<p>U radu su ispitane mogucnosti separacaije<br />nesaharoznih jedinjenja ultrafiltracijom iz rastvora<br />B i C &scaron;ecera sadržaja suve materije 60 i 30 ^oBx.<br />Eksperimentalna ispitivanja su izvedena na<br />keramickim membrana sa otvorom pora od 20 i 5<br />nm, bez i sa primenom statickog me&scaron;aca kao<br />promotora turbulencije. Tokom recirkulacije i<br />koncentrovanja napojne sme&scaron;e pracen je uticaj<br />nezavisno promenljivih (transmembranskog<br />pritiska, protoka, temperature i vremena trajanja<br />procesa) na fluks, boju, mutnocu i kvocijent<br />cistoce permeta. Ispitan je uticaj statickog me&scaron;aca<br />na prljanje membrane, na potro&scaron;nju energije i<br />smanjenja proizvodnih tro&scaron;kova. Eksperimentalni<br />rezultati su jasno pokazali da se najveca razlika u<br />vrednosti fluksa permeata rastvora B &scaron;ecera dobija<br />kada se uporedi nacin rada bez i sa upotrebom<br />me&scaron;aca. Ta razlika iznosi 30% na 80^oC, odn. 65%<br />kada se temperatura održava na 70^oC. Pri<br />ultrafiltraciji rastvora C &scaron;ecera, koji sadrži<br />mnogostruko vecu kolicinu nesaharoznih<br />jedinjenja, registruje se brža koncentraciona<br />polarizacija, te se pri istim uslovima postiže za<br />70% manji fluks od fluksa permeata rastvora B<br />&scaron;ecera. Sadržaj saharoze permeata i retentata se ne<br />menja tokom ultrafiltracije, nema merljive<br />retencije saharoze, &scaron;to je presudno za buducu<br />primenu ovog separacionog postupka u industriju<br />&scaron;ecera. Dekoloracija rastvora B &scaron;ecera bez<br />upotrebe me&scaron;aca ?? na nivou 40%, ? postiže se na<br />pritisku nižem od 6 bar i protoku od 250 L/h.<br />Upotrebom me&scaron;aca se efekat dekoloracije<br />pobolj&scaron;ava za oko 60%, i to pri protoku ispod 200<br />L/h. Izdvajanje bojenih materija pri ultrafiltraciji<br />rastvora C &scaron;ecera je prividno manje efikasno, jer<br />ne prelazi vrednost od 25% racunato na napojnu<br />sme&scaron;u, mada se u apsolutnim vrednostima iz<br />rastvora B i C &scaron;ecera izdvoji približno ista kolicina<br />bojenih materija (900 IJ). Ultrafiltracijom se<br />mutnoca napojne sme&scaron;e redukuje za 85%.<br />Ispitivanja prljanja membrane pri ultrafiltraciji su<br />pokazala da koncentraciona polarizacija i<br />formiranje sloja sastavljenog od nesaharoznih<br />jedinjenja na povr&scaron;ini membrane predstavljaju<br />dominantan udeo ukupnog hidraulicnog otpora. U<br />membrani sa otvorom pora 20 nm, tokom<br />ultrafiltracije meduproizvoda f?ze kristalizacije,<br />otpor poraste usled prljanja za 20 &ndash; 50 puta, a u<br />membrani sa otvorom pora 5 nm za 100 &ndash; 300 puta<br />u odnosu na otpor ciste membrane. Kori&scaron;cenje<br />me&scaron;aca je opravdano u intervalu gubitaka<br />hidraulicke snage od 0 &ndash; 7 W, jer se time postiže<br />povecanje fluksa i do 60%. Pri vecim gubicima<br />hidraulicne snage, odn. pri vecim brzinama<br />proticanja, nivo turbulencije u praznoj cevi je<br />znacajan, tako da se i bez upotrebe me&scaron;aca<br />registruju vece vrednosti fluksa. Povecanje stepena<br />koncentrovanja napojne sme&scaron;e sa 1,0 na 1,2 prati<br />smanjenje ukupnih prizvodnih tro&scaron;kova u opsegu<br />od 30 &ndash; 77% kada se proces ultrafiltracije realizuje<br />uz upotrebu me&scaron;aca.</p> / <p>This work presents the study of possibility to<br />separate of non-sucrose compounds from B and C<br />sugar solutions, with a dry matter content of 60 and<br />30 oBx by ultrafiltration. Experimental<br />investigations were performed on ceramic tubular<br />20 and 5 nm pore diameters membranes, with and<br />without kenics static mixer as turbulence promoter.