confirmed by atomic force microscopy (AFM), optical microscopy, and scanning electron microscopy (SEM). The AFM scan image of the graphene on SiO2/Si in −1) and G (1587 cm−1) bands (>2) indicates the single layer of graphene, and the low intensity of the D band (1347 cm−1), shows its high quality (All monolayer graphene films were prepared (see Methods) through chemical vapor deposition. Monolayers of graphene grown initially on copper foil were wet-transferred to three various substrates: SiO quality e. Additi2/Si sample, in which the percentage contribution of sp2-graphene, C–O and C=O bonds to C1s are 80.72%, 14.89% and 4.39%, respectively. To investigate the surface composition on top and under the graphene, we made the angle-resolved XPS measurements for the C1s and O1s core level signals in the range of take-off angles from 10° to 70° (measured from the sample surface) that can change the explored depth  and their contribution to the accuracy of graphene dielectric response characterization, we performed X-ray photoelectron spectroscopy. epth see  28]. Bo. Bo2/Si rp/rs, where rp and rs are sample’s reflection amplitude for p- and s-polarized light. First, we analyzed these Ψ and Δ data by point-by-point inversion to get the initial results presented in We performed spectroscopic ellipsometry (SE) measurements at multiple incident angles to explore the dielectric response of graphene samples, Interestingly, graphene’s optical response is similar in shape to other carbon materials such as graphite  and sing2/Si) to explore substrate effect, which could explain discrepancies observed in the literature for graphene optical constants. We proceeded with the same procedure as for quartz: first, with the point-by-point approach and the Drude–Lorentz model afterward. The resulting parameters for the Drude–Lorentz model and corresponding optical constants for graphene on quartz, glass, and SiO2/Si substrates are collected in We also investigated graphene transferred on different substrates  with a 20 nm thickness on top of the standard SiOs design . We evals design , the zers design , zero rehttps://graphene-supermarket.com accessed on 27 April 2021). Graphene was grown via chemical vapor deposition on a copper foil and wet-transferred onto silicon wafer covered by a 285-nm-thick layer of SiO2, glass , and fused quartz  substrates. Monolayer graphene covered about 95% of the substrate area. Before measurements, graphene substrates were washed in acetone and isopropyl alcohol baths and annealed at 200 °C in a vacuum chamber 10−6 Torr for more than 1 h to remove residual PMMA and water after the transfer process.Full area coverage graphene samples were purchased from Graphene Laboratories Inc., Ronkonkoma, NY, USA . All measurements were carried out using linearly polarized excitation at wavelength 532 nm, 1800 lines/mm diffraction grating, and × 100 objective (N.A. = 0.90). Meanwhile, we used unpolarized detection to have a significant signal-to-noise ratio. The spot size was ~0.4 µm. The Raman spectra were recorded with 0.9 mW incident powers and an integration time of 10 s at each point. The statistics were collected at least 10 points for each sample.For the detailed study of the transferred CVD graphene optical response, we carried out the angle-dependent measurements of the O1s and C1s core level XPS spectra to determine contaminants’ presence on top of graphene. Three take-off angles, 10°, 40° and 70° (measured from the surface of the sample), were used to change the explored depth in XPS measurements. In order to investigate the contributions of different bonds, the core-level spectra of the O1s and C1s were decomposed using the XPS peak fitting software package.The roughness and homogeneity of the graphene were measured by an atomic force microscope . The surface images (2400 × 2400 pixels) of the graphene samples were captured by an optical microscope  with a digital camera DS-Fi3. To investigate graphene’s surface, we additionally used the scanning electron microscope using the acceleration voltage of 3 kV .ε0 is the vacuum dielectric constant, ħ is Planck’s constant, ρ is the resistivity, τ is the mean scattering time, and AL, BL, and EL are the amplitude, the linewidth, and the resonance energy of the Lorentz oscillator.Spectroscopic ellipsometry was performed at room temperature at multiple incident angles , over a broad spectral range from 240 to 1000 nm (1.24–5.17 eV). The measurements were done using a variable-angle spectroscopic ellipsometer . To avoid any crushes or large tears of graphene, we measured samples in different areas, excluding from consideration the areas close to the edges where graphene’s substrate coverage is minimal. For ellipsometry analysis we implemented the Drude–Lorentz model :ε=εDrude2/Si substrates. To obtain an accurate dielectric function suitable for engineering purposes, we thoroughly cleaned and annealed our samples prior to measurements and carried out XPS analysis confirming