Multifunktionale mesoporöse bioaktive Gläser auf SiO2 CaO Basis zur Freisetzung von therapeutischen Ionen und Biomolekülen

Abstract Synthetic bone grafts are being used to treat severe bone fractures and damage of natural bone tissue. Over the past two decades, bioactive glasses (BGs) have been widely developed as promising synthetic biomaterials for bone tissue engineering (BTE) applications since BGs possess the potential to stimulate bone regeneration. In recent years, a new class of BGs, i.e., mesoporous bioactive glasses (MBGs), have been receiving increasing attention. MBGs consist of ordered mesoporous structures with tunable pore sizes in the range of 2-50 nm, which enable their use as drug delivery carriers to achieve controlled drug release in a variety of biomedical applications. Biologically active metallic ions such as manganese, cerium, copper, strontium, magnesium, zinc and silver can be incorporated in BGs to enhance their biological performance. The release of these ions is exploited to induce additional therapeutic outcomes, including osteogenesis, angiogenesis and antibacterial effects. The present work developed novel multifunctional BGs with the potential to incorporate and release simultaneously therapeutic ions and biomolecules/therapeutic agents targetting bone tissue engineering and cancer treatment. This thesis presents three different types of BGs: i) standard 45S5 BG derived by sol-gel method, ii) mesoporous BG nanoparticles (MBGNs) based on the SiO2-CaO system, and iii) manganese doped MBGNs (Mn-MBGNs), which were prepared using the sol-gel process and microemulsion-assisted based sol-gel method. The prepared BGs were extensively investigated using state-of-the-art characterization techniques. In the first part of this project, 45S5 BG powder was prepared using a sol-gel process from tetraethyl orthosilicate, calcium nitrate, sodium nitrate and triethyl phosphate precursors. X-ray diffraction (XRD) was done to assess the impact of sintering temperature and time on the formation of crystalline phases. Results revealed that both the treatment temperature and time strongly influence the formation of crystalline phases in as-prepared sol-gel derived 45S5 BG. The fractions of the formed crystalline phases could be adjusted by controlling their nucleation and growth through pre-determined thermal treatment profiles. The main crystalline phases formed were calcium silicate-phosphate, sodium-calcium silicate, rhenanite (CaNaPO4), and combeite (Na2Ca2Si3O9). Nano-computed tomography (nano-CT) images revealed the morphology of the formed crystalline phases, which were confirmed to be embedded in an amorphous matrix. Regarding bioactivity, both amorphous and crystalline 45S5 BGs showed the formation of hydroxyapatite (HA)-like layer on their surfaces (using powders of 2 microns size) upon immersion in simulated body fluid (SBF) for three days. However, amorphous BG powder showed a higher dissolution rate than crystallized powders, thereby offering higher bioactivity. Cell culture studies were conducted using MG-63 osteoblast-like cells. The indirect cell viability of aliquots of amorphous and crystalline BGs was comparable to the control (tissue culture well plate), revealing a dose-dependent (released ionic products from the BG powders) cell viability profile. In the second part of this investigation, highly dispersed MBGNs (composition: 50 SiO2, 40-X CaO, 10 P2O5, X= 0,3,5,7 MnO (mol %)) were synthesized using a microemulsion-assisted sol-gel process. A variation in nominal and actual (calculated using X-ray fluorescence (XRF)) compositions was noticed. MBGNs were also doped with different concentrations of manganese (Mn). Mn ion was chosen as an active biological ion due to its previously known positive biological features such as: improvement in bone mineralization, extracellular matrix remodeling, osteoblast cell adhesion, and proliferation. Brunauer Emmett Teller (BET) results revealed that MBGNs (both doped and undoped) exhibited high surface area (309-444 m2/g) and mesoporosity (characterized by TEM), which are valuable features for the loading of therapeutic biomolecules for drug delivery applications. The in vitro mineralization results revealed the formation of a typical hydroxyapatite structure in physiological