| 1. |
- Johannesson, Jenny, 1990-
(author)
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3D printing of lipid-based formulations into personalized solid oral dosage forms
- 2023
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Doctoral thesis (other academic/artistic)abstract
- The pharmaceutical development process starts with patient populations and their unmet therapeutic needs. Traditional pharmaceutical manufacturing of solid oral dosage forms is based on the strategy of one-size-fits-all. This is problematic, especially for patient populations with high patient-to-patient variability, as in pediatrics. Historically, pharmaceutical development has focused on the adult population, neglecting the therapeutic needs unique to children. As a result, there is a lack of age-appropriate formulations—available in acceptable dosage forms and suitable dosage strengths—for safe and efficient drug therapies for children. To address this, additive manufacturing, more commonly known as three-dimensional (3D) printing, has emerged as a flexible manufacturing platform for production of dosage forms based on patient needs. Interest in 3D printing for pharmaceutical production has grown rapidly; however, to date the research has mainly focused on water-soluble drugs not in need of more advanced drug delivery systems to enable oral absorption. The overall aim of this thesis was therefore to develop lipid-based drug delivery strategies for poorly soluble drugs to be 3D printed into personalized solid oral dosage forms. In the first part, an observational study was performed at a pediatric oncology ward, together with analysis of the age-appropriateness of the oral medications. Administration through enteral feeding tubes was identified as the main reason for manipulation of the solid dosage forms. Furthermore, active pharmaceutical ingredients requiring age-appropriate, personalized dosage forms were identified. In the next part, emulsion gels from emulsified lipid-based formulations stabilized by surfactants (surfactant-stabilized emulsion gels) or solid particles (Pickering emulsion gel) were developed to incorporate a poorly water-soluble model compound. The rheological properties of the emulsion gels were investigated. The developed emulsion gels were successfully 3D printed into solid oral dosage forms by semi-solid extrusion (SSE). In the last part, central quality control attributes, including both the printable formulation and the 3D-printed tablets, were studied in the 3D-printing method developed for one of the emulsion gels. The SSE 3D-printed tablets complied with standardized uniformity tests for both mass and drug content and demonstrated high dose accuracy and short-term storage stability. To conclude, a method for SSE 3D printing of emulsion gels into lipid tablets was developed with promising potential for personalized dosing of lipophilic drugs in a clinical setting.
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| 2. |
- Åhlén, Michelle, 1992-
(author)
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Porous Sorbents for Environmental Applications and Selective Laser Sintering 3D Printing of Dosage Forms
- 2021
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Doctoral thesis (other academic/artistic)abstract
- The rising levels of greenhouse gas emissions from vehicular and industrial pollution constitute a serious concern not only for the environment but for our entire society. Traditional gas capture and separation techniques, such as amine scrubbing for CO2 gas separation, have been commonly used at a commercial scale, however issues relating to high costs and high energy requirements for sorbent regeneration have limited the efficiency of many of these techniques. The use of porous sorbents, such as metal-organic frameworks (MOFs), has garnered significant attention as an alternative method for the capture and separation of greenhouse gases in recent years, particularly due to their structural and functional tunability. Thus, part of this thesis explores the selective capture of CO2 and SF6 in five new MOFs and mixed-linker zeolitic imidazolate frameworks (ZIFs). The CO2 and SF6 adsorption in microporous bismuth-based MOFs containing narrow ultramicro-pores (e.g. UU-200) was not found to be correlated to the N2-accessible surface area of the framework but was related to pore size effects and possibly framework flexibility. Similar mechanisms for SF6 capture were observed in vanadium- and gallium-based MOFs (UU-201-4) in which an enhanced van der Waals interaction between the gas molecules and the pore surface was obtained due to the pore size of the materials coinciding with the kinetic diameter of SF6 (5.5 Å). This further resulted in good uptake capacities as well as SF6-over-N2 selectivites above 2.75 mmol g-1 and 43, respectively. Furthermore, the selective uptake of CO2 and SF6 could be modified in mixed-linker ZIF-7-8s by tuning of the pore aperture size through a controlled incorporation of the bulkier benzimidazolate linker in the frameworks.The removal of other environmental pollutants (e.g. phosphates) in porous materials such as amorphous mesoporous magnesium carbonate (MMC) was also investigated and showed that the material had superior sorption capacities as compared to its crystalline, non-porous counterpart. MMC was also found to be a capable functional support for other materials such as semiconducting TiO2 and ZnO nanoparticles. The TiO2/ZnO-composite was observed to retain the porosity as well as UV-blocking properties of the respective pristine materials.A part of this thesis was also devoted to the fabrication of personalized solid dosage forms for pharmaceutical applications. To achieve this, 3-dimensional selective laser sintering (SLS) printing was utilized to print both purely polymeric and drug-loaded tablets (containing 10 wt.% naproxen). The subsequent weight and mechanical strength of the obtained tablets could be tuned by either modifying the NIR-active pigment concentration in the powder formulation or by changing the laser energy input that is used during the printing process. Amorphization of the crystalline drug was also achieved in-situ during printing thus showing that the SLS 3D printing may be a promising technique for the manufacturing of solid amorphous dispersions with tailorable properties.