an ultra-low level of contamination on the graphene’s surface. As a result, we achieved good convergence using a simple ellipsometric model comprising layers of substrate and graphene layer, without auxiliary layers, which are typically introduced to account for residual water and PMMA. The accuracy of the measured optical response was further confirmed by transmittance measurements, which demonstrate remarkable agreement with calculations based on the measured optical constants. Notably, our optical constants show less than 5% variation with changes of the substrate and are very similar to those of graphite, which implies that the measured optical constants are applicable to multilayer graphene structures as well. From a broader perspective, our work provides accurate and universal graphene optical response for the design of photonic devices.To summarize, we have presented a UV-visible-near-IR (240–1000 nm) spectroscopic ellipsometry of graphene grown by chemical vapor deposition and transferred onto glass, quartz, and SiO


Graphene-based devices have important applications attributed to their superior performance and flexible tunability in practice. In this paper, a new kind of absorber with monolayer graphene sandwiched between two layers of dielectric rings is proposed. Two peaks with almost complete absorption are realized. The mechanism is that the double-layer dielectric rings added to both sides of the graphene layer are equivalent to resonators, whose double-side coupled-cavity effect can make the incident electromagnetic wave highly localized in the upper and lower surfaces of graphene layer simultaneously, leading to significant enhancement in the absorption of graphene. Furthermore, the influence of geometrical parameters on absorption performance is investigated in detail. Also, the device can be actively manipulated after fabrication through varying the chemical potential of graphene. As a result, the frequency shifts of the two absorption peaks can reach as large as 2.82 THz/eV and 3.83 THz/eV, respectively. Such a device could be used as tunable absorbers and other functional devices, such as multichannel filters, chemical/biochemical modulators and sensors. Monolayer graphene, a semimetallic two-dimensional material of hexagonally arranged carbon atoms, has attracted significant attention due to its extraordinary mechanical, thermal, electronic, and optical properties. Similar to three-dimensional noble metal nanoparticles, monolayer graphene can also support surface plasmon-polaritons (SPPs), and it exhibits more remarkable properties such as flexible electrical tunability, strong light confinement, and relatively low ohmic losses ,2,3,4. DRecently, great attention has been devoted to graphene-based absorbers. However, the absorption of monolayer graphene is very low. In order to solve this problem, some strategies have been proposed. For instance, high-efficiency absorbers have been realized by designing graphene patterns with different shapes, such as split ring, fishing-net and E-shaped models ,15. AnotIn this paper, in order to improve the absorption of monolayer graphene and simultaneously keep the size of device compact, a new kind of absorber with monolayer graphene sandwiched between two layers of dielectric rings is proposed. The double-layer dielectric rings equivalent to resonators that are symmetrically added to both sides of monolayer graphene. Due to the double-side coupled-cavity effect, almost complete absorption is obtained. The influence of geometrical parameters on absorption performance is further discussed in detail. Also, the result demonstrates that a wide frequency range of absorption spectrum could be tuned by varying the chemical potential of graphene. Such a device could be used as tunable absorbers and other functional devices, such as multichannel filters, chemical/biochemical modulators and sensors.Here, there are two points need to be emphasized. Firstly, different from some research in which only single-side coupled-cavity structures have been investigated ,28,29, tnsub = 1.45, monolayer graphene is sandwiched between two layers of identical dielectric-ring arrays. The dielectric is chosen as silicon with refractive index nsilicon = 3.4. The upper and lower layers of dielectric-ring arrays are symmetric with respect to the graphene plane. The lower layers of dielectric-ring arrays are embedded in polymethyl methacrylate (PMMA) layer with refractive index nPMMA = 1.48. The thickness of the insulator substrate is set as subD = 12 μm. A gold layer is deposited at the back side of the insulator substrate to present any transmission through the structure. In this way, perfect absorption can be obtained when the reflection is close to zero. The structure is periodic in the x-axis and the y-axis directions with periodic constant P = 8.5 μm. x-y cross section of a single dielectric ring. The inner and outer radii of dielectric ring are assumed as inR = 1.4 μm and outR = 2.4 