<br />The influence of independent parameters<br />(transmembrane pressure, flow rate, temperature<br />and ultrafiltration time duration) on permetate flux,<br />colour, turbidity and purity during feed<br />recirculation and feed concentration were<br />examined. The efficiency of static mixer was<br />investigated on membrane fouling, on energy<br />consumption and on economical calculations. The<br />experimental results showed that, the greatest flux<br />difference of B sugar solution was obtained when<br />the operation mode was with a static mixer in<br />comparation to the operation mode without one,<br />showing 30% difference at temperature 80 oC and<br />65% at 70 oC. While ultrafiltering the C sugar<br />solution, which contains more non-sucrose<br />compounds, a faster concentration polarization was<br />noticed, thus at the same working conditions 70%<br />less flux was reached in comparison with to the B<br />sugar solution permeate flux. The permeate and<br />retentate sugar content did not changed during<br />ultrafiltration, there is no measurable retention of<br />sucrose, which is important for the implementation<br />of this type of separation into sugar industry. The<br />decoloration of B sugar solution without static<br />mixer is 40%, and can be reached at<br />transmembrane pressure bellow 6 bar and flow rate<br />of 250 L/h. By using a static mixer the decoloration<br />effect is improved for 60%, when flow rate is held<br />bellow 200 L/h. The separation of coloured<br />compounds during ultrafiltration of C sugar<br />solution is apparently less efficient since the value<br />did not reach 25% calculated on feed, even though<br />measured in absolute values the same level of<br />coloured compounds was separated from B and C<br />sugar solution (900 IU). The turbidity of B and C<br />solution was reduced by ultrafiltration for 85%.<br />The examinations of membrane fouling during<br />ultrafiltration showed that the concentration<br />polarization and formation of a non-sucrose<br />compound layer on the membrane surface are<br />dominant parts of the total hydraulic resistance.<br />During ultrafiltration of intermediate products of<br />sugar crystallization using 20 nm pore membrane<br />diameter the resistance increased for 20 &ndash; 50 times<br />due to fouling. Using a 5 nm pore diameter<br />membrane the resistance increased for 100 &ndash; 300<br />times comparing to clean membrane. The use of<br />static mixer is justified when 0 &ndash; 7 W loss of<br />hydraulic power was determined, because in that<br />interval a 60% flux increase was detected. At<br />higher levels of hydraulic power loss, and at higher<br />values of flow rates the turbulency in empty tubular<br />membrane is significant, so even without using<br />static mixers higher values of flux are detected.<br />When a static mixer was used with the increase of<br />volume concentration ratio from 1,0 to 1,2 the total<br />production costs decreased in a range of 30 &ndash; 77%.</p>

Kritiskt sjuka patienter med infektioner är en börda för sjukvården och 70 % av alla patienter på intensivvårdsavdelningar är ordinerade antibiotika. Antibiotika binder till proteiner i blodet, men enbart den icke-proteinbundna (fria) fraktionen kan diffundera över kapillära membran och binda till receptorer. Standardproteinbindningsgrad för olika antibiotika har utvecklats från studier på friska frivilliga och doseringen av läkemedlen är anpassade därefter. Den totala koncentrationen av antibiotika i patienters blod är vanligen representativ för den farmakologiska effekten. Dock kan vissa sjukdomar påverka proteinbindningsgraden vilket resulterar i en större eller mindre mängd fria antibiotika i blodcirkulationen. Det här kan i sin tur resultera i toxicitet eller otillräcklig effekt av läkemedlet. Syftet med det här projektet var att utveckla en analytisk metod för att bestämma den fria koncentrationen av Beta-Lactam antibiotikan cefotaxim, flukloxacillin, kloxacillin och piperacillin i plasma. En metod utvecklades med ultrafiltrering för extraktion av den fria fraktionen och högupplösande vätskekromatografi och tandem masspektrometri, UHPLC-MS/MS, för kvantifiering av analyterna. Metoden validerades delvis enligt den Europeiska Läkemedelsmyndighetens riktlinjer för