Insights into infusion-based targeted drug delivery in brain: perspectives, challenges and opportunities

Targeted drug delivery in the brain is instrumental in the treatment of lethal brain diseases, such as glioblastoma multiforme, the most aggressive primary central nervous system tumour in adults. Infusion-based drug delivery techniques, which directly administer to the tissue for local treatment, as in convection-enhanced delivery (CED), provide an important opportunity; however, poor understanding of the pressure-driven drug transport mechanisms in the brain has hindered its ultimate success in clinical applications. In this review, we focus on the biomechanical and biochemical aspects of infusion-based targeted drug delivery in the brain and look into the underlying molecular level mechanisms. We discuss recent advances and challenges in the complementary field of medical robotics and its use in targeted drug delivery in the brain. A critical overview of current research in these areas and their clinical implications is provided. This review delivers new ideas and perspectives for further studies of targeted drug delivery in the brain

Cell Sorting in Deterministic Lateral Displacement Devices

The ability to sort cells is extremely desirable in many fields such as diagnostics, chemical processing, and biological analyses. Label-free sorting schemes in microfluidic devices represent a promising alternative to the fluorescence and immunomagnetic activated cell sorting methods which are current industry standards; permitting reduced costs, simpler operation, and increased portability. Furthermore, passive label-free sorting schemes such as deterministic lateral displacement (DLD) devices pose further advantages; for instance, sorting cells in accordance with their physical properties with no need for the application of external fields, magnetic beads, or fluorescent labels. Many of the cells and particles which require sorting are non-spherical and deformable, however the majority of theory for predicting particle behaviour in Deterministic Lateral Displacement (DLD) devices is only applicable to the limited case of rigid spheres in circular post arrays. The concept behind the separation mechanism for rigid spheres relies upon the assumption that DLD device geometry uniquely determines the fluid flow field, which subsequently defines a critical particle size and the lateral separation of particles of different sizes. Whilst the developed theories are exceedingly successful for designing devices for separating rigid beads, they are restricted to sorting particles by size, a characteristic which is ill-defined for non-spherical deformable particles in flow. Furthermore, this design approach squanders the full potential of DLD, which could utilise alternative particle characteristics such as elasticity and dynamic behaviour as the bases for separation of non-spherical deformable particles. This work uses a combination of mesoscale hydrodynamic simulations and microfluidics experiments to demonstrate how cells’ mechanical and dynamic properties can be used as separation criteria within different DLD device geometries. Two mesoscopic particle-based methods are employed in simulations to represent fluid; the dissipative particle dynamic (DPD) technique and the smoothed dissipative particle dynamic method (SDPD). Additionally, two-dimensional(2D) mesoscopic models of rigid beads and red blood cells (RBC) are employed to investigate particle motion in DLD devices in a qualitative manner, and a three-dimensional (3D) model of Red Blood Cell (RBC)s is used to obtain a more precise quantitative picture. RBCs are chosen because they represent a ubiquitous non-spherical deformable particle, and sorting based on their mechanical properties in DLD devices would aid in diagnosis of lethal diseases such as malaria. The 2D simulation results show that a critical particle size can be well defined for rigid spherical particles in circular post arrays depending on the inter-post spacing, the row-shift fraction, and the corresponding flow field; in quantitative agreement with current empirical findings and theory. Additional 2D simulations allow the empirical equation for the critical size of rigid spherical particles in circular post arrays to be generalized and extended for diamond, square and triangular post arrays. In contrast, 2D simulation results demonstrate that RBCs exhibit far more complex dynamics within DLD post arrays than rigid spheres, and the particle motion cannot be predicted by a single parameter such as the critical size. Instead, the dynamic behaviour and deformation of the RBC are found to strongly influence transit behaviour through DLD devices, providing the potential for novel sorting schemes. The 2D work motivates the further study of RBC behaviour in DLD devices using 3D simulations and supplementary experiments to gain a more quantitative understanding of the underlying physical mechanisms at play. 3D simulations and microfluidic experiments achieve excellent quantitative agreement and reveal that RBCs can travel in transit modes which are inaccessible to rigid spheres due to the complex interplay between hydrodynamic interactions with posts, RBC deformations, and RBC dynamic behaviour. The dynamic behaviour of RBCs is investigated by confining cells within flow channels of different heights and by altering the ratio between the intra-cellular fluid and the suspending medium. Thin devices inhibit the dynamic behaviour of RBCs, resulting in trajectories which are more like those of rigid spheres, however deformation still plays a key distinctive role. Thick devices which allow full re-orientation of RBCs and different dynamic behaviours are observed at different viscosity contrasts: At physiological viscosity contrasts RBC s are found to move in a tumbling motion and, under conditions where the intra- and extra- cellular fluid are equal, RBCs are found to favour tank-treading behaviour. Each of these distinct dynamic behaviours result in dramatically different RBC trajectories through DLD post arrays, demonstrating how non-spherical deformable particles can be sorted according to characteristics other than size, such as membrane shear modulus, membrane bending rigidity, or internal viscosity. Finally, 3D simulations are used to demonstrate a potential DLD device design for deformability-based sorting of RBCs; achieving good lateral separation between healthy RBCs and RBCs with pathological values for their shear modulus