μm, respectively. The height is set as ringH = 3 μm. The PMMA layer has the same thickness HPMMA = ring =H 3 μm. For convenience in the following analysis, a new parameter ringW = out − RinR standing for the width of the dielectric rings is defined.The schematic of graphene-based absorber we proposed is shown in gD = 0.35 nm in the simulations. The surface conductivity σ in THz range can be expressed by the Drude model according to the Kubo formula, as given by [ω is the radian frequency, cμ is the chemical potential of graphene, Γ = (2τ)−1 is the phenomenological scattering rate with τ standing for the relaxation time due to charge carrier scattering, T is the temperature, ħ is the reduced Plank constant, Bκ is the Boltzmann constant, e is the electron charge. The relaxation time satisfies the relationship τ = µµc/eνF2. Here, νF = 106 m/s represents the Fermi velocity and µ is the carrier mobility of graphene. According to reported result, µ can be changed and the value as high as 4 m2/Vs can be obtained at room temperature [µc is obtained by changing the dc voltage bias.For the structure, monolayer graphene is modeled as a conductive surface with thickness given by ,(1)σ are used at the outside of the top and bottom planes of calculation space to absorb the electromagnetic wave. In x-z plane, θ0 represents incident angle. When the incident electromagnetic wave reaches the gold layer, it is completely reflected if the thickness of gold substrate is set large enough. Therefore, the transmission is zero. The absorption of structure is calculated by A = 1 − R with R = reP/inP, in which inP and reP stand for the input and reflection energy flows, respectively. reP is detected at the back of incident wave plane.In the calculation, the finite difference time domain (FDTD) method is employed to calculate the reflection properties and simulate the electromagnetic field distributions of structure. As shown in T = 300 K, τ = 1 ps, cμ = 1.0 eV and μ = 1 m2/Vs are chosen. The period unit for calculating is given in the inset. Here, Under TE-polarized normal incident wave , it can be seen that there are two obvious absorption peaks at f1 = 5.18 THz and f2 = 7.02 THz. For convenience, they are denoted as modes M1 and M2, respectively. The two peaks exhibit ultra-high absorption, reaching to 98.6% and 99.8%, respectively. In order to explore this absorption phenomenon, the electric-field amplitude distributions corresponding to the two absorption peaks are simulated and shown in 1 at the x-z plane (y = 0) and x-y plane (z = 0), respectively, and 2. It can be observed that the electric-field amplitude distributions of modes M1 and M2 are highly localized at the interfaces of the upper-layer dielectric rings and graphene layer, and the lower-layer dielectric rings and graphene layer. Not only that, there are also strong electric-field amplitude distributions localized in the inner space of the double-layer dielectric rings. As shown in 1 and M2, the electric-field intensities of the upper and lower graphene interfaces are simultaneously enhanced by the resonance of double-side coupled cavities, which reinforces the graphene-wave interaction and enhances the absorption of graphene layer. On the other hand, referring to the literature [τ = 0.05 ps (cμ = 0.5 eV), the absorption spectrum is also calculated, as shown by the green line in In terature , when th1 and cavity C2, and the unit cell of graphene layer is denoted as plane-I. Cavity C1 and cavity C2 are symmetric related to plane-I. The model of plane-I coupled with cavity C1 and cavity C2 can be considered as a coupled-cavity system, as shown in ai  is the mode amplitude of cavity Ci, iω  is the resonance frequency of cavity Ci, Si+ and S‒i are the amplitudes of the incoming and the outgoing waves for cavity Ci, respectively, and κ is the mutual coupling coefficient between the two cavities C1 and C2, iβ is the coupling coefficient between cavity Ci and free space. We have ω1 = ω2 and β1 = β2 if considering the symmetry in structure, so new symbols ω0 = ω1 = ω2 and β = β1 = β2 are defined. In our case, it has S+2 = 0. Assuming that Si± and ai  have time dependence exp(jωt), we can obtain the following relation from Equation (3):In order to further explain the numerical results above, the absorption performance based on the double-side coupled-cavity effect is also investigated by coupled mode theory (CMT) . AccordiFrom Equations (2), (4) and (5), the absorption of structure can be calculated as:ω = ω0), if β is equal to κ, perfect absorption occurs. This critical coupling condition suggests that the impedance matching between cavities C1 and C2 must be equal to that between cavity C1 (or cavity C2) and free space. When the incident wave is chosen at the resonance frequency (ω = ω0) and the system satisfies critical coupling condition (β = κ), resonant modes are excited at the interface of the upper-layer dielectric ring and graphene layer , and simultaneously excited at the interface