Research questions To compare the efficacy of nintedanib and pirfenidone in the treatment of progressive pulmonary fibrosis; and to compare the efficacy of anti-fibrotic therapy (grouping nintedanib and pirfenidone together) in patients with IPF versus patients with progressive lung fibrosis not classified as IPF.A search of databases including MEDLINE, EMBASE, PubMed, and clinicaltrials.gov was conducted. Studies were included if they were randomised controlled trials of pirfenidone or nintedanib in adult patients with IPF or non-IPF patients, and with extractable data on mortality or decline in forced vital capacity (FVC). Random effects meta-analyses were performed on changes in FVC and where possible on mortality in the selected studies.p < 0.001) and in the non-IPF studies the figures were − 0.307 (SE 0.063) (p < 0.001). There was no evidence of any difference between the two groups for standardised rate of FVC decline (p = 0.979). Pooling IPF and non-IPF showed a significant reduction in mortality, with mean risk ratio of 07.01 in favour of antifibrotic therapy (p = 0.008). A separate analysis restricted to non-IPF did not show a significant reduction in mortality (risk ratio 0.908 (0.547 to 1.508), p = 0.71.13 trials of antifibrotic therapy were pooled in a meta-analysis (with pirfenidone and nintedanib considered together as anti-fibrotic therapy). The change in FVC was expressed as a standardised difference to allow pooling of percentage and absolute changes. The mean effect size in the IPF studies was − 0.305 (SE 0.043) (Anti-fibrotic therapy offers protection against the rate of decline in FVC in progressive lung fibrosis, with similar efficacy shown between the two anti-fibrotic agents currently in clinical use. There was no significant difference in efficacy of antifibrotic therapy whether the underlying condition was IPF or non-IPF with progressive fibrosis, supporting the hypothesis of a common pathogenesis. The data in this analysis was insufficient to be confident about a reduction in mortality in non-IPF with anti-fibrotic therapy.Trial Registration PROSPERO, registration number CRD42021266046. Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia (IIP). IIPs are spontaneously occurring (idiopathic) diffuse parenchymal lung diseases. IPF is defined as a spontaneously occurring (idiopathic) specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with a pattern of Usual Interstitial Pneumonia (UIP) on imaging or histology . NICE guMany cases of lung fibrosis, including progressive disease, are not UIP, either because they belong to another clearly defined group, or because they are unclassifiable despite MDT analysis. The other IIPs include nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis associated interstitial lung disease (RB-ILD), acute interstitial pneumonia (AIP), lymphocytic interstitial pneumonia (LIP), and cryptogenic organizing pneumonia (COP). All of these, plus hypersensitivity pneumonitis, may be treated differently from IPF initially, but can lead to progressive and ultimately fatal fibrosis; and anti-fibrotic therapy with nintedanib or pirfenidone is not licensed in the UK in these circumstances.Two anti-fibrotic drugs are currently recommended (under specified circumstances) as treatment options in ILD in the UK: pirfenidone  and nintTo assess efficacy comparing nintedanib and pirfenidone in the treatment of progressive pulmonary fibrosis (grouping IPF and non-IPF together), using changes in FVC and mortality relative to controls as outcomes.For current anti-fibrotic therapy (grouping nintedanib and pirfenidone together), to assess any difference in efficacy between IPF and progressive lung fibrosis not classified as IPF, using changes in FVC and mortality relative to controls as outcomes.Our two central aims were:Our primary analysis was on changes in FVC, with a secondary analysis based on total deaths during studies.We performed a systematic review and meta-analysis. It was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The trial was registered with PROSPERO: registration number CRD42021266046.A search of databases using Healthcare Databases for the NHS in England (HDAS) was performed. The searches were from 1990  until the end of July 2021. The databases searched were MEDLINE, EMBASE and PubMed. The precise search strategy from these databases is given below:37: ~ "(((pirfenidone).ti,ab OR (Esbriet).ti,ab OR (nintedanib).ti,ab OR (Ofev).ti,ab OR (Vargatef).ti,ab OR (antifibrotic).ti,ab OR (anti-fibrotic).ti,ab OR (anti fibrotic).ti,ab) AND ((lung fibrosis).ti,ab OR (pulmonary fibrosis).ti,ab OR (idiopathic pulmonary fibrosis).ti,ab OR (IPF).ti,ab OR (INTERSTITIAL LUNG*).ti,ab OR (UIP).ti,ab OR (NSIP).ti,ab)) [DT 2001–2021] [Languages English] [Humans]".MEDLINE: 1,611 combined results for (53 AND 54): ~ "((pirfenidone).ti,ab OR (Esbriet).ti,ab OR (nintedanib).ti,ab OR (Ofev).ti,ab OR (Vargatef).ti,ab OR (antifibrotic).ti,ab OR (anti-fibrotic).ti,ab OR (anti fibrotic).ti,ab) AND ((lung fibrosis).ti,ab OR (pulmonary fibrosis).ti,ab OR (idiopathic pulmonary fibrosis).ti,ab OR (IPF).ti,ab OR (INTERSTITIAL LUNG*).ti,ab OR (UIP).ti,ab OR (NSIP).ti,ab).PUBMED: 2,456 combined results for 18: ~ "(((pirfenidone).ti,ab OR (Esbriet).ti,ab OR (nintedanib).ti,ab OR (Ofev).ti,ab OR (Vargatef).ti,ab OR (antifibrotic).ti,ab OR (anti-fibrotic).ti,ab OR (anti fibrotic).ti,ab) AND ((lung fibrosis).ti,ab OR (pulmonary fibrosis).ti,ab OR (idiopathic pulmonary fibrosis).ti,ab OR (IPF).ti,ab OR (INTERSTITIAL LUNG*).ti,ab OR (UIP).ti,ab OR (NSIP).ti,ab)) [DT 2001–2021] [English language] [Languages English] [Human age groups Adult 18 to 64 years OR Aged 65 + years] [Humans]".EMBASE: 1,666 combined results for By inspection of titles, papers were saved from each search, and HDAS was used to remove duplicates. The remaining papers were then screened by their abstracts as outlined below.A search of ClinicalTrials.gov was performed: the conditions used were idiopathic pulmonary fibrosis and pulmonary fibrosis; the limits were Adults (any age); and the interventions were nintedanib and pirfenidone and BIBF 1120. Data from ClinicalTrials.gov was cross-tabulated with the above search, and used to check data extracted for use in the meta-analysis. A search of PROSPERO was performed for meta-analyses including interstitial lung disease as a subject: no analyses were completed or proposed that are current and cover the same ground as the current study.Abstracts of above searches were reviewed by two investigators independently, looking for possible studies for inclusion. The criteria were: 1. the study should include reference to use of pirfenidone or nintedanib, in lung disease in adult subjects; and 2. the abstract should report the results of a trial. Full text papers fulfilling the above criteria were obtained. Studies were excluded if a full text published in the English language was not available, and if studies were in animal or laboratory models.Data were independently extracted by two investigators (AP and JF). The study design, antifibrotic type, study duration, number of subjects, changes in FVC (however recorded), and all-cause mortality during the study period were tabulated. Disagreements were settled by a third party (PD).Risk of bias assessment was evaluated using the Cochrane risk-of-bias tool for randomised controlled trials, by two investigators (AP and JF), and disagreements settled by a third party (PD).p value of < 0.10 regarded as significant. If heterogeneity was demonstrated, an estimate of tau and its 95% confidence intervals was made. Publication bias was assessed by inspection of funnel plots. All analyses were performed using the software Comprehensive Meta-Analysis [A meta-analysis was performed on two separate variables: change in FVC (expressed as standardised change to account for different metrics in the papers) and all-cause mortality, treated as a binomial variable. Data were pooled using random effects models. Sensitivity studies were performed using one study removed. Heterogeneity was assessed using the Q test, with a The number of studies initially identified by the search are given in Fig. Key to abbreviations for Table 1. Idiopathic non-specific interstitial pneumonitis; 2. unclassifiable idiopathic interstitial pneumonitis; 3. Chronic hypersensitivity pneumonitis; 4. Rheumatoid arthritis related interstitial lung disease; 5. Mixed connective tissue disease associated ILD; 6. Systemic sclerosis-associated ILD.Of the 13 trials included, all had data extracted on FVC changes, and 11 had data available on all-cause mortality . The main variables of these studies are summarised in Table A consensus on bias assessment was achieved. Three studies were identified as having “some concerns” in one domain of five. The study of Maher et al. (2020) was rated as “some concerns” on domain 5 (selection of the reported result): this was because the primary outcome of home spirometry could not be used because of some impossible or implausible values, and the site spirometry  is presented in this analysis instead. In Behr et al. (2021), the fact that a large quantity of data had to be imputed led to “some concerns” in domain 3 . In Azuma et al. (2005), we assessed as having “some concerns” in domain 5 (selection of reported result), as the FVC data used was among several outcomes reported, as the primary outcome  had not proved significant. All other studies were rated as low risk of bias on all domains.In several of the trials, co-administration of medication previously thought to have efficacy in IPF was noted. In the study by Huang et al. , all patIn the TOMORROW and INPULSIS trials, up to 15 mg daily of prednisolone was permitted: its use was well balanced between the treatment and control groups in all those trials, with about 21% of the study population on prednisolone therapy. In the INPULSIS trials, after 6 months, treating physicians could increase the dose of prednisolone, or add azathioprine, ciclosporin or cyclophosphamide: the numbers in which this happened are not given in the paper or its supplement.In the study by Azuma et al., azathioprine was not permitted, but prednisone up to a dose of 10 mg per day was permitted: the frequency of oral corticosteroid use was not stated in the paper, but it is clarified that acute exacerbations were treated with high dose corticosteroids. In the study by Taniguchi et al., the same entry criteria were used, and this time