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| 3. |
- Carlsson, Daniel O
(author)
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Structural and Electrochemical Properties of Functionalized Nanocellulose Materials and Their Biocompatibility
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Nanocellulose has received considerable interest during the last decade because it is renewable and biodegradable, and has excellent mechanical properties, nanoscale dimensions and wide functionalization possibilities. It is considered to be a unique and versatile platform on which new functional materials can be based.This thesis focuses on nanocellulose from wood (NFC) and from Cladophora algae (CNC), functionalized with surface charges or coated with the conducting polymer polypyrrole (PPy), aiming to study the influence of synthesis processes on structural and electrochemical properties of such materials and assess their biocompatibility.The most important results of the work demonstrated that 1) CNC was oxidized to the same extent using electrochemical TEMPO-mediated oxidation as with conventional TEMPO processes, which may facilitate easier reuse of the reaction medium; 2) NFC and CNC films with or without surface charges were non-cytotoxic as assessed by indirect in vitro testing. Anionic TEMPO-CNC films promoted fibroblast adhesion and proliferation in direct in vitro cytocompatibility testing, possibly due to its aligned fibril structure; 3) Rinsing of PPy-coated nanocellulose fibrils, which after drying into free-standing porous composites are applicable for energy storage and electrochemically controlled ion extraction, significantly degraded the PPy coating, unless acidic rinsing was employed. Only minor degradation was observed during long-term ambient storage; 4) Variations in the drying method as well as type and amount of nanocellulose offered ways of tailoring the porosities of nanocellulose/PPy composites between 30% and 98%, with increments of ~10%. Supercritical CO2-drying generated composites with the largest specific surface area yet reported for nanocellulose/conducting polymer composites (246 m2/g). The electrochemical oxidation rate was found to be controlled by the composite porosity; 5) In blood compatibility assessments for potential hemodialysis applications, heparinization of CNC/PPy composites was required to obtain thrombogenic properties comparable to commercial hemodialysis membranes. The pro-inflammatory characteristics of non-heparinized and heparinized composites were, to some extent, superior to commercial membranes. The heparin coating did not affect the solute extraction capacity of the composite.The presented results are deemed to be useful for tuning the properties of systems based on the studied materials in e.g. energy storage, ion exchange and biomaterial applications.
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| 4. |
- Sterby, Mia, 1989-
(author)
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Electrochemical Characterizations of Conducting Redox Polymers : Electron Transport in PEDOT/Quinone Systems
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Organic electrode materials for rechargeable batteries have caught increasing attention since they can be used in new innovative applications such as flexible electronics and smart fabrics. They can provide safer and more environmentally friendly devices than traditional batteries made from metals. Conducting polymers constitute an interesting class of organic electrode materials that have been thoroughly studied for battery applications. They have high conductivity but are heavy relative to their energy storage ability and will hence form batteries with low weight capacity. Quinones, on the other hand, are low weight molecules that participate in electron transport in both animals and plants. They could provide batteries with high capacity but are easily dissolved in the electrolyte and have low conductivity. These two constituents can be combined into a conducting redox polymer that has both high conductivity and high capacity. In the present work, the conducting polymer PEDOT and the simplest quinone, benzoquinone, are covalently attached and form the conducting redox polymer used for most studies in this thesis. The charge transport mechanism is investigated by in situ conductivity measurements and is found to mainly be governed by band transport. Other properties such as packing, kinetics, mass changes, and spectral changes are also studied. A polymerization technique is also analyzed, that allows for polymerization from a deposited layer. Lastly, two different types of batteries using conducting redox polymers are constructed. The thesis gives insight into the fundamental properties of conducting redox polymers and paves the way for the future of organic electronics.
