CYP3A5 genotype and the age of pediatric liver recipients. However, an optimization of a genotype-based algorithm for determining TAC starting is needed to earlier achieve stable target levels. As the graft itself is responsible for its metabolism, the Graft-to-Recipient Weight Ratio (GRWR) might play a role in TAC dose requirements. A single-center study was carried out in a cohort of 49 pediatric recipients to analyse the impact of patient and graft characteristics on TAC pharmacokinetics during the first 15 post-transplant days. Children < 2 years received grafts with a significantly higher GRWR (4.2%) than children between 2–8 (2.6%) and over 8 (2.7%). TAC concentration/weight-adjusted dose ratio was significantly lower in recipients from CYP3A5*1/*3 donors or with extra-large (GRWR > 5%) or large (GRWR 3–5%) grafts. The donor CYP3A5 genotype and GRWR were the only significant predictors of the TAC weight adjusted doses. Patients with a GRWR > 4% had a higher risk of acute rejection, observed in 20/49 (41%) patients. In conclusion, TAC starting dose could be guided according to the donor CYP3A5 genotype and GRWR, allowing for a quicker achievement of target concentrations and eventually reducing the risk of rejection.Tacrolimus (TAC) pharmacokinetics is influenced by the donor  Nevertheless, the best way of employing this drug is still a matter of intense debate4.Therefore, TAC therapeutic drug monitoring (TDM) in whole blood is essential to optimize clinical outcomes and minimize adverse effects. Nevertheless, the use of the TDM results for dose adjustment is time consuming before a stable and optimum TAC blood concentration can be reached and may lead to over or under-dosing determining drug toxicity or acute rejection. Therefore, better strategies for TDM are required to establish the optimal TAC dosage, especially in the early post-transplant period3. CYP3A4 and CYP3A5 are the primary enzymes responsible for TAC metabolism in the liver and to a lesser extent in enterocytes5. It is already well known that CYP3A5*3 allele, that is found in 90% of the Caucasian population, determines a lower TAC catabolism, whilst the *1 allele is related to a fast metabolism and, consequently, to a relatively lower TAC exposure6: non-expresser patients are poor metabolizers, have higher TAC blood concentrations and should be given the standard recommended starting dose, whereas individuals carrying at least one CYP3A5*1 allele are intermediate or extensive metabolizers and require a higher tacrolimus dose. The role of CYP3A5 genotype was established by a systematic review carried out on 596 pediatric transplant recipients7. In the most recent consensus report on TAC personalized therapy, CYP3A5 genotype is indicated as the main pharmacogenetic biomarker to be used in clinical practice for determination of the initial dose of tacrolimus in order to rapidly reach a therapeutic concentration2. Particularly, the donor CYP3A5 genotype was reported to influence TAC pharmacokinetics in liver transplant patients, whereas the recipient CYP3A5 genotype had no impact on TAC blood concentration12. Beyond CYP3A5, the determination of CYP3A4*22 genotype could explain the residual variability in TAC pharmacokinetics3. Lastly, ABCB1  polymorphisms seem to be less relevant in TAC pharmacokinetics13.Orally administered TAC, a lipophilic drug, has a variable absorption, first pass metabolism and limited bioavailability14. Among these, the recipient age has been pointed out as a main factor influencing TAC concentrations: younger pediatric patients require higher TAC doses than do older patients or adults to achieve similar TAC concentrations, probably due to a wider volume of distribution or a faster drug metabolism16.Apart from the genetic make-up, clinical and graft factors may affect TAC concentrations, e.g. patient age and gender, transplant type, baseline renal and liver function, concomitant use of corticosteroids or other drugs, serum albumin concentration and hematocrit, food administration or diarrhoeaCYP3A5 non-expressers and the highest dose in younger (≤ 6 years) CYP3A5 expressers. This genotype-guided dosing was compared to a standard dosing in a cohort of pediatric solid organ transplant patients17, obtaining an earlier attainment of target levels and stable therapeutic concentrations with significantly fewer out-of-range results.In this regard, a sliding scale algorithm for a genotype guided TAC starting dose, stratified by the recipient age, was designed by Min et al., with the lowest dose in older (> 6 years) 18. GRWR has recently been correlated to TAC pharmacokinetics in a large Japanese cohort of pediatric living donor liver transplants19.Indeed, TAC clearance could be dependent on the graft size, as the graft itself is responsible for its metabolism. This implies that, theoretically, the best marker of graft size could well be the Graft-to-Recipient Weight Ratio (GRWR), indicating the normalized size of the graft based on the patient’s weight. GRWR remains the most commonly used parameter for decision making in transplant surgery to calculate the optimal graft size for the recipient, so far due to its simplicity and practicality for clinical application. GRWR should be within the range 1% to 3% to avoid major complications related to size mismatching between the graft and the recipient, which may result in graft failure or even patient death if not appropriately handledA further refinement and optimization of a genotype-based algorithm for determining TAC starting dose would be of advantage, in order to reach an earlier achievement of stable target immunosuppression levels and avoid adverse effects.We present here our single-center study designed to evaluate the influence genetic polymorphisms and other patient and graft factors have onTAC blood levels in a cohort of pediatric liver transplant patients in the first two post-transplant weeks.AOU Città della Salute e della Scienza di Torino, Italy, were assessed for eligibility. This study is an extended pharmacokinetic and pharmacogenetic analysis on a previously published study by our group, which was limited to the first post-transplant day12 and did not take graft weight into account.All pediatric patients who consecutively underwent liver transplantation from January 2007 to December 2014 at Inclusion criteria were as follows: (a) age < 18 years old at listing; (b) oral TAC immunosuppressive monotherapy and (c) informed consent of legal guardian. Exclusion criteria were as follows: (a) contra indications to oral tacrolimus; (b) multiple organ transplants or retransplants; and (c) declined consent.Donor and recipient DNA samples were provided by the Regional Transplantation Center , extracted after enrollment and analyzed.Donor, recipient and graft characteristics, along with laboratory data, were collected from the medical records.small-for-size graft, if GRWR was < 1%;size-matched graft, if GRWR was between 1 and 3%;large-for-size graft, if GRWR was between 3 and 5%;extra-large-for-size graft, if GRWR was > 5%.For the analysis, the recipients were divided into groups according to their age: under 2 years of age, between 2 and 8 and older than 8 years. GRWR was calculated using the formula graft weight/recipient weight and it was expressed as a percentage. The liver transplants were categorized into the following three groups according to the GRWR:AOU Città della Salutee della Scienza di Torino, Italy) and written informed consent was obtained from all patients’ parents. The study was carried out in compliance with the provisions of the Declaration of Helsinki and the Good Clinical Practice guidelines. No organs from executed prisoners were used.The study was approved by the Institutional Review Board  and on day 4 and/or steroids as induction. All patients were postoperatively administered oral TAC as capsules; naso-gastric administration was used in few cases.0). The target C0 for the first 2 weeks was set between 8 and 12 ng/mL, in line with our center’s protocol and in agreement with other study protocols.The initial target TAC dose was 0.075 mg/Kg every 12 h, subsequently adjusted according to TAC whole blood concentrations , trough TAC blood concentrations (ng/mL) and the concentration/weight-adjusted dose ratio (C/D/Kg) were determined daily during the first 2 post-liver transplantation weeks. C/D/Kg was used as a marker of TAC bioavailability to avoid any confounding effect due to the different TAC pro-kilo doses and dose variations during treatment.Blood sampling was performed at the end of the inter-dose interval (just before the new drug intake), with sodium/EDTA Vacutainer tubes. The TAC concentrations were determined by the Masstrak Immunosuppressants XE kit , based on a UltraPerformance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS) method.CYP3A5*3, CYP3A4*22, ABCB1 3435C > T and 1199A > G using the polymerase chain reaction (PCR) with TaqMan (Thermo Fisher Scientific). The other most common polymorphisms of ABCB1, i.e. 2677G > T and 1236 C > T, were not analyzed, since they are generally reported to be in linkage disequilibrium with 3435C > T polymorphism14.Donor and recipient DNA samples were genotyped for 2-square test were used for categorical data. Univariate and multivariate linear regression analysis were performed to test the predictive value of variables showing significant correlation with TAC concentrations. Absence of significant collinearity of covariates and significant correlation with the dependent variables were considered as preliminary assumptions for regression analysis. In case of collinearity, only the variable with the highest predictive value by univariate regression was included in the multivariate analysis. All the tests were two tailed and a p value of ≤ 0.05 was considered statistically significant. The confidence intervals (CI) were calculated at the 95% level. ROC curve was used to identify cut-off values.Data were analyzed by SPSS 24.0 software package . Categorical variables were summarized as counts and percentages and continuous variables as means + /- SD or medians and inter-quartiles ranges. Differences between groups in the continuous variables were determined by the Mann–Whitney or Kruskal–Wallis tests when more than one group was involved. The Fisher exact test or χA total of 49 pediatric patients on TAC immunosuppressive monotherapy were included in this study.Patient and graft characteristics are summarized in Table CYP3A5, CYP3A4 and ABCB1 genotype frequencies did not deviate from the Hardy–Weinberg equilibrium. Genotype frequency was not significantly different between transplant recipients and donors and showed no association with age or gender. The