Theses supervised by Doç. Dr. Seda Kızılel
10 theses · Koç University
Design, fabrication and characterization of light-responsive functionalized hydrogel for tissue engineering applications
Stimuli-responsive hydrogels have gained immense consideration due to the unique properties such as spectacular volume transition in response to a variety of physical and chemical stimuli. These hydrogels have been particularly effective, considering exceptional degree of authority over material properties because of external signals. The precise control over the hydrogel properties resulted in significant advancements in medical devices and improved methodologies for tissue engineering applications. In this thesis, we aimed to develop biocompatible and biodegradable stimuli-responsive hydrogels for tissue engineering applications. Different methods of hydrogel fabrication were studied throughout the study such as free radical photopolymerization and photodimerization reactions. In the first part of the thesis, we pursued the conventional method of hydrogel formation where polymers were functionalized with light-sensitive anthracene. Glycan-based alginate hydrogels have great potential in creating new vehicles with responsive behavior and tunable properties for biomedicine. However, precise control and tunability in properties present major barriers for clinical translation of these materials. We reported the synthesis of pH responsive anthracene modified glycan-based hydrogels for selective release of therapeutic molecules. Hydrogels were crosslinked through simultaneous photopolymerization of vinyl groups and photodimerization of anthracene. Incorporation of anthracene into these gels lead to reversible control on crosslinking and transition between gel/sol states through dimerization/dedimerization of anthracene groups. Chemotherapeutic drug doxorubicin-loaded hydrogels were then tested in a cancer mimetic microenvironment where 85% of the drug was released from anthracene-conjugated hydrogels at pH 2 for 6 days. Control on gelation with anthracene incorporation was observed through alterations in modulus, where storage modulus was increased two- and five-fold with anthracene conjugation during photopolymerization and photodimerization, respectively. Furthermore, cell survival analysis revealed that anthracene conjugation could selectively compromise cancer cell viability without inducing significant toxicity on healthy fibroblasts. This study combines light-induced control of crosslink density due to the anthracene and pH-triggered therapeutics delivery with alginate. The approach would be applicable for systems where multiple control is required with high precision. Further, we reported the synthesis of single and dual-crosslinked anthracene-functional chitosan-based hydrogels in the absence of toxic initiators. Single crosslinking was achieved through dimerization of anthracene, whereas dual-crosslinked hydrogel was formed through dimerization of anthracene and free radical photopolymerization of methacrylated-chitosan in the presence of non-toxic initiator riboflavin, a well-known vitamin B2. Both single and dual-crosslinked hydrogels were found to be elastic, as was determined through rheological analysis. We observed that the dual-crosslinked hydrogels exhibited higher Youngs modulus than the single-crosslinked hydrogels, where the modulus for single and dual-crosslinked hydrogels were measured as 9.2±1.0 kPa and 26±2.8 kPa, respectively resulting in significantly high volume of cells in dual-crosslinked hydrogel (2.2x107 µm3) compared to single-crosslinked (4.9x106 µm3). Furthermore, we investigated the cytotoxicity of both hydrogels towards 3T3-J2 fibroblast cells through CellTiter-Glo assay. Finally, immunofluorescence staining was carried out to evaluate the impact of hydrogel modulus on cell morphology. This study comprehensively presents functionalization of chitosan with anthracene, uses nontoxic initiator riboflavin, modulates the degree of crosslinking through dimerization of anthracene and free radical photopolymerization, and further modulates cell behavior through the alterations of hydrogel properties. In the second part of the thesis, a novel technique was introduced and photocrosslinked hydrogels were synthesized from natural and synthetic polymers in the absence of any photoinitiator or coinitiator. Very simple and facile method was developed to synthesize biocompatible and non-toxic hydrogels through free-radical polymerization. The potential of the developed procedure is shown against natural and synthetic polymers both. For this, acrylated forms of alginate, chitosan, gelatin, hyaluronic acid, and polyethylene glycol (PEG) were used and mechanically robust hydrogels were developed under UV (365 nm) and visible (430 nm) light as determined through rheological analysis. We also observed that the UV light-crosslinked hydrogels exhibited higher crosslinking and showed high Youngs modulus as compared to visible light-crosslinked hydrogels. Cell viability analysis shows that the developed hydrogels are non-toxic towards fibroblast cells. The biomedical potential of these hydrogels was further explored by encapsulating the two model cell lines where NIH-3T3 fibroblast cells and bone-marrow derived mesenchymal stem cells (rBM-MSCs) were encapsulated in the