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| 5. |
- Tammela, Petter, 1986-
(author)
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On the electrochemical performance of energy storage devices composed of cellulose and conducting polymers
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Applications that require electrical energy storage are becoming increasingly diverse. This development is caused by a number of factors, such as an increasing global energy demand, the advent of electric vehicles, the utilization of intermittent renewable energy sources, and advances in disposable and organic electronics. These applications will set different demands on their electrical energy storage and, thus, there will be no single technology used for all applications. For some applications the choice of energy storage materials will be extremely important. Conventional batteries and supercapacitors rely on the use of nonrenewable inorganic materials mined from depleting ores, hence, requiring large amounts of energy for their processing. Such materials also add a significant cost to the final product, making them less attractive for large scale applications. Conducting polymers, on the other hand, constitute a class of materials that can be used for organic matter based energy storage devices.The aim of this thesis was to investigate the use of a composite consisting of the conducting polymer polypyrrole (PPy) and cellulose derived from Cladophora sp. algae for electrical energy storage. The polymer was coated onto the cellulose fibers by chemical polymerization resulting in a flexible material with high surface area. By using this composite as electrodes, electrochemical cells consisting of disposable and non-toxic materials can be assembled and used as energy storage devices. The resistances of these prototype cells were found to be dominated by the resistance of the current collectors and to scale with the thickness of the separator, and can hence be reduced by cell design. By addition of nanostructured PPy, the weight ratio of PPy in the composite could be increased, and the cell voltages could be enhanced by using a carbonized negative electrode. Composites of cellulose and poly(3,4-ethylenedioxythiophene) could also be synthesized and used as electrode materials. The porosities of the electrodes were controlled by mechanical compression of the composite or by coating of surface modified cellulose fibers with additional PPy. Finally, the self-discharge was studied extensively. It was found that oxygen was responsible for the oxidation of the negative electrode, while the rate of self-discharge of the positive electrode increases with increasing potential. Through measurements of the charge prior to and after self-discharge, as well as with an electrochemical quartz crystal microbalance, it was found that the self-discharge of the positive electrode was linked to an exchange of the counter ions by hydroxide ions. It is also demonstrated that the self-discharge rate of a symmetric PPy based device can be decreased dramatically by proper balancing of the electrode capacities and by reducing the oxygen concentration. The results of this work are expected to contribute towards future industrial implementation of electric energy storage devices based on organic materials.
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| 6. |
- Tikhomirov, Evgenii
(author)
-
Selective laser sintering for 3D printing of medications
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Suboptimal treatment caused by inaccurate dosing of prescribed medications is a challenging issue for the pharmaceutical industry. As a result, certain groups of patients, especially pediatric patients, may suffer from a lack of specific dosage forms, leading to potential side effects. To address this issue, various manipulation techniques are being applied, such as tablet crushing, splitting, and solution preparations. Unfortunately, these methods lack accuracy and economic efficiency.3D printing technology has been considered one of the potential solutions for manufacturing limited batch dosage forms. Dosage forms produced through 3D printing can be fabricated on demand for specific patients. Furthermore, the unique properties of these dosage forms, such as API amorphization, can be adjusted due to the high tunability of the 3D printing process. The work conducted in this thesis is dedicated to investigating the potential applications of Selective Laser Sintering (SLS) and the associated aspects of this method for manufacturing solid dosage forms.The investigations into printing parameters and formulation content enabled the establishment of correlations between these factors and the properties of the final dosage forms. Higher print temperature, Laser Power Ratio, and colorant concentration led to increased mass and hardness of the dosage forms.The polymer constitutes the major portion of the formulation in terms of mass. Consequently, various grades of polymer were examined to ascertain their chemical influence on the properties of the dosage forms. The findings revealed that the type of polymer, degree of hydrolysis, and dynamic viscosity of the polymer significantly impact both the dissolution rate and API amorphization.Utilizing FDM for printing the shell component of the drug delivery device improved its durability, whereas the SLS-printed insert resulted in a faster and adjustable dissolution rate. This experiment showcased the potential of combining the advantages of each technique to produce dosage forms with additional features.A thermal image analysis device was developed and employed to monitor temperature conditions throughout the printing process. The outcomes demonstrated that the collected data could be utilized for in-process quality control objectives and serve as a dataset for machine learning algorithms. This capability allows for real-time process monitoring, defect detection, and automated process refinement.In conclusion, a comprehensive study was conducted on the application of SLS and its limitations. This study will hopefully pave the way for further discussions and the implementation of this technology.