NUMERICAL AND EXPERIMENTAL STUDY OF EQUILIBRIUM SWELLING OF STIMULI RESPONSIVE COMPOSITE HYDROGELS

Ph.DDOCTOR OF PHILOSOPH

Book of Abstracts 15th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering and 3rd Conference on Imaging and Visualization

In this edition, the two events will run together as a single conference, highlighting the strong connection with the Taylor & Francis journals: Computer Methods in Biomechanics and Biomedical Engineering (John Middleton and Christopher Jacobs, Eds.) and Computer Methods in Biomechanics and Biomedical Engineering: Imaging and Visualization (JoãoManuel R.S. Tavares, Ed.). The conference has become a major international meeting on computational biomechanics, imaging andvisualization. In this edition, the main program includes 212 presentations. In addition, sixteen renowned researchers will give plenary keynotes, addressing current challenges in computational biomechanics and biomedical imaging. In Lisbon, for the first time, a session dedicated to award the winner of the Best Paper in CMBBE Journal will take place. We believe that CMBBE2018 will have a strong impact on the development of computational biomechanics and biomedical imaging and visualization, identifying emerging areas of research and promoting the collaboration and networking between participants. This impact is evidenced through the well-known research groups, commercial companies and scientific organizations, who continue to support and sponsor the CMBBE meeting series. In fact, the conference is enriched with five workshops on specific scientific topics and commercial software.info:eu-repo/semantics/draf

Physical processes in polymeric filters used for dialysis

The key physical processes in polymeric filters used for the blood purification include transport across the capillary wall and the interaction of blood cells with the polymer membrane surface. Theoretical modeling of membrane transport is an important tool which provides researchers with a quantification of the complex phenomena involved in dialysis. In the paper, we present a dense review of the most successful theoretical approaches to the description of transport across the polymeric membrane wall as well as the cell-polymer surface interaction, and refer to the corresponding experimental methods while studying these phenomena in dialyzing filters

NOVEL ELECTROACTIVE SOFT ACTUATORS BASED ON IONIC GEL/GOLD NANOCOMPOSITES PRODUCED BY SUPERSONIC CLUSTER BEAM IMPLANTATION