bioanalytisk metodvalidering. / Infections in critically ill patients are a problem for the healthcare system and at any one time, 70 % of all intensive care unit (ICU) patients are treated with antibiotics. Antibiotics bind to proteins in the blood, but only unbound drug can diffuse over capillary membranes and bind to the targeted receptor. Standard protein binding percentages for antibiotics have been developed from studies on healthy volunteers and dosing regimens for patients are adapted accordingly. The determination of the total concentration of antibiotics in patients’ blood samples is, based on the standard percentages, ordinarily representative for the pharmacological effect of the antibiotic. However, certain conditions that are common in critically ill patients can alter protein binding percentages, resulting in a larger or smaller unbound fraction. This in turn can result in toxicity or therapeutic failure. The aim of this project was to develop an analytical method for the determination of the unbound concentration of the Beta-Lactam antibiotics cefotaxime, flucloxacillin, cloxacillin and piperacillin in plasma. A method was successfully developed using ultrafiltration for the extraction of unbound analytes and ultra high performance liquid chromatography tandem mass spectrometry, UHPLC-MS/MS, for their quantification. The method was partly validated according to the European Medicines Agency’s guidelines on bioanalytical method validation.

In the production of biodiesel via the transesterification of vegetable oils, purification to international standards is challenging. A key measure of biodiesel quality is the level of free glycerol in the biodiesel. In order to remove glycerol from fatty acid methyl ester (FAME or biodiesel), a membrane separation setup was tested. The main objective of this thesis was to develop a membrane process for the separation of free glycerol dispersed in FAME after completion of the transesterification reaction and to investigate the effect of different factors on glycerol removal. These factors included membrane pore size, pressure, temperature, and methanol, soap and water content. First, a study of the effect of different materials present in the transesterification reaction, such as water, soap, and methanol, on the final free glycerol separation was performed using a modified polyacrylonitrile (PAN) membrane, with 100 kD (ultrafiltration) molecular weight cut off for all runs at 25°C. Results showed low concentrations of water had a considerable effect in removing glycerol from the FAME. The mechanism of separation of free glycerol from FAME was due to the removal of an ultrafine dispersed glycerol-rich phase present in the untreated (or raw) FAME. The size of the droplets and the free glycerol separation both increased with increasing water content of the FAME. Next, three types of polymeric membranes in the ultrafiltration range with different molecular weight cut off, were tested at three fixed operating pressures and three operating temperatures (0, 5 and 25oC) to remove the free glycerol from a biodiesel reactor effluent. The ASTM standard for free glycerol concentration was met for the experiments performed at 25°C. The results of this study indicate that glycerol could be separated from raw FAME to meet ASTM and EN standards at methanol feed concentrations of up to 3 mass%. The process was demonstrated to rely on the formation of a dynamic polar layer on the membrane surface. Ceramic membranes of different pore sizes (0.05 µm (ultrafiltration (UF) range) and 0.2 µm (microfiltration (MF) range)) were used to treat raw FAME directly using the membrane separation set up at temperatures of 0, 5 and 25°C. The results were encouraging for the 0.05 µm pore size membrane at the highest temperature (25°C). The effect of temperature on glycerol removal was evident from its relation with the concentration factor (CF). Higher temperatures promoted the achievement of the appropriate CF value sooner for faster