hyaluronic acid (HA)-based hydrogel. The enhanced growth rate of the cells shows that the crosslinking procedure is non-toxic to the cells. Scope of this study was further expanded to sustained release of therapeutics. DOX was successfully loaded into HA-based hydrogel. The maximum loading was observed as 97% and an accelerated release rate was seen in visible light-based crosslinked hydrogel due to the open pore structure compared to the UV-based hydrogel. Another potential application for such initiator-free hydrogel might be the vascularization which was also explored in this part of the thesis. Engineering of organized vasculature is a key step in the improvement of functional and clinically relevant tissue constructs. Various hydrogel-based culture systems are used to make in vitro models for angiogenesis. Here, we developed initiator-free photocrosslinked gelatin-based hydrogels under UV (365 nm) and visible light (430 nm) for the tubular formation of functional vascular networks. Detailed rheological analysis revealed that Gel-MA hydrogels were robust and viscoelastic in nature. We tuned the mechanical properties of Gel-MA hydrogel depending on the type of exposed light. By this way, we obtained stiff and soft Gel-MA hydrogels. Immunofluorescence labeling was used to track the impact of hydrogel modulus over the cell shape and tubular formation. We found higher tubular formation in soft Gel-MA hydrogel compared to the stiff hydrogel. Further, we also investigated the tubular formation in the presence and absence of growth factors and found that tubular formation was much higher in the presence of growth factors as expected. The cytotoxicity of the developed hydrogel was evaluated towards HUVECs by using the CellTiter-Glo assay and found to be non-toxic.
Developing a novel recombinant IL-1 receptor antagonist to treat the cytokine storm in Covid-19
One of the deadliest symptoms of Covid-19 is the development of acute respiratory distress syndrome (ARDS) in the patients. The hyperactivation of immune system due to SARS-CoV-2 infection results in the sudden release of numerous cytokines including interleukins which is called cytokine storm. Interleukin-1β (IL-1β) is known as one of the most important cytokines playing a role in the emergence of this phenomenon in inflammatory diseases. Therefore, blocking the pathway induced by IL-1β has been considered a promising treatment approach in the presence of cytokine storm. Endogenous interleukin-1 receptor antagonist (IL-1Ra) binds to the same receptor as IL-1β and inhibits the pathway. The commercially available recombinant version of IL-1Ra, anakinra, has already been used in the treatment of autoinflammatory diseases such as rheumatoid arthritis (RA), type II diabetes, and familial Mediterranean fever (FMF) since 2001 in order to alleviate the inflammatory response. Therefore, it has been used on Covid-19 patients in clinical trials and shown to be a potential medication due to its role in the attenuation of the cytokine storm. In the first part of this thesis, in vitro characterization of two novel recombinant IL-1Ra proteins was performed. The recombinant proteins were produced by Dr. Cem Albayrak's and Dr. Serdar Uysal's group as local alternatives to anakinra, which is not commercially available in Turkey. In this part of the thesis, the bioactivity of the recombinant proteins and their effects on cell viability were investigated. In order to assess the bioactivity of the proteins, genetically modified HEK-Blue cells were used to determine the impact of the proteins in IL-1β-induced SEAP production using QUANTI-Blue agent to measure, and IC50 value was calculated. Also, the ability of IL-1Ra-His6 protein to inhibit IL-1β-induced IL-6 production in MRC-5 lung fibroblasts was evaluated via ELISA. Finally, the viability of HEK293T and MRC-5 cells were inquired using CTG assay. Chitosan is one of the most promising biomaterials due to its unique properties such as biocompatibility, biodegradability, mucoadhesivity, and low immunogenicity. These properties make chitosan an excellent candidate for various biomedical applications such as wound healing, tissue engineering, and gene/drug delivery. Using chitosan in nanoparticle-based delivery systems increases its potential even further, primarily enabling the delivery of a high amount of genetic material. In the second part of the thesis, transfection and permeation enhancing capabilities of TRAIL encapsulated PEGylated chitosan nanoparticles were investigated. 5 kDa PEG was used to PEGylate chitosan to improve its physicochemical properties. Nanoparticles were synthesized using a crosslinking agent (TPP) and PEGylated chitosan derivative. In order to encapsulate tumor necrosis factor (TNF) α-related apoptosis-inducing ligand (TRAIL) inserted plasmid DNA was added in the process of crosslinking. Synthesized nanoparticles were characterized using scanning electron microscopy (SEM). Also, TRAIL encapsulated nanoparticles were incubated with 3 different glioblastoma (GBM) cell lines (A172, LN18, T98G), and transfection efficiencies of nanoparticles were experimentally investigated using flow cytometry. For the assessment of permeation enhancing capability of nanoparticles, Calu-3 cells were used, and the change in the transepithelial electrical resistance (TEER) was measured.