Ionic electro-active polymers (IEAPs) constitute a promising solution for developing self-regulating, flexible and adaptive mechanical actuators in the area of soft robotics, micromanipulation and rehabilitation. These smart materials have the ability to undergo large bending deformations as a function of a low applied voltage (1 to 5 V), as a result of the ions migration through their inner structure when the network is liquid filled. Among this broad family of materials, ionic-polymer-metal composites (IPMC) based on DuPont\u2019s Nafion\uae have attracted an increasing interest for the production of light weight controllable soft machines due to their easiness to be metalized (e.g. by mean of electroless plating), fast response and capability of working exposed to air. However, the high cost of the material, its relatively low working density (i.e. the maximum mechanical work output per unit volume of active material that drives the actuation) and weak force output, as well as the considerable fatigue effects endured by the surface electrodes upon cycling, is limiting the performance of these IPMC actuators and hindering their implementation in traditional mechatronic and robotic systems. On the other hand, ionic hydrogels, such as poly(acrylic acid) (PAA) and poly-styrene sulfonate (PSS) based polymers, exhibit controllable mechanical properties and porosity and have shown to be excellent candidates to be used as electrically triggered artificial muscles and miniaturized robots operating in aqueous environments. Although the relatively low cost of these materials render them appealing for mass production scale up, the applicability of these polymeric actuators is limited to a liquid environment, which is intrinsically facilitating the solvent evaporation when the hydrogels are exposed to air. Furthermore, because of the difficulty encountered in fabricating stable and anchored metal structures on these polymer surfaces, these smart soft systems operate in a non-contact configuration with respect to the pilot electrodes, therefore increasing the actuators response time up to few tenths of seconds. In order to achieve an efficient electromechanical transduction along with a stable and durable performance for electro-active actuators operating in air, two main interplaying characteristics must be tailored when designing the system. On one hand side, the need of electrodes that are physically interpenetrating with the polymeric basis is of absolute priority, since the intercalation of ions into the electrode layers and the resulting material volumetric change are fundamental for strain generation. On the other hand, the formulation and engineering of new low cost materials able to merge highly elastic properties and efficient ionic transport features is of crucial importance. The present thesis work deals with the formulation, synthesis and manufacturing of a novel ionic gel/metal nanocomposite (IGMN) that was designed and developed to merge the advantageous properties of both IPMCs and ionic hydrogel actuators and to contextually overcome many of the above mentioned drawbacks characteristic of these two families of polymers. These composites were obtained by mean of Supersonic Cluster Beam Implantation (SCBI). This technique, developed in-house, relies on the use of supersonically accelerated gas-phase metal cluster beams directed onto a polymeric substrate in order to generate thin conductive layers (few tenths to few hundreds of nanometers thick) anchored to the polymer. This scalable approach already proved to be suitable for the manufacturing of elastomer/metal functional nanocomposites, and, as described in this work, it enabled the production of cluster-assembled gold electrodes (100 nm thick) interpenetrating with an engineered ionic gel matrix. This novel approach led to the fabrication of highly conductive metal nanostructures, large surface area for ions storage and providing minimal interfacial stresses between the metal layer and the polymeric basis upon deformation. The key features of this novel system comprise the control on the polymer elasticity, bending actuation in air from 0.1V to 5V, fast response time ( 5 cm), high work density ( >10 J/cm3), minimal electrodes fatigue upon cycling and low manufacturing costs. A bottom-up approach was firstly adopted to engineer and produce Uv photo-cross-linked ionic co-polymers (iongel) with tailored mechanical properties and provided with inorganic nano-structures embedded in the macromolecular matrix which show excellent long-term performance. The polymer is based on poly(acrylic acid)-co-poly(acrylonitrile) (PAA-co-PAN) co-polymers, which are chemically cross-linked in a hydrogel-like fashion and swollen with suitable imidazolium-based ionic liquid. The materials are produced as 100 um freestanding layers using a one-pot synthesis and a simple molding process. Due to the incommensurably low vapor pressure of the ionic liquid, issues concerning the shrinkage of traditional water swollen gels operating exposed to air could be avoided. An organic cation (tetraethyl ammonium, TEA+) is stably coordinated to the carboxyl groups of the PAA and free to move in the polymer sieve-like structure when a small voltage is applied at the electrodes. PAN was introduced to enhance the elastic properties of whole polymer. In the bulk polymer, halloysite nanoclays (HNC) are physically embedded into the gel in order to both improve the toughness of the gel and to improve the ionic conductivity of the system. In fact, the nanostructures interacts with the imidazolium cation of the ionic liquid through an oxygen reduction reaction, and therefore the latter is able to contribute to the charge transport phenomena induced by the electric field due to the solvent partial dissociation. Furthermore, the porosity of the polymer, tailored by the cross-linker, creates physical channels to favor the mobility of positive ions when an electric field is applied. The contribution of both the positive charged species (TEA+ and cations of ionic liquid) that accumulates at the nanostructured electrode in a double layer capacitance regime generates a differential swelling at the opposite sides of the actuator, which bends towards the anode. As it will be shown in the next sections, the actuation mechanism of the IGMN could be modeled according to both the material structure and design, as well as to the experimental data on its electrochemical and electro-mechanical properties.Comparing with traditional soft polymers incompatibility with current metallization processes, like electroless plating or surface silver laminated electrodes fabrication, which are not suitable to guarantee long-term actuation of the components, SCBI demonstrated to be a suitable technique for the production of next generation electro-active soft actuators. The IGMN-based actuators showed superior performance, such as large bending displacement, fast response time, long durability in a low voltage regime during the actuation process. The combination of the SCBI fabrication technology with the ionic gel synthesis and fabrication renders the manufacturing of these systems time-saving and costs-effective, and the unique properties of these actuators render them good candidates for potential scale up and for applications in micro-electromechanical systems, microfluidics, soft robotics, and rehabilitation