total allelic frequency was similar to that observed in other populations made up in great majority of Caucasian subjects22.The 2 0.664, p value < 0.001), indicating a not perfectly proportional graft matching.Patients’ weight and graft weight resulted significantly correlated . Among all the enrolled patients, respectively 43%, 41% and 16% showed a GRWR between 1 and 3% , 3% and 5% (large) or more than 5% (extra-large). No small-for-size grafts (GRWR < 1%) were transplanted.2 = 0.229, p value < 0.001). Median GRWRs were 4.2% (IQR 3.45–5.17), 2.6% (IQR 2.01–4.13) and 2.7% (IQR 1.59–2.98) for patients’ age groups < 2 years old, between 2 and 8 and > 8 years old, respectively . Children under 2 years of age received liver grafts with a higher GRWR than children between 2–8  and over 8 . There was no difference in the GRWR values between children 2–8 years old and those over 8 years .GRWR was statistically significantly correlated with the recipient age , 16%, 16% and 68% of large grafts (GRWR 3–5%) and 62.5%, 12.5%, and 25% of extra-large grafts (GRWR > 5%).2 = 0.155;p value = 0.043), thereafter this correlation did not reach statistical significance.Median values of ALT values were significantly higher in patients who received large and extra-large grafts. There was a statistically significant correlation between ALT and GRWR on the 1st post-transplant day (r0 level (8–12 ng/mL) during this period, most likely due to TDM-guided dose adjustments, i.e. the percentage of patients who achieved target therapeutic ranges at day 1 and 15 increased from 23.6% to 42.9%.Figure p values between 0.008 and 0.044 in the range of 2–8 days), with the dose corrected by the patients’ weight  and with the graft weight . These data suggest that graft weight may affect the achievement of the desired TAC concentrations.In the first 7 days of treatment, there was a significant correlation with the initial (day 1) dose corrected by graft weight  than male patients. TAC C/D/Kg was significantly lower in children under 8 years of age, particularly in those under 2, from the 1st post-transplant day to the 7th  and female donors  had a significantly higher TAC C/D/Kg on the 1st post-transplant day and on the 3rd and 4th post-transplant days, respectively.Attention was then focused on the factors affecting the inter-individual variability in the TAC C/D/Kg. Female recipients showed significantly higher C/D/Kg on the 1st post-transplant day  and between the 10th and the 15th day , respectively. Corticosteroids administered as induction therapy did not influence TAC C/D/Kg.The levels of ALT were not correlated to TAC C/D/Kg, whereas a higher value of PT-INR on the 1st and the 5th post-transplant days correlated to a higher TAC C/D/Kg in the time-lapse between the 2nd and the 4th day , as reported in Table The TAC C/D/Kg data were stratified by the main parameters showing a statistically significant association over a longer time range , probably due to the low sample size and the variability in the administered dose between groups.The influence GRWR has on TAC pharmacokinetics according to the donor CYP3A5 polymorphism was analyzed. Recipients from *1/*3 donors rarely achieved TAC concentrations within the therapeutic range, whereas only patients with extra-large grafts did not reach adequate target TAC concentrations among recipients from *3/*3 donors. Indeed, patients who received an extra-large-for-size graft required higher TAC doses than recipients with a large or size-matched graft regardless the donor CYP3A5 genotype also resulted to be an independent predictor of the weight-adjusted dose of TAC  patients developed acute rejection during the first 15 post-transplant days, at a median of 9 post-transplant days (range 7–30). None of these events led to graft failure or patient death.Genetic, anthropometric or demographic variables were not significantly associated with the onset of acute rejection.Only ALT levels on the 1st post-transplant day were significantly higher in patients who developed acute rejection in the following days. The protocol assumption of corticosteroids as induction immunosuppression did not prevent the onset of acute rejection.p value = 0.005). Patients with a GRWR > 4% had a higher risk of acute rejection than those with a ratio < 4% , with a 70% sensitivity and an 82% specificity .Patients with acute rejection had a lower TAC C/D/Kg than patients with no rejection, even if this did not reach statistical significance. This trend was present from the first to the 10th post-transplant day, followed by a reversed trend. Acute rejection was not significantly associated with recipient or donor genotype, age or gender. Noteworthy was the fact that acute rejection occurred with statistical significance more frequently in the group of patients who received an extra-large graft (GRWR > 5%). The logistic regression analysis evidenced that only the GRWR had a statistically significant predictive value for the occurrence of acute rejection . However, although a minor role of CYP3A4 polymorphisms on TAC pharmacokinetics has been recently reported in the consensus report on TAC personalized therapy2, data are more controversial in pediatric liver transplant patients, whereas it may be more relevant in kidney transplant patients25.The TAC pharmacokinetic analysis we performed in the first two post-transplant weeks confirmed some results from our previous studyABCB1 gene) may have a role in TAC disposition (particularly in lymphocytes30), we did not observe any significant association with dose requirements, in line with previous reports28.Moreover, although P-glycoprotein  had no relevant influence on TAC blood levels, as previously reported36.Nevertheless, when the pharmacokinetic analysis was extended to cover the first two post-transplant weeks, we observed that the impact of the aforementioned factors had on TAC pharmacokinetics changed during the first post-transplant days and most likely reflected changes in the patient’s physiology and pharmacokinetics. Indeed, the patients’ gender and age had no significant effect on the TAC exposure, whereas an increase in the influence of GRWR on TAC blood concentrations was observed. The recipient age could play an important role in determining TAC concentrations during the first two post-transplant days, probably due to differences in the volume of distribution, whereas the graft size could become a better predictive factor of TAC concentrations later. According to this hypothesis, younger recipients might require higher TAC doses since they generally receive relatively larger livers. As already reported, the standard liver volume to body weight ratio (as well as GRWR) of children decreases as age increases until approximately the age of 16 years old19, and suggests that patients who receive a larger graft, due to their higher amount of hepatic tissue (and hence enzymes), have enhanced TAC metabolism. This evidence is theoretically quite reasonable, so much that graft weight is a key variable for the calculation of the metabolic capability of individuals, and it is considered as a main feature for the physiologically based pharmacokinetic (PBPK) modeling37. Therefore, a GRWR-based TAC initial dose could be more accurate than the current standard weight-based dose.Our evidence about the impact of GRWR on TAC metabolism is in line with a recent study on a large Japanese cohort19. Other factors could contribute to this difference with the Japanese study. The study by Shoji et al.19 was focused on transplants from living donors, while our patients received graft from deceased donors. The median graft size was larger in our study (GRWR 3.3% vs 2.37%) and a different distribution in GRWR groups was observed, e.g. no small-for-sizegrafts were observed in our population.Nevertheless, probably due to the low sample size , the significant correlation between GRWR and TAC C/D/Kg was observed up to the 10th post-transplant day (and then it lost of significance), whereas in the Japanese study it occurred from 6 to 12 months after transplant42: this may occur very early in the first post-transplant weeks, with 80% of volumetric recovery after 1 week from transplant38 and graft size normalization within the 2nd post-transplant month. Moreover, in our sample, we observed higher ALT levels, underlying more cytolysis, and probably a consequent reduction in the amount of functional liver tissue, in patients with higher GRWR. These concomitant mechanisms, e.g. liver regeneration and cytolysis, may progressively reduce the differences in TAC metabolism between small-for-size and large or extra-large-for-size grafts: the interindividual variability in GRWR would rapidly decrease within the first weeks according to the initial graft size, reaching a very low variability after two months, thus explaining both our results and those by Shoji et al.19.On the other hand, the regeneration of the transplanted liver may be relatively fast in the first post-transplant weeks, as already reported previouslyMost important, in our cohort the vast majority of acute rejections and TDM-guided dose adjustments were applied around the 9th day of treatment: acute rejection can slightly decrease the hepatic metabolism of TAC , leading to an increase in the TAC C/D/Kg in patients with rejection. Interestingly, acute rejection was more frequent in patients with high GRWR, so this phenomenon would also explain the change in the predictive power of GRWR for TAC C/D/Kg.Finally, the dose adjustments applied (particularly around the 9th post-transplant day), based on TDM results and/or on the occurrence of acute rejection, may also cause a slight bias in the C/D/Kg; in fact, the observed trough TAC blood levels in the following days cannot be considered as the steady-state concentrations, causing fluctuations in the ratio until a new steady-state is reached.Therefore, the most reliable data in terms of prediction of C/D/Kg are surely the ones within the 9th post-transplant day, before the introduction of these sources of bias.18. Other authors observed that acute rejection rate was not associated to GRWR43, however, these different findings could be related to the adoption of different induction immunosuppression protocols.Safety criteria of GRWR for pediatric patients are greatly influenced by the age of recipients and still represent a matter of intense debate, especially for infant recipients, where the impact of graft-to-recipient size mismatching on outcomes remains unclear. Liver transplant techniques using living-related grafts, reduced-size livers, and split livers have been widely exploited due to the shortage of size-matched cadaveric organs. Nevertheless, the reasonable range