of the lower-layer dielectric ring and graphene layer , as can be shown by the electric-field amplitude distributions of modes M1 and M2 in As can be observed from Equation (6), at resonance frequency (upf = 6.22 THz for simple structure 1 (see blue line) with absorption 75.5%, denoted as upM, and downf = 9.44 THz for simple structure 2 (see red line) with absorption 85.6%, denoted as downM. For mode upM, its electric-field amplitude distributions in down, its electric-field amplitude distributions in For comparison, two relatively simple structures are considered, one is the structure only with the upper-layer dielectric rings , and the other is the structure only with the lower-layer dielectric rings . Their absorption spectra are plotted in ringW, ringH in In addition, the influence of the geometrical parameters  is not of avail to the localization of electromagnetic wave, and an ringH too large (ringH > 5.0 μm) is not necessary for fabrication in practice.Next, the influence of the height cμ can be manipulated over a wide range through adjusting direct-current bias voltage gV that is added between the graphene layer and gold substrate. Due to this characteristic, graphene-based devices can be actively manipulated after final design and fabrication. As shown in cμ of graphene on absorption performance. The parameters ringW = 1.0 μm, ringH = 3.0 μm are chosen, referring to 1 and M2 can be observed. In cμ increases from 0.1 eV to 1.5 eV (μ = 1 m2/Vs), both of the two absorption peaks M1 and M2 exhibit obvious blue shifts and the frequency shifts can reach as large as 2.82 THz/eV for the left peak M1 and 3.83 THz/eV for the right peak M2, which demonstrates the remarkable tunability of structure. Meanwhile, when cμ increases from 0.1 eV to 1.5 eV, the absorption of the left peak M1 increases from 12.6% to 98.8%, and that of the right peak M2 also increases from 10.7% to 99.8%. It indicates that the absorptions of the two peaks are enhanced with the increase of cμ. Such a characteristic could be used as tunable absorbers and other functional devices, such as multichannel filters, chemical/biochemical modulators and sensors.On the other hand, one remarkable advantage of graphene is that its chemical potential The frequency spectra of the absorption are represented in θ0 = 0°). Finally, the absorption spectra at different θ0 are illustrated for TE and TM polarizations, as shown in θ0 is defined as the angle between the incident plane wave and the positive z-direction, as shown in n0 is the refractive index of air, n1 is the effective refractive index of absorption domain and θ1 is the refraction angle. Here, n1 is complex due to the absorption. We can define n1 = nr1 + i·ni1, where nr1 and ni1 are the real and imaginary components of n1. Therefore, the refraction angle θ1 is also complex. It can be expressed as θ1 = θr1 + i·θi1, where θr1 and θi1 are the real and imaginary components of θ1. Therefore, the complex refraction angle θ1 is related to the parameters θ0, n0, nr1 and ni1. With FDTD Solutions software, the simulation model can be calculated by setting the parameters θ0, n0, nr1 and ni1, in which n0, nr1 and ni1 depend on the parameters of graphene and dielectric materials. It should be noted that the refracted plane wave into the absorber is nonuniform since it is closely related to the corresponding material in the refraction region. The absorption of structure can be indirectly calculated by collecting the total reflection energy flow at the detection plane, as shown in 1 and M2 are almost unchanged at incident angles as large as 35° for TE polarization and 45° for TM polarization. This phenomenon is attributed to the high symmetry in the structure. The results would have important applications for wide-angle absorbers in practice.In the discussions above, absorption spectra have been investigated for normal incidence (In summary, we introduce a new kind of high-quality graphene-based absorber using a double-side coupled-cavity effect. In this structure, monolayer graphene is sandwiched between two layers of dielectric rings, which are equivalent to resonators coupled to both sides of graphene layer. The double-side coupled-cavity effect can greatly enhance the absorption of graphene. The result shows that two peaks with almost complete absorption are obtained. The influence of geometrical parameters on absorption performance are investigated in detail. Furthermore, through varying the chemical potential of graphene, the frequency shifts of the two absorption peaks can reach as large as 2.82 THz/eV and 3.83 THz/eV, respectively. The proposed structure also could be used for applications related to multichannel filters, chemical/biochemical modulators and sensors.