conditions (upon soaking in simulated body fluid at 37 °C), which suggests the bone-bonding ability of the manganese-doped MBGNs (Mn-MBGNs). The ion release study in a cell culture medium showed a sustained release of Mn ions under dynamic conditions, which is an essential feature when considering the intended applications in BTE, where a slow and sustained release of Mn ions is required to achieve the required biological effects (osteogenesis, angiogenesis). Cell viability assay (WST-8) showed excellent biocompatibility of Mn-doped MBGNs towards MC3T3-E1 (pre-osteoblast) and MG-63 (osteosarcoma cells) cell lines. Antibacterial tests were carried out using P. aeruginosa, E. coli, B. subtilis and S. aureus bacteria stains. The turbidity test showed a decrease in the optical density (OD) of the bacterial cultured medium for the Mn-MBGNs. In the third part of the study, as-synthesized MBGNs were used to load biomolecules to demonstrate the suitability of the nanoparticles as drug delivery carriers. Two natural herb-derived therapeutic agents, namely icariin and silibinin, were used as natural drugs. They were successfully loaded into the MBGNs to impart additional biofunctionality. The physiochemical, structural, compositional, loading efficiency, and cellular properties of icariin and silibinin-loaded MBGNs were investigated. The icariin release study showed a sustained release of the drug under dynamic conditions for 50 days, which is significantly important for sustained therapeutic drug release. The icariin loaded MBGNs showed excellent bioactivity upon immersion in simulated body fluid. Cell viability assay (WST-8) revealed that icariin exhibits a dose-dependent cytocompatibility against the MG-63 osteosarcoma cell line. Silibinin was released in a sustained manner, which is required for treating neoplastic pathologies. Silibinin-loaded MBGNs were tested using MG-63 (osteosarcoma cells), MDA-MB-231 (metastatic breast cancer cells) and MCF-10A (non-malignant breast endothelial cells) cell lines. The initial results suggest that silibinin exhibits chemotherapeutic potential towards metastasized cancer cells. It was observed that silibinin is non-toxic to MG-63 cells at all concentrations, whereas a higher concentration of silibinin (18 μg/mL) strongly affects the proliferation and viability of cancer cells. In the final part of the study, 45S5 BG scaffolds suitable for bone tissue engineering were successfully prepared using a foam replica technique. The scaffolds were coated with Mn-MBGNs and gelatin by impregnating the 3D structures with Mn-MBGNs (15 wt./vol %) and gelatin (5 wt./vol %) in ethanol and water solutions, respectively. The gelatin coating improved the compressive strength of 45S5 BG scaffolds to achieve values of 0.2 MPa. The coatings were charcterized by EDX (by detecting Mn peaks) and FTIR spectra (by detecting the presence of amide groups), respectively. All scaffolds exhibited high pore interconnectivity and bioactivity upon immersion in SBF (e.g., formation of HA layer after three days in SBF). Preliminary cell culture results obtained using both direct and indirect approaches indicated the non-toxicity of the scaffolds toward MG-63 cells. Results revealed favorable cell attachment and proliferation on the surfaces of the struts. However, gelatin/Mn-MBGNs coated 45S5 scaffolds showed superior cell attachment and proliferation on the scaffold surfaces in contrast to uncoated scaffolds. It is proposed that the dual release of gelatin and Mn ions plays a positive role in cell attachment and proliferation and the quantitative evaluation of this effect remains an interesting topic for further research. Altogether, the unique texture properties of synthesized MBGNs, their capability to incorporate metallic ions in their structure (in the present case, the focus was Mn), and the loading of different biomolecules (in the present case, phytotherapeutics) suggested that these multifunctional MBGNs are very attractive carriers for drug delivery and for their use as bioactive fillers for the advancement of nanocomposites for biomedical applications, particularly for BTE. The present research opens different research avenues for the application of ion doped MBGNs in the context of bone tissue engineering and controlled drug delivery.