of GRWR in infants has not been well defined. The reduction in the graft mass may be an adequate strategy in selected cases to limit collateral risks of oversizing, but it should not be proposed systematically as it may incur an added risk of complications caused by greater parenchymal surface and suboptimal vascular flow. In our series, the high median GRWR was dependent on the surgical decision to prefer whole liver transplants in children < 2 years old and to eventually use temporary tension-free abdominal closure in cases of increased abdominal pressure. Our data showed that all the patients who received a large o extra-large graft achieved excellent post-transplant survival outcomes, suggesting that the accumulation of technical experience is relevant for the successful implant of large/extra-large grafts in infants. Nevertheless, our personal experience with this research showed that the onset of acute rejection was significantly associated with the patient’s GRWR, meaning that patients who have a larger than proportional graft size also run a higher risk of developing rejection, i.e. we observed that a GRWR cut-off value of > 4% was strongly predictive of acute rejection. This observation is in line with those of Kiuchi et al., who found that acute rejection was more frequent in larger-for-sizegraftsAcute rejection was not significantly associated to other donor/recipient and graft characteristics, but it occurred more frequently in patients with lower TAC blood concentrations, even if this association did not reach statistical significance, probably due to the small sample size. This indicated that acute rejection might depend on the size of the graft, not only because there is more tissue capable of metabolizing the TAC, leading to lower systemic concentrations, but probably also because an extra-large sized graft means more allo-antigens and a more extended tissue damage, as sustained by the correlation between ALT levels and the GRWR on the 1st post-transplant day. Moreover, a larger liver could mean also a less homogeneous drug penetration in the first days after transplantation, so it could take longer to achieve therapeutic levels in the whole graft. Nevertheless, the surgical decision to use large or extra-large grafts should not be limited on the basis of our results, if it is supported by a valid technical experience. On the other hand, we believe that the TAC starting dose should be increased when a pediatric liver transplant is performed by using a proportionally large or extra-large graft.CYP3A5 genotype. Therefore, the TAC starting dose could be successfully guided and individualized according to the donor metabolic activity and graft size, allowing to achieve the TAC concentrations in the therapeutic in a shorter time and reduce the risk of acute rejection.The multivariate regression analysis suggests that the best predictors of the final TAC dose needed to reach therapeutic concentrations are GRWR and the donor 17. We reported in Fig. CYP3A5 and the GRWR, where the recommended doses need to be validated in larger sample sizes. This hypothesis might lay the groundwork for a future prospective trial that would allow implementation of an efficacious guided dosing for the TAC starting dose and the subsequent dose titrations in the early post-transplant period.Our findings suggest that it may be of advantage stratifying genotype-guided dosing by the graft size (GRWR) instead of the recipient age46. Confirmation of whether a more precise individualized dosing has a potential to improve patients’clinical outcomes and reduce hospital length of stay and costs associated with complications is to be obtained through further research.Prior studies in adults reported a higher risk of rejection, poor graft outcomes and longer hospital stay in patients with sub-therapeutic or supra-therapeutic concentrations compared to those with therapeutic concentrationsCYP3A5 genotype) and the graft size (GRWR) of the liver transplant before starting the TAC–based immunosuppression may be an attractive option for the prediction of the individual dose required and could well allow for a quicker achievement of target blood concentrations. We confirmed that the testing of the donor CYP3A5 genotype should be routinely implemented by clinical pharmacology and pharmacogenetics laboratories for all children. Although the donor CYP3A5 genotype seems to be the most relevant predictive factor on TAC pharmacokinetics, we suggest that GRWR, which is readily available to clinicians at the time of transplant, could be used not only for its surgical impact, but also as a predictive factor to guide the TAC starting dose.In conclusion, defining the donor genetic profile (The findings of this study should be an incentive for developing TAC dosing algorithms, incorporating clinical and genetic factors, in order to minimize the inter-individual variability in TAC concentrations and potentially reduce post-transplant complications. Multicenter large-scale studies are required to more comprehensively explore the impact of the use of large grafts on TAC pharmacokinetics and the risk of acute rejection in infants < 5 kg.


Abu-Romman, SaeidMájek, PavelAryal, Uma K.Mao, MengBaran, JaroslawMartienssen, MarionBaudin, BrunoMartins, IsabelBenndorf, DirkMetzger, JochenBindschedler, Laurence VeroniqueMoertl, SimoneBurger, ThomasMuhovski, YordanBurniston, Jatin G.Muramoto, KojiChardot, ThierryNaryzhny, StanislavChavez, FermanNawaz, MuhammadChen, ZhenNestler, UlfCheng, ZheNguyen, Van KhanhChoi, Yeung JoonNoren Hooten, NicoleCologna,StephanieOhlendieck, KayCondorelli, Daniele FilippoOkumura, NobuakiCoorssen, JensPadula, Matthew P.Cross, MichaelPardo, MaríaCytlak, UrszulaPerišić, OgnjenD’Argenio, ValeriaPuhka, MaijaDolo, VincenzaRakus, DariuszDoucette, Alan A.Redell, MicheleDu, MingRomo, Maria Del Mar Ortega-villaizanEcke, ThorstenSainlos, MatthieuFischer, RomanSgarra, RiccardoFurber, KendraSharma, Bhesh RajGabernet, GiselaSinitcyn, PavelGámez-Valero, AnaSmith, JenniferGraves, Steven W.Soler-Vasco, LauraHammer, ElkeSung, Wang ChouHsin, Kun-YiSzafranek-Nakonieczna, AnnaHsu, Fei-TingTao, W. AndyHsuan, JustinThéron, LaëtitiaIadarola, PaoloTimperio, Anna MariaJahn, OlafTyan, Yu-ChangKalamvoki, MariaUrbanelli, LorenaKalkum, MarkusVeenstra, TimothyKalló, GergőVergara, DanieleKatselis, GeorgeVoss, MatthiasKosova, KlaraVyatkina, KiraKowalski, KonradWang, JiongweiKrijgsveld, JeroenWang, XueKumar, ManojWang, ShengLasonder, EdwinWessels, Hans J. C. T.LeDuc, Richard D.Xie, ZhiqunLópez, Susana B BravoXu, PengMacDonald, Matthew L.Young Ryu, SoMaity, ShuvadeepThe editorial team greatly appreciates the reviewers who have dedicated their considerable time and expertise to the journal’s rigorous editorial process over the past 12 months, regardless of whether the papers are finally published or not. In 2019, a total of 29 papers were published in the journal, with a median time to first decision of 19.86 days and a median time from submission to publication of 49.9 days. The editors would like to express their sincere gratitude to the following reviewers for their generous contribution in 2019:


Journal of Biomedical Optics editor-in-chief Brian W. Pogue outlines a revision of scope for the journal. Journal of Biomedical Optics.The field of biomedical optics has evolved over many decades, where devices and methods now penetrate nearly every aspect of medicine, healthcare, and daily life. We have transitioned from a field dominated by laser use and therapeutic interventions, to a highly differentiated array of diagnostic and lower-energy therapeutic uses of optics. This field benefits enormously by massive numbers of discoveries in optoelectronic devices that reduce size and costs as components of biomedical systems, and this is paralleled by biomedical applications that have found use for these tools. At this time in the history of our field, it is critical to reexamine the current and future directions where biomedical optics and photonics innovations are having the largest impact, and where they will go in the future. It is with this goal that I wish to give some perspective on this transition of the field and the revision of the scope of the It is a constant editorial challenge to ensure that we are presenting what our editorial board, SPIE BiOS society members, and our readers are looking for. Our field has grown from the journal being the only one in the field with a small number of papers per issue, to the situation where there are numerous competing journals and a nearly unlimited number of papers in the field. It is imperative to periodically reassess our publication mandate within this ongoing expansion, using the experienced guidance of the editorial board. There are two major observations offered below which together help make the conclusions of the revised scope.A first observation is that our goal should be to shape the field of biomedical optics by publishing studies that are clearly contextualized as to the hypothesis, discovery, or technical advance, and that this needs to be presented with a comprehensive understanding of the field in which the manuscript is written. In a world where all fields of study are drowning in research publications, it is even more critical to ensure that what gets published in JBO is done so by authors who understand the history and landscape of ‘what is known’ and even more importantly ‘what is not known’ in the field of their manuscript. Indeed, the exponential expansion of journals and published papers today would suggest that all scientific disciplines will continue to be awash in observational studies or papers without the appropriate context. This trend will only increase, and while the search tools to find high-quality studies are getting better, the journals that seek to publish the most impactful state-of-the-art will be the lasting independent markers of quality. This is especially important for community-based journals, such as JBO.use optical devices for biomedical observations has vastly outpaced the number of studies that report optical innovations or discovery. This is one measure of success in a field that has wide penetration into all aspects of medicine, biology, and society. However, we should not confuse the use of devices, with impactful research. The core of the SPIE JBO community has always been advancing physics and engineering of biomedical optical innovations, involving nearly equal parts of:A second observation is that the number of biomedical studies that 1)advances in optics & photonics devices or systems,2)computational tools & analysis methods,3)light–tissue interaction theory and tissue phantoms,4)initial device/system testing in biology, medicine, or