Nanojel içeren pH'a duyarlı kompozit hidrojel sisteminin kontrollü ılaç salımı için kullanımı
In this study, both ultraviolet (UV) and visible-light have been used for the synthesis of novel hybrid pH responsive systems composed of poly(methacrylic acid-grafted-ethylene glycol), P(MAA-g-EG), and acryloyl group modified-cholesterol-bearing pullulan (CHPOA) nanogels. The system developed here has been utilized for controlled delivery of an anticonvulsant model drug pregabalin (PGB). The hydrophilic P(MAA-g-EG) network allows for pH dependent release of a loaded therapeutic agent, where CHPOA nanogel allows for the loading of a protein or hydrophobic drug into its structure. The hybrid hydrogels were synthesized under both UV and visible light, where bulk and surface initiated photopolymerization approaches were used. Bulk polymerized hydrogels were obtained through suspension of photoinitiator within the prepolymer solution, where uniform permeability properties were achieved for the synthesized pH responsive gel network. Surface initiated photo-polymerization was based on adsorption of photoinitiator onto an underlying substrate, where pH responsive hybrid gels with crosslink density gradients were obtained. Covalently attached nanogel within P(MAA-g-EG) hydrogel was characterized by Field Emission- Scanning Electron Microscope (FE-SEM). Swelling and release studies were carried out at pH 2.2 and 7.4 to mimic the physiological conditions in stomach and small intestine. Dynamic and reversible swelling experiments demonstrated higher swelling ratio profiles for visible light cured composite hydrogels. In addition, hybrid hydrogels incorporated with 5% nanogel, or synthesized with bulk photopolymerization demonstrated higher swelling. PGB release profiles at neutral pH demonstrated similarities for altered nanogel concentrations within the composite network. Biocompatibility of the hybrid network was also characterized using HeLa cell line in vitro. This approach for multifunctional membranes could be utilized for incorporation of specific molecules such as drug or protein with specific functionalities, so that sequential molecule delivery in response to specific stimuli could be achieved.