the paper states that 8% of the pirfenidone group and 5% of the control group were on oral corticosteroids. In the CAPACITY trials, “other IPF therapy” was excluded. In Huang et al., prednisone up to 15 mg/day was permitted, and was a past or current medication, possibly also with azathioprine, in 74% of the pirfenidone group and 68% of the control group. In the ASCEND trial, no patients were receiving azathioprine, and prednisone was only permitted if required for conditions other than IPF: the number to whom that applied is not stated, but it is reasonable to suppose it was very low. In summary, of the studies of nintedanib in IPF, about 21% of the study population was on prednisolone up to 15 mg daily. Of the studies of pirfenidone in IPF, the majority of subjects were in the CAPACITY and ASCEND trials, where prednisolone was not permitted, so any effect of anti-inflammatory therapy is likely to be nugatory.The above studies were in IPF. Those below are the four studies in non-IPF, where anti-inflammatory therapy was administered to some patients in all the studies reviewed. In the study by Maher et al., subjects were stated to be not on oral corticosteroids or azathioprine, and 5% were on mycophenolate in both pirfenidone and control groups. In the study by Behr et al., for the pirfenidone group 27% were on monotherapy with oral corticosteroids, 36% were on combination therapy with oral corticosteroids and another agent, usually azathioprine (17% of the treatment group) or mycophenolate, with similar figures for the control group. In the INBUILD study, up to 20 mg prednisolone was permitted: at baseline, 17.2% of subjects on nintedanib and 17.8% of control subjects were on at least one anti-inflammatory drug, mainly non-biologics such as methotrexate, with less than 1% on prednisolone and 0% on azathioprine. Over the course of the study period, anti-inflammatory therapy was added or altered in 10.8% of the nintedanib group and 21.1% of the control group . In the Distler study of patients with Systemic Sclerosis, 48.3% of the nintedanib group were on mycophenolate, and 8% were on methotrexate, with similar figures for both drugs in the placebo group. Patients who had recently received oral corticosteroids or azathioprine were excluded.A meta-analysis was performed on included trials assessing the effect of antifibrotic therapy on the rate of decline in FVC, using a standardised effect size to allow comparison of studies using different metrics for the rate of decline in FVC. The total number of subjects in trials in IPF was 2872 (of whom 1564 took the active medication), and the total number of subjects in trials in non-IPF was 1292, of whom 647 took active medication. Of the studies in IPF, 3 were with nintedanib and 6 were with pirfenidone. Of the studies in non-IPF, 2 were with nintedanib and 2 were with pirfenidone , p < 0.001) and in the non-IPF studies the figures were − 0.307 (SE 0.063) (p < 0.001). The Q statistic for the group difference was 0.001, df 1, with p = 0.979: there was no evidence of any difference between the two groups for standardised rate of FVC decline.A further analysis was performed between two groups of studies (those on IPF and those on non-IPF) using a mixed effects model with the difference between the two groups treated as a fixed effect. The forest plot for that analysis is shown in Fig. Although when all studies are considered together, no significant heterogeneity was shown, we can analyse the data as if there were heterogeneity, and calculate a prediction interval for the distribution of true effects: this gives an interval for the true effect size (disregarding sampling error) which would be found in 95% of studies from a comparable universe of similar studies, using either pirfenidone or nintedanib, and performed in patients with IPF or non-IPF. That interval, expressed as a standardised difference between treatment and control groups is − 0.18 to − 0.43.p < 0.001) and in the pirfenidone studies the figures were − 0.266 (SE 0.045) (p < 0.001). The Q statistic for the group difference was 1.139, df 1, with p = 0.286: there was no statistically significant evidence of any difference between the two groups by anti-fibrotic treatment given.A further analysis was performed between two groups of studies, namely those where nintedanib was the treatment and those where pirfenidone was the treatment. This was performed over all studies in the meta-analysis, so both IPF and non-IPF. Again, this used a mixed effects model with the difference between the two groups treated as a fixed effect. The forest plot for that analysis is shown in Fig. p = 0.008. The Q value was 5.613, df 8, p = 0.69, so no evidence of heterogeneity was evident. A further analysis was performed grouping the studies by disease type: IPF (n = 5) versus non-IPF (n = 4). The estimate for risk ratio  for the IPF studies was 0.637 (0.469 to 0.866), p = 0.004. The estimate for risk ratio  for the non-IPF studies was 0.908 (0.547 to 1.508), p = 0.71. An all-cause mortality benefit in the non-IPF group was not demonstrated.A meta-analysis of 9 studies where all-cause mortality was stated in the publications used in this paper was performed. The forest plot of that analysis is given in Fig. This systematic review and meta-analysis showed that, when IPF and non-IPF studies are grouped together, there is an overall reduction in all-cause mortality , and a clear-cut effect in reducing the rate of decline in FVC  attributable to anti-fibrotic therapy. While a pooled effect on mortality was not demonstrated in the non-IPF studies in isolation, the beneficial effect on decline in FVC is shown for both IPF and non-IPF studies: it is very close in value and statistically highly significant for both groups.The impetus to perform this meta-analysis was a combination of recent studies on non-IPF and the recognition of the absence of effective therapy in progressive fibrosis in these conditions. A review by Athol Wells in 2018 summarised the data for the following propositions: that there is IPF-like disease progression in subgroups of patients with non-IPF progressive disease; and there may be a common pathway, that is, common pathogenetic mechanisms leading to fibrosis . They arOne important aspect of any meta-analysis is assessment of heterogeneity. The assumption when using a meta-analysis to compare two groups, in this case IPF and non-IPF, is that we can reliably measure heterogeneity in the data: that is, the variation between study effect sizes attributable to the true distribution of effect sizes with the sampling error removed. In our study, addressing the standardised effect size of FVC decline for all studies, no statistically significant evidence of heterogeneity was found: the Q value was 13.9, where the expected value was 12, and the excess variation above expected was not statistically significant. The prediction interval calculated assuming heterogeneity was narrow; from which we can say that if we have failed to detect heterogeneity, it is of a modest degree. It can be supposed that in this meta-analysis, heterogeneity for the standardised change in FVC has been estimated with sufficient precision to draw conclusions: the number of studies was adequate, and greater than 10, which is sometimes given as a ballpark figure for adequate estimation of heterogeneity; all the studies were RCT’s with narrow and similar inclusion criteria (other than for the disease state); and nine of the studies were of good size with greater than 100 patients in the treatment arm. This is our justification for including only RCT’s: incorporation of other types of study such as cohorts can introduce bias by well-known mechanisms and hence heterogeneity that arises from the type of study rather than from the condition being studied . The datEven in a RCT of ILD, the outcomes can be biased if differences in treatment within the study period, particularly of exacerbations, have unintended consequences. The well-known PANTHER-IPF trial in IPF patients published in 2012 was terminated after about 50% of the planned data had been collected because an interim analysis showed increased mortality compared with placebo in the group treated with a combination of prednisolone, azathioprine and NAC . The figAnti-inflammatory therapy was widely used in the non-IPF studies, with a frequency between 5 and 63% of the study populations, and varied markedly between studies. Although anti-inflammatory therapy is frequently administered in non-IPF lung disease, the evidence for its efficacy (or harm) in progressive non-IPF is variable –29. The Limitations apply to this meta-analysis. The studies for non-IPF contain more patients on nintedanib than pirfenidone (494 versus 153), so conclusions for non-IPF can be more confidently applied to nintedanib than pirfenidone, although no significant heterogeneity in outcomes was shown. For FVC data, the method of analysis of data led to extracted data being in both an absolute metric (mls) or relative to predicted values, necessitating the use of standardised differences. The use of ranked data analyses is justifiable statistically, but does not give the reader a clear handle for the change that has been demonstrated. Different approaches to imputation of data also complicate interpretation of the scale of effects, although a review of data imputation techniques for the ASCEND trial showed that the outcomes are robust in relative terms, that is to say, the magnitude of the absolute changes in FVC was significantly affected, but the effect of the anti-fibrotic therapy remained about a 50% inhibition of the control response . This ofWe believe that this meta-analysis is the first to attempt to pool data from RCT’s on both commonly used anti-fibrotic drugs in both IPF and non-IPF. Several cohort studies, some looking at both pirfenidone and nintedanib in IPF have been published, including a recent large retrospective cohort analysis which excluded systemic sclerosis associated ILD and progressive fibrosing ILD . We haveFor changes in FVC, anti-fibrotic therapy offers protection against the rate of decline, similar between the two anti-fibrotic agents currently in clinical use, with no obvious difference in efficacy whether the underlying condition was IPF or non-IPF with progressive fibrosis. Larger controlled studies in non-IPF are required to be confident about any general effect on mortality by anti-fibrotic therapy.