healthcare.These are at the core of our advances and the biomedical optics component of the SPIE society.The journal must make difficult choices about what we publish in biomedical optics, with the balance shifted towards excellence in technical innovation and discovery rather than biomedical utility and practice. The editorial board recognizes this phenomenon in our own research circles, and we recognize that seeking to publish innovation and discovery that advance capabilities must outweigh publishing scientific observations that merely document measurements.The numbers show that technical innovations receive higher downloads and citations than biologically driven innovations, and this is in part because of the fact that biologically driven innovations have many more venues for publication, and the best of these latter papers do not get offered to our journal. In every field of medicine and healthcare there are hundreds of journals that publish relevant papers, and newly emerged systems to image, sense, or measure them are part of their mandate. While we want to encourage and apply the use of optical devices in medicine and via commercialization, if these scholarly activities have impact, they should wind up penetrating into the medical field via medical journals that represent them. For the good of the field, we should be actively advocating for the best biomedical papers to be published in the best biomedical journals, and similarly the best technical papers should be published in the best technical journals. JBO has always represented the edge of both fields, but with a center of gravity that places it as a technical journal primarily.Technical innovations that have biomedical utility as their goal are well placed in our journal and in the SPIE society. It is with this vision that a slightly revised scope for the journal has been approved by the editorial board. This change is a necessary reassessment of our compass, to tack our trajectory towards the best of our field, and one that will ensure the longevity of the journal and the shape of our field.Journal of Biomedical Optics have approved the following recommendation of a revised scope:In summary, the board of editors and the editorial staff of the Journal of Biomedical Optics (JBO) is an open access journal that publishes peer-reviewed papers on innovations in optical systems and techniques that will improve health care and lead to discoveries in biomedical research. Growth in the capabilities of biomedical optical technology has fueled new areas of contrast, resolution, and spectral capacity in imaging and sensing, which have enabled widespread applications throughout biology and medicine. Topics suitable for JBO include significant in-depth studies of:The •fundamentally new discoveries in biomedical optical devices for imaging or sensing using: optical spectroscopy, near infrared spectroscopy, photoacoustics, microscopy, optical coherence, tomography, fluorescence, phosphorescence, elastography, hyperspectral, using features unique to optics such as spatial, spectral, temporal, interference, polarization, or quantum nature;•increasing knowledge of light–tissue interaction, through theoretical transport models such as Monte Carlo, diffusion, electromagnetic and empirical methods, and through physical methods to model light–tissue interactions such as tissue-simulating phantoms;•computational advances in optical image and signal processing, and image reconstruction, including new methods in machine learning and artificial intelligence that improve insight into the utility, detection, or performance value;•novel medical optical systems used in definitive animal or human studies or clinical trial testing that can impact the field by their design or the optical innovation, including discoveries and technical advances in optics emerging from mobile, remote, wearable, or implantable technologies that can improve health and wellness;•discoveries in photonics, nanophotonics, plasmonics, biosensors, and optical reporters that have direct relevance to biomedical needs or utility;•hybrid imaging or interventional systems where optics are combined with other tools such as ultrasound, x-rays, magnetic resonance, molecular sensing, or electromagnetics.


Although the number of vascular surgeries using vascular grafts is increasing, they are limited by vascular graft-related complications and size discrepancy. Current efforts to develop the ideal synthetic vascular graft for clinical application using tissue engineering or 3D printing are far from satisfactory. Therefore, we aimed to re-design the vascular graft with modified materials and 3D printing techniques and also demonstrated the improved applications of our new vascular graft clinically. We designed the 3D printed polyvinyl alcohol (PVA) templates according to the vessel size and shape, and these were dip-coated with salt-suspended thermoplastic polyurethane (TPU). Next, the core template was removed to obtain a customized porous TPU graft. The mechanical testing and cytotoxicity studies of the new synthetic 3D templated vascular grafts (3DT) were more appropriate compared with commercially available polytetrafluoroethylene (PTFE) grafts  for clinical use. Finally, we performed implantation of the 3DTs and SGs into the rat abdominal aorta as a patch technique. Four groups of the animal model  were enrolled in this study. The abdominal aorta was surgically opened and sutured with SG or 3DT with 8/0 Prolene. The degree of endothelial cell activation, neovascularization, thrombus formation, calcification, inflammatory infiltrates, and fibrosis were analyzed histopathologically. There was significantly decreased thrombogenesis in the group treated with the 3DT for 30 days compared with the group treated with the SG for 7 and 30 days, and the 3DT for 7 days. In addition, the group treated with the 3DT for 30 days may also have shown increased postoperative endothelialization in the early stages. In conclusion, this study suggests the possibility of using the 3DT as an SG substitute in vascular surgery. In 2016, cardiovascular disease (CVD) led to 1.68 million deaths in the European Union . In otheCommercial vascular grafts  have been frequently used in clinical applications. However, the SG has low efficacy relative to an autologous and tissue-engineered vascular graft because of the slow rate of endothelialization and increased risk of thrombogenesis. Endothelialization is a crucial factor for long-term implantation due to its outstanding anticoagulant effects, resulting in resistance to inflammation and thrombosis ,8,9,10. Therefore, we re-designed the vascular graft with modified materials and 3D printing techniques and also demonstrated the improved clinical applications of our new vascular graft. First, we developed the 3D templated vascular graft (3DT), followed by mechanical testing and cytotoxicity studies comparing 3DTs and SGs. Rats and humans exhibit similar blood pressure and homeostatic mechanisms . Later, w/w). The TPU  granules were dissolved in dimethylformamide  at a concentration of 15% (w/v) to obtain the solution. After dipping the PVA template into the TPU–salt suspension, the dip-coated template was dried and thereafter immersed in sonicated water to leach out the salt powders. In the final step, the core template was removed through cut ends in the sonicated water, resulting in a customized porous TPU graft.The original techniques for the fabrication of artificial vascular grafts have been reported previously in detail . In brieThe mechanical properties of customized graft were evaluated and compared with those of an SG. Uniaxial tensile tests were performed using a typical universal testing machine . Tensile specimens were cropped from the as-prepared artificial graft measuring 15 mm in diameter and 45 mm in length. The graft was cut into rectangular sheet pieces with a width of 6 mm and a length of 40 mm. Using the resized samples, the tensile tests were performed at a rate of 500 mm/min and a gauge length of 20 mm. In total, five samples were tested for the measurement of average elongation at break and elastic modulus (20% secant).The porous structure of 3DT and SG inner surfaces was analyzed via field emission scanning electron microscopy . Prior to imaging, the samples were sputter-coated with gold for 250 s using a 15 mA current.2 environment.L-929 mouse fibroblast cells obtained from the Korean Cell Line Bank  were cultured in RPMI 1640 medium (Hyclone) supplemented with 10% fetal bovine serum  and 1% penicillin/streptomycin at 37 °C in a humidified 5% CO® AQueous Cell Proliferation Assay kit . Extracts of sterilized grafts  were obtained by placing in RPMI 1640 medium at an extraction ratio of 0.1 g/mL at 37 °C, 100 rpm for 24 h. L-929 cells were seeded in a 96-well culture plate at a density of 1 × 104 cells/well and incubated for 24 h. The culture medium was replaced with graft extracts and incubated for an additional 48 h. Cell morphology in each well was observed with an inverted light microscope . Then, the medium was replaced with the medium containing MTS -5-(3-carboxymethoxyphenyl)-2-(4- sulfophenyl)-2H-tetrazolium) reagent and incubated for 3 h. Absorbance was measured with a microplate reader  at a wavelength of 490 nm. The cell viability (%) was calculated using the following equation:Cell viability was evaluated based on ISO 10993-5 using a CellTiter 96Sixteen-week-old specific pathogen-free Sprague Dawley male rats  were used in this study. All of animal housing, breeding, and experiments were approved by the Animal Care and Use Committee of Korea University (KOREA-2019-0060-C1).The operation was done according to our previously described method . On day After extraction of the aorta and surrounding tissues, these samples were fixed with 4% paraformaldehyde and stained with hematoxylin and eosin (H&E). After that, histopathological analysis including the luminal thrombus, neovascularization, calcification, fibrosis, and inflammatory infiltrates was conducted.Histopathology grading of thrombi, calcification, neovascularization, inflammatory cell infiltrates, and fibrosis was evaluated and rated by a pathologist in a blinded manner. This grading consisted of grade 0 (for none), 1 (for mild), 2 (for moderate), and 3 (for severe) and scoring was calculated as a mean value.p-value of <0.05 is considered to indicate statistical significance. All statistical analyses were conducted using GraphPad Prism software .The data are expressed as the mean ± standard deviation (SD). Statistical significance was determined using the Mann–Whitney test. A We previously reported a template-based fabrication of tubular tissue