Health-monitoring technologies for automatically detecting the early signs of Alzheimer's disease (AD) have become increasingly important. Speech responses to neuropsychological tasks have been used for quantifying changes resulting from AD and differentiating AD and mild cognitive impairment (MCI) from cognitively normal (CN). However, whether and how other types of speech tasks with less burden on older adults could be used for detecting early signs of AD remains unexplored. In this study, we developed a tablet-based application and compared speech responses to daily life questions with those to neuropsychological tasks in terms of differentiating MCI from CN. We found that in daily life questions, around 80% of speech features showing significant differences between CN and MCI overlapped those showing significant differences in both our study and other studies using neuropsychological tasks, but the number of significantly different features as well as their effect sizes from life questions decreased compared with those from neuropsychological tasks. On the other hand, the results of classification models for detecting MCI by using the speech features showed that daily life questions could achieve high accuracy, i.e., 86.4%, comparable to neuropsychological tasks by using eight questions against all five neuropsychological tasks. Our results indicate that, while daily life questions may elicit weaker but statistically discernable differences in speech responses resulting from MCI than neuropsychological tasks, combining them could be useful for detecting MCI with comparable performance to using neuropsychological tasks, which could help develop health-monitoring technologies for early detection of AD in a less burdensome manner. As the world's elderly population increases, the number of people living with dementia is increasing rapidly, making dementia an increasingly serious health and social problem. According to World Alzheimer Report published in 2018, around 50 million people globally were living with dementia, corresponding to about 7.3% of the world's over-65-year-olds, and this number is projected to increase to 115 million by 2050 . AlthougOne of the clues for monitoring daily behaviors and detecting cognitive impairment due to AD might be speech data. While most typical hallmarks of both AD and MCI are deficits in memory and executive functions , 10, botPrevious computational studies attempted to measure these language and speech impairments in AD and MCI patients on the basis of such findings by using acoustic, prosodic, and linguistic features. For example, difficulties with word-finding and word-retrieving during verbal-fluency tasks have been measured by tallying pause frequency and fillers such as “umm” or “uh” –23. The There is growing interest in using speech data that can be collected from everyday situations for healthcare applications due to the expansion of mobile devices and voice-based interaction systems such as smartphones, tablets, and smart speakers. For example, mobile applications for collecting speech responses to neuropsychological tasks such as verbal fluency, counting backward, and picture description, have been developed and showed accurate classification rates for detecting patients with AD and MCI , 33. As In this study, we developed a tablet-based application and investigated whether speech responses to daily life questions could be used to differentiate elderly patients with MCI from CN participants. For comparison, we also collected speech responses to neuropsychological tasks using the same tablet application and analyzed them. We first conducted statistical analysis to investigate speech features with significant differences between CN and MCI and compared them between responses to daily life questions and to neuropsychological tasks. By combining these speech features, we then constructed binary classification models for detecting MCI and compared their accuracies between the use of daily life questions and neuropsychological tasks. Through the analyses of both speech responses, we discuss how speech responses to daily life questions can be used for automatic tablet-based assessment for detecting MCI with less burden on older adults that is comparable in accuracy to using speech responses to neuropsychological tasks.We recruited patients with MCI or dementia from University of Tsukuba Hospital, and other participants were the spouses of the patients and were recruited from local recruiting agencies and advertisement in the community in Ibaraki, Japan. All participants could speak Japanese and all examinations were conducted in Japanese. Participants were excluded if they had severe mental illness , evidence of stroke affecting motor function, or poor command of the Japanese language. This study was conducted under the approval of the Ethics Committee, University of Tsukuba Hospital. We obtained informed written consent from all participants.Irrespective of their diagnoses before attending the study, two psychiatrists of the authors (K. N. and T. A.) reviewed the patients' clinical notes and study assessments to verify their diagnoses. Cognitive performance of all participants was assessed using the following neuropsychological