separation. Membrane pore size was also found to affect separation performance. A subsequent study revealed the effect of different variables on the size of the glycerol droplets using dynamic light scattering (DLS). A key parameter in the use of membrane separation technology is the size of the glycerol droplets and the influence of other components such as water, methanol and soaps on that droplet size. The effect of water, methanol, soap and glycerol on the size of suspended glycerol droplets in FAME was studied using a 3-level Box-Behnken experimental design technique. Standard statistical analysis techniques revealed the significant effect of water and glycerol on increasing droplet size while methanol and soap served to reduce the droplet size. Finally, a study on the effect of trans-membrane pressure (TMP) at different water concentrations in the FAME phase on glycerol removal using UF (0.03 µm pore size, polyethersulfone (PES)) and MF (0.1 and 0.22 µm pore sizes, PES) membranes at 25, 40 and 60°C was performed. Results showed that running at 25°C for the two membrane types produced the best results for glycerol removal and exceeded the ASTM and EN standards. An enhancement of glycerol removal was found by adding small amounts of water up to the maximum solubility limit in biodiesel. An increase in temperature resulted in an increase in the solubility of water in the FAME and less effective glycerol removal. Application of cake filtration theory and a gel layer model showed that the gel layer on the membrane surface is not compressible and the specific cake resistance and gel layer concentration decrease with increasing temperature. An approximate value for the limiting (steady-state) flux was reported and it was found that the highest fluxes were obtained at the lowest initial water concentrations at fixed temperatures. In conclusion, dispersed glycerol can be successfully removed from raw FAME (untreated FAME) using a membrane separation system to meet the ASTM biodiesel fuel standards. The addition of water close to the solubility limit to the FAME mixture enables the formation of larger glycerol droplets and makes the separation of these droplets straightforward.

Integrating ultrafiltration (UF) membranes in lieu of traditional media filters within conventional surface water coagulation-flocculation-sedimentation processes is growing in popularity. UF systems are able to produce low turbidity filtered water that meets newer drinking water standards. For typical drinking water applications, UF membranes require periodic chemically enhanced backwashes (CEBs) to maintain production; and citric acid is a common chemical used for this purpose. Problems may arise when the backwash recycle stream from a citric acid CEB is blended with raw water entering the coagulation basin, a common practice for conventional surface water plants. Citric acid is a chelating agent capable of forming complexes that interfere with alum or ferric chloride coagulation. Interference with coagulation negatively affects settled water quality. Acetic acid was investigated as a potential substitute for citric acid in CEB applications. A jar testing study was conducted to compare the impacts of both citric acid and acetic acid on the effectiveness of aluminum sulfate (alum) and ferric chloride coagulants. Citric acid was found to adversely affect coagulation at lower acid to coagulant (A/C) molar ratios than acetic acid, and a coagulation interference threshold was identified for both acids based on settled water turbidity goals recommended by the U.S. Environmental Protection Agency (EPA). Pilot testing was conducted to assess the viability of acetic acid as a UF CEB chemical. Acetic acid CEBs maintained pilot performance in combination with sodium hypochlorite CEBs for filtering a raw California surface water. It is believed that this is the first ultrafiltration membrane process application of acetic acid CEBs for municipal potable water production in the United States.