engineering scaffolds ,18. In tTo evaluate the mechanical flexibility quantitatively, tensile tests were conducted using the as-prepared sheet specimens cut from the artificial grafts. Next, the viability of L-929 cells with or without extracts of 3DT or SG was investigated using an MTS assay. As shown in To evaluate the postoperative effects of the 3DT vascular patch, the endothelial cell activation was compared with that of the SG for 7 or 30 days postoperation. The endothelial cells are originally flat cells, but when activated they become round. The SG and 3DT groups revealed endothelial cell activation on day 7 , whereasTo further investigate the postoperative effects of the 3DT vascular patch, the histopathological findings of neovascularization, luminal thrombus, calcification, inflammatory cell infiltrates, and fibrosis were compared with those of the SG for 7 or 30 days postoperation . Among tThe ideal vascular graft should exhibit appropriate mechanical strength and compressibility, permeability and viscoelasticity, biocompatibility and biostability, hemocompatibility and non-thrombogenicity. These prerequisites have already been reported in many studies ,23,24,25This study introduces a new synthetic 3DT. Although this study had some limitations due to the small sample size and animal operations using a patch technique, which is not a full graft technique, it suggests the possibility of clinical applications using the newly fabricated synthetic 3DT. Our synthetic graft was not inferior compared to the commercially available SG, which is used worldwide clinically, in terms of mechanical strength, surface morphology, cytotoxicity, and histological results following in vivo implantation. The elastic moduli of typical vascular tissues range from approximately 1 MPa to 40 MPa, depending on the type of artery or vein ,37,38. IOur study revealed that the 3DT was biocompatible and reduced the risk of thrombogenesis in the early postoperative stages of vascular surgery compared with the SG. These results suggest the possibility of clinical applications using the 3DT as a substitute for pre-existing SGs in vascular surgeries.


In this work, we demonstrated a strategy to design a modified starch/polyvinyl alcohol composite (CCSP), which was employed as a highly efficient and economical fixed-bed adsorbent for treating textile wastewater. Characterization revealed that most of the CCSP was shaped with the morphology of sphericity, and had some water swelling properties. The crystallinity of the CCSP was lower than that of native starch and polyvinyl alcohol, and its average particle size gradually increased with the dosage increase of cationic starch in the preparation. Adsorption experiments showed that the adsorption capacities of CCSP were more than 605 and 539 mg/g for Reactive Black 5 and Reactive Orange 131, respectively, which were over 10 times larger than that of commercial activated carbon (AC). The mixture adsorbent composed of CCSP and AC could remove starch, polyvinyl alcohol, and dyes from textile wastewater completely and simultaneously combined with the fixed-bed technique, and its adsorption capacity was conducted as a function of the bed height and flow rate. Most importantly, the disabled mixture adsorbent could be converted into regenerated AC through a chemical activation process, thereby avoiding the production of solid waste. This study will provide a new efficient green sustainable method for treating textile wastewater. The environmental problems caused by textile printing and dyeing wastewater have become the focus of attention. Typical textile printing and dyeing wastewater usually contains dyes, polyvinyl alcohol (PVA), starch, and so on ,2. Some Starch and its derivatives are of increasing interest because of their higher biodegradability and renewability ,31. CatiIn this paper, the cationic cross-linked starch/PVA composite microspheres (CCSP) were synthesized for the purpose of removing the starch, PVA, and dyes from the textile wastewater concurrently, and their properties were determined. Combined with fixed-bed adsorption techniques, the adsorption capacities of CCSP for treating textile wastewater were investigated. Most importantly, the CCSP used exhibited great sustainable reutilization by converting into regenerated AC, thereby avoiding secondary solid-waste pollution. It is expected that the strategies shown in this work will provide new inspiration and ideas for the development of environmentally-friendly textile wastewater treatment techniques.Corn starch containing approximately 71% amylopectin and 29% amylose was supplied by Tianjin Tingfung Starch Development Co., Ltd., Tianjin, China. Polyvinyl alcohol  was obtained from China Petroleum and Chemical Corporation, Shanghai, China. 3-Chloro-2-hydroxypropyltrimethylammonium chloride (CHPTAC) was obtained from Sigma-Aldrich Chemie Gmbh, Steinheim, Germany. Colour Index (C.I.) Reactive Black 5 and C.I. Reactive Orange 131 were supplied by BASF SE, Ludwigshafen, Germany. Their structures are displayed in Cross-linked cationic PVA (CCP) was obtained by a two-stage process. First, the cationic PVA (CP) was prepared by PVA with CHPTAC, in the presence of sodium hydroxide, at 40 °C for 4 h [The modified starch/PVA composite sample (denoted as CCSP1) was prepared based on the preparation procedures of CCP, by replacing only the CP with a mixture of CS and CP (CS/CP with a mass ratio of 2:1). The same treatments were repeated in order to obtain the samples of CCSP2 and CCSP3, by changing only the mass ratios of CS/CP from 2:1 to 1:1 and 1:2, respectively. The FT-IR spectra of the samples were measured using a Nicolet IS 10 FT-IR spectrophotometer . The particle size analyses were carried out using a laser light-scattering-based particle sizer , and ethyl alcohol and distilled water were used as the dispersion medium. The sample microtopography was observed using a scanning electron microscope , and the morphology was observed using a transmission electron microscopy . The samples were treated with supersonic dispersion before the TEM measurement . The cryThe adsorption properties of the samples were investigated using a fixed-bed column (1.2 cm in diameter × 30 cm in height) connected to a spectrophotometer detector. The fixed-bed column was prepared according to the method of Zhang et al. . In view2 atmosphere. Next, the carbon spheres were impregnated with the activating agent KOH [2 atmosphere. The obtained material, signed as regenerated activated carbon (RAC), was washed with diluted HCl and deionized water separately, and finally dried. After adsorption, the disabled mixture adsorbent was recycled as follows. First, the disabled adsorbent was dried at 110 °C for 12 h under an air atmosphere, and then carbonized at 350 °C for 3 h under an Ngent KOH , and theThe schematic representation of the adsorption-recycle process is shown in −1. The peak at 3396 cm−1 was attributed to the stretching vibration of hydroxyl. The peak at 2931 cm−1 was caused by the stretching vibration of C–H. The peak at 1027 cm−1 was attributed to the stretching vibration of C–O–C. The peak at 1444 cm−1 was assigned to the bending vibration of C–N [−1 were attributed to the stretching vibration of O–H, C–H, and C–O–C, respectively. The peak at 1430 cm−1 in curve b (CCP) was similarly assigned to the bending vibration of C–N. The FT-IR spectra of the mixture adsorbent composed of CCSP and AC before and after treating the textile wastewater are shown in −1) was enhanced relatively after treating the textile wastewater, and the peak at 1475 cm−1 confirmed the existence of azo groups in the dye molecules.The FT-IR spectra of samples are shown in n of C–N ,44. For θ degrees). However, the XRD pattern of CCS had only a dispersed broad peak, and the crystallization peaks of starch disappeared (see curve c), indicating that the modification could inhibit the crystallization of starch molecules [As shown in olecules . As for From the SEM images a–e, the The particle size distributions of CCS, CCP, and the CCSPs are shown in The adsorption properties of the samples were investigated using the fixed-bed column. Previous research has shown that the cationic group built-in CCS molecule could interact with dye molecules in wastewater via charge neutralization . The resFrom It is worthwhile to note that the mixture adsorbent composed of CCSP2 and AC (1:1 in weight) had the largest adsorption capacity compared with the other adsorbents when treating the simulated textile wastewater, which indicated that the combination of AC and CCSP2 could show an obvious synergetic effect on each other for adsorption, and that the starch, PVA, and dyes could be removed effectively from the simulated textile wastewater simultaneously. The effect of the bed height and flow rate on the adsorption capacity of the mixture adsorbent (CCSP2 and AC) to treat the textile wastewater was investigated, and the results are shown in After treating the simulated textile wastewater, the particle surfaces of the mixture adsorbent composed of CCSP and AC would gather a large amount of starch, PVA, and dyes. It was difficult to be regenerated by the conventional desorption methods. In order to avoid producing solid waste, a chemical activation process was carried out to convert these disabled adsorbents into regenerated activated carbon. The SEM images of the original activated carbon (AC) and the regenerated activated carbon (RAC) that came from the disabled mixture adsorbent composed of CCSP2 and AC (mass ratio of 1:1) are shown in A novel modified starch/polyvinyl alcohol composite (CCSP) was prepared and employed as a highly efficient adsorbent for textile wastewater treatment. The CCSP was shaped with sphericity, and had some of the swelling properties of water absorption and a lower crystallinity. The dye adsorption capacity of CCSP was much larger than that of AC. The mixture adsorbent composed of CCSP and AC could make full use of the respective advantages of its components, and could remove starch, PVA, and dyes from the textile wastewater simultaneously, combined with the fixed-bed adsorption technique. The fixed-bed column adsorption process could be influenced by the bed height and flow rate. After adsorption, the disabled mixture adsorbent was converted into regenerated activated carbon for sustainable use by the chemical activation process, and the regenerated activated carbon had a higher adsorption capacity to the textile wastewater than AC. The developed method, through fixed-bed adsorption using CCSP, would be an excellent green textile wastewater treatment, on account of the high adsorption capacity, recycling ability, and no solid waste.


