Towards a microfluidics platform for the continuous manufacture of organic and inorganic nanoparticles.

In the last decade, microfluidics has opened new avenues for the synthesis of nanomaterials. However, the adoption of this production technique has been limited to a few high-value, low-production-volume organic nanoparticles. While there are several technical factors that can be attributed to this slow adoption, an important aspect to consider is the lack of a unified platform capable of producing a wide range of nanomaterials. In this work, we highlight a micro-mixing platform that can manufacture both organic and in-organic nanoparticles over a wide size range (nm-µm). We show that the platform can predictably and reproducibly create size and shape-controlled formulations with high homogeneity through input flow parameters. We further explore parallelization of this platform and discuss key technical constraints for high-volume production. We believe that the platform presented in this work can accelerate the adoption of nanomaterials relevant to a range of industries that encompass pharmaceutics, diagnostics, and cosmeceuticals.

A Microfluidic Perfusion Platform for In Vitro Analysis of Drug Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships.

Static in vitro cell culture studies cannot capture the dynamic concentration profiles of drugs, nutrients, and other factors that cells experience in physiological systems. This limits the confidence in the translational relevance of in vitro experiments and increases the reliance on empirical testing of exposure-response relationships and dose optimization in animal models during preclinical drug development, introducing additional challenges owing to species-specific differences in drug pharmacokinetics (PK) and pharmacodynamics (PD). Here, we describe the development of a microfluidic cell culture device that enables perfusion of cells under 2D or 3D culture conditions with temporally programmable concentration profiles. Proof-of-concept studies using doxorubicin and gemcitabine demonstrated the ability of the microfluidic PK-PD device to examine dose- and time-dependent effects of doxorubicin as well as schedule-dependent effects of doxorubicin and gemcitabine combination therapy on cell viability using both step-wise drug concentration profiles and species-specific (i.e., mouse, human) drug PK profiles. The results demonstrate the importance of including physiologically relevant dynamic drug exposure profiles during in vitro drug testing to more accurately mimic in vivo drug effects, thereby improving translatability across nonclinical studies and reducing the reliance on animal models during drug development.

Microfluidics-based 3D cell culture models: Utility in novel drug discovery and delivery research.

The implementation of microfluidic devices within life sciences has furthered the possibilities of both academic and industrial applications such as rapid genome sequencing, predictive drug studies, and single cell manipulation. In contrast to the preferred two-dimensional cell-based screening, three-dimensional (3D) systems have more in vivo relevance as well as ability to perform as a predictive tool for the success or failure of a drug screening campaign. 3D cell culture has shown an adaptive response to the recent advancements in microfluidic technologies which has allowed better control over spheroid sizes and subsequent drug screening studies. In this review, we highlight the most significant developments in the field of microfluidic 3D culture over the past half-decade with a special focus on their benefits and challenges down the lane. With the newer technologies emerging, implementation of microfluidic 3D culture systems into the drug discovery pipeline is right around the bend.

The integrin-adhesome is required to maintain muscle structure, mitochondrial ATP production, and movement forces in Caenorhabditis elegans.

The integrin-adhesome network, which contains >150 proteins, is mechano-transducing and located at discreet positions along the cell-cell and cell-extracellular matrix interface. A small subset of the integrin-adhesome is known to maintain normal muscle morphology. However, the importance of the entire adhesome for muscle structure and function is unknown. We used RNA interference to knock down 113 putative Caenorhabditis elegans homologs constituting most of the mammalian adhesome and 48 proteins known to localize to attachment sites in C. elegans muscle. In both cases, we found >90% of components were required for normal muscle mitochondrial structure and/or proteostasis vs. empty vector controls. Approximately half of these, mainly proteins that physically interact with each other, were also required for normal sarcomere and/or adhesome structure. Next we confirmed that the dystrophy observed in adhesome mutants associates with impaired maximal mitochondrial ATP production (P < 0.01), as well as reduced probability distribution of muscle movement forces compared with wild-type animals. Our results show that the integrin-adhesome network as a whole is required for maintaining both muscle structure and function and extend the current understanding of the full complexities of the functional adhesome in vivo.

Locomotion of C. elegans: a piecewise-harmonic curvature representation of nematode behavior.

Caenorhabditis elegans, a free-living soil