Kanser hücresi hedeflenmesi için su içinde su emülsiyonu yöntemiyle PEG hidrojel sentezi
In this study, the influence of multiple selective targeting ligands through the use of PEG hydrogel particles on targeting cancer cell surface and environment was studied. PEG based drug delivery vehicles were prepared via water-in-water emulsion technique in aqueous dextran solution. RGDS, IKVAV and cysteine–arginine–glutamic acid–lysine–alanine (CREKA) small peptides and/or combinations were conjugated to hydrogel particles as targeting ligands. Peptide conjugates were analyzed through Fourier Transform Infrared Spectroscopy (FT-IR) and X-ray Fluorescence Spectroscopy (XRF). Size and morphology of composed gel particles were characterized via Scanning Electron Microscopy (SEM). SEM micrographs showed that the sizes of synthesized particles were within the range of 16 nm-5 µm. In addition viability and uptake of PEG hydrogels by human cervical cancer cells (HeLa) was investigated using confocal microscopy in vitro. For particle uptake experiments, particles were loaded with Doxorubicin (Dox) and cell nucleus was fluorescently stained with 4', 6-diamidino-2-phenylindole (DAPI). Quantitative characterization of particle uptake was calculated from fluorescence intensities using ImageJ software. Cell survival experiments carried out in the presence and absence of PEG hydrogels demonstrated higher viability for the cells treated with CREKA conjugated hydrogel particles. In addition, fibrin binding assay showed that CREKA conjugated particles can bind to fibrin with 94% binding affinity compared to particles in other groups, suggesting the targeting potential of PEG hydrogel particles through CREKA functionalization. This study is promising for the development of targeted delivery vehicles, and provides the foundation of CREKA and RGDS/IKVAV mediated targeting of cancer cells.
Emulsiyon kalıplama yöntemiyle fonksiyonel malzeme tasarımı: Enerji ve biyomedikal uygulamalar
Incorporating functional materials into immiscible mediums has been a conventional challenge in materials science. Solid structures are formed via templating stable liquid emulsions to overcome this challenge. In the first part of thesis, we designed a composite membrane via Pickering Emulsion templating, which integrates a hydrophobic styrene-butediene-styrene (SBS) polymer phase and hydrophilic agar phase that incorporates ionic salts for anti-icing property on bitumen surfaces. We demonstrated significant freezing delay with composite-modified bitumen compared to base bitumen in different temperature controlled chambers with temperatures of -14 and -2 °C. In addition, we investigated morphological and salt release properties of composite modified bitumen and observed potassium formate release for 67 days. Furthermore, we investigated altered ionic salts consisting of potassium formate, sodium chloride or magnesium chloride. These results are promising and suggest the potential of this polymer composite-modified bitumen for anti-icing functionality and for industrially relevant applications. In seond part of thesis, we synthesized polyethylene glycol (PEG) nanospheres via water-in-water emulsion templating method based on phase separation of dextran and PEG prepolymer and achieved the synthesis of nano-scale PEG hydrogel particles for biomedical applications. Next, we investigated the release kinetics of a model drug, pregabalin from PEG nanospheres. In the last part, we synthesized photocrosslinked SBS network and designed SBS-PEG hybrid gels for sustained drug release purposes. We achieved extended release of anti rheumatoid arthritis drug from SBS-PEG gels up to 28 days. Cell-survival assay suggested that PEG nanospheres and SBS-PEG gels are non-toxic, and can be considered for controlled drug/molecule delivery.
Nakil edilen adacıkların vücuttan reddedilmesini önlemek amacıyla bağışıklık sisteminden ayrı tutulabilen bir bölgesel mikroortam dizayn edilmesi
The development of tolerance induction approaches via immune engineering that can restore and/or replace non-functional tissues and organs represents the leading front of emerging regenerative therapies. Type-1 diabetes (T1D) is an organ-specific autoimmune disease characterized by destruction of pancreatic β cells, which are insulin-secreting cells by autoreactive T cells and other immune cells. Loss of β-cell, thus insulin, makes patients dependent on exogenous insulin or to overcome this need; transplantation of pancreas or intact islets. One of the promising approaches used for treatment of diabetes is the transplantation of islets; however, it also comes with its pitfalls. First and most obvious one is the limitation of donor source. In addition, transplantation of islets or entire pancreas requires suppression of the immune system to prevent graft rejection. This suppression is achieved through immune suppressor drugs, which leaves the body defenseless against infections and increases its susceptibility to other complications such as cancer. Considering all these limitations, immunotherapeutic strategies have focused on restoring immunologic self-tolerance, thus removing the problem at it roots; preventing β cell destruction by patients's own immune system. The main focus of this approach is regulatory T cells (Tregs), which are essential cells in suppression of autoreactive immune responses and maintenance of self-tolerance. Stellate cells (SCs) have various effects on the immune system such as recruitment of Tregs and induction of T cell apoptosis. Besides, they can promote vascularization, secreting vascular endothelium growth factor (VEGF). Some chemokines are also key modulators in recruitment of Tregs. Macrophage-derived chemokine or C-C motif chemokine ligand 22 (MDC/CCL22) is one of the novel chemokines used for Treg recruitment by binding to CCR4 receptor on their membrane. In this study, we designed an immune privileged microenvironment around implantable insulin secreting islets site to provide local graft tolerance and to overcome limitations associated with donor cells. We focused on achieving local immunosuppression through overexpression of CCL22 proteins by SCs, which recruited immunosuppressive Tregs. We prepared insulin-secreting pseudoislets through aggregation of mouse insulinoma 6 (MIN6) cells as a model system to mimic naïve islet morphology. Our results demonstrated that transfected SCs can secrete CCL22 and recruit a population of Tregs towards the implant in vivo. This study is promising to provide fundamental understanding of the SC-islet interaction, ligand synthesis and transport from stellate cells at the graft site for ensuring local immune tolerance to target Type I diabetes. Our results also establish a new paradigm for creating tolerable grafts for other chronic diseases such as diabetes, anemia, cancer, CNS diseases and advance the science of graft tolerance.