examinations conducted by neuropsychologists: the Mini-Mental State Examination (MMSE), immediate and delayed recall of the logical memory-story A of the Wechsler Memory Scale-Revised, the Frontal Assessment Battery, trail making test-part A and B, and clock drawing test. For clinical scales, all participants were administered the Geriatric Depression Scale and received a structural MRI scan using a three-dimensional magnetization prepared rapid gradient echo sequence. The Clinical Dementia Rating (CDR) for all patients was also used for diagnosis.Regarding diagnosis of MCI and dementia, we applied standard research diagnostic criteria of the National Institute on Aging and Alzheimer's Association (NIA-AA) and AD Neuroimaging Initiative 2 (ADNI 2)The participants with CN and MCI were 76 Japanese seniors . The CN group consisted of 39 participants  and the MCI group consisted of 37 participants . Participants sat down in front of the tablet and answered questions presented by a voice-based application on the tablet. The tablet showed a screen indicating whether it was speaking or listening . We usedThe daily life questions consisted of eight questions designed to capture changes in memory and executive functions, in addition to language function, associated with MCI and dementia. Regarding memory function, three questions were related to episodic memory and asked participants to recall and explain old personal episodes about a fun childhood activity as well as recent episodes about what was eaten for dinner yesterday and the day before yesterday. In addition, one question was related to semantic memory regarding general knowledge and asked participants to explain a Japanese traditional event. Questions designed to capture executive function included two questions. One was related to planning and asked about response plans for an earthquake. The other was related to decision-making and asked participants to choose one option from among two regarding future travel destinations and to give three reasons for the choice. In addition to the above six questions, we used two questions frequently used in daily conversations, that is, how one feels today and one's sleep quality last night. For the actual sentences for the daily life questions, please see The five neuropsychological tasks were, counting backward, subtraction, phonemic and semantic verbal fluency, and picture description with the Cookie Theft picture adapted from the Boston Diagnostic Aphasia Examination . These tUsing the speech data, we investigated the feasibility of tablet-based assessments for early detection of AD by automatically extracting speech features and constructing binary classification models for differentiating participants with MCI from CN. We extracted 369 features consisting of 321 acoustic features and 48 prosodic features from responses to each task based on previous studies see . For theThe acoustic features consisted of four feature types related to Mel-frequency cepstral coefficients (MFCCs), the first three formant frequencies (F1–F3), jitter , and shimmer . We used the first 14 MFCCs, which represent the short-term power spectrum of the speech signal. The features of jitter and shimmer are measures of the cycle-to-cycle variations of fundamental frequency and amplitude . The proWe used the binary classification model for differentiating CN and MCI participants by using the speech features. Parameters that we searched were kernel functions including linear and radial basis function, the width of the radial basis function kernel, and the penalty parameter. We also carried out feature selection on the basis of area under the curve of receiver operating characteristic after removing highly correlated features. The number of features and the threshold for pair-wise correlation between features were also parameters. We conducted an exhaustive grid search by using average scores resulting from iterative 10-fold cross validation and determined the above parameters. We used the algorithm for the SVM implemented in MATLAB .We evaluated model performance based on accuracy resulting from 20 iterations of 10-fold cross-validation. We also evaluated their classification accuracy for individual participant to measure how reliably each participant was classified across the nested models on the basis of previous studies , 50. We t-test with false discovery rate correction was used to assess differences in each variable between CN and MCI participants. The P values below 0.05 were considered significantly different. Effect size was calculated using Cohen's d. We categorized the magnitude of Cohen's d in accordance with a previous study: small (0.2 ≦ d < 0.5), medium (0.5 ≦ d < 0.8), and large (d ≧ 0.8)  .p > 0.05, Two-tailed Mann–Whitney U-test, We obtained an average of 319.7 s (SD: 108.5) of speech responses to the eight daily life questions and 261.4 s (SD: 48.5) of speech responses to the five neuropsychological tasks using the tablet. The average