Treatments of interstitial lung diseases (ILDs) mainly focus on disease stabilization and relief of symptoms by managing inflammation or suppressing fibrosis by (in part costly) drugs. To highlight economic burden of drug treatment in different ILD-subtypes we assessed cost trends and therewith-associated drivers.Using data from the German, observational HILDA study we estimated adjusted mean medication costs over 36-month intervals using one- and two-part Generalized Estimating Equation (GEE) regression models with a gamma distribution and log link. Next, we determined factors associated with costs.In Idiopathic pulmonary fibrosis (IPF) mean per capita medication costs increased from €1442 before to €11,000€ at the end of study. In non-IPF subtypes, the increase took place at much lower level. Mean per capita ILD-specific medication costs at the end of the study ranged between €487 (other ILD) and €9142 (IPF). At baseline, higher FVC %predicted values were associated with lower medication costs in IPF (−9%) and sarcoidosis (−1%). During follow up higher comorbidity burden escalated costs in progressive fibrosing ILD (PF-ILD) (+52%), sarcoidosis (+60%) and other ILDs (+24%). The effect of disease duration was not uniform, with cost savings in PF-ILD (−8%) and sarcoidosis (−6%), but increased spending in IPF (+11%).Pharmacological management of ILD, in particular of IPF imposes a substantial economic burden on the healthcare system. Strategies to reduce comorbidity burden and early treatment may reduce the impact of ILDs on the healthcare system.The online version contains supplementary material available at 10.1186/s12931-021-01807-8. The rare group of interstitial Lung Diseases (ILDs) comprises of over 200 subtypes that are heterogeneous regarding etiology, patterns and prognosis, but have similar pathophysiological pathways regarding inflammation and/or fibrosis of the lung parenchyma . ILDs arMany ILDs are triggered by environmental, occupational, or medication-related exposures  such as Within the various non-IPF ILDs, a proportion of patients can develop a progressive, fibrosing phenotype. This phenotype is characterized by declining lung function and high mortality , 12. In ILD treatments mainly focus on disease stabilization and on relief of symptoms by managing inflammation and/or suppressing fibrosis . In thisGiven their mostly chronic, often progressive course combined with the often non-standardized treatment regimens, ILDs might be associated with high healthcare utilization and a significant strain and burden on health services, and healthcare systems –15. MostTo close this knowledge gap, our analysis of the HILDA-cohort study portrays the course of medication costs over an 18-months interval and delineates essential cost drivers in pharmacological treatment. The anticipated results are expected to aid German policy makers in planning and allocating healthcare services.The German longitudinal HILDA  cohort is a prospective, observational study , 20. RecInclusion criteria were an ILD-diagnosis confirmed by the multidisciplinary team board meeting of the recruiting center, a minimum age of 18 years, proficiency in the German language and the provision of written informed consent. In total, 271 patients enrolled into the study.We calculated drug costs based on information on the Pharmaceutical Central Number of the distinct drug and dosage of drug intake per day during the study period by applying drug-specific prices stemming from the medication database of Scientific Institute of the AOK Statutory Health Insurance funds (WIdO 2016). Apart from nutritional supplements, we considered all pharmaceuticals taken by the patient. Each drug was classified as an ILD-related medication  or other drug. Subsequently, we calculated medication costs for the three study intervals, 6 months before baseline (t0), baseline to 6 months after baseline (t1) and 6 to 12 months after baseline (t2).We considered the baseline covariates age (in years), sex, duration of disease (in years), smoking status (current or former and never-smoker), study center, comorbidity burden and physician-reported information on forced vital capacity (FVC) % predicted. In addition, we considered four different ILD subtypes: 1) Sarcoidosis, (2) IPF, (3) PF-ILD  % predicted in our analyses because this led to multicollinearity problems .We disregarded participants with missing information on any variable of interest, which however only applied to disease duration (N = 12) and comorbidity sum score (N = 2). Furthermore, analyses were restricted to complete cases at the distinct assessment points. The respective samples comprised of 257 patients at t0, 229 patients at t1 and 204 patients at t2. We stratified all analyses by ILD subtype and clustered by center to account for correlation between patients from the same treatment center.To identify structural differences between the distinct ILD subtypes, we compared baseline characteristics by Pearson’s chi-square tests , and Kruskal Wallis tests (continuous variables). Next, we determined the proportion of patients receiving either immunosuppressant medication, steroids or established treatment for IPF at each assessment point and assessed unadjusted mean medication costs.The outcome of interest was the cost of all medications in ILD patients. The primary analysis estimated covariate-adjusted mean medication costs throughout the study period by ILD subtype. To address intra-subject correlation in context of repeated measures, we applied Generalized Estimating Equation (GEE) regression models with first order auto-regression . To accoIn our secondary analyses, we first assessed factors influencing baseline costs using simple gamma models, and subsequently we estimated the factors associated with costs during the study period, using gamma-distributed GEEs. We interpreted the exponentials of the regression coefficients in each of these two analyses as surcharge factors. We adjusted for the same covariates investigated at baseline and additionally accounted for the time point in the GEE models.As a sensitivity analysis, we re-ran all analyses for those patients who participated at all three assessment points (study completers).All statistical analyses were performed using the SAS software package  and we considered a p-value less than 0.05 statistically significant.Table The majority of non-IPF patients were administered steroids for the treatment of ILD, 52.5% (N = 135/257), 57.6% (N = 132/229) and 50.0% (N = 102/204) at t0, t1 and t2 respectively. Immunosuppressant medication was used by 33.1% (N = 85) at t0, 28.4% at t1 (N = 65) and 29.9% (N = 61) at t2. A few patients received the combination therapy of steroids and immunosuppressant medication 19.5% (N = 50), 21.4% (N = 49) and 22.1% (N = 45) during the respective time points. At t0 and t1, respectively, about one in five IPF patients received either pirfenidone or nintedanib , whereas this treatment quota at t2 was 100% (N = 55). Furthermore, a small subset of patients who started on steroid therapy switched to either pirfenidone or nintedanib during the 6-month interval after receiving an official IPF diagnosis, (N = 3 (1.2%), N = 7 (3.1%) and N = 9 (4.4%) at t0, t1 and t2 respectively).At t0, unadjusted medication costs ranged between €132 (Fibrosing ILD) and €332 (IPF). For sarcoidosis and IPF, costs had multiplied by t1 already and for all subtypes, there was a steep increase of costs between t1 and t2.Figures Table Table The results for the influencing factors on baseline costs and cost development for complete cases are illustrated in Additional file In this study, we illustrated the pharmaceutical treatment costs in patients diagnosed with various ILDs and determined the associated cost drivers in Germany. Our results showed that IPF patients had the highest medication costs of all ILD groups within the study period, which rose sharply after baseline. The reason beyond this observation is the high cost of the two approved anti-fibrotic medications for IPF, pirfenidone and nintedanib . Indeed For non-IPF ILDs, treatment mainly relies on relatively inexpensive steroids and immunosuppressant medication, as illustrated by our results. Nevertheless, we observed a general increase in total medication costs in non-IPF patients during the study, especially in PF-ILD patients. This suggests intensified pharmaceutical treatment of comorbidities, mainly in the first six months of the study period, as depicted by the corresponding reduction of ILD-specific medication costs at t1. Regardless, 12 months after baseline, ILD-related costs had increased again, indicating intensified pharmaceutical treatment of ILD in non-IPF patients. The steep increase in medication costs in PF-ILD patients was due to three patients that were administered pirfenidone or nintedanib in t2 for compassionate use. It is to note however, that at the time of the HILDA study, these medications were not yet approved for the treatment of PF-ILD in Germany as nintedanib was approved in 2020 . In futuComorbidity burden was a cost-driving factor in all subtypes either at baseline or throughout the study period. In addition to pharmaceutical management of the index disease, a sensitive pharmaceutical management of comorbidities is required in treatment of ILD. In IPF, a study found that comorbidities influence the clinical course of the disease and survival . AccordiLower FVC % predicted values were a determinant for higher medication costs in IPF and sarcoidosis. Studies have found that declining values of FVC % predicted are linked to disease progression . PatientIn our study, a longer disease duration was associated with higher medication costs in IPF but lower medication costs in non-IPF subtypes. With anti-fibrotic treatment one only achieves slowing down the inevitable lung function decline in IPF , 31. ThuAge was a cost-driver in both IPF and PF-ILD. Age has been identified as a risk factor for ILD progression . FurtherMale sex was associated with higher costs in PF-ILD and sarcoidosis. Risk prediction in ILD can be determined by the Gender, Age and Physiology (GAP) index model, which places men at a higher risk of mortality than women . IncreasWe demonstrated that current or former smokers had higher costs than never-smokers in IPF at baseline and in sarcoidosis patients during the study. Smoking is linked to increased inflammation in the lung, which may lead to worse outcomes . Over tiFactors influencing medication costs were similar in both the main and sensitivity analyses. The differences found in IPF can be explained by dropout analysis (Additional file So far, data on the pharmacological management of ILD in Germany are sparse. One strength of our study is that we simultaneously analyzed different ILD subtypes and compared their burden on the healthcare system as opposed to the previous study conducted in Germany that only included two subtypes of ILD and did not include clinical parameters . MoreoveThere are several limitations to our study. An important limitation is that we did not adjust for lung transplantations, as the study did not collect the information. Several studies have found that lung transplantation and associated medications is one of the most costly component of ILD management . HoweverThe results of our study suggest that the pharmacological management of ILD, in particular that of IPF imposes a substantial economic burden on the healthcare system in Germany. Strategies to reduce comorbidity burden and lung function decline could essentially reduce the burden of all ILD on both caregivers and the healthcare system.Additional file 1: Table S1. List of ‘Other’ ILD subtypes. Table S2. Influencing factors on medical costs at baseline across ILD subtypes in complete cases. Table S3. Influencing factors on longitudinal medication costs across ILD subtypes in complete cases. Table S4. Characteristics of the complete and incomplete cases. Table S5. Frequency of comorbid conditions present at baseline by ILD subtype.