The failed surfaces were examined under field emission scanning electron microscope (FE-SEM), and adhesive remnant index (ARI) was evaluated. SBS was significantly higher in ZB and significantly lower in X in both T0 and Tf. There was no significant difference between Z and B. In X and B, adhesive failure occurred while ZB showed mixed failures. There was no apparent change in the zirconia surface except for the existence of some adhesive and resin remnants. The application of ceramic primer on the bracket base increased the bonding strength to the level of conventional bonding with fewer adhesive remnants. The highest bonding strength was obtained when the primer-treated bracket was bonded on the primer-treated zirconia.The purpose of this study is to evaluate the shear bond strength (SBS) of a primer-treated ceramic bracket on dental zirconia and to compare it with conventional ceramic bracket bonding on surface-treated zirconia. Sintered and finished dental zirconia was sandblasted. Samples were divided according to the treated surfaces: no treatment (X), ceramic primer on zirconia (Z), ceramic primer on bracket base (B), and ceramic primer on both zirconia and bracket base (ZB). The ceramic bracket was bonded on zirconia and SBS was measured before (T Increasing interest in esthetics and the need to overcome the disadvantages of traditional porcelain-fused metal crowns, e.g., the low strength of porcelain and greyish shade of gingiva from metal substructures, have resulted in the development of a wide range of ceramic systems ,2. AmongPolycrystalline zirconia, a frequently used ceramic system in load bearing areas with esthetic demands, primarily consists of yttria-stabilized tetragonal zirconia polycrystals 3Y-TZP) Y-TZP 3,,5. The p. The p5.Zirconia is acid-resistant because it does not contain silica particles, unlike most other dental ceramics. This makes it less reactive to hydrofluoric acid etching, an effective surface treatment method for other glass ceramic systems ,11,12,13As the number of adult patients going through orthodontic treatment is growing, the number of cases of bracket bondings on zirconia restorations are also increasing. The problem of bracket bonding failure on posterior teeth can be solved by using other devices such as orthodontic bands. However, in the anteriors, where esthetic considerations are important, there is a frequent need of minor tooth movement due to traumas that cause tooth loss or fracture. In these cases, bracket bonding to zirconia is often inevitable for forced eruption in a short period. Previously, primer-treated metal brackets were used to increase the bond strength on gold alloy surfaces ,15, but Different from previous work that focused mostly on surface treatment of zirconia, in this study, the shear bond strength (SBS) of primer-treated ceramic brackets was tested and compared with those treated by conventional bonding protocols, before and after artificial aging. This study shows that the new strategy, i.e., primer treatment on the bracket base, can not only sufficiently increase the SBS of brackets, but can also provide an option for stronger bonding on zirconia.Eighty high translucency zirconia  specimens of 15 (width) × 15 (height) × 2 (thickness) mm were prepared and sintered according to the manufacturer’s instructions. Each specimen was finished with a diamond disc  up to 500 grit under water irrigation to obtain uniform surface roughness. The samples were cleaned in an ultrasonic bath with distilled water for 10 min, and then dried. The surfaces of the samples were sandblasted with 50 μm alumina at a vertical distance of 20 mm for 20 s in a circular motion under a pressure of 0.4 MPa. n = 20) (The zirconia samples were randomly divided into four groups (n = 20) . In X, nIn Z, B and ZB, after the surfaces were primed, an adhesive primer  was applied on the zirconia surface. Then, a monocrystalline ceramic bracket with a spherical attachment on the base  was bonded using adhesive paste  under gentle pressure. After removing the excess paste, the brackets were light-cured  for 10 s on each side for a total of 40 s .The surface of the bracket base (as-received) was observed under field emission scanning electron microscopy . The retentive structures of the intact bracket base were analyzed with an energy dispersive x-ray spectrometer . The surface roughness (2). The bond failure interface was evaluated under FE-SEM, and both failure mode and ARI (A standardized index that demonstrates the amount of remnant in the bonding interface after bonding failure) were evaluated using modified ARI scores  for 10,000 cycles at 5 °C and 55 °C. The dwelling time was 30 s and the transfer time was 20 s. SBS was measured with a universal testing machine  at a crosshead speed of 0.5 mm/min. The bracket-zirconia specimens were embedded in acrylic molds, and were then fixed on a jig. The crosshead was aligned as closely as possible to the zirconia surface so that it could exert a vertical shear force upon the brackets. Also, the center point of the crosshead was set to meet at the center point of brackets for equal force distribution. The SBS at failure was calculated in MPa by dividing the maximum load (N) by the area of the bracket base (12.24 mmI scores  16]. . 2). The0 and Tf were analyzed by Student’s t-test, since the data were parametric and homogeneous. SPSS was used for the statistical analysis . A p-value lower than 0.05 was considered statistically significant.Surface roughness before and after sandblasting was analyzed by Mann-Whitney test. Shear bond strengths among the experimental groups were analyzed by Kruskal-Wallis test, since the data were proven to be nonparametric. Shear bond strengths between Ta) of 0.104 μm. Sandblasted surfaces showed multiple short but deeper scratches that were uniformly distributed with increased median surface roughness (Ra) of 0.773 μm , significantly higher bonding strength was obtained in ZB, whereas it was significantly lower in X. Z and B showed no significant differences between the groups (p > 0.05). After thermocycling (Tf), SBS significantly decreased in X (p = 0.000), B (p = 0.007), and ZB (p = 0.001), while there was no significance found in Z (p > 0.05). Still, ZB which was treated with ceramic primer on both the zirconia surface and the bracket base showed the highest SBS, while X showed the lowest . All the samples of Z showed adhesive failure at the resin and bracket interface with the resin left on the zirconia surface (ARI score 1). In B, most of the samples showed adhesive failure at the zirconia and resin interface with no resin left on the zirconia surface (ARI score 5). All the samples in ZB showed mixed failure with some resin left on the zirconia surface as well as on the bracket base (ARI score 3).In ARI scoring, the small amounts of tagged resin which remained between the retention beads of the bracket were not considered. In Tf, 90% of the samples of X showed adhesive failure at the zirconia and resin interface. In Z, all samples showed adhesive failure at the resin and bracket interface, in which remnants of resin were left on zirconia surfaces (ARI score 1). In B, adhesive failures with no resin remaining on the zirconia surface mainly occurred (ARI score 5). Most of the samples in ZB showed mixed failure in which some resin was left on the zirconia surface as well as on the bracket base (ARI score 3) (In Tscore 3) .This study evaluated the effect of the ceramic primer treatment on the SBS between zirconia and the bracket. All the zirconia surfaces were uniformly prepared to obtain the surface roughness of full-contoured zirconia crown prepared by diamond cutting burs. Micromechanical retention formed by sandblasting is a simple and effective way to increase the bonding strength, despite the risk of decreased mechanical properties of the zirconia ,18. In tWhen the surface was sandblasted only (group X), the lowest bonding strength was obtained, which decreased by more than 64% after aging. Thermocycling is an artificial aging method to simulate the long-term use of the brackets in situ ,21. It cIn the cementation of zirconia restoration with less retention, the application of 10-MDP in combination with sandblasting of the inner surface is recommended for effective long-term bonding . It is kThe major components of the spherical retentive beads on the surface of the bracket base were aluminum and oxygen. Alumina also forms a chemical bond with the 10-MDP because it is a metal oxide like zirconia . In B anA significantly higher bonding strength was observed when the primer was applied to both the zirconia and bracket surfaces (ZB), even after the aging process. It seemed that the 10-MDP containing primer clearly played a role in increasing the bonding strength between zirconia/resin and also between the ceramic bracket/resin. Although the ceramic primer also contained 3-methacryloxypropyltriethoxysilane, its effect on bonding strength was not considered in this study, since the effect of silane is known to be weakened in acidic environments due to self-condensation . Also, iWhen the primer was applied only to the ceramic bracket base (B), the bonding strength increased to as much as that of primer-treated zirconia (Z). From the results of ARI, 100% of the samples in Z showed that the resin had continuity with the zirconia surface, meaning that the debonding stress was concentrated at the