Characteristics and Functionalities of Natural and Bioinspired Nanomaterials

Green nanoscience is a rapidly emerging field that aims to achieve the maximum performance and benefits from nanotechnology, while minimizing the impact on the environment. In this study, several methods for the green nanomanufacturing of biomedically important nanomaterials, specifically through the use of natural plants, have been extensively investigated. It was found that natural nanomaterials are inherent within plants, and can be further manipulated for potential biomedical applications. In addition, the metabolites and reductive capacity of plant extracts can be used to synthesize metallic nanoparticles with advantages over semi-conductor based nanomaterials. Nanoparticles were found to exist in the extracts produced from tea leaves, the adventitious roots of English ivy (Hedera helix), the adhesive of the sundew (Drosera sp.), and the rhizome of the Chinese yam (Dioscoera opposite). These nanoparticles showed highly uniform repeating structures varying in size from 50-200 nm. Plant-derived nanofibers were also observed in the traditional Chinese medicine, Yunnan Baiyao, and from the polysaccharide components of the sundew adhesive and the viscous pulp extract from the Chinese yam. The nanofibers observed from the dried polysaccharides of the sundew and Chinese yam formed network structures with various pore sizes and fiber diameters. Due to their organic backbone, advantageous material properties, and biocompatibility, these natural nanomaterials offer significant advantages for biomedical applications. As such, these natural nanomaterials were further tested from medical prospects. Ivy nanoparticles were found to have unique optical property, blocking the transmission of ultraviolet light, which has potential for sunscreen and cosmetic applications. Nanofiber networks created from the sundew and Chinese yam showed strong cell attachment and proliferation with multiple cell lines, indicating their potential use as coatings for implants in the field of tissue engineering. Finally, gold and silver nanoparticles were synthesized using the extracts from homogenized ivy rootlets, by live sundew plant, or by herbicide additive. Through this study, the potential of plants has been demonstrated to vastly expand the current field of nanomanufacturing, and to reduce the environmental concerns associated with synthetic nanomaterials

Micro/Nano-Chip Electrokinetics

Micro/nanofluidic chips have found increasing applications in the analysis of chemical and biological samples over the past two decades. Electrokinetics has become the method of choice in these micro/nano-chips for transporting, manipulating and sensing ions, (bio)molecules, fluids and (bio)particles, etc., due to the high maneuverability, scalability, sensitivity, and integrability. The involved phenomena, which cover electroosmosis, electrophoresis, dielectrophoresis, electrohydrodynamics, electrothermal flow, diffusioosmosis, diffusiophoresis, streaming potential, current, etc., arise from either the inherent or the induced surface charge on the solid-liquid interface under DC and/or AC electric fields. To review the state-of-the-art of micro/nanochip electrokinetics, we welcome, in this Special Issue of Micromachines, all original research or review articles on the fundamentals and applications of the variety of electrokinetic phenomena in both microfluidic and nanofluidic devices

Tracing back the source of contamination

From the time a contaminant is detected in an observation well, the question of where and when the contaminant was introduced in the aquifer needs an answer. Many techniques have been proposed to answer this question, but virtually all of them assume that the aquifer and its dynamics are perfectly known. This work discusses a new approach for the simultaneous identification of the contaminant source location and the spatial variability of hydraulic conductivity in an aquifer which has been validated on synthetic and laboratory experiments and which is in the process of being validated on a real aquifer