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Kittana N, Assali M, Zimmermann WH, et al. Int J Nanomedicine. 2021;16:989–1000. The authors have advised that the Funding statement on pages 997 and 998 is incorrect. The correct funding statement is: Funding NK and MA: The project was kindly funded and supported by the Palestinian Ministry of Higher Education (fund ID number ANNU-MoHE-1819-Sc010), the Deanship of Scientific Research at An-Najah National University (ANNU-1920-Sc016) and by the German Academic Exchange Service (DAAD). This work was further funded by the German Research Foundation (DFG) through the project IRTG 1816 and by the German Cardiac Society (DGK) through a Research Fellowship to GLS. AR was funded by the Higher Education Commission of Pakistan. SL is supported by the German Center for Cardiovascular Research (DZHK). W.H.Z is supported by the German Research Foundation (DFG; CRC 1002 C04 and S01, IRTG 1816), the German Center for Cardiovascular Research (DZHK), and the Leducq Foundation. The authors apologize for this error. Read the original article

Naim Kittana, 1 Mohyeddin Assali, 2 Wolfram-Hubertus Zimmermann, 3, 4 Norman Liaw, 3, 4 Gabriela Leao Santos, 3, 4 Abdul Rehman, 3, 4 Susanne Lutz 3, 4 1Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, An-Najah National University, Nablus, Palestine; 2Department of Pharmacy, Faculty of Medicine & Health Sciences, An-Najah National University, Nablus, Palestine; 3Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany; 4DZHK (German Center for Cardiovascular Research) Partner Site Göttingen, Göttingen, GermanyCorrespondence: Naim KittanaDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, An Najah National University, Akademia Street, Nablus, PalestineTel +970 (9) 2345113Fax +970 (9) 2345982Email naim.kittana@najah.eduBackground: Under certain conditions, the physiological repair of connective tissues might fail to restore the original structure and function. Optimized engineered connective tissues (ECTs) with biophysical properties adapted to the target tissue could be used as a substitution therapy. This study aimed to investigate the effect of ECT enforcement by a complex of multiwall carbon nanotubes with chitosan (C-MWCNT) to meet in vivo demands.Materials and Methods: ECTs were constructed from human foreskin fibroblasts (HFF-1) in collagen type I and enriched with the three different percentages 0.025, 0.05 and 0.1% of C-MWCNT. Characterization of the physical properties was performed by biomechanical studies using unidirectional strain.Results: Supplementation with 0.025% C-MWCNT moderately increased the tissue stiffness, reflected by Young’s modulus, compared to tissues without C-MWCNT. Supplementation of ECTs with 0.1% C-MWCNT reduced tissue contraction and increased the elasticity and the extensibility, reflected by the yield point and ultimate strain, respectively. Consequently, the ECTs with 0.1% C-MWCNT

Kittana N, Assali M, Zimmermann WH, et al. Int J Nanomedicine. 2021;16:989–1000. The authors have advised that the Funding statement on pages 997 and 998 is incorrect. The correct funding statement is: Funding NK and MA: The project was kindly funded and supported by the Palestinian Ministry of Higher Education (fund ID number ANNU-MoHE-1819-Sc010), the Deanship of Scientific Research at An-Najah National University (ANNU-1920-Sc016) and by the German Academic Exchange Service (DAAD). This work was further funded by the German Research Foundation (DFG) through the project IRTG 1816 and by the German Cardiac Society (DGK) through a Research Fellowship to GLS. AR was funded by the Higher Education Commission of Pakistan. SL is supported by the German Center for Cardiovascular Research (DZHK). W.H.Z is supported by the German Research Foundation (DFG; CRC 1002 C04 and S01, IRTG 1816), the German Center for Cardiovascular Research (DZHK), and the Leducq Foundation. The authors apologize for this error. Read the original article

