Karin Schroën

Oil-filled polymer microcapsules for ultrasound-mediated delivery of lipophilic drugs

The use of ultrasound contrast agents as local drug delivery systems continues to grow. Current limitations are the amount of drug that can be incorporated as well as the efficiency of drug release upon insonification. This study focuses on the synthesis and characterisation of novel polymeric microcapsules for ultrasound-triggered delivery of lipophilic drugs. Microcapsules with a shell of fluorinated end-capped poly(L-lactic acid) were made through pre-mix membrane emulsification and contained, apart from a gaseous phase, different amounts of hexadecane oil as a drug-carrier reservoir. Mean number weighted diameters were between 1.22 microm and 1.31 microm. High-speed imaging at approximately 10 million fames per second showed that for low acoustic pressures (1 MHz, 0.24 MPa) microcapsules compressed but remained intact. At higher diagnostic pressures of 0.51 MPa, microcapsules cracked, thereby releasing the encapsulated gas and model lipophilic drug. Using conventional ultrasound B-mode imaging at a frequency of 2.5 MHz, a marked enhancement of scatter intensity over a tissue-mimicking phantom was observed for all differently loaded microcapsules. The partially oil-filled microcapsules with high drug loads and well-defined acoustic activation thresholds have great potential for ultrasound-triggered local delivery of lipophilic drugs under ultrasound image-guidance.

Pickering Emulsions for Food Applications: Background, Trends, and Challenges

Particle-stabilized emulsions, also referred to as Pickering emulsions, have garnered exponentially increasing interest in recent years. This has also led to the first food applications, although the number of related publications is still rather low. The involved stabilization mechanisms are fundamentally different as compared to conventional emulsifiers, which can be an asset in terms of emulsion stability. Even though most of the research on Pickering emulsions has been conducted on model systems, with inorganic solid particles, recent progress has been made on the utilization of food-grade or food-compatible organic particles for this purpose. This review reports the latest advances in that respect, including technical challenges, and discusses the potential benefits and drawbacks of using Pickering emulsions for food applications, as an alternative to conventional emulsifier-based systems.

Covalently Attached Organic Monolayers on SiC and SixN4 Surfaces: Formation Using UV Light at Room Temperature

We describe the formation of alkyl monolayers on silicon carbide (SiC) and silicon-rich silicon nitride (SixN4) surfaces, using UV irradiation in the presence of alkenes. Both the surface preparation and the monolayer attachment were carried out under ambient conditions. The stable coatings obtained in this way were studied by water contact angle measurements, infrared reflection absorption spectroscopy, X-ray reflectivity, and X-ray photoelectron spectroscopy. Besides unfunctionalized 1-alkenes, methyl undec-10-enoate, and 2,2,2-trifluoroethyl undec-10-enoate were also grafted onto both substrates. The resulting ester-terminated surfaces could then be further reacted after hydrolysis using amide chemistry to easily allow the attachment of amine-containing compounds.

Covalent Attachment of Organic Monolayers to Silicon Carbide Surfaces

This work presents the first alkyl monolayers covalently bound on HF-treated silicon carbide surfaces (SiC) through thermal reaction with 1-alkenes. Treatment of SiC with diluted aqueous HF solutions removes the native oxide layer (SiO2) and provides a reactive hydroxyl-covered surface. Very hydrophobic methyl-terminated surfaces (water contact angle theta = 107 degrees ) are obtained on flat SiC, whereas attachment of omega-functionalized 1-alkenes also yields well-defined functionalized surfaces. Infrared reflection absorption spectroscopy, ellipsometry, and X-ray photoelectron spectroscopy measurements are used to characterize the monolayers and show their covalent attachment. The resulting surfaces are shown to be extremely stable under harsh acidic conditions (e.g., no change in theta after 4 h in 2 M HCl at 90 degrees C), while their stability in alkaline conditions (pH = 11, 60 degrees C) also supersedes that of analogous monolayers such as those on Au, Si, and SiO2. These results are very promising for applications involving functionalized silicon carbide.

Characterization of emulsification at flat microchannel Y junctions

Y junctions with a large width-to-depth ratio were used for the emulsification of hexadecane in various ethanol-water mixtures with different static interfacial tension and viscosity. The resulting droplets were monodisperse. To describe droplet size a force-balance model was derived and was found to apply well. The model shows that the droplet size scales with the channel depth, and with the square root of the inverse capillary number (Ca-1/2) based on the continuous phase, the disperse-phase flow rate was found to be unimportant.

Parallelized edge-based droplet generation (EDGE) devices.

