Volume 9, Issue 5, September 2015
Index of content:
- SPECIAL TOPIC: MICROFLUIDICS IN DRUG DELIVERY (GUEST EDITOR BRIGITTE MARIA STADLER)
- Contributed Articles
Sustained release of hydrophobic drugs by the microfluidic assembly of multistage microgel/poly (lactic-co-glycolic acid) nanoparticle composites9(2015); http://dx.doi.org/10.1063/1.4916230View Description Hide Description
The poor solubility of many newly discovered drugs has resulted in numerous challenges for the time-controlled release of therapeutics. In this study, an advanced drug delivery platform to encapsulate and deliver hydrophobic drugs, consisting of poly (lactic-co-glycolic acid) (PLGA) nanoparticles incorporated within poly (ethylene glycol) (PEG) microgels, was developed. PLGA nanoparticles were used as the hydrophobic drug carrier, while the PEG matrix functioned to slow down the drug release. Encapsulation of the hydrophobic agents was characterized by fluorescence detection of the hydrophobic dye Nile Red within the microgels. In addition, the microcomposites prepared via the droplet-based microfluidic technology showed size tunability and a monodisperse size distribution, along with improved release kinetics of the loaded cargo compared with bare PLGA nanoparticles. This composite system has potential as a universal delivery platform for a variety of hydrophobic molecules.
9(2015); http://dx.doi.org/10.1063/1.4916508View Description Hide Description
We demonstrate an evaporation-based microfluidic strategy to produce oil-free cell containing hydrogel particles. Perfluoro-n-pentane, which is used as the continuous oil phase to generate cell-containing hydrogel (Extracel) particles, is removed at an elevated temperature. Human colon cancer cells (HCT116) encapsulated in the hydrogel particles show higher viability than cells encapsulated in particles that are produced via a non-evaporative oil phase. In addition, single HCT116 cells can be cultured for a week in such particles and respond to inflammatory stimuli, highlighting the potential applications of the developed strategy for 3D cell culture, drug testing, and cell-based drug delivery.
9(2015); http://dx.doi.org/10.1063/1.4917181View Description Hide Description
Nebulizers have considerable advantages over conventional inhalers for pulmonary drug administration, particularly because they do not require coordinated breath actuation to generate and deliver the aerosols. Nevertheless, besides being less amenable to miniaturization and hence portability, some nebulizers are prone to denature macromolecular drugs due to the large forces generated during aerosolization. Here, we demonstrate a novel portable acoustomicrofluidic device capable of nebulizing epidermal growth factor receptor (EGFR) monoclonal antibodies into a fine aerosol mist with a mass median aerodynamic diameter of approximately 1.1 μm, optimal for deep lung deposition via inhalation. The nebulized monoclonal antibodies were tested for their stability, immunoactivity, and pharmacological properties, which confirmed that nebulization did not cause significant degradation of the antibody. In particular, flow cytometry demonstrated that the antigen binding capability of the antibody is retained and able to reduce phosphorylation in cells overexpressing the EGFR, indicating that the aerosols generated by the device were loaded with stable and active monoclonal antibodies. The delivery of antibodies via inhalation, particularly for the treatment of lung cancer, is thus expected to enhance the efficacy of this protein therapeutic by increasing the local concentration where they are needed.
Microfluidic based high throughput synthesis of lipid-polymer hybrid nanoparticles with tunable diameters9(2015); http://dx.doi.org/10.1063/1.4922957View Description Hide Description
Core-shell hybrid nanoparticles (NPs) for drug delivery have attracted numerous attentions due to their enhanced therapeutic efficacy and good biocompatibility. In this work, we fabricate a two-stage microfluidic chip to implement a high-throughput, one-step, and size-tunable synthesis of mono-disperse lipid-poly (lactic-co-glycolic acid) NPs. The size of hybrid NPs is tunable by varying the flow rates inside the two-stage microfluidic chip. To elucidate the mechanism of size-controllable generation of hybrid NPs, we observe the flow field in the microchannel with confocal microscope and perform the simulation by a numerical model. Both the experimental and numerical results indicate an enhanced mixing effect at high flow rate, thus resulting in the assembly of small and mono-disperse hybrid NPs. In vitro experiments show that the large hybrid NPs are more likely to be aggregated in serum and exhibit a lower cellular uptake efficacy than the small ones. This microfluidic chip shows great promise as a robust platform for optimization of nano drug delivery system.
9(2015); http://dx.doi.org/10.1063/1.4923324View Description Hide Description
Over the last decades, researchers have developed an ever greater and more ingenious variety of drug delivery vehicles (DDVs). This has made it possible to encapsulate a wide selection of therapeutic agents, ranging from proteins, enzymes, and peptides to hydrophilic and hydrophobic small drugs while, at the same time, allowing for drug release to be triggered through a diverse range of physical and chemical cues. While these advances are impressive, the field has been lacking behind in translating these systems into the clinic, mainly due to low predictability of in vitro and rodent in vivo models. An important factor within the complex and dynamic human in vivo environment is the shear flow observed within our circulatory system and many other tissues. Within this review, recent advances to leverage microfluidic devices to better mimic these conditions through novel in vitro assays are summarized. By grouping the discussion in three prominent classes of DDVs (lipidic and polymeric particles as well as inorganic nanoparticles), we hope to guide researchers within drug delivery into this exciting field and advance a further implementation of these assay systems within the development of DDVs.