Pankreatik adacık engrafmanını iyileştirmek için biyomimetik hücre dışı ortam dizayn edilmesi
Pancreatic islet transplantation has emerged as a promising treatment for type 1 diabetes (T1D) and engraftment of beta cells after transplantation determines the success of clinical setting. However, clinical application of islet transplantation is still limited by life-long use of immunosuppressive drugs and insufficient number of islets to achieve normoglycemia. In this study, we tailored biochemical and biophysical properties of hydrogels to promote insulin secretion function and immunoregulatory potential through incorporation of mesenchymal stem cells (MSCs) and natural extracellular matrix mimetic peptides such as RGDS, IKVAV and insulinotropic peptide (GLP-1). Co-encapsulation of islets with MSCs and/or peptides contributed to significant increases in insulin secretion compared to control. Although deleterious effects of cytokines were not completely inhibited, we observed that protection against pro-inflammatory cytokines can be achieved in free and PEG hydrogel encapsulated MIN6-MSC heterospheroids. To tailor biophysical properties of islet microenvironment, we developed unique type of nano-thin coating for insulin secreting beta cell aggregates. These aggregates which were prepared as pseudoislets through hanging drop method were coated with sequential layers of nanogels using physiologically compatible medium without toxic prepolymer solutions. These coated pseudoislets were determined as viable and functional for insulin secretion. We also confirmed in vivo biocompatibility of CHPOA nanogels through subcutaneous transplantation into CD1 mouse. This study is promising and offers new opportunities through coating of insulin secreting islets with advanced functional materials under completely physiological conditions and will contribute to longer functional islets for clinical translation of cell transplantation technology and particularly for the treatment of T1D.
Biyomedikal mühendisliği uygulamaları için kitosan bazlı taşıyıcıların tasarımı
Chitosan-based materials have gained enourmous attention due to unique properties of chitosan such as biodegrability, biocompatibility and cationic nature. Especially, chitosan-based drug/gene delivery systems became a promising alternative for the treatment of various diseases. This thesis includes studies about nanoparticle and microrobotic-based chitosan carriers. In the first part of the thesis, the main aim is to synthesize colloidally stable ionically crosslinked chitosan nanoparticles. Ionically-crosslinked chitosan nanoparticles have gained considerable attention due to their cationic nature and sub-100 nm size. However, low solubility of chitosan in neutral media restricts its potential clinical translation. PEGylation is a simple solution to increase solubility of chitosan and chitosan nanoparticles in neutral media. Yet, effect of PEG chain length and chitosan/PEG ratio on particle size and zeta potential of nanoparticles are not known. This chapter of the thesis presents a systematic analysis of the effect of PEG chain length and chitosan/PEG ratio on size and zeta potential of nanoparticles. PEGylated chitosan polymers were prepared before the nanoparticle synthesis with different PEG chain lengths and chitosan/PEG ratios. Effect of PEG chain length (2, 5 and 10 kDa), chitosan/PEG ratio (25 mg chitosan to 4, 12 and 20 μmoles of PEG) and pH (within 6.0-7.4) on nanoparticles were investigated. Having obtained the experimental size and zeta potential values, artficial neural networks were created to predict size and zeta potential values of different groups. Artificial neural networks is a modelling tool used in nanomedicine to optimize and predict inherent properties of the system. Inherent properties of a nanoparticle system such as size and zeta potential can be estimated based on previous experiment results. Namely, nanoparticles with desired properties can be synthesized using an ANN. We were able to estimate the size and zeta potential of nanoparticles under different experimental conditions. After that, we performed cell attachment experiments with different nanoparticle groups. Nanoparticle groups having higher zeta potentials had better adhesion ability to HEK293-T cells, which was estimated through ANN model prior to experiments. Overall, this chapter presents the PEGylation of chitosan, synthesis