Interfacial moiré superlattices in van der Waals vertical assemblies effectively reconstruct the crystal symmetry, leading to opportunities for investigating exotic quantum states. Notably, a two-dimensional nanosheet has top and bottom open surfaces, allowing the specific case of doubly aligned super-moiré lattice to serve as a toy model for studying the tunable lattice symmetry and the complexity of related electronic structures. Here, we show that by doubly aligning a graphene monolayer to both top and bottom encapsulating hexagonal boron nitride (h-BN), multiple conductivity minima are observed away from the main Dirac point, which are sensitively tunable with respect to the small twist angles. Moreover, our experimental evidences together with theoretical calculations suggest correlated insulating states at integer fillings of −5, −6, −7 electrons per moiré unit cell, possibly due to inter-valley coherence. Our results provide a way to construct intriguing correlations in 2D electronic systems in the weak interaction regime. The alignment of three 2D nanosheets leads to the formation of super-moiré atomic lattices, which can influence the electronic properties of van der Waals structures. Here, the authors report evidence of possible correlated insulating states in doubly-aligned hBN/graphene/hBN heterostructures, in a weak-interaction regime. As a result, emerging quantum phenomena, such as strong-correlation superconductivity,5 orbital ferromagnetism,8 unusual excitonic properties,10 and nematic electronic orderings,14 have been intensively investigated in twist-angled 2D heterostructures that are fundamentally influenced by the moiré superpotentials.Lattice symmetry of a crystal often defines its fundamental physical properties, yet the measures to manipulate in real space the crystallographic symmetries are so far rather limited in solid-state systems. Owing to the feasibility of controllable twisting of van der Waals (vdW) two-dimensional (2D) building blocks, a direct reconstruction of the interfacial moiré superlattice can be realized18 Indeed, doubly aligned h-BN/graphene/h-BN interfaces give rise to an extra moiré wavelength (defined as composite super-moiré) that is possible to arrange the spectrum reconstruction at arbitrary low energies.17 More recently, scanning probe tip-assisted dynamic rotating of a top h-BN reveals a subtle distinction of symmetry for 0∘/0∘ and 0∘/60∘ configurations of the h-BN/graphene/h-BN doubly aligned sandwich.15 Nevertheless, experimental demonstrations of such model systems in a broader gate range and more detailed understandings of the unusual band modification, such as possible flat bands and correlated electronic states, remain unexplored.Although moiré-dominated electronic and optical behaviours have been largely investigated, it is noticed that a 2D vdW electronic layer with duplicated moiré superlattices on both of its surfaces is of particular interests. However, restricted by a sophisticated stacking and twisting operation of doubly aligned moiré superlattice, very few reports have been focused on such a model.∘–0∘–0∘ aligned), there is only one single moiré superlattice, which yields expected flat minibands. Experimentally, the minibands of doubly aligned composite moiré in h-BN/graphene/h-BN heterostructure can be sensitively tuned by the twisting angle. In the best-aligned double moiré sample S7, we observed resistive peaks at fillings of −4, −8, −12 electrons per moiré unit cell. In other samples S12 and S4 with slightly different, yet rather close to zero, dual twists from top and bottom h-BN/graphene interfaces, evidence of possible correlated insulating (CI) states was observed in −5, −6, −7 electrons per moiré unit cell. Our results suggest that lattice reconstruction of graphene using dually aligned moiré superpotential can be an effective way to realize correlated states.In this work, we investigate the case of doubly aligned h-BN/graphene/h-BN devices, in which close-to-zero angle alignments were achieved on both top and bottom graphene/h-BN interfaces, allowing one to fully map the detailed fillings of each emerging minibands thanks to the composite super-moiré lattices. We first demonstrate theoretically that in the scenario when encapsulating h-BNs are in perfect alignment  will be about 1.5 times higher than the central major Dirac peak  at electron fillings of −4 n0, −8 n0 and −12 n0, as illustrated in Fig. θ, while band III has a minimum at about 0.65∘ with a bandwidth of about 35 meV. More details can be found in the Supplementary Information.Before further experimental measurements, we study the electronic band structures of the doubly aligned h-BN/graphene/h-BN with a composite moiré superlattice  that satisfy Eq. (1) are identified as black solid lines in Fig. ν to be ±2, ±6, ±10, etc. More data on other samples with less well alignment can be found in Supplementary Figs. Bearing in mind with a band structure of 0n0 filling corresponds a fixed h-BN/graphene moiré with a smaller twist (wavelength Lα), and all extra peaks are from another moiré with a larger twist (wavelength Lβ). Thus, one can then extract and fix Lα, and solve Lβ using the formula23a is graphene’s lattice constant, lβ is the reciprocal lattice vector of Lβ, and δ is the lattice mismatch between graphene and h-BN24. Experimentally, Lα can be larger than the theoretical maximum of 13.8 nm in a graphene/h-BN superlattice, due to possibly existing strains in the heterostructures25. The above-mentioned analytical formula yields six solutions at each side of the charge neutrality, because of the six vectors formed by the two of moiré Brillouin zone from top and bottom surfaces of graphene23. With this method, one can have access to the relatively precise twist angles in measured samples via their resistive peaks in the field-effect spectra. For example, twist angles in sample S7 is found to be of 0∘–0∘–0.45∘. Besides the above discussed geometrical model, we also performed atomic force microscopy characterizations of the doubly aligned moiré superlattice in real space, as shown in Supplementary Figs. Except for those resistive maxima at full band fillings, extra resistive peaks can be observed. These peaks may come from the slightly non-perfect alignment. To quantitatively analyse them, a phenomenological model was given, which, for simplicity, assumes that the −4 ∘–0∘–0∘ moiré superlattice. The minibands are actually super sensitive to twisting angles of each constituent layer. When at slightly different finite dual twists, the resulted composite moiré superlattices will lead to tunable resistive peaks in their spectra of field effect. Calculated density of states (DOS) for the band structure in Fig. B = 0 in the renormalized axis of n/n0, in Fig. ∘–0∘–0.45∘ (sample S7) to 0∘–0∘–0.5∘ (sample S12 and S4), the resistive peaks are largely tuned. For sample S2 with relatively larger twist angle (0.5∘–0∘–1.5∘), only n = 4 n0 band filling was observed. Notice that samples S12 and S4 are almost identical in their field-effect curves. Interestingly, resistive peaks in the second miniband are seen in them, as indicated by the black solid arrows in Fig. n0, −6 n0 and −7 n0, where the host miniband has calculated bandwidth to be of a few tens of meV, marked in purple. It thus suggests possible CI behaviour as observed in other flat band samples previously reported, depicted by the correlation-driven gap opening picture at integer fillings of the moiré unit cell.28 Notably, flat band with bandwidth of similar energy was reported theoretically,29 and were found experimentally possible for the construction of correlated superconductivity in Bernal-stacking bilayer graphene/h-BN superlattice30. Among the over 60 samples fabricated, we have 5 dual-moiré samples showing the correlated states at integer fillings from −5 to −7 n0. However, none of them exhibit superconductivity in a reachable doping range and to the lowest temperature we could obtain. Possible explanations for the absence of superconductivity in our samples, even though correlated states signatures are observed, could be that the microscopic mechanism of interaction-induced superconductivity in such as magic angle twisted bilayer graphene are different from that in our case.With sample S7, we obtained a filling sequence that resembles perfect aligned 0sample S1 and S4, n0 at the ground state. These insulating pseudogaps are located in band II, with the ones at fillings of −5, −6 and −7 n0 attributed to electron correlation, as in the non-interacting picture, the doped system is metallic at these three fillings. We thus extract the thermal activation gaps for representative peaks marked by black dashed lines in Fig. n0, respectively. This energy scale is relatively smaller than the theoretically calculated bandwidth as shown in Fig. 27. Moreover, among four samples  that exhibit similar resistive peaks at integer fillings from −5 to −7 n0, the thermal activation gaps are extracted to be rather consistent, as shown in Supplementary Fig. To further characterize the CI states in such as sample S12, we performed temperature dependence of its field-effect curves, shown as the colour map in Fig. Rxx) and transverse resistance (Rxy) shown in Fig. Rxx and Rxy at different magnetic fields are plotted in Fig. n0 to −8 n0, insulating states are seen at each integer fillings, with positive longitudinal magnetoresistances at finite magnetic fields. Direct comparisons of samples showing similar CI behaviours are shown in Supplementary Figs. n0, as will be discussed in the coming text.We further performed, in a typical sample (S60), the zoomed-in scan of these CI states in the parameter space of carrier density and magnetic field, with the longitudinal (U(1) symmetry is broken or not, a gapped state driven by Coulomb interactions can be divided into two types: in the first type the gap is induced by valley and/or spin polarization, while in other type originates from an inter-valley coherent (IVC) order that couples the two valleys and breaks valley charge conservation  symmetry) spontaneously. First, we consider the characteristic screened Coulomb interaction in this moiré system UM = e2/(4πεε0LM) (see more details in “Methods”), with LM being the moiré lattice constant in real space. It is noticed that, using the above relation, at a twist angle θG = 0.5∘, the amplitude of UM is only ~28 meV, which is roughly the energy scale of the valley and spin splittings if a valley- and/or spin-polarized state were the ground state at partial integer fillings. However, this value is still far lower than the bandwidth of band II (~80 meV) shown in Fig. n0, respectively. However, it is worthwhile to note that at all of the three fillings, the IVC order amplitudes are highly dependent on the moiré wavevector, which can reach a maximal value of 50–90 meV at some small regions in the moiré Brillouin zone . In our calculations, one target band per valley per spin is taken into consideration, thus total four energy bands are involved in the Hartree–Fock analysis. Depending on whether valley θG = 0. 