duration of responses to each question varied, and the ranges were 4.2–75.4 s for the daily life questions and 32.5–73.1 s for the neuropsychological tasks . There wWe first investigated whether and how the speech features differed between the CN and MCI participants. We found that among the 369 speech features, the average number of significant different features for each question was 8.4  for the eight daily life questions and 29.0  for the five neuropsychological tasks, respectively . The topWe next investigated what types of speech features showed significant difference between CN and MCI participants. We first compared significantly different feature types in speech responses to the neuropsychological tasks with those in previous studies on speech data during neuropsychological tasks. Previous studies reported the following eight types of speech features as statistically significant measures for MCI and/or AD: MFCCs, pause, pitch variation, speech rate, shimmer, jitter, phonation time, and response time see . Among tp = 0.5, Student's t-test; p < 0.0005, Student's t-test).We next constructed binary classification models for differentiating the MCI from CN participants with feature-selection methods and evaluated them with 20 iterations of 10-fold cross-validation. The model using speech responses to daily life questions achieved 86.4 ± 1.5% accuracy , while the model using responses to neuropsychological tasks achieved 86.8 ± 2.1% accuracy . We did not find significant difference between these two accuracies  had 100% individual accuracy in both speech data related to daily life questions and neuropsychological tasks. Fifty-one participants overlapped, that is, 9 participants each showed 100% individual accuracy in only 1 of the 2 task types, i.e., daily questions and neuropsychological tasks, . In addiIn response to the increasing demand for early detection of AD, we investigated the possibility of tablet-based automatic assessment using speech data. Although previous studies have succeeded in differentiating MCI and AD patients from cognitive normal older adults by using speech responses to neuropsychological tasks, whether and how other types of speech responses to such tasks with sufficiently less burden could be used for detecting early signs of AD has not been sufficiently investigated. We developed a tablet-based application and collected speech responses to daily life questions, such as regarding today's feeling and future travel plans, from 76 Japanese seniors including 37 patients with MCI. We then investigated whether these responses could be used to differentiate MCI and CN participants through a comparison of speech responses to neuropsychological tasks conducted with the same tablet.The statistical analysis showed that daily life questions could elicit discernable differences between CN and MCI participants in speech responses, although the number of features with significant differences and their discriminative power might decrease compared with those from neuropsychological tasks. This may be explained using neuropsychological tasks designed to measure subtle changes by imposing a heavy load on target cognitive domains; thus, speech features extracted from their responses could show a more discernable difference in accordance with the degree of cognitive impairment compared with other types of speech responses –54. DailWe also reported similarities and differences in speech-feature types with significant differences between CN and MCI participants between daily life questions and neuropsychological tasks. We found that MFCCs were the most robust and showed significant differences in all responses to both daily life questions and neuropsychological tasks. Many studies suggested the MFCC is a good representation for detecting various types of diseases including depression, Parkinson's disease, and AD , 57, 58.Results of evaluating binary classification models for detecting MCI showed that daily life questions could achieve high accuracy, comparable to neuropsychological tasks by using more responses to daily life questions (eight) than responses to neuropsychological tasks (five). The need for more questions about daily life might be explained by the smaller number of speech features with significant differences and smaller effect sizes than those in neuropsychological tasks. This might also suggest the trade-off between the degree of cognitive workload of each question and the number of questions needed to achieve the target classification performance, although this relationship may be more complex; for example, adding questions with similar profiles of cognitive workload might have little effect on classification performance. Moreover, the average response duration to all eight daily life questions was about 320 s in our study, which means 61 s longer than the response duration to the five neuropsychological tasks. Thus, the impact of the additional questions did not seem to be large, and the