of PEGylated chitosan nanoparticles and the use of ANN model as a tool to predict important properties such as size and zeta potential. In the second part of the thesis, plasmid DNA loaded and tumor homing peptide (CREKA) modified stable chitosan nanoparticle carriers were synthesized for gene delivery applications. Peptide modification and DNA loading was confirmed with certain assays and these nanoparticles will be used for cancer therapy applications in the future. In the third part of the thesis, we propose a magnetically-actuated chitosan-based microrobotic system that can release the chemotherapeutic drug using external light stimulus. We fabricated the chitosan-based microswimmers by two-photon direct laser writing (TDLW) technique using of a photosensitive derivative of chitosan in the form of a magnetic polymer nanocomposite. Amino groups on the microswimmers were modified with doxorubicin using a photocleavable linker. Controlled moving ability of the microswimmers was shown under rotating magnetic field. 60% of doxorubicin was released from the microswimmers in 5 minutes with light stimulus at 365 nm wavelength and 30 mW laser output power. Enzymatic degradation of the microswimmers was shown in 204 hours. This part of the thesis presents the combination of light-triggered drug delivery with magnetically-powered microswimmer mobility. Overall, it was shown that chitosan-based carriers can be fabricated in various forms for different applications. Our results suggested that chitosan-based materials are promising for biomedical applications.
Fonksiyonel adacıkların bağışıklık atağından korunması için biyomimetik yaklaşımların geliştirilmesi
Type 1 diabetes (T1D) is a chronic autoimmune disease of pancreas, where insulin secretion function is lost due to destruction of insulin secreting β cells. People with T1D have high blood glucose levels, while their cells are deprived from glucose for their metabolic actions. Islets are "islands of β cells" and responsible for glucose metabolism in the body. Islet transplantation has transitioned from an experimental and occasionally-employed strategy to a routine clinical therapy for T1D in the past decade. Nevertheless, lifelong immunosuppression and the necessity of multiple transplantations limit wider application of this strategy. Islet immunoisolation techniques have emerged to eliminate immunosuppression permanently or to reduce immunosuppressive drug doses significantly. The concept of immunoisolation is to create a local secure microenvironment for islets to prevent graft rejection. Regulation of immune system can be done by several material-based and biologic strategies. While material-based strategies focus on preserving islets within semi-permeable membranes that allow nutrient exchange and block immune system components, biological strategies deal with regulation of immune system through chemokines and manipulation of immune cells. This thesis focuses on two of those strategies to create tolerable grafts and overcome islet graft rejection. We firstly engineered pseudoislets, or islet organoids, that are composed of insulin secreting β cells (β-TC-6) and hepatic stellate cells (HSCs). HSCs have the ability to secrete ECM proteins, angiogenesis factors and expand regulatory T cell (Treg) population in their vicinity. Tregs are crucial in modulating the immune system by suppressing and downregulating actions of effector T cells. A macrophage derived chemokine, CCL22, also has the ability to recruit Tregs and provide a local immunosuppression. We combined these two concepts and transfected Tregs with CCL22 gene. Then we prepared insulin-secreting multicellular organoids with β-TC-6 and CCL22-transfected HSCs. Implantation of these multicellular organoids to diabetic animal model resulted in more than 5-fold increase in Treg recruitment towards implantation site. This result suggested that tolerable grafts could be v fabricated through modulation of the immune system not only for islet therapy but also for other cell/organ transplantation therapies. To create another type of immunoisolation for islets, we also designed biocompatible hydrogels and formed ultra-thin coatings around islet organoids. Lipid group baring microgels were synthesized by water-in-water emulsion (W/W) followed by photopolymerization steps. We optimized microgel diameter by changing emulsion and photopolymerization