5∘, in Fig. ν = −5, −6 and −7 n0, respectively. The calculated correlated gaps are larger than the experimentally extracted thermal activation ones, which may come from the underestimated quantum fluctuations (thus overestimated gaps) in the Hartree–Forck simulations. It is known that the gap itself also strongly depends on experimental details, such as errors in the twist angle, and the exact dielectric constant in the materials. Nevertheless, the general trend of the three correlated gaps are in qualitative agreement with the ones obtained in Supplementary Fig. θG, shown in Supplementary Fig. n0 in the dual-moiré h-BN/graphene/h-BN devices, one has also to minimize as much as possible the inhomogeneities, as distortion of the superlattice can be seen in the AFM scans in Supplementary Fig. n0 in multiple dual-moiré samples, are self-consistent in this work.As shown in the calculated energy bands, when taking IVC order into account at n0, in resemblance to the perfect align scenario. We also found correlated insulating states at integer fillings at −5 n0 to −7 n0 in typical doubly aligned single layer graphene samples S12, S4, S60 and S63. This correlated behaviour is further attributed to a concurrence of the doubly aligned moiré superlattice and the existence of inter-valley coherent orders in the weak coupling regime. Our results suggest that composite super-moiré lattices with a dual twist from both graphene/h-BN interfaces can be a platform for the effective tuning of moiré minibands, and may provide insights for future correlated states engineering in such systems.We have demonstrated a series of monolayered graphene samples with a dual moiré constructed from both top and bottom h-BN/graphene interfaces. Thanks to the lattice symmetry tuned by the composite double moiré super potential, the system exhibits tunable band structure, with minibands at the order of a few tens meV for perfect alignment analysed using tight-binding and continuum models. By experimentally controlling the small twist angles of the doubly aligned superlattice, the signatures of the accompanied high order resistive peaks can indeed be sensitively tuned in multiple samples. In a best-aligned sample, the experimental observations agree with the picture of a hole-side filling sequence of each moiré minibands with −4, −8 and −12 The BN-encapsulated graphene heterostructures were fabricated in ambient condition, using the dry-transfer method, with the crystals aligned to each of their exfoliated straight edges by a mechanical rotator. A Bruker Dimension Icon AFM was used for thicknesses and morphology tests. Raman measurements were performed by an HR 800 JobinYvon Horiba Raman spectroscopy. The electrical performances of the devices were measured using a BlueFors LD250 at mK temperature, a Cryogenics 4K system for temperature scannings, and a probe station (Cascade Microtech Inc. EPS150) for room temperature tests. Standard 4-probe measurements were applied with the low frequency lock-in technique.pz orbitals were considered since only the states near the Fermi level are of interest. The TB Hamiltonian has the form31pz orbital of the atom located at ϵi is the onsite energy, and tij is the coupling parameter. For the h-BN/graphene/h-BN heterostructure, both ppπ and ppσ interactions are important. According to the Slater-Koster formula32, tij is given by:n is the direction cosine along the z-direction of the vector rj − ri = rij, and rij = ∣rij∣. Following previous studies34, the functions Vppπ and Vppσ are assumed to have the following forms:For band structure calculations of the moiré superlattice, we employed a tight-binding (TB) model. Only ppπ and ppσ interactions, respectively. q = 2.218 is chosen so that the next-nearest intralayer hopping is 0.1a0 = 1.418 Å is the C-C bond length in graphene, and d0 = 3.35 Å is the spacing between the graphene and BN layers. The intra- and inter-layer hoppings are truncated with a 6 Å cutoff. The onsite energies for C, B and N are 0 eV, 3.34 eV and −1.40 eV, respectively. These parameters have been widely used to study bilayer graphene and graphene/BN systems33.Here, HC as:α refers to layer and sublattice indices. k and q are atomic wavevectors expanded around the Dirac points, and ε ~ 4.0 is background dielectric constant, and will be further changed as a variable in our calculations. ds = 200 Å is the screening length. ΩM is the area of moiré Brillouin zone. The screened Coulomb interaction can be re-written as UM = e2/(4πεε0LM) is characteristic Coulomb interaction. It is noted that at the twist angle of θG = 0. 5∘, the amplitude of UM is only ~28 meV which is far lower than the bandwidth of band II (~80 meV).We consider the inter-site Coulomb interaction μ and −μ and get annihilated in −μ and μ valleys with the interaction energy In this system, the Coulomb interactions can be divided into the intra-valley term Supplementary InformationPeer Review File


Graphene-based actuators featuring fast and reversible deformation under various external stimuli are promising for soft robotics. However, these bimorph actuators are incapable of complex and programmable 3D deformation, which limits their practical application. Here, inspired from the collective coupling and coordination of living cells, we fabricated a moisture-responsive graphene actuator swarm that has programmable shape-changing capability by programming the SU-8 patterns underneath. To get better control over the deformation, we fabricated SU-8 micropattern arrays with specific geometries and orientations on a continuous graphene oxide film, forming a swarm of bimorph actuators. In this way, predictable and complex deformations, including bending, twisting, coiling, asymmetric bending, 3D folding, and combinations of these, have been achieved due to the collective coupling and coordination of the actuator swarm. This work proposes a new way to program the deformation of bilayer actuators, expanding the capabilities of existing bimorph actuators for applications in various smart devices. Actuators that can convert various environmental stimuli to mechanical works have revealed great potential for developing smart devices such as soft robots ,2, microet al. prepared energetic moisture-responsive actuators comprising poly(acrylic acid)/poly hydrogels and UV-cured Norland Optical Adhesive 63, in which the moisture changes induced the large mismatch in hygroscopic expansion of the two materials, and led to the bending behavior of the bilayer [et al. reported light-responsive smart curtains and motors based on a polycarbonate/single-walled carbon nanotube double-layer structure, realizing bending deformation [et al. introduced soft electrothermal actuators with a polyimide (PI)/silver nanowire/polydimethylsiloxane (PDMS) sandwich structure, which could bend towards the PI side under electrical actuation [et al. prepared an intelligent Cr/VO2 bi-layer claw with a size of ∼100 μm using a deposition and etching method, and drove the claw via temperature change-induced phase transition of VO2 [To date, various SRMs have been successfully developed and employed for bimorph actuators. For instance, hydrogel that is very sensitive to environmental humidity has been used for moisture-responsive actuators ; phototh bilayer . Zhang eormation . Zhu et ctuation . Liu et n of VO2 .et al. successfully performed surface plasma treatment of hexane and oxygen on the positive and negative sides of the reduced graphene oxide, producing an electrochemically driven smart actuator [Recently, graphene and graphene oxide (GO) that possess a series of outstanding properties such as high electrical/thermal conductivity, good mechanical flexibility, excellent biocompatibility and good stability have emerged as a new type of smart material for actuator design . Typicalactuator . In our actuator . Despiteactuator ,42, theiIn this work, inspired from the collective coupling and coordination of living cells, we developed a self-healing graphene actuator swarm that enables programmable 3D deformation by integrating SU-8 pattern arrays with GO. The SU-8 micropattern arrays with specific geometries and orientations can couple with the GO film, forming a swarm of bimorph actuators in which an individual SU-8/GO bilayer can serve as an actuator ‘cell’. Therefore, by controlling the size, shape and orientation of the SU-8 patterns, more complex deformations can be programmed due to the collective coupling and coordination of the actuator swarm. The present method may open up a new way for precisely controlling the deformation of graphene-based actuators.Figure −1, the bending vibration of O–H at 1373 cm−1, the stretching vibration of C–OH at 1246 cm−1 and the stretching vibration of C–O in epoxy groups at 1080 cm−1). Since GO contains abundant hydrophilic OCGs, it can adsorb a large amount of water molecules because of the formation of hydrogen bonds under moisture conditions. Thermogravimetric (TG) analysis was also conducted under air atmosphere to evaluate the thermal stability and the mass loss upon thermal reduction  is a common method to quantitatively investigate the chemical composition of GO. As shown in eduction . A weighd-spacing of ∼0.8 nm. When the humidity was increased to 86% and 100% RH, the diffraction peaks shifted to 10.2° and 9.6°, respectively, indicating the increase of interlayer d-spacing. At 100% RH, the d-spacing is determined to be ∼0.92 nm, which indicates an increase of 15% compared to that at 33% RH. Based on the above-mentioned experimental results, it is reasonable to deduce that a GO film can absorb abundant water molecules and then swell in both normal and in-plane directions. However, it is well known that the photopolymer of SU-8, mainly epoxy resin, is inert in moisture. Therefore, the difference in volume change under moisture actuation leads to a strain mismatch at the SU-8/GO interface, inducing the bending of the bilayer towards the SU-8 side  to measure the interlayer spacing changes of GO nanosheets under different relative humidity (RH). As shown in Fig. S) as:To quantify the deformation behavior of the SU-8/GO bilayer film, we measured the bending curvature of an SU-8/GO ribbon  under different RH conditions . Under external stimulation, each actuator deforms individually, and the deformation of the entire structure is the collective coupling and coordination of the actuator swarm. To get better control over the moisture-triggered deformation, we further explored the size of the SU-8 patterns (e.g. width and spacing) on the humidity response properties. In our experiments, we first set the duty ratio  at 1.0, and evaluated the influence of periods on the bending performance. As shown in −1 can be achieved under moisture actuation. Interestingly, when the SU-8 stripes are patterned into a tri-block array with the width of 500 μm, 300 μm and 100 μm, respectively, three different bending curvatures of 1.98 cm−1, 1.36 cm−1 and 0.77 cm−1 appear from left to right, respectively  were mixed together at 0°C under stirring. Secondly, 12 g of KMnO4 was slowly put in the mixed solution within 30–60 min. Then the mixture was stirred at 0°C for 90 min and at 35°C for 120 min. After that, 80 mL of deionized water was added to the resultant solution drop by drop. After 15 min at 95°C, another 200 mL deionized water was added into the solution. Finally, 10 mL of H2O2 (30%) was dropped into the mixture slowly to remove the residual KMnO4. The resulting GO suspension was washed repeatedly with deionized water and collected by high-speed centrifugation until the pH was 7. The homogeneous GO suspension was collected after a small amount of black residue was removed by centrifugation at 5000 rpm for 15 min.Graphene oxide suspension (5 mg/mL) was prepared by the Hummers’ method using commercial graphite powder  as the original material. Firstly, 2 g graphite power, 2 g NaNOSU-8 photoresist, an epoxy-negative-tone resist product purchased from Microlithography Chemical company (USA) was coupled with GO film as a moisture-inert material layer. Firstly, GO suspension was dropped on the clean glass and dried at room temperature in the air to form GO film. Then, we spin-coated SU-8 on it with a speed of 5000 rpm for 60 s and placed it in the oven under 95°C for 30 min. After that, the entire device was exposed with designed mask using a lithography machine. Continuously, it was kept in the oven for 15 min and a developer was used to remove the unpolymerized SU-8 to construct the expected patterns. Finally, bilayer paper based on SU-8/GO was peeled off from the clean glass. Except for special emphasis, we chose the duty ratio of 1.0 and the period of 400 μm for all of the subsequent experiments.2, K2CO3, NaBr, NaCl, KCl, K2SO4 and H2O in an enclosed container, which generated ∼33%, 44%, 57%, 75%, 86%, 97% and 100% RH, respectively. The relative humidity of our ultra-clean laboratory was measured to be 23%. We switched the RH values by placing the samples inside and outside the closed containers with saturated solution inside. Theoretical simulation was achieved using finite element analysis software.The SEM images of the samples were characterized by a JEOL JSM-7500 field-emission scanning electron microscope (FE-SEM). The XRD patterns were recorded using a Rigaku D/MAX 2550 diffractometer with Cu Kα radiation (λ = 1.5418 Å). XPS data were measured with an ESCALAB 250 spectrometer. The FTIR spectrum was taken on an FTIR Nicolet 5700 spectrometer. The relative humidity was controlled by using saturated aqueous solutions of MgClnwz219_Supplemental_FilesClick here for additional data file.