Infollution (Information Pollution) Management, Filtering Strategy, Scalable Workforce, and Organizational Learning: A Conceptual Study

Information generation is increasing rapidly on a global scale. The exponential advancement in information technology and communication has accentuated the problem of effective information management. Yet, employees’ cognitive ability to process information has not increased in parallel with information generation. With the exponential rise of information, information pollution (infollution) emerges as a problem on an exponential basis. Infollution is among the greatest challenges of the 21st century. Nevertheless, based on information processing theory and dynamic capability, researchers have conceptualised that agile organisations can cope with information pollution by promoting scalable workforce and organisational learning. By employing coping strategies, filtering has been hypothesised as moderating the association of scalable workplace and organisational learning with infollution management. This research will extend the literature in the domain of information management and agile organisations. It will be particularly useful for information processors to identify quality information for improved decision-making.&nbsp

Incidence of COVID-19 in random trauma patients at DHQ Teaching Hospital, Rawalpindi, measures to prevent its spread among patients and health care workers

Background: The objective of the study was to see the incidence of COVID-19 positive, in random trauma patients received in the emergency of abdomen or chest may be penetrating or blunt. Materials and Methods: This study was conducted in the Accident and Emergency department of District Head Quarter Hospital, Rawalpindi. All trauma patients of abdomen or chest either penetrating or blunt admitted from 1-3-20 to 10-6-20 were included, irrespective of age, gender, comorbidities, and COVID-19 status at the time of admission to hospital. Also to see steps of preventive measures taken in the emergency department, operation theatres, and inwards. Results: Total number of trauma patients received in the emergency department of District Headquarter Hospital Rawalpindi during this period was 163. Total male patients: 116. Total female patients:47. Penetrating injuries (firearm or stab wounds): 93. Blunt injuries: 70. All the penetrating injuries were operated as an emergency. Among blunt injuries, 51 were operated 19 were treated conservatively. Preoperatively none of the patients’ COVID-19 test was performed because none of them showed any symptoms likely of COVID-19 such as chest infection, flue, malaise, or fever. After the second postoperative day, 12 of the patients developed respiratory distress and their COVID-19 test was sent. Out of 12 patients, 7 turned out to be COVID-19 positive. Other on the second or third postoperative day 7 patients had fever without chest symptoms and underwent COVID-19 testing. 3 turned out to be COVID-19 positive. So a total of 11 patients were found to be positive for COVID-19. The percentage became 6.7% which is quite high. Conclusion: From this study, its clear in acute trauma patients where you can’t go for the COVID-19 test even then we have to operate may be positive. So every trauma patient should have suspected COVID-19 positive and preventive measures should be taken starting from the emergency department till operation theatres

Design of Experiment Approach in the Industrial Gas Carburizing Process

Carburized samples were prepared under different sets of conditions at Millat Equipment Limited, Lahore, Pakistan, using continuous carburizing furnace under a reducing atmosphere. The gas carburizing process parameters were determined by the Taguchi design of experiment (DoE), an orthogonal array of L9 type with the mixed level of control factors. The key process parameters in gas carburizing process such as delay quenching interval, hardening temperature, and soaking time in oil were optimized in terms of core hardness, effective case depth (ECD), and surface hardness. DoE approach elucidated that the best results in terms of core hardness are A2 (delay quenching for 60 seconds), B2 (hardening temperature of 800°C), and C2 (soaking in quenching oil for 300 seconds). However, the best results in terms of ECD were A1 (delay quenching for 45 seconds), B3 (hardening temperature of 820°C), and C1 (soaking in quenching oil for 180 seconds). In order to choose the optimized parameters from the results given by DoE, microscopic analysis was conducted. Microscopic analysis showed coarse bainitic structure in core and tempered martensite at the surface of the samples processed at A2 (delay quenching for 60 seconds), B2 (hardening temperature of 800°C), and C1 (soaking in quenching oil for 180 seconds) compared to the other process conditions (A1, B3, and C1), which shows fine bainitic structure at core and relatively higher amount of retained austenite at the surface. Finally, defect per million opportunities (DPMO) model exhibited that the samples produced from the optimized set of parameters (A2, B2, and C1) are highly reproducible, gaining DPMO of 83 parts per million (PPM)

Regenerative Medicine in Liver Cirrhosis: Promises and Pitfalls

Liver cirrhosis is irreversible and mostly ends up with complete loss of liver function/end‐stage liver failure, and the only proven treatment is liver transplantation. Scarcity of donor, high cost, lifelong immunosuppression, and surgical complications are the major issues associated with liver transplantation and these urge to look for alternate therapeutic approaches. Advancements in the field of regenerative medicine are arising hope for the treatment of liver cirrhosis. This chapter deals with the scope of liver regenerative medicine in the treatment of liver cirrhosis. Review of the literature showed that liver regenerative medicine no doubt holds great promises and added a lot of hope to the cure of liver diseases. Primarily, cell‐based therapies had shown great potential to treat liver cirrhosis. Successful clinical human trials further strengthen their significance in the field. However, recent trends in liver regenerative medicine are focusing on the development of tissue engineering leading to generation of the whole organ. Despite advantages, liver regenerative medicine has several limitations and sometimes been over‐optimistically interpreted. In conclusion, the current scenario advocates to conduct more preclinical and clinical trials to effectively replace liver transplantation with liver regenerative medicine to treat liver diseases

Exploring discontinuous intentions of social media users: a cognition-affect-conation perspective

IntroductionDrawing on the cognition-affect-conation (C-A-C) framework, this study investigates how perceived information and social and system feature overload induce depression and anxiety, which leads to affect discontinuous intentions of the social media users.MethodsThe data collected from 570 social networking site users in China are analyzed through structural equation modeling (SEM).Results and DiscussionThe findings show that perceived information overload, perceived social overload, and perceived system feature overload directly affect depression and anxiety among social networking site users, which directly leads to discontinuous intentions. This study fulfills the identified need for an in-depth investigation of discontinuous behavior in social networking sites. The findings provide social networking site providers with guidelines on how to actively manage social networking site user’s behavior to reduce the effects of negative emotions on social networking sites

New α-Glucosidase inhibitors from Croton bonplandianum Croton bonplandianum Baill (Euphorbiaceae)