We here report on three parallelized designs of the new edge-based droplet generation mechanism, which, unlike existing mechanisms, produces many equally sized droplets simultaneously at a single droplet formation unit. Operation of the scaled-out systems is straight forward; only the oil inlet pressure has to be controlled to let all the units produce oil droplets, given certain basic design constraints. For systems with a typical nozzle depth of 1.2 microm, the mean droplet diameter is 7.5 microm and the coefficient of variation is below 10%. The number of droplets that is formed per unit can easily be increased by increasing the length of the unit. The stable pressure range in which monodisperse droplets are formed can be extended by small adjustments to the design. Overall, the EDGE devices are simple in design and robust in use, making them suitable for massive outscaling.

Dynamic interfacial tension measurements with microfluidic Y-junctions.

Emulsification in microdevices (microfluidic emulsification) involves micrometer-sized droplets and fast interface expansion rates. In addition, droplets are formed in less than milliseconds, and therefore traditional tensiometric techniques cannot be used to quantify the actual interfacial tension. In this paper, monodisperse droplets formed at flat microfluidic Y-junctions were used to quantify the apparent dynamic interfacial tension during (microfluidic) emulsification. Hexadecane droplets were formed in ethanol-water solutions with a range of static interfacial tensions to derive a calibration curve, which was subsequently used to access the dynamic interfacial tension of hexadecane droplets formed in surfactant solutions. For SDS and Synperonic PEF108, various continuous- and disperse-phase (hexadecane) flow rates were studied, and these conditions were linked to interfacial tension effects, which also allowed convective transport of surfactants to be investiagted. On the basis of these findings, various strategies for the formation of emulsion droplets can be followed and are discussed.

The mechanism of droplet formation in microfluidic EDGE systems

Edge-based droplet generation (EDGE) emulsification, which produces multiple, monodispersed droplets simultaneously at one droplet forming unit (introduced recently by our group), is studied in more detail with high-speed imaging, computational fluid dynamics and geometric modeling as research tools. Complete filling of the plateau, essential for multiple droplet generation, is caused by the difference in pressure needed to invade the plateau and the pressure necessary to start droplet formation. In addition, the droplet formation unit has the highest hydrodynamic flow resistance in the system, which ensures oil supply and promotes plateau filling. The locations at which droplets are formed were found to be very evenly spaced with about 25 times the plateau height between them. CFD simulations showed that there is a scaling relation with the viscosity ratio, similar to that of microchannel systems. At high viscosity ratios, a minimal droplet diameter is found, which is typically 5.5–6.5 times the plateau height and can be estimated from geometric considerations only.

Mechanical Characterization and pH Response of Fibril-Reinforced Microcapsules Prepared by Layer-by-Layer Adsorption

Despite the fair number of microencapsulation principles that have been developed, the actual protection and targeted delivery of sensitive ingredients remains a challenge in the food industry. A suitable technique should use food-grade and inexpensive materials, and ensure tight control over the capsule size and release trigger mechanism. For example, encapsulates may need to survive the low pH of the stomach to release their contents in the neutral environment of the small intestine. In this work we present layer-by-layer (LbL) microcapsules assembled from whey protein isolate (WPI), high-methoxyl pectin (HMP) and WPI-fibrils. The narrow size distribution of these capsules is determined by the oil-in-water droplets used as templates, and their mechanical properties and pH response can be tuned by the number of layers adsorbed. Capsules with more than eight layers have a mechanical strength comparable to chemically cross-linked polymer capsules, because of the reinforcement by the WPI-fibrils in combination with the shell completion. Typically, capsules with five layers survive pH 2 for more than 2 h, but dissolve within 30 min at pH 7. At higher number of layers, the capsules are even more stable. Contrary to other encapsulates, these capsules can be dried and are suitable for application in dry products.

Membrane-facilitated bioproduction of 3-methylcatechol in an octanol/water two-phase system.

Bioproduction of 3-methylcatechol from toluene by Pseudomonas putida MC2 was studied in the presence of an additional 1-octanol phase. This solvent was used to supply the substrate and extract the product, in order to keep the aqueous concentrations low. A hollow-fibre membrane kept the octanol and aqueous phase separated to prevent phase toxicity towards the bacterium. Volumetric production rates increased approximately 40% as compared to two-phase 3-methylcatechol production with direct phase contact. Preliminary investigations on downstream processing of 3-methylcatechol showed that 1 M of sodium hydroxide selectively extracted the disodium salt of 3-methylcatechol into an aqueous phase.