parameters. The smallest microgel diameter (2,13 μm) was achieved at 60% ultrasonication power for 30 minutes. In W/W emulsion and photopolymerization steps, each reaction step was carried out in aqueous solutions at physiological pH values. We prepared β-TC-6 organoids by hanging drop method and deposited lipid-microgels on organoid surface via non-covalent hydrophobic interactions. Unlike covalent bonding, hydrophobic interactions between lipid functionalities in our microgels and phospholipid bilayer on cell membranes present no harm to cells. Hydrophobic interactions do not damage membrane proteins and perturb the integrity of the membrane. We studied the coating of microgels with two different lipid concentrations, 2.5 and 5 mM. Furthermore, we coated islet organoids with two different microgel concentrations, 10 and 20 mg/ml. We observed that coating efficiency was higher when lipid concentration was increased due to more hydrophobic interactions. We obtained high and similar metabolic activity and viability for microgel coated islet organoids compared to non-coated controls. Insulin secretion functionality was also preserved, meaning that our approach of immunoisolation allowed us to engineer functional insulin secreting organoids. Our findings suggest that biological and material-based immunotherapeutic strategies hold great potential for islet transplantation in T1D treatment.
Elektrikli araçlarda kullanılan lityum iyon akü paketleri için termal yönetim sistemi tasarımı
Lithium ion batteries are a normally used kind of rechargeable batteries as a result of their high specific energy and power. Expanding considerations have been paid to rechargeable Li-ion batteries with the developing popularity of electric vehicles and hybrid electric vehicle. However, safety problems, high cost, and poor performance in low ambient temperatures and high current rates are big obstacles for commercially utilization of these batteries. Most of the mentioned limitations could be eliminated by proper thermal management. Temperature profile of the Li-ion cells has noteworthy impacts on the performance, safety, and cycle life of the battery. That is the reason little temperature gradient can prompt incredible loss in the performance of battery packs. Lately, various analysts recommend new procedures to suggest a superior thermal management on Li-ion batteries. Keeping the battery cells in an optimum range is the primary goal of battery thermal management. In the first part of the study, a 3D model with new multilayer approach was developed to study the electrochemical-thermal behavior of the high capacity pouch type Lithium ion battery cells. In this approach, the 1D electrochemical module was coupled with the 3D thermal module using the COMSOL program which solves the differential equations numerically by finite element method (FEM). The developed Electrochemical-Thermal model was validated with the experimental measurements. The developed model was used to study the effects of multilayer structure and the number of electrodes on thermal behavior of the batteries for the first time in the literature. Then, the effects of cell dimensions and configuration were investigated on the temperature rise and nonuniformity of the battery cells. In the second part, an air-based and a water-based thermal management system were developed, and the cooling performance of them were optimized. As cooling system, aluminum plates with mini-channel system was designed to a single-cell and battery packs. Design parameters, for example, channel number and width, inlet flow rate, and cooling material were optimized. As cooling material, water- and air-cooling performances were compared. Pressure drop and velocity profiles inside the channels were illustrated. Both internal and external temperature profiles of a single cell and battery packs were investigated with and without cooling systems. In the last part, the optimized cooling systems were applied on the developed 4S1P battery modules. The needed inlet flow rates and power consumption values were calculated to keep the battery pack in an optimal operation temperature range (10-40 °C). The outcomes of this work showed that using upgraded mini-channel cooling plates adequately controls the temperature level and uniformity of the single cells and battery packs. With increasing the inlet flow rate, cooling efficiency can be as high as 60%.