The detection of toxic gases has long been a priority in industrial manufacturing, environmental monitoring, medical diagnosis, and national defense. The importance of gas sensing is not only of high benefit to such industries but also to the daily lives of people. Graphene-based gas sensors have elicited a lot of interest recently, due to the excellent physical properties of graphene and its derivatives, such as graphene oxide (GO) and reduced graphene oxide (rGO). Graphene oxide and rGO have been shown to offer large surface areas that extend their active sites for adsorbing gas molecules, thereby improving the sensitivity of the sensor. There are several literature reports on the promising functionalization of GO and rGO surfaces with metal oxide, for enhanced performance with regard to selectivity and sensitivity in gas sensing. These synthetic and functionalization methods provide the ideal combination/s required for enhanced gas sensors. In this review, the functionalization of graphene, synthesis of heterostructured nanohybrids, and the assessment of their collaborative performance towards gas-sensing applications are discussed. Secondary air pollutants are formed from chemical reactions of primary air pollutants, which may often involve natural environmental components such as oxygen and water. These include ozone (O3), oxides of nitrogen, and secondary particulate matter (PM) [The globe has been faced with a burden of diseases linked to air pollution exposure which has had a massive toll on human health. The effects caused by exposure to air pollution have been estimated to cause millions of deaths and yearly losses of a healthy lifestyle. This burden has been reported to be on a par with other major global health risks, namely, unhealthy diets and tobacco smoking. Air pollutants are attributable as the single main environmental threat to the human health . Air pol3, NO2, and SO2 [10 had a 15 µg/m3 annual mean and a 45 µg/m3 24-h mean; PM2.5, a 5 µg/m3 annual mean and 15 µg/m3 24-h mean; O3, a 100 µg/m3 8-h daily maximum and 60 µg/m3 8-h mean on a six-month basis; NO2, a 10 µg/m3 annual mean and 25 µg/m3 24-h mean; SO2, a 40 µg/m3 24-h mean [Air pollution exposure is said to be largely determined by the concentration of air pollutants disposed in the environment to which people are exposed and the amount of time spent in that environment . The Wor and SO2 . Carbon 3), and CO has been stated as a major hazard to environmental security and individual health protection [2 has generated substantial attention as it is not only harmful for the respiratory system but also causes acid rain formation [2S), which is also a toxic gas produced from the process of oil and natural gas production, is highly dangerous for the human body with reported health effects following exposure including death and respiratory, ocular, neurological, cardiovascular, metabolic, and reproductive effects [3) is an irritant and corrosive gas, to the extent such that its low concentrations in air or liquid can lead to severe irritations and coughing in the case of skin or eye contact [The generation of toxic gases including nitrogen oxides (NOx), sulfur oxides (SOx), ammonia  is an oxide form of graphene that is covered by a high density of oxygen functional groups such as hydroxyl, epoxy, and carboxyl on its basal plane and carboxyl on its edges, making it easy to suspend in water and other polar media . Its carne plane . The abity of GO .A material related to GO is reduced graphene oxide (rGO), which possesses sheets that are regarded as chemically derived graphene . MeasureGraphene has emerged as a possible contender for sensing applications, among other things. Experimental and theoretical research has reported on the demonstrated monolayer graphene as a promising candidate to detect a variety of molecules, including gases, due to its appealing advantages . Graphenmoieties ,23. Chemmoieties . The rGOmoieties .Functional materials have been reported to be used in chemiresistive gas sensors. Volanti et al.  report oMetal oxides have been used as a sensing material in low-cost sensors. Due to their good sensing capability, fast response, and recovery, gas sensing devices based on metal oxide sensors have been thoroughly investigated. These sensors do, however, have an operational limitation due to their failure to work at temperatures much higher than room temperature. Complex circuitry and high power consumption are required for operation or optimal response at higher temperatures . There aGraphene has been synthesized using various methods as shown in In thermal decomposition of SiC, the compound is heated under an ultrahigh vacuum (UHV) and the Si atoms sublimate from the substrate. The formed few-layer graphene (FLG) typically needs a short period of time to anneal at a temperature of 1200 °C. The graphene layers can be grown directly on a semiconducting substrate, but production is still not producible . In CVD,2 [2 [3O4 [3O4 [2 and graphene/silica nanocomposites created both of which have fascinating electrical characteristics [Graphene-semiconductor nanocomposites could open new possibilities for graphene-based catalytic and photocatalytic reactions . To impr2 , ZnO [492 [2 , Co3O4 [ [2 [3O4 , NiO [523O4 [3O4 , and met3O4 [3O4  were amoeristics . Coulomberistics ,57. Throeristics ,59. FiguInorganic nanostructures have been used to make graphene-based composites ,49,51,60The high carrier mobility, radiative recombination rate, and long-term stability of inorganic semiconductor nanostructures enable the creation of high-performance optoelectronic and electrical devices ,79,80. G3 selectively and accurately. Inkjet printing was employed to deposit ZnO-graphene functional inks directly onto the interdigitated Au electrodes (IDEs) on the Si3N4 membrane substrate  of the CMOS HP during the sensor fabrication process. The process described allowed for the automated manufacture of many devices at the same time. Kim et al. [2 nanocomposites via explosive microwave synthesis for use in gas sensors. The fabrication technique was able to achieve rapid and large-scale production thanks to the fast surface chemical reactions enabled by microwave-generated plasmas, which could lead to the commercialization of semiconductor-type gas sensors by lowering production costs and improving sensing capabilities.Alfano et al.  developem et al.  develope3 concentrations. Following that, an AgNPs–GO-coated fiber optic gas sensor for NH3 detection was created. The composites were proven to have superior sensitivity and sensing performances to rGO. Jiang et al. [2/NiO were produced. The GO/SnO2/NiO materials were created using a hydrothermal growth composition in a neutral environment. A gas sensitivity test system was used to determine the composite’s sensitivity, ideal working temperature, and selectivity.In comparison with graphene, GO presents advantages such as a low production cost, large-scale production, and easy processing ,87. A vag et al.  conducte2O3–rGO nanocomposites using a simple hydrothermal technique, with great selectivity, high response, and a quick response/recovery time. The experimental results showed that the In2O3–rGO nanocomposite-based gas sensor had a good chance of being a good candidate for NO2 monitoring in the environment. Karthik et al. [2 thin films. The entire sensing nature of the rGO/TiO2 sensor was allegedly owing to the design component of rGO, which reduced TiO2 nanoparticle accumulation and advanced porosity and conductivity.Graphene oxide is typically used as a precursor in the preparation of rGO . Li et al.  used a ok et al.  used a s2/Au sensor in which rGO/SnO2 nanocomposites were decorated with Au nanoparticles at high concentrations of a GO precursor, which was obtained by adding HAuCl4 and SnCl2 to the reaction system. Following that, hybrid nanomaterials were used as gas sensors, and they performed well. Wang et al. [2–rGO hybrids synthesized using the hydrothermal synthesis approach. When compared to SnO2–rGO hybrids, the gas-sensing results showed that adding AgNPs to the SnO2–rGO hybrids considerably improved the gas-sensing capability at room temperature. Ifterkhar Uddin et al. [Zhang et al.  developeg et al.  successfn et al.  used a s2 carbonaceous lattice [In general, different gases possess molecules with electron-withdrawing or -donating abilities that can adsorb onto the surface of graphene and thereby alter its conductivity. The sensing platform of this nature has intrinsically high sensitivity. This can be attributed to the conical band structure of graphene that ensures significant conductivity changes. Nonetheless, selectivity is an issue for a sensitive chemiresistor where many gases can result in large sensing responses. Therefore, functionalization of graphene surfaces has been proposed as a solution to this issue . Chemica lattice . In the  lattice . Combini lattice ,107,108. lattice ,110.2 atom of carbon is characterized by a 3-fold symmetric electronic hybridization where the p-orbitals extend out of the atomic plane [Graphene on its own does not exhibit good sensing properties; however, derivatives have shown exceptional sensing ability due to better optical, mechanical, electrical, and chemical properties ,111,112.ic plane . In thisic plane . Disruptic plane .2.The oxides which are functionalized with various oxygen groups produce GO and rGO, which provide more adsorption sites for gases and so improve the sensitivity of the film. The presence