Naim Kittana, 1 Mohyeddin Assali, 2 Wolfram-Hubertus Zimmermann, 3, 4 Norman Liaw, 3, 4 Gabriela Leao Santos, 3, 4 Abdul Rehman, 3, 4 Susanne Lutz 3, 4 1Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, An-Najah National University, Nablus, Palestine; 2Department of Pharmacy, Faculty of Medicine & Health Sciences, An-Najah National University, Nablus, Palestine; 3Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany; 4DZHK (German Center for Cardiovascular Research) Partner Site Göttingen, Göttingen, GermanyCorrespondence: Naim KittanaDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, An Najah National University, Akademia Street, Nablus, PalestineTel +970 (9) 2345113Fax +970 (9) 2345982Email naim.kittana@najah.eduBackground: Under certain conditions, the physiological repair of connective tissues might fail to restore the original structure and function. Optimized engineered connective tissues (ECTs) with biophysical properties adapted to the target tissue could be used as a substitution therapy. This study aimed to investigate the effect of ECT enforcement by a complex of multiwall carbon nanotubes with chitosan (C-MWCNT) to meet in vivo demands.Materials and Methods: ECTs were constructed from human foreskin fibroblasts (HFF-1) in collagen type I and enriched with the three different percentages 0.025, 0.05 and 0.1% of C-MWCNT. Characterization of the physical properties was performed by biomechanical studies using unidirectional strain.Results: Supplementation with 0.025% C-MWCNT moderately increased the tissue stiffness, reflected by Young’s modulus, compared to tissues without C-MWCNT. Supplementation of ECTs with 0.1% C-MWCNT reduced tissue contraction and increased the elasticity and the extensibility, reflected by the yield point and ultimate strain, respectively. Consequently, the ECTs with 0.1% C-MWCNT

Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI in relation to oral doses and blood concentrations. This method can be used to estimate DILI risk if the maximal blood concentration (C-max) of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced, the toxicity separation index (TSI) which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI) which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of 28 compounds, based on TSI and TEI, demonstrating that (1) concentrations where cytotoxicity first becomes evident in vitro (EC10) yielded better metrics than higher toxicity thresholds (EC50); (2) compound incubation for 48h was better than 24h, with no further improvement of TSI after 7days incubation; (3) metrics were moderately improved by adding gene expression to the test battery; (4) evaluation of pharmacokinetic parameters demonstrated that total blood compound concentrations and the 95%-population-based percentile of C-max were best suited to estimate human toxicity. With a support vector machine-based classifier, using EC10 and C-max as variables, the cross-validated sensitivity, specificity and accuracy for hepatotoxicity prediction were 100, 88 and 93%, respectively. Concentrations in the culture medium allowed extrapolation to blood concentrations in vivo that are associated with a specific probability of hepatotoxicity and the c

Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI in relation to oral doses and blood concentrations. This method can be used to estimate DILI risk if the maximal blood concentration (C-max) of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced, the toxicity separation index (TSI) which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI) which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of 28 compounds, based on TSI and TEI, demonstrating that (1) concentrations where cytotoxicity first becomes evident in vitro (EC10) yielded better metrics than higher toxicity thresholds (EC50); (2) compound incubation for 48h was better than 24h, with no further improvement of TSI after 7days incubation; (3) metrics were moderately improved by adding gene expression to the test battery; (4) evaluation of pharmacokinetic parameters demonstrated that total blood compound concentrations and the 95%-population-based percentile of C-max were best suited to estimate human toxicity. With a support vector machine-based classifier, using EC10 and C-max as variables, the cross-validated sensitivity, specificity and accuracy for hepatotoxicity prediction were 100, 88 and 93%, respectively. Concentrations in the culture medium allowed extrapolation to blood concentrations in vivo that are associated with a specific probability of hepatotoxicity and the c

Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI in relation to oral doses and blood concentrations. This method can be used to estimate DILI risk if the maximal blood concentration (Cmax) of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced, the toxicity separation index (TSI) which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI) which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of 28 compounds, based on TSI and TEI, demonstrating that (1) concentrations where cytotoxicity first becomes evident in vitro (EC10) yielded better metrics than higher toxicity thresholds (EC50); (2) compound incubation for 48 h was better than 24 h, with no further improvement of TSI after 7 days incubation; (3) metrics were moderately improved by adding gene expression to the test battery; (4) evaluation of pharmacokinetic parameters demonstrated that total blood compound concentrations and the 95%-population-based percentile of Cmax were best suited to estimate human toxicity. With a support vector machine-based classifier, using EC10 and Cmax as variables, the cross-validated sensitivity, specificity and accuracy for hepatotoxicity prediction were 100, 88 and 93%, respectively. Concentrations in the culture medium allowed extrapolation to blood concentrations in vivo that are associated with a specific probability of hepatotoxicity and th

Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI in relation to oral doses and blood concentrations. This method can be used to estimate DILI risk if the maximal blood concentration (Cmax) of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced, the toxicity separation index (TSI) which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI) which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of 28 compounds, based on TSI and TEI, demonstrating that (1) concentrations where cytotoxicity first becomes evident in vitro (EC10) yielded better metrics than higher toxicity thresholds (EC50); (2) compound incubation for 48 h was better than 24 h, with no further improvement of TSI after 7 days incubation; (3) metrics were moderately improved by adding gene expression to the test battery; (4) evaluation of pharmacokinetic parameters demonstrated that total blood compound concentrations and the 95%-population-based percentile of Cmax were best suited to estimate human toxicity. With a support vector machine-based classifier, using EC10 and Cmax as variables, the cross-validated sensitivity, specificity and accuracy for hepatotoxicity prediction were 100, 88 and 93%, respectively. Concentrations in the culture medium allowed extrapolation to blood concentrations in vivo that are associated with a specific probability of hepatotoxicity and th

Naim Kittana,1 Mohyeddin Assali,2 Hanood Abu-Rass,1 Susanne Lutz,3,4 Rama Hindawi,2 Lina Ghannam,2 Marah Zakarneh,2 Ahmad Mousa1 1Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine; 2Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine; 3Institute of Pharmacology and Toxicology, University Medical Center, Göttingen, Germany; 4German Center for Cardiovascular Research e.V., Partner Site, Göttingen, Germany Background: Impaired wound healing is commonly associated with many health problems, including diabetes, bedsores and extensive burns. In such cases, healing often takes a long time, which subjects patients to various complications. This study aims to investigate whether single-wall or multi-wall carbon nanotubes complexed with chitosan hydrogel can improve wound healing. Materials and methods: Initially, the effects of the complexes on the viability and functionality of fibroblasts were investigated in engineered connective tissues. Then, their activity on wound healing was investigated in a mouse model with induced full-thickness wounds, in which the wounds were treated daily with these complexes. Finally, the effect of the complexes on collagen deposition by fibroblasts was investigated in vitro. Results: The engineered connective tissue studies showed that fibroblasts were viable in the presence of the complexes and were still able to effectively organize and contract the extracellular matrix. In vivo data showed that both types of complexes improved the re-epithelialization of the healing wounds; however, they also increased the percentage of wounds with higher fibrosis. In particular, the chitosan-multi-wall carbon nanotube complex significantly enhanced the extensiveness of this fibrosis, which is in line with in vitro data showing a concentration-dependent enhancement of collage deposition by these c

Naim Kittana,1 Mohyeddin Assali,2 Hanood Abu-Rass,1 Susanne Lutz,3,4 Rama Hindawi,2 Lina Ghannam,2 Marah Zakarneh,2 Ahmad Mousa1 1Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine; 2Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine; 3Institute of Pharmacology and Toxicology, University Medical Center, Göttingen, Germany; 4German Center for Cardiovascular Research e.V., Partner Site, Göttingen, Germany Background: Impaired wound healing is commonly associated with many health problems, including diabetes, bedsores and extensive burns. In such cases, healing often takes a long time, which subjects patients to various complications. This study aims to investigate whether single-wall or multi-wall carbon nanotubes complexed with chitosan hydrogel can improve wound healing. Materials and methods: Initially, the effects of the complexes on the viability and functionality of fibroblasts were investigated in engineered connective tissues. Then, their activity on wound healing was investigated in a mouse model with induced full-thickness wounds, in which the wounds were treated daily with these complexes. Finally, the effect of the complexes on collagen deposition by fibroblasts was investigated in vitro. Results: The engineered connective tissue studies showed that fibroblasts were viable in the presence of the complexes and were still able to effectively organize and contract the extracellular matrix. In vivo data showed that both types of complexes improved the re-epithelialization of the healing wounds; however, they also increased the percentage of wounds with higher fibrosis. In particular, the chitosan-multi-wall carbon nanotube complex significantly enhanced the extensiveness of this fibrosis, which is in line with in vitro data showing a concentration-dependent enhancement of collage deposition by these c