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| 7. |
- Alvebratt, Caroline
(author)
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Advanced Methods for Evaluation of the Performance of Complex Drug Delivery System
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Low oral bioavailability of drugs originating from poor aqueous solubility is a common issue in drug development. Various enabling formulations have been presented to circumvent this limitation, many making use of supersaturation. In these, the drug is delivered to the gastro-intestinal lumen in a high energy state e.g. in amorphous form or a liquid lipid vehicle. Concentrations surpassing the equilibrium solubility of the crystalline drug are achieved, which facilitate increased absorption for dissolution-rate limited compounds. Meanwhile the use of the enabling formulation can be beneficial to increase the bioavailability of poorly water-soluble drugs, in vitro evaluation of these systems remain challenging. Limited methods have also evaluated several different types of enabling formulation in the same experimental setup. The overall aim of this thesis was therefore to develop assays to study the performance of various complex drug delivery systems. In the first part, a small scale dissolution apparatus, the µDiss Profiler, was used to study drug release from drug-loaded mesoporous magnesium carbonate (MMC). A protective filter was developed to minimize particle interference on the UV-measurements, enabling studies of supersaturation from the amorphous carrier. In the second paper, lipids were adsorbed onto the MMC. A modified in vitro lipolysis setup was established and the samples were analyzed with nuclear magnetic resonance spectroscopy. A stability study of the lipid-loaded MMC was also performed. The methods developed in the first two projects provided an insight to events occurring in the intestinal lumen. The intestinal absorption has however been shown to be a complex interplay between dissolution-digestion and permeation. In the final two projects, two devices comprising of a donor (luminal) chamber and a receiver (serosal) chamber were studied (the µFLUX and the enabling absorption, ENA, device). The two chambers were separated by a semipermeable membrane (cell-based and/or phospholipid-based). A wide range of enabling formulations were evaluated in the two assays. As the exposure in the donor correlated poorly with the exposure in the receiver compartment, this emphasizes the importance of in vitro methods taking both the dissolution-digestion and permeation into account. The ENA results also predicted the in vivo performance in rats well. To conclude, several models have been established in the thesis to study the in vitro performance of enabling formulations, which will be valuable for screening of appropriate drug delivery systems.
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| 8. |
- Kong, Xueying, 1993-
(author)
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Porous Materials and Their Cellulose-Based Composites : Synthesis, Nanoengineering, and Applications
- 2024
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Doctoral thesis (other academic/artistic)abstract
- Porous materials, such as porous carbons (PCs), metal-organic frameworks (MOFs), and covalent organic frameworks (COFs), show considerable potential across various fields because of their rich microporous and mesoporous structures and large surface areas, yet they grapple with challenges like environmentally unfriendly fabrication methods and poor processability. In this thesis, we investigated environmentally friendly fabrication methods for porous materials, nanoengineering techniques for processing these materials, and their potential applications.Cladophora cellulose (CC), a naturally abundant biopolymer, was used to prepare PC via a one-step physical carbonization/activation method without using any corrosive activation agents. The obtained CC-derived PC (CPC) showed a high specific surface area (507.2 m2 g−1) and rich microporous structure. Additionally, we introduced a simple and environmentally friendly method for synthesizing imine-linked COFs at room temperature using water as the solvent. The method involves a key step in which aldehyde monomers are pre-activated by acetic acid, which promotes the aldehyde monomers to dissolve in water, enhancing their reactivity with amine monomers, and ensuring the formation of crystalline COFs. Consequently, we synthesized 16 distinct imine-linked COFs with high crystallinity and specific surface areas. Furthermore, this thesis focusses on improving the poor processability of these materials caused by the infusible and insoluble nature of their powders. The poor processability of these porous materials makes them difficult to process into desired structures and shapes. Here, we introduce two nanoengineering methods: i) Interweaving porous materials with CC nanofibers (CNFs) to form CNF-porous material aqueous solutions; and ii) Interfacial synthesis of porous materials on the surface of carboxylated CNFs to form CNF@porous materials with nanofiber structures in aqueous solutions. The obtained composite suspensions can be fabricated into freestanding and flexible composite nanopapers via a vacuum filtration and drying process. In addition, they can be processed into freestanding aerogels through a freeze-drying process. Consequently, we have successfully prepared freestanding and flexible CC-CPC nanopapers and CC-CPC aerogels, c-CNT@COF/CNT/CNF nanopapers (c-CNT: carboxylated carbon nanotube), CNF@MOF nanopapers, and CNF@COF nanopapers and demonstrated their potential in various applications, from efficient CO2 capture and organic pollutant removal to advanced energy storage and solar vapor generation. In summary, we used environmentally friendly methods to synthesize PC and imine-linked COFs, circumventing the need for corrosive chemical agents and toxic organic solvents, respectively. Furthermore, by combining CNFs with porous materials, we successfully created freestanding and flexible nanopapers and aerogels, thereby addressing the issue of poor processability associated with porous materials.