of oxygen groups in GO renders it an insulating material  and sincChemical functionalization of graphene using synthetic chemistry methods allows for the creation of p- and n-doped graphene by selecting electron-donating or electron-withdrawing complexes that are covalently bound to the graphene carbon network. The doping concentration could often control the electrical characteristics . The ban2, H2O, NH3, or charge transfer complexes have been utilized. However, NO2, H2O, and NH3 are highly reactive compounds that should not be used in electronic materials [To generate p-type doping in graphene, several chemicals such as NOaterials ,135,136.aterials . The coraterials .2/TiSiO-coated fabrics towards various gases. Martinez-Orozco et al. [Hybridization with metal oxide nanostructures improves graphene-based sensors even more  by offero et al.  presente2, and a sensitivity of ~25% over 50 ppm gas concentration was reported. However, the recovery was slow as it took time to fully recover to its baseline resistance before the exposure timescales were tested.A wet chemical route through Hummers’ method for the synthesis of functionalized rGO was achieved by Panda et al. , for whi2 gas sensor where rGO adsorbs NO2 gas molecules as well as transports electrical signals, and the AgNPs act as catalysts to enhance the sensing response. Kang et al. [2 nanoclusters in order to improve the recovery performance. The sensor was used to measure NO2 under UV illumination, and it was discovered that the rGO device that was functional near the percolation threshold had the best recovery and then the best sensitivity in subsequent cycles. The rGO–metal-oxide semiconductor nanocomposites, however, were reported to be not suitable to detect other gases, such as H2, CO, and C2H5OH, from a power consumption point of view and may not be favorable due to their operation at high temperatures [In regard to the response time, Jia and Wang  reportedg et al.  designederatures .2) towards CO2 gas. The gas-sensing mechanism involved CO reacting when it came into contact with ionized oxygen. As reaction products, CO2 and surplus electrons were to be emitted and the extra electrons contributed to the material’s increased conductivity. When compared to the air atmosphere, the nanocomposite material showed a decrease in resistance, which led to an increase in conductivity owing to the synergistic effect of GO and TiO2 nanoparticles. This was attributed to the higher charge-carrier density at the nanocomposite material surfaces due to adsorbed CO. When these two come together, the n-n intersection is detected, and the charge carriers are transferred from TiO2 to GO. Due to the tall depletion layer of TiO2, handle electrons in GO were rapidly incremented at the interface. The chemisorbed interaction between oxygen atoms from GO and gas atoms was mostly responsible for the change in resistance. The sensing nature of the rGO/TiO2 sensors was attributed to the design component of rGO, which reduces TiO2 nanoparticle accumulation and therefore advances porosity and conductivity.Karthik et al.  studied 2O3 as an n-type semiconductor, but in the rGO/Fe2O3 hybrid structure it behaves similarly to p-type rGO. Both chemisorbed O2 and NO2 act as electron traps, decreasing the concentration of electrons, with a decrease of resistance (hole density increases). Pure Fe2O3 is nearly insensitive to NO2, but, within an rGO/Fe2O3 composite, NO2 reacts with O2− adsorbed on the Fe2O3 surface, resulting in the formation of an intermediate NO3 complex. The unbalanced charges on the Fe2O3 surface are compensated by the transfer of additional electrons from rGO to Fe2O3, which results in additional holes in the rGO and increased conductivity, as shown in 2O3 grains, the p-n heterojunctions can be formed. The concentration of holes in the accumulation layer increases after interaction with NO2, leading to the increased conductivity of GO flakes in the presence of NO2 gas.A technique used by Tadeusz Pisarkiewicz and co-workers  demonstr2)/rGO/polyaniline (PANI) sensor constructed by Zhang et al. [2S-gas-detection capabilities. The SnO2/rGO/PANI nanocomposites, with PANI, rGO, and SnO2, were tightly wrapped together to form a porous nanostructure. In the heterostructure, two different types of depletion layers were seen during the gas sensing process. The adsorption of oxygen (O) species at the surface of SnO2 was attributed to the first depletion layer, whereas the other depletion layer was linked to the SnO2 and PANI heterojunction. The performance of chemiresistive gas sensors has been shown to be influenced by the sensing properties of metal-oxide-based surface reactions between chemically adsorbed oxygen species [2 surface by the chemisorption of oxygen species [2-(ads)) adhered to the SnO2 surface of the SnO2/rGO/PANI film [2S. The sensor resistance was reduced when the thickness of the electron depletion layer was reduced [2/rGO/PANI heterojunction was shown to contribute significantly towards enhancing the H2S sensing properties [A tin oxide  as sensor platforms. The sensing process involved SO2 molecules dissociating and adsorbing on the accessible apertures. O2 around the sensing material was surely adsorbed on the surface of the non-stoichiometric TiO2 and transformed to an O species by releasing a hole due to the gap of the oxygen atom [2 surface were facilitated as the majority of carriers, the resistance of the MOFs TiO2 decreased. When the sensor was exposed to air, a portion of the oxygen molecules decomposed into O ions, releasing holes (h+) inside the Debye length. Upon exposure of the sensor in a SO2 atmosphere, the amount of O ions on the surface of the MOFs TiO2 and its positive-charge hole (h+) were reduced compared to when the sensor was in a dry gas, which resulted in a decrease in the majority carrier concentration, and thus the resistance of the TiO2 film climbed. When the sensor was exposed to SO2, O ions adsorbed on the surface of the MOFs TiO2 interacted with SO2 (reducing gas), resulting in the production of unstable SO3 via trapping holes in the surface of the MOFs TiO2. The number of positively charged carriers began to reduce, resulting in a decrease in the majority carrier concentration, causing the resistance of the MOFs TiO2/rGO film sensor to rapidly increase [2/rGO nanocomposite, p-type semiconductor activity was observed. The resistance of p-type nanomaterials was affected by the thickness of the hole accumulation layer (HAL), which resulted in poor resistance [To detect SOg et al.  used TiOgen atom . When a increase . In the sistance .2S sensing properties of SnO2, SnO2/PANI, SnO2/rGO, and in situ polymerized SnO2/rGO/PANI sensors at 25 °C, observing that the responses of the in situ polymerized SnO2/rGO/PANI sensor were about 3.18%, 8.34%, 24.07%, 32.16%, 44.91%, 60.11%, 76.25%, and 91.11% toward the corresponding H2S concentration of 50 ppb, 100 ppb, 200 ppb, 500 ppb, 1 ppm, 2 ppm, 5 ppm, and 10 ppm, indicating that the sensor can achieve a sub-ppm-level detection of 50 ppb H2S gas. The sensor also showed long-term stability where it was measured every day over a period of a month; the little change in response confirmed its good long-term stability. The rGO/TiO2 sensor outperformed the bare rGO and TiO2 sensors in terms of sensitivity, with the rGO/TiO2 sensor having a maximum sensitivity of 77% compared to 38% for the bare rGO and TiO2 sensors with over 1500 ppm H2S, respectively. Similar results were achieved for CO2 gas sensitivities, which were 42% and 92% for the bare TiO2 and rGO/TiO2 sensors, respectively, and these were also measured with a gas concentration of against 1500 ppm [2 sensor demonstrated good reproducibility for SO2 sensing at 1, 3, and 5 ppm over a time span of 0 to 1600 s [Revolved around the discussed works, graphene-based resistive gas sensors possess the advantages of rapid responsivity, outstanding sensitivity, excellent repeatability, and stability. Zhang et al.  comparedo 1600 s . Hence, A major cause of the rising environmental hazards is toxins in the atmosphere. The scientific community continually examines new sensing materials for environmental gases at a laboratory level  which shows good performances. In this review, we focused on the design and optimization strategies of graphene surfaces, in particular the synthesis of graphene composites and the assessment of their performance potential towards their use in resistive gas sensors. Functionalization aspects are discussed, highlighting the properties of the graphene surface interaction with the target toxic gases, whilst also observing the shortcomings regarding response time, full recovery to baseline of the gas sensor, power consumption, and elevated temperatures. Modified graphene surfaces and their derivatives achieved by doping/functionalization have been displayed to overcome these issues by adopting metal oxide and/or heterostructured nanohybrids in effective synthetic routes towards sensitive and selective gas sensing. The synergistic effect of the graphene–metal oxide combination and proposed mechanisms have indicated that there are still more investigations to be done towards developing the next generation of graphene-based gas sensors. Therefore, it is pivotal for scientists to develop novel innovative materials which are reported at the lab level to compete with existing commercial technology in terms of good stability and the ability to operate for long times without any need for re-calibration.