response duration was still not long compared with typical neuropsychological tests in spite of high detection accuracy. From this perspective, daily life questions might be easier to use regularly with less burden on older adults than neuropsychological tasks and may be a promising approach for timely and early detection of AD by frequent tablet-based automatic assessments. In addition, this approach may be useful for other neurodegenerative diseases and mental illnesses. For example, cognitive impairment is commonly observed in non-demented Parkinson's disease patients, and its early detection and intervention have been needed to prevent progressive cognitive decline and dementia –61. In bResults of classification accuracy for individual participant showed that both classification models using daily life questions and neuropsychological tasks could achieve high reliability for classification of each individual participant: 78.9% of the participants were classified correctly 100% of the time . We also found that 11% of participants (8 out of the 76 participants) showed 100% individual accuracy on one of the task types  but less than chance level on the other. This suggests that combining both types could improve the accuracy of a binary classification model regarding each individual.in-situ study, we will evaluate how many and what kinds of daily life questions are acceptable for older adults to answer on a daily basis. Fourth, the number of participants was limited, although we decided the minimum sample size on the basis of previous studies on speech analysis for MCI and AD (post-hoc power analysis for our results exceeded 0.90, but given the wide clinical profile of MCI and AD, a larger study on more participants may be needed to confirm our results. Fifth, the results were obtained by analyzing speech data in Japanese. We thus need to investigate speech data in other languages to confirm our results regarding the usefulness of speech responses to daily life questions for early detection of AD. In this study, we used only acoustic and prosodic features without linguistic features. Our analysis results of speech responses to neuropsychological tasks in Japanese were consistent with those in previous studies on speech responses in English. Therefore, we believe that our results will be confirmed in other languages.There were several limitations in this study. First, we collected speech data in a lab setting. The controlled setting might influence how people respond to questions. Therefore, we need to investigate speech responses collected in various living situations, such as at home, by using our tablet-based application. Second, the number of questions was small and limited. Although our study provided the first empirical evidence of the usefulness of daily life questions for detecting early stages of AD, what types of daily life questions that could elicit discernable changes related to AD remains uninvestigated. To achieve this, data collection at home would be good way to collect many speech responses by having participants use applications on a daily basis. Third, we did not directly evaluate the usability of the tablet-based application with the daily life questions. In a future I and AD , 65. TheIn summary, we investigated the possibility of using speech responses to daily life questions for tablet-based automatic assessments for detecting MCI through by comparing them with those to neuropsychological tasks. We argued that daily life questions can elicit weaker but statistically discernable differences in speech responses associated with MCI than neuropsychological tasks. In addition, a classification model using the daily life questions could detect MCI with high accuracy, statistically comparable to that using neuropsychological tasks. We believe that our results can help promote future efforts toward early detection of AD by using speech responses to various types of less burdensome questions.ysnr@jp.ibm.com; Kaoru Shinkawa, kaoruma@jp.ibm.com.The datasets presented in this article are not readily available, but derived and supporting data may be available from the corresponding authors on reasonable request and with permission from the Ethics Committee, University of Tsukuba Hospital. Requests to access the datasets should be directed to Yasunori Yamada, The studies involving human participants were reviewed and approved by Ethics Committee of University of Tsukuba Hospital. The patients/participants provided their written informed consent to participate in this study.YY, KS, MK, and MNi contributed to conception and design of the study. YY, KS, and MNe conducted the experiments. ET, MO, KN, and TA contributed to the recruitment of patients and diagnosis for participants. YY and KS performed the analysis and wrote the manuscript. All authors have approved the final version of this manuscript.YY, KS, and MK are employed by the IBM Corporation. The remaining 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.