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| 9. |
- Nyström, Gustav
(author)
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Nanocellulose and Polypyrrole Composites for Electrical Energy Storage
- 2012
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Doctoral thesis (other academic/artistic)abstract
- To meet the predicted increase in demand for energy storage in tomorrow's society, the development of inexpensive, flexible, lightweight and sustainable energy-storage materials is essential. In this respect, devices based on electroactive organic molecules, such as conducting polymers, are highly interesting. The aim of this thesis was to evaluate the use of nanocellulose as a matrix material in composites of cellulose and the electroactive polymer polypyrrole (PPy), and the use of these composites in all-polymer paper-based energy-storage devices. Pyrrole was polymerized using FeCl3 onto cellulose nanofibers in the form of a hydrogel. The resulting PPy-coated fibers were washed with water and dried into a high surface area, conductive paper material. Variations in the drying technique provided a way of controlling the porosity and the surface area of wood-based cellulose nanofibers, as the properties of the cellulose were found to have a large influence on the composite structure. Different nanocellulose fibers, of algal and wood origin, were evaluated as the reinforcing phase in the conductive composites. These materials had conductivities of 1–6 S/cm and specific surface areas of up to 246 m2/g at PPy weight fractions around 67%. Symmetrical supercapacitor devices with algae-based nanocellulose-PPy electrodes and an aqueous electrolyte showed specific charge capacities of around 15 mAh/g and specific capacitances of around 35 F/g, normalized with respect to the dry electrode weight. Potentiostatic charging of the devices was suggested as a way to make use of the rapid oxidation and reduction processes in these materials, thus minimizing the charging time and the effect of the IR drop in the device, and ensuring charging to the right potential. Repeated charging and discharging of the devices revealed a 10–20% loss in capacity over 10 000 cycles. Upon up-scaling of the devices, it was found that an improved cell design giving a lower cell resistance was needed in order to maintain high charge and discharge rates. The main advantages of the presented concept of nanocellulose-PPy-based electrical energy storage include the eco-friendly raw materials, an up-scalable and potentially cost-effective production process, safe operation, and the controllable porosity and moldability offered by the nanocellulose fiber matrix. Integrating energy storage devices into paper could lead to un- precedented opportunities for new types of consumer electronics. Future research efforts should be directed at increasing the energy density and improving the stability of this type of device as well as advancing the fundamental understanding of the current limitations of these properties.
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| 10. |
- Strömberg, Mattias, 1980-
(author)
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Molecular Diagnostics Using Volume-Amplified Magnetic Nanobeads : Towards the Development of a Novel Biosensor System
- 2009
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Doctoral thesis (other academic/artistic)abstract
- Micro- or nanometer sized magnetic particles (beads) currently have a vast range of life science applications in, for example, bioseparation techniques, cancer therapy, development of contrast agents and biosensing techniques. In the latter field, magnetic beads offer several unique advantages, including minimal background signals, physical and chemical stability and low manufacturing costs. Because of these properties, magnetic biosensing techniques are potential candidates for low-cost, easy-to-use molecular diagnostic devices. This doctoral thesis focuses mainly on the proof of principle and further development of a new magnetic biosensor platform for detection of DNA targets, a potential candidate for a new generation of low-cost, easy-to-use diagnostic devices: the Volume-Amplified Magnetic Nanobead Detection Assay (VAM-NDA). The VAM-NDA principle combines target recognition by padlock probe ligation followed by rolling circle amplification (RCA) of the reacted probes with changes in Brownian relaxation behaviour of magnetic nanobeads (typically ~100 nm in diameter) induced by a change in hydrodynamic bead volume. More specifically, the RCA products (coils, typically ~1 μm in diameter) are detected magnetically by adding magnetic beads tagged with detection probes complementary to part of the repeating RCA-coil sequence. Thus, depending on the target concentration, a certain quantity of beads binds to the coils by base-pair hybridisation (bead immobilisation), resulting in a dramatic bead volume increase, which is then detected by measuring the complex magnetisation spectrum. Use of a commercial SQUID magnetometer for measuring complex magnetisation resulted in a detection limit in the low pM range for DNA targets with excellent quantification accuracy. Simultaneous multiplexing was also evaluated. The stability and aging of typical commercial ferrofluids (suspensions of magnetic beads) were investigated by measuring the complex magnetisation of and interbead interactions in oligonucleotide-functionalised ferrofluids. In summary, the bead surface characteristics were found to have a strong impact on the measured dynamic magnetic properties.
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