9(2015); http://dx.doi.org/10.1063/1.4923263View Description Hide Description
Biomicrofluidics is an emerging field at the cross roads of microfluidics and life sciences which requires intensive research efforts in terms of introducing appropriate designs, production techniques, and analysis. The ultimate goal is to deliver innovative and cost-effective microfluidic devices to biotech, biomedical, and pharmaceutical industries. Therefore, creating an in-depth understanding of the transport phenomena of cells and biomolecules becomes vital and concurrently poses significant challenges. The present article outlines the recent advancements in diffusion phenomena of cells and biomolecules by highlighting transport principles from an engineering perspective, cell responses in microfluidic devices with emphases on diffusion- and flow-based microfluidic gradient platforms, macroscopic and microscopic approaches for investigating the diffusion phenomena of biomolecules, microfluidic platforms for the delivery of these molecules, as well as the state of the art in biological applications of mammalian cell responses and diffusion of biomolecules.
9(2015); http://dx.doi.org/10.1063/1.4927324View Description Hide Description
Droplet microfluidic technology has the potential to significantly reduce reagent use, and therefore, lower costs of assays employed in drug discovery campaigns. In addition to the reduction in costs, this technology can also reduce evaporation and contamination which are often problems seen in miniaturized microtitre plate formats. Despite these advantages, we currently advise caution in the use of these microfluidic approaches as there remains a lack of understanding of the artefacts of the systems such as reagent partitioning from droplet to carrier oil and interaction of the biological reagents with the water-oil interface. Both types of artefact can lead to inaccurate and misleading data. In this paper, we present a study of the partitioning of a number of drug-like molecules in a range of oils and evidence of protein binding at the water-oil interface which results in reduced activity of a cytochrome P450 enzyme. Data presented show that the drug-like molecules partitioned the least into fluorocarbon oils and the interaction of the 1A2 cytochrome at the water-oil interface resulted in a lower or complete absence of enzyme activity. This loss of activity of cytochrome 1A2 could be restored by the use of secondary blocking proteins although changes in the pharmacology of known 1A2 inhibitors were observed. The artefacts described here due to reagents partitioning into the carrier oil or protein binding at the water-oil interface significantly impact the potential use of these microfluidic systems as a means to carry out miniaturized biological assays, and further work is needed to understand the impact and reduction of these phenomena.
9(2015); http://dx.doi.org/10.1063/1.4927436View Description Hide Description
Implantable drug delivery devices are becoming attractive due to their abilities of targeted and controlled dose release. Currently, two important issues are functional lifetime and non-controlled drug diffusion. In this work, we present a drug delivery device combining an electrolytic pump and a thermo-responsive valve, which are both remotely controlled by an electromagnetic field (40.5 mT and 450 kHz). Our proposed device exhibits a novel operation mechanism for long-term therapeutic treatments using a solid drug in reservoir approach. Our device also prevents undesired drug liquid diffusions. When the electromagnetic field is on, the electrolysis-induced bubble drives the drug liquid towards the Poly (N-Isopropylacrylamide) (PNIPAM) valve that consists of PNIPAM and iron micro-particles. The heat generated by the iron micro-particles causes the PNIPAM to shrink, resulting in an open valve. When the electromagnetic field is turned off, the PNIPAM starts to swell. In the meantime, the bubbles are catalytically recombined into water, reducing the pressure inside the pumping chamber, which leads to the refilling of the fresh liquid from outside the device. A catalytic reformer is included, allowing more liquid refilling during the limited valve's closing time. The amount of body liquid that refills the drug reservoir can further dissolve the solid drug, forming a reproducible drug solution for the next dose. By repeatedly turning on and off the electromagnetic field, the drug dose can be cyclically released, and the exit port of the device is effectively controlled.
9(2015); http://dx.doi.org/10.1063/1.4928947View Description Hide Description
With the fast development of acoustic systems in clinical and therapeutic applications, acoustically driven microbubbles have gained a prominent role as powerful tools to carry, transfer, direct, and target drug molecules in cells, tissues, and tumors in the expanding fields of targeted drug delivery and gene therapy. The aim of the present study is to establish a biocompatible acoustic microfluidic system and to demonstrate the generation of an acoustic field and its effects on microbubbles and biological cells in the microfluidic system. The acoustic field creates non-linear oscillations of the microbubble-clusters, which results in generation of shear stress on cells in such microsystems. This effectively helps in delivering extracellular probes in living cells by sonoporation. The sonoporation is investigated under the combined effects of acoustic stress and hydrodynamic stress during targeted drug and gene delivery.
9(2015); http://dx.doi.org/10.1063/1.4929405View Description Hide Description
Recently, the combination of lipids and block copolymers has become an alternative to liposomes and polymersomes as nano-sized drug carriers. We synthesize novel block copolymers consisting of poly(cholesteryl acrylate) as the hydrophobic core and poly(N-isopropylacrylamide) (PNIPAAm) as the hydrophilic extensions. Their successful phospholipid-assisted assembly into vesicles is demonstrated using the evaporation-hydration method. The preserved thermo-responsive property of the lipid-polymer hybrids is shown by a temperature dependent adsorption behaviour of the vesicles to poly(l lysine) coated surfaces. As expected, the vesicle adsorption is found to be higher at elevated temperatures. The cellular uptake efficiency of hybrids is assessed using macrophages with applied shear stress. The amount of adhering macrophages is affected by the time and level of applied shear stress. Further, it is found that shorter PNIPAAm extensions lead to higher uptake of the assemblies by the macrophages with applied shear stress. No inherent cytotoxicity is observed at the tested conditions. Taken together, this first example of responsive lipid-polymer hybrids, and their positive biological evaluation makes them promising nano-sized drug carrier candidates.