Purpose: To isolate and evaluate α-glucosidase inhibitors from dichloromethane extract of Croton bonplandianum Baill as probable remedy for management of diabetes.Methods: Activity-guided isolation of constituents from dichloromethane extract was carried out. Fractionation of dichloromethane extract by column chromatography on silica gel and Sephadex LH 20 using different mobile phase systems led to the isolation of compounds (A-I). The structures of these isolated compounds were established by ultraviolet (UV) and infrared (IR) spectroscopy. Proton nuclear magnetic resonance (1H NMR), 13C NMR and mass spectrophotometry, electron impact mass spectroscopy (EIMS) and high resolution mass spectroscopy (HRMS) were used for structural elucidation. All the isolated compounds were screened for their α-glucosidase inhibitory activity using standard in vitro α-glucosidase inhibition assay. Acarbose was used as positive control.Results: On the basis of their physical and spectral data from literature, the isolated compounds were identified as n-pentacosanyl-n-nonadeca-7′-en-9′-α-ol 1′-oate (A), n-tridecanyl n-octadec-9,12-dienoate (B), nonacosyl hexadecanoate (C), heptacosanoic acid (D), 1,3,5-trihydroxy-2-hexadecanoylamino- (6e,9e) heptacosdiene (E),cumarin (F), betulin (G), stigmasterol (H), and 3,5-dimethoxy 4-hydroxy cinnamic acid (I).Compounds F, GandI possessed significant α glucosidase inhibitory activity in a concentration-dependent manner with 50 % inhibitory concentration (IC50) values ranging from 23.0 to 26.7 μg/mL, relative to that of the positive control, acarbose (IC50, 38.2 μg/mL).Conclusion: The plant contains bioactive compounds with α-glucosidase inhibitory activity. This lendssome support for the traditional use of this herb in the management of diabetes. Compound F, GandI possessed significant α glucosidase inhibitory activity in a concentration-dependent manner and may be developed as a new α-glucosidase inhibitor.Keywords: α-Glucosidase, Inhibition, Diabetes, Acarbose, Cumarin, Betulin, 3,5 Dimethoxy 4-hydroxy cinnamic acid, Croton bonplandianu

Combination of Selective Etching and Impregnation toward Hollow Mesoporous Bioactive Glass Nanoparticles

In this study, binary SiO2-CaO hollow mesoporous bioactive glass nanoparticles (HMBGNs) are prepared by combing selective etching and impregnation strategies. Spherical silica particles (SiO2 NPs) are used as hard cores to assemble cetyltrimethylammonium bromide (CTAB)/silica shells, which are later removed by selective etching to generate a hollow structure. After the removal of CTAB by calcination, the mesoporous shell of particles is formed. Calcium (Ca) is incorporated into the particles using impregnation by soaking the etched SiO2 NPs in calcium nitrate aqueous solution. The amount of incorporated Ca is tailorable by controlling the ratio of SiO2 NPs:calcium nitrate in the soaking solution. The produced HMBGNs are bioactive, as indicated by the rapid formation of hydroxyapatite on their surfaces after immersion in simulated body fluid. In a direct culture with MC3T3-E1 cells, HMBGNs were shown to exhibit concentration-dependent cytotoxicity and can stimulate osteogenic differentiation of MC3T3-E1 cells at concentrations of 1, 0.5, and 0.25 mg/mL. Our results indicate that the combination of selective etching and impregnation is a feasible approach to produce hierarchical HMBGNs. The produced hollow particles have potential in drug delivery and bone tissue regeneration applications, and should be further investigated in detailed in vitro and in vivo studies.European Union’s Horizon 2020 research and innovation program 685872-MOZAR

Assessment of anti-diabetic activity of Cassia sophera (Caesalpiniaceae)

Purpose: To examine the ethnomedicinal claims regarding the antidiabetic uses of Cassia sophera L. (Caesalpiniaceae) using an alloxan-induced diabetes model.Methods: The methanol extracts of leaves (CSLM) and roots (CSRM) of C. sophera were evaluated for hypoglycemic and anti-diabetic activities in normal and alloxan-induced diabetic rats. Alloxan (120 mg/kg, i.p.) was administered to induce diabetes in rats. A dose regime of 50, 100 and 200 mg/kg of CSLM and CSRM was given orally to the respective groups (n = 6). Blank group consisted of normal animals maintained on saline. The diabetic untreated group served as negative control while the group that received glibenclamide (5 mg/kg) was positive control.Results: A significant (p < 0.05) lowering of fasting blood glucose level FBG in oral glucose tolerance test (OGTT) in normal rats was observed after daily  administration of the extract for 7 days. Both extracts demonstrated decreased (p < 0.05) BGL with significantly (p < 0.05) improved glucose tolerance and body weight at the end of 4th, 7th and 14th day in extract-treated diabetic rats when compared with negative control and normal untreated group, respectively. In normoglycemic rats, CSLM and CSRM showed dose-dependent decrease in BGL.Conclusion: These results suggest that both extracts possess significant blood glucose lowering activity in normal as well as in diabetic rats.Keywords: Cassia sophera, Hypoglycemic activity, Anti-diabetic activity, Alloxan, Weight los