Within the density functional theory approach, we investigatethe electronic property modifications of graphane by progressive hydroxylation,that is, by progressively substituting −H with −OH groups.When 50% of graphane is hydroxylated, the energy bandgap reaches itslargest value of 6.68 eV. The electronic affinity of 0.8 eV for graphanecan widely change in the 0.28–1.60 eV range depending on thegeometric configuration. Hydroxylated graphane has two interfaceswith vacuum, hence its electron affinity can be different on eachinterface with the formation of an intrinsic dipole perpendicularto the monolayer. We envisage the possibility of using hydroxylatedgraphane allotropes with tunable electronic affinity to serve as interfaciallayers in 2D material-based heterojunctions.The thermodynamicstability of hydroxylated graphane, that is,fully sp The synthesis ofhydroxylated graphane (HyGH), that is, fully functionalized graphenederivatives with −H, and −OH groups bonded to the carbonatom network in full sp3 hybridization, and graphol (highlyhydroxylated graphene) was achieved through hydroboration of grapheneoxide (GO) followed by protonation.6 Thesecompounds showed catalytic properties toward the oxidation of biomarkersand even in hydrogen evolution reactions. Large scale synthesis of hydroxylated graphene has been reported in ref .d in ref  through 8 The thermodynamic stability of HyGH structures has beenrecently theoretically investigated in ref , and the electronic affinity(EA) are calculated for each geometry, as a function of the levelof hydroxylation. Finally, we show that it is possible to tune thework function (WF) of graphene by forming heterostructures with HyGH.The work is organized as follows: 213 We used the generalized gradientapproximation (GGA) with the Perdew, Burke, and Ernzerhof (PBE) exchange-correlationfunctional.14 The pseudopotential plane-wavecalculations were performed using Vanderbilt ultrasoft pseudopotentials.15 It is well-known that calculations based onGGA functional perform well in the evaluation of structural properties,but they underestimate the energy bandgap. Therefore, we also usedthe more computationally expensive screened hybrid functional of Heyd,Scuseria, and Ernzerhof (HSE)16 which mixesthe Hartree–Fock (HF) exchange with the GGA exchange and correlationin the short-range portion of the potential. Indeed, the HSE hybridfunctional has been demonstrated to successfully predict the electronicproperties of graphene derivatives.17 Wehave calculated the HSE total energy using the default value of 0.25for the fraction of exact exchange (EXX) and then used a value ofEXX equal to 0.50 such that the resulting electronic band gap of graphanewas 5.4 eV, as predicted by more accurate GW calculations.5 We indicate this latter functional with the nameHSE2.The computational approach was based on a pseudopotentialplane-wavemethod using the PWSCF code as implemented in the QUANTUM-ESPRESSOpackage.18 to take into account dispersion forces.All geometry optimizations were performed usingthe PBE exchange-correlationfunctional with an energy cutoff for the wave functions of 60 Ry,a cutoff for the charge density of 600 Ry, and 12 × 12 ×1 k-points Monkhorst–Pack grid. The systems were fully relaxedwith a convergence threshold of 0.001 Ry/Å on the interatomicforces and imposing a final stress less than 0.04 GPa. We verifiedthat the chosen cut-offs for the wave functions and charge densityallow a convergence of the total energy better than 0.002 eV/atom.In all of the examined structures, we have added O and/or H atomsto the hexagonal 2 × 2 unit cell of the graphene, which containseight carbon atoms. The distance between each monolayer and its periodicimage was set to 20 Å. Moreover, in the graphene/HyGH heterostructurecalculations, we used the semiempirical Grimme’s DFT-D3 correctionnOHOH), where nOH hydroxide groups (OH) substitute the same number of hydrogenatoms in the ideal graphane (GH) supercell. The HyGH structures differfor the percentage of hydroxylated C atoms, varying from 12.5% forGH(1OH) to 100%, for GH(8OH). The GH(nOHOH) structures have all C atoms sp3 hybridized as in graphane.The HyGH structures here considered are indicated with the symbolGH of pristine graphane are shown in By progressive hydroxylation, the electronic band structures becomemore and more complex, as shown in nOH ≤ 4 and becomes more dispersive for nOH > 4. By further increasing the hydroxylation,the number of PDOS peaks associated with O(p) states increases andthe bands become denser. For example, the PDOS of GH(8OH) shows adense sequence of peaks related to O(p) states which are more intensethan those associated with C(p) states. Indeed, the structure of valencebands becomes quite complex, with several intersecting bands. At thesame time, the presence of O(s) and O(p) states in the lowest conductionbands starts to be evident for nOH ≥4. However, the intensity of C(p) and H(s) PDOS is higher. In mostof the hydroxylated structures, the degeneration at M is removed withthe exception of GH(2OH) and GH(8OH).The PDOS of GH(2OH) has a largepeak at −1.3 eV relatedto O(p) states overlapping to a less intense peak associated withC(p). The large peak is due to the oxygen-related flat band. We observethat along the M-K path the highest valence band is flat until 2) to 6.68 eV for GH(4OH). When more than 50% of hydrogen atomsare substituted with OH, the gap starts decreasing, reaching its minimumvalue of 5.57 eV for GH(8OH), where graphene is fully hydroxylated.A qualitatively similar behavior is also found when using other XCfunctionals, HSE and PBE. This trend of the fundamental gap is dueto the interplay between oxygen p states, which create new occupiedflat bands, and the change in character of the conduction states,which become less H related.As summarized in Evac – EMCB, where the vacuum energy Evac is defined as the electrostatic potential energy in the vacuum,far away from the system, and EMCB isthe energy of the bottom of the conduction band. The EA can be modifiedby the presence of different adsorbates on the surface. The EA ofgraphane calculated within the HSE2 functional resultsto be 0.79 eV, to be compared with the more accurate GW value of 0.4eV.19 Discrepancies between GW and DFTcalculations, even when using hybrid functional, are expected. PBEand HSE functionals give EA values of 1.35 and 1.02 eV, respectively,further decreasing the agreement with the GW value. Therefore, inthe following we will discuss the EA referring to HSE2 results.When hydrogen is adsorbed on graphene, outward-pointing surface dipolesare produced because hydrogen is less electronegative with respectto C. For example, in 20In a material,the EA is calculatedas EA = The EA of the up and down symmetric structures GH(4OH) and GH(8OH)is 0.40 and 0.84 eV as shown in z, are reported in Evac – EF can be modified,where EF is the Fermi energy. For example,it is possible to tune the WF of graphene by forming heterostructurewith HyGH. In z  are shown for graphene and two graphene/GH(1OH) heterostructures.The heterostructures differ for the orientation of the HyGH intrinsicdipole. The flat potential regions on the right of 21 When the heterostructures are formed, the distance of the bottomHydrogen atoms of C–H from the graphene sheet is 2.9 (3.37)Å when the O–H is on the top (bottom) of GH(1OH). Thevacuum level is shifted downward of 0.6 eV when the OH group is atthe bottom of graphane, resulting in a WF of 3.9 eV; in the othercase, when the OH is on top of graphane, the vacuum level is shiftedupward of 0.7 eV resulting in a WF of 5.2 eV. The dipole potentialof the isolated GH(1OH) , that is, for the50% hydroxylated graphane structure. Next, the gap decreases to 5.57eV on GOH(8OH), where graphene is fully hydroxylated. ThroughPDOS analysis we find that the orbitals of C and H hybridize withthose of oxygen, so that new bands appear below and above Fermi energy.Although graphane has a smaller fundamental band gap, it has largerenergy gaps at K and M high symmetry points. The calculated energygaps imply electrical insulation and the presence of an optical absorptionedge at low wavelengths, in contrast with graphene which is semimetalwith high electronic conductivity and low energy optical absorptionedge (zero gap when isolated from the environment) due to the sp2 hybridization which frees mobile π-orbital electrons.Therefore, HyGH appears as an extremely interesting novel 2D materialwith in-plane insulating electrical properties.Our results show that the sp22 since hydrogen is less electronegativethan C. An outward-pointing surface dipole is produced leading tothe EA decrease and consequently a reduced local vacuum level.23 The same mechanism occurs in graphane. Whenhydrogen is substituted by hydroxyl groups, inward-pointing surfacedipoles are produced that lead to a EA increase on one side and aEA decrease on the opposite side. We found that HyGH EA can be reducedto 0.28 eV, allowing for low-EA 2D materials. However, the hydroxylationprocess induces asymmetric EA changes because graphane has two interfaceswith vacuum, and thus the EA can be different on the two structuresides. This difference results from the formation of an intrinsicdipole through the monolayer, making GH(nOHOH) a 2D ferroelectric material. The different orientations of theOH in the GH(1OH) allow to decrease or increase the WF of grapheneof about 0.6–0.7 eV.We have calculatedthe EA of the different HyGH structures. TheEA depends on the specificity of the surface geometry and on the presenceof different adsorbates. In particular, EA variations due to the presenceof adsorbates can be assessed very intuitively by comparing the electronegativityof the adsorbate atoms with respect to the substrate ones. In thecase of hydrogenated diamond surface, the electron affinity becomesnegative25Having a commensurate lattice structureto graphene and affordingthe WF tunability of different isomers, HyGH family materials couldbe ideal interlayers in graphene-based devices and 2D heterostructures.Transparent HyGH structures could be designed to serve as interfacialor electron/hole transport layer (ETL/HTL) in optoelectronic devices,such as OLED and solar cells, matching the interfacial energy levelsof different materials.53 bonds determine the large energy gaps ofHyGH. The EA is in the range 0.28–1.60 eV depending on thegeometric configuration. A finite dipole may appear making GH(nOHOH) a 2D ferroelectric material. Togetherwith the already known possible applications of HyGH as novel biomaterialto be used in bone and skin regeneration, we envisage the possibilityto use HyGH as 2D material with low EA. Moreover, by exploiting theintrinsic dipole we found in some of the structures, we demonstratethat the WF of graphene can be easily tuned by building GH(1OH)/grapheneheterostructures. Finally, heterostructures fabricated with HyGH monolayersmay play the role of electron transport layer or hole transport layerin solar cells, depending on the polarity of the 2D crystal.In conclusion, we investigated the modifications of the electronicbands structure, the DOS and the EA of graphane as a consequence ofprogressive substitution of −H with −OH groups. TheC–C sp