resin/bracket interface. In 80–90% of the samples in B, on the other hand, the bonding strength of resin/bracket exceeded that of zirconia/resin, so there was no adhesive resin left on the zirconia surface. This phenomenon suggests its potential for clinical applications, considering that proper bracket removal is also important in orthodontic treatments. As such, being supported by ARI, a better zirconia surface cleanness was obtained when a surface-primed bracket was removed under shear stress. This implies that fewer remnants on zirconia would decrease the chair-time on the day of bracket removal.There has been considerable research on the use of MDP-containing primers for zirconia bonding. Many previous works have successfully showed its prominent contribution in increasing SBS of metal brackets on zirconia ,36. HoweDespite the newly discovered advantages of the study, it also had some limitations. Adhesion in the oral environment is a very sophisticated process and is vulnerable to many factors. For example, pH changes of saliva and the presence of bacteria or chemical byproducts generated by digestion, respiration, etc. might affect the SBS. However, the experimental conditions in the study were limited to the most optimal situation. Further studies conducted under situations better simulating biological and chemical interactions of the oral cavity would definitely extend the scope of the present experiments.Moreover, the zirconia specimens prepared in this study were not exactly representative of clinical situations. The specimens were finished with a diamond disc up to 500 grit. This was successful in providing a clean bonding surface, but it could not completely simulate the final roughness of zirconia in the clinic. Also, when preparing zirconia specimens, alumina blasting pressure could have induced phase transformation of zirconia from tetragonal to monoclinic. It was reported that a pressure of 0.23 MPa resulted in a 7% phase transformation . In thisTo further evaluate the significance of this study, the surface quality before and after bonding could have been observed. Based on that result, it may be possible to determine whether the new bonding strategy suggested here induced surface damage during debonding.From this study, it was concluded that primer application on the bracket base increases bonding strength to a sufficient level with less adhesive paste on the zirconia. In addition, the highest bonding strength was achieved by applying ceramic primer on both the bracket base and zirconia surfaces. Based on these results, dentists would be able to apply various bonding strategies depending on the situation, e.g., primer on the bracket for quick bonding and primer on both the bracket and the zirconia for strong bonding.


Objective: To report on the survival of a retinal pigment epithelium (RPE)-choroid graft translocated to treat a patient with drusenoid pigment epithelial detachment (DPED).Methods: We describe a patient with bilateral high-risk DPED where one eye was treated with RPE-choroid translocation surgery and followed up for more than two years.Results: The RPE-choroid graft surgery was straightforward and the fully perfused graft was able to support stable vision of 0.5 Snellen acuity for more than two years despite the development of a choroidal neovessel at the edge of the graft. The vision in the fellow eye dropped from 0.5 to 0.2 Snellen in the same period.Conclusion: RPE-choroid translocation may slow the progression of DPED to atrophy but it can also transform dry age-related macular degeneration (AMD) into neovascular AMD. Although the majority of neovascular age-related macular degeneration (AMD) patients can now be treated effectively with anti-VEGF injections, there is still no treatment available for dry AMD. Drusenoid pigment epithelial detachment (DPED) arises from the confluence of large areas of soft drusen .It is well documented that the natural history of eyes containing DPED is characterized by a high rate of progression to geographic atrophy , 2], , . . 10]. Taking into account the fact that the previously described high-risk characteristics of DPED were clearly present in our patient and were considered predictive of imminent atrophy while the outer retina still appeared healthy on OCT, we considered the timing for surgery to be optimal.We describe a patient who underwent RPE-choroid graft translocation surgery to treat a DPED on the verge of collapsing. Despite the postoperative development of a CNV at the edge of the graft requiring anti-VEGF injections, functional outcome was favorable compared to the natural history of the fellow eye during the one-and-a-half years of follow-up. Regarding the results of the RPE-choroid graft translocation surgery in this patient, a prospective, randomized trial appears necessary to evaluate safety and efficacy of such a procedure in DPED patients.RPE: retinal pigment epitheliumPED: pigment epithelial detachmentDPED: drusenoid pigment epithelial detachmentAMD: age-related macular degenerationVEGF: vascular endothelial growth factor SD-OCT: spectral-domain optical coherence tomographyVA: visual acuityCNV: choroidal neovascularizationFA: fluorescein angiographyOCTA: optical coherence tomography angiographyThe authors declare that they have no competing interests.The authors declare that the patient‘s consent was received to use her medical records to write this case report.


Results: the highest shear bond strength values were presented by the laser treated group (23.97 ± 3.7 MPa). No statistically significant differences were found among the Cl, Al50, Al90 and FEMTO groups. The lowest mean value was presented by the glass-beads treated group (11.93 ± 2.88 MPa) which was significantly lower compared to all other groups (p < 0.001). Conclusions: under the limitations of this in vitro study, femtosecond laser treatment of High-translucent monolithic zirconia (HTZ) ceramics is a promising alternative method for the mechanical retention of resin cements.Background: currently applied surface treatments for zirconia bonding may create undesired microcracks and surface flaws. The aim of the present study was to evaluate the efficacy of alternative surface treatments on the shear bond strength of high translucency zirconia to 10-Methacryloyloxydecyl dihydrogen phosphate (MDP)-containing resin-based cement. Methods: fifty disk-shaped specimens (10 mm × 5 mm) were fabricated from a commercial yttria-stabilized zirconia with 5 mole% yttrium oxide tetragonal zirconia polycrystal (5Y-TZP), and underwent air-abrasion with alumina particles (50 μm-AL50 and 90 μm-AL90), glass beads (GB 10–60 μm), and ablation with femtosecond laser (FEMTO). Shear bond strength was evaluated with a universal testing machine under a crosshead speed of 0.5 mm/min until fracture. Fracture type was evaluated with an optical stereomicroscope. Differences among groups were evaluated by one-way ANOVA and Bonferroni pairwise comparison tests ( High-translucent monolithic zirconia (HTZ) has gained much interest from patients with esthetic demands because of its superior optical properties. In clinical practice, high-translucent zirconia has been used to produce monolithic anterior crowns and ultrathin restorations. Its higher translucency is achieved by a slight increase in the Yic-phase ,2. On thic-phase ,5. DecemThere are limited scientific data about the bonding strength of translucent zirconia subjected to different surface treatments. As other types of zirconia, HTZ possesses a dense polycrystalline structure with no vitreous phase, which makes its surface processing quite complicated. Methods such as airborne abrasion with alumina particles , triboch2O3) or silica-coated alumina (Al2O3/SiO2) particles and further surface conditioning with an MDP-containing primer [2O3/SiO2 particles was effective at increasing the bond strength of both conventional and highly translucent zirconia. On the other hand, recent in vitro studies reported that airborne-particle abrasion with coarse particles may create microcracks, initiating fractures on the zirconia surface [Currently, the most reliable bonding protocols for zirconia is the combination of air-abrasion with alumina , have been suggested for zirconia surface treatment [2 lasers can cause surface microcracking [Another promising method for modifying the zirconia surface, is application of a laser. Laser surface treatment is rapid, non-contact and precise, as it allows one to obtain high-resolution features, down to the nanoscale. Several short pulse lasers such as Nd:YAG, Er:YAG, and Er,Cr:YSGG continuous wave carbon dioxide   (LOT HT–BZ0014192) were used. For air abrasion, Al2O3 particles of size 50 μm , Al2O3 particles with size 90 μm  and glass beads  with particle diameter of 10–60 μm were used. Commercially available methylacrylate-based dual-cured resin cement Panavia V5 together with Clearfil ceramic primer plus  were chosen as experimental materials because they incorporate MDP functional monomers.For the experiments, white colored blocks of commercial yttria-stabilized zirconia 5Y-TZP (92% ZrO(a).CL group: Control group with no further processing after polishing;(b).AL50 group: air-abraded by 50 μm alumina particles;(c).AL90 group: air-abraded by 90 μm alumina particles;(d).GB group: air-abraded by glass beads of various diameters of 10–60 μm;(e).FEMTO group: in which parallel grooves of 50 μm in the central area of 5 × 5 mm were processed by femtosecond laser ablation.Fifty disk-shaped specimens with diameter 10 mm and height 5 mm were fabricated using Computer Aided Design/Computer Aided Manufacturing (CAD/CAM). Then, the specimens were impregnated in epoxy resin  using Plexiglas molds of 25 mm height, 12 mm internal diameter and 16 mm external diameter and were kept for 12 h under atmospheric pressure until the complete polymerization of epoxy resins. After removal of the specimens from the molds they were ground in a rotary motion metallurgical grinding apparatus at speed of 200 rpm and water irrigation. Grinding and polishing of specimens was performed under constant pressure using metallic holder with 220 and 1200 grit silicon carbide grinding discs for 10 min. In order to check for surface defects during construction and processing, each specimen was examined using a stereo microscope  connected to a PC with the appropriate software at magnifications of 7.5× to 60×. Specimens with surface defects were removed and replaced with new ones. Finally, all specimens were ultrasonically cleaned in a pure ethyl alcohol for 15 min, dried with a mild air stream and divided into 5 equal groups (N = 10) based on surface treatment, as following:The air abrasion process for the AL50, AL90 and GB groups was performed using an intraoral sandblaster device , equipped with a 0.048 diameter nozzle, at the air pressure 36 psi (2.5 bar) for 10 s and distance of 10 mm and incidence angle of 45° to the free zirconia surface. A special holder was fabricated to maintain exact distance and incidence angle in all air abraded specimens.2 and sample scanning speed, v = 1 mm/s.For the experiments, a Yb: KGW laser was used, emitting linearly polarized light with central wavelength of 1026 nm, pulse duration 170 fs and repetition rate of 1 KHz. The laser beam was focused on the sample through 100 mm achromatic convex lens while the estimated Gaussian spot size, had 35 μm diameter, as measured with a CMOS camera. The zirconia samples were mounted in a 3-axis support and movement device and placed vertically to the incident beam. Laser radiation was emitted under normal environmental conditions with normal incidence direction. The designed surface pattern included an area of 5 mm × 5 mm and consisted of continuous horizontal line scans with 50 μm line spacing. For the surface processing the zirconia samples the laser parameters were: laser fluence, F = 9.6 J/cm2 for 20 s. After polymerization and complete removal of the teflon guides, the specimens were kept in deionized water at 37 °C in a temperature controlling apparatus for one week.At first, each specimen was coated by one component adhesive primer (Clearfil Ceramic Primer plus) using an applicator brush, as described by the manufacturer. For repeatability and precision of the bonding procedures, five special two-piece teflon guides with a center hole (3 × 3 mm) were constructed for zirconia specimens. Then, the resin-based cement (Panavia V5) was injected using self-mixing syringe in the center of each teflon guide until the empty space was filled. After 1 min the cement was photo-activated using light emitting diode-LED  with output power 800 mW/cm2 the bonded surface.For shear bond strength test a universal testing machine  was used operating in shear mode with a crosshead speed of 0.5 mm/min until fracture of the zirconia/cement interface. Maximum values of shear strength (peak points), expressed as N, were recorded for each specimen. In order to calculate the maximum shear stress, these values were conversed to MPa, using the equation P = F/S, where F is the force in Newton (N) and S = πRp < 0.05.For the evaluation of the type of fracture, the detached surfaces were photographed using an optical stereomicroscope at magnifications of 10–60X. Quantification of the remaining ceramic mass or resin-based cement on the surface of zirconia was done with the help of a PC software program . Fracture was defined as adhesive in cases where more than 75% of the zirconia surface was visible. The fracture was defined as cohesive when more than the 75% of the core surface was covered with resin. All other cases were defined as mixed fractures. For further evaluation of the debonded surfaces and elemental analysis, Scanning Electron Microscopy  and Energy Dispersive Spectroscopy (Oxford INKA-300) were applied. A vacuum evaporator (JEOL-4X) was used to coat the surfaces with a carbon coat of 200 Å for SEM-EDS evaluation. Shear bond strength values were analyzed for normality and homogeneity of variance with Kolmogorov–Smirnof and Levene tests, respectively, while differences among groups were evaluated by one-way ANOVA and Bonferroni multiple comparison test. The results of failure type were also were also evaluated with one-way ANOVA. Statistical analysis was performed with the IBM Statistics SPSS 20.0 software with significance level set at The results of the maximum shear strength and the standard deviations in MPa of the five experimental groups are presented in p < 0.001). The lowest mean value was recorded for the GB group (11.93 ± 2.88 MPa) which was statistically significantly different compared with all other groups (p < 0.001)  .p < 0.001). According to adhesive failure modes (ADFM) analysis FEMTO, Cl, AL50 and AL90 groups presented significantly lower ADFM values than the GB group  which was statistically significantly different only compared to the GB group  were observed in specimens of the FEMTO group, which presented a moderated surface roughness of 307.3 ± 32.7 nm , which wProcessing of HTZ in femtosecond regime enabled precise micropatterning and creation of parallel retention microgrooves, to obtain extra space for cement. SEM images revealed increased microroughness within the grooves due to ablation while the untreated surface remained smooth and free of microcracks, pores and signs of melting. These findings suggest that the ultrashort pulses with high intensity applied in the present study caused ablation only within laser generated plasma, without causing thermal damage to the adjacent regions due to heat conduction; a phenomenon usually observed with conventional lasers (nanosecond or longer pulses) .According to recent studies, both irradiation patterns  and diff2O3 particles onto the ceramic surfaces during alumina air-abrasion. However, statistically significant differences in SBS between AL50 and AL90 groups were not observed. In this way, the surface roughness profile from the different alumina particle sizes did not influence the bonding strength in the HTZ material, similarly to conventional zirconia, as previously reported [Air-borne particle abrasion was applied to HTZ using alumina particles of different sizes (50 μm and 90 μm) and GB. The AL50 and AL90 groups had similar bond strength values and similar types of fracture, covering a high percentage of the zirconia surface with resin material, suggesting that surface roughness profile did not significantly affect the shear strength. The obtained values of bond strength for alumina air-borne treated groups (AL50 and AL90) were comparable to other studies with high-translucent zirconia . It was reported .The GB group presented very low shear strengths and very small percentages of the resin material remained on the surface, resulting in a high percentage of adhesive fracture mode. Based on our previous study and SEM analysis, it was observed that GB created a smooth surface with slightly higher toughness than the control  , likely Bonding is known to be affected by many factors, such as micro-mechanical retention, chemical adhesion, surface features, and the type of adhesives . RecentlApparently, surface treatments such as air abrasion often leave traces of contaminants on the material’s surface. Even though their amount is small, they can alter surface properties and compromise mechanical behavior as is the case with glass bead contamination. In this respect, ultrafast laser patterning is effective in creating an uncontaminated surface, as it can produce surfaces without any impurities. Besides, FS laser processing is a gentle and precise procedure, as it allows for the creation of different surface patterns without causing damage to the bulk material or significantly increasing the monoclinic phase , which mDespite predictable and well-documented results, several limitations of this study should be mentioned. For example, the small number of experimental materials studied. Further research should include different HTZ materials with other commercial resin-based cements and conditions that mimic, with high precision, the oral environment such as cycling loading.Under the limitations of this in vitro study, it can be concluded that airborne particle abrasion with alumina particles of different sizes (50 μm and 90 μm) and an FS laser, can yield similar bond strengths of HTZ ceramics to resin cements. However, none of the investigated treatments were superior to the others or compared to control polished zirconia surfaces. FS laser surface treatment of HTZ ceramics is a promising alternative method to enhance the mechanical retention of a resin cement as it is related to effective bond strengthening, without causing any surface contamination of zirconia specimens. On the contrary, abrasion with glass beads is not recommended for HTZ ceramics, as it presented significantly lower bond strengths compared to all other treatments.