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Kommunalförbundet Norrvatten är en av Sveriges största producenter av dricksvatten och förser över 50 miljoner vatten till över 700 000 invånare i norra Stockholm. Vattnet är renat i Görvälnverket som har sedan år 2016 planlagt en expansion av verkets kapacitet och kvalité. Ett fokusområde för att förbättra reningsprocessen är implementering av membranteknik. I det här projektet har experiment utförts som ett fortsatt arbete av att integrera ultrafiltration med koagulering på en mikropilot. Syftet med projektet är att optimera driftparameterar (koaguleringsdos, pH och alkalitet, uppehållstid och omblandning) för processen och jämföra pilotens effektivitet för två typer av matarvatten (kol- och sandfiltrat). En lägre koaguleringsdos på 2.5 mg Al/L resulterade i en 18.9 % avskiljning av TOC och 21.3% minskning i UV254. I jämförelse med en högre dos på 3.8 mg Al/L, var effektiviteten 2 % bättre för TOC och 3 % bättre för UV254. Till följd av en låg ökning i effektivitet för en högre koagulantdos påvisar en lägre dosering ett bättre alternativ. Dessutom är det rekommenderat att vid uppskalandet av piloten mer försök genomförs för att få mer pålitliga data och att automatisk dosering implementeras eftersom dosering av koagulant var en svårkontrollerad parameter.pH inom intervallet 6.8 till 7.2 visade vara mest optimal för att minimera mängden aluminiumrester i permeatet. Experimenten på pH konstaterar att flockning är pH beroende och optimalt vid pH 7. Effektiviteten var också beroende av alkaliteten. Där bäst alkalinitet anpassades till mellan 40 och 50 mg HCO3/L, med högre än 50 mg HCO3/L minskade effektiviteten av avskiljningen, vilket tyder på sämre flockning vid basiska förhållanden. Karbonatdosering av 5 mL 0.01 M Na2CO3 /L obehandlat vatten uppnådde önskad alkalinitet och minimerade aluminiumrester i permeatet.  Uppehållstiden och konfigurationen av blandning indikerade ingen optimal justering. Emellertid, en jämförelse av försök med uppehållstiden och försök utan koaguleringdos visade dramatisk minskning i effektivitet till endast 2 % TOC avskiljning och 6 % UV254 minskning. Placering av ultrafiltrationsenheten efter kolfiltret jämfört med efter sandfiltret visade inga tecken på nedsatt effektivitet. Transmembrantrycket över membranet ökade över den experimenterade perioden från 0.02 till 0.06 bar och fluktuerade under drift mellan det första och sista försöket. Det var däremot ingen skillnad i trycket mellan kolfilter och sandfilter, vilket styrker beslutet att placera ultrafiltrationsenheten efter kolfiltret. / The municipal association Norrvatten is one of Sweden's largest drinking water producers and distributes over 50 million m3 of drinking water to around 700 000 inhabitants in northern Stockholm. The water is treated in the Görväln plant, which has since 2016 planned to expand its capacity and improve its water quality. One researched area for improving the treatment process is implementing membrane technology. In this project, experiments are performed as a continued work of integrating ultrafiltration with coagulation on a bench-scale plant. The purpose is to optimise the operating parameters (coagulant dosage, pH &amp; alkalinity, retention time, and mixing) and compare the ultrafiltration removal efficiency for two types of feed water (carbon and sand filtrate).  A lower coagulant dosage of 2.5 mg Al/L resulted in removal efficiencies on average of 18.9 % TOC removal and 21.3 % UV254 reduction. Compared to the higher dosage of 3.8 mg Al/L, the removal efficiency was only decreased with 2 % TOC and 3 % UV254. Therefore, a lower dosage is a more suitable option. Although, more data needs to be collected for a more reliable optimal dosage. In addition, for the up-scaling of the pilot, automatic dosage control needs to be implemented as the coagulant dosage is difficult to control as a parameter. pH showed the best removal efficiency in the range of 6.8 to 7.2 and minimised aluminium residue in the permeate. It verifies that flock formation is pH-dependent and optimal close to 7. The efficiency also depended on the alkalinity, with the optimal alkalinity between 40 to 50 mg HCO3/L. Higher alkalinity decreased the efficiency, which supports the theory that too basic water hinders flock formation. With minimum dosage of 5 mL 0.01 M Na2CO3/L untreated water, the required alkalinity could be achieved without affecting the amount of aluminium in the permeate residue.  The retention time and mixing configuration did not result in an optimum adjustment. However, with no retention time at a coagulant dosage of 0 mg Al/mL, the efficiency was reduced drastically to 2 % TOC removal and 6 % UV254 reduction. The placement after the carbon filter showed no adverse signs on the removal efficiency compared with placing it after the sand filter. The TMP of the membrane increased over time from 0.02 to 0.06 bar, and higher fluctuations in TMP were noted in the last experiment compared to the first. The differences were identical for both carbon and sand filtrate, strengthening the decision to place the ultrafiltration unit after the carbon filter.

Patients on peritoneal dialysis (PD) are reliant on the peritoneum to provide a semi-permeable barrier to allow for dialysis (solute clearance), salt and water removal (ultrafiltration). PD patients are at risk of developing peritoneal fibrosis and angiogenesis which can lead to a decline in peritoneal membrane function. Specifically, PD patients develop increased solute transport and decreased osmotic conductance leading to ultrafiltration failure. Peritoneal angiogenesis is the leading factor that results in augmented peritoneal membrane solute transport which is associated with worse outcomes – increased risk of mortality and PD technique failure. Transforming growth factor beta (TGFB) is one of the primary cytokines involved in inducing epithelial to mesenchymal transition (EMT) and fibrosis. We hypothesize that PD leads to injury of the epithelial lining of the peritoneum – the mesothelial cells. These cells undergo a transition process and transitioned mesothelium are a source for angiogenic and fibrogenic growth factors. Matrix Metalloproteinase (MMP) 9 is an angiogeneic factor and has been observed to correlate with increased expression of vascular endothelial growth factor (VEGF). MMP9 has the ability to cleave and activate membrane bound factors such as E-cadherin and b-catenin respectively. There is substantial evidence that the canonical WNT/b-catenin pathway is active during fibrosis, and angiogenesis in different biological contexts. Thus, we investigated the role of MMP9 and WNT signaling in peritoneal angiogenesis. Limited evidence exists describing the role of noncanonical WNT signaling but some reports suggest that non-canonical WNT signaling inhibits WNT/b-catenin signaling. Non-canonical WNT5A has differential effects based on receptor context and has been shown to block WNT/b-catenin signaling in the presence of Receptor Tyrosine Kinase Like Orphan Receptor 2 (Ror2). The overall hypothesis of this PhD thesis is that MMP9 and WNT signaling play a key role in inducing peritoneal angiogenesis and are associated with changes in peritoneal membrane function. We expect WNT5A and Ror2 to protect against peritoneal membrane injury. From the overnight effluent of stable PD patients, we cultured mesothelial cells and assayed these for expression of MMP and WNT related genes. MMP9 and WNT1 gene expression were observed to be strongly correlated with peritoneal membrane solute transport in patients on PD. WNT2 mRNA was also positively correlated with peritoneal solute transport. We overexpressed MMP9 in the mouse peritoneum to demonstrate its role in angiogenesis and confirmed these findings using MMP9 -/- mice. In addition to this, we have shown a novel mechanism by which MMP9 induces angiogenesis by E-cadherin cleavage and b-catenin mediated signaling. The observed cross-talk between MMP9 and b-catenin prompted investigation of the activation of canonical WNT/b-catenin signaling in development of peritoneal membrane injury. In an experimental model of TGFB induced pertioneal injury, we confirmed the activation of WNT/b-catenin signaling. In addition to this we, we blocked the WNT pathway and observed that WNT/b-catenin signaling is required to induce peritoneal angiogenesis. WNT5A mRNA was downregulated during TGFB induced injury suggesting a more protective role. Furthermore, several studies have demonstrated its ability to antagonize the WNT/b-catenin signaling pathway. We demonstrated that WNT5A protected against angiogenesis by blocking the canonical WNT pathway. WNT5A is thought to antagonize the WNT/b-catenin signaling pathway by signaling through receptor Ror2. In cell culture, we overexpressed TGFB and blocked Ror2. This resulted in elevated levels of VEGF and fibronectin suggesting that Ror2 is involved in mediating protection. Therefore, Ror2 possesses the ability to regulate VEGF and may be a potential candidate by which WNT5A mediates its protective effects. In conclusion, our findings identified MMP9 and WNT1 as potential biomarkers of increased peritoneal solute transport in patients that are on PD. We have also found a novel mechanism by which MMP9 interacts with b-catenin to induce peritoneal angiogenesis and have provided a first look at WNT/b-catenin signaling in peritoneal angiogenesis. Lastly, we have shown WNT5A to protect against peritoneal angiogenesis. Taken together, our findings are not only significant to the realm of PD research but hold wide applicability to research in the biomedical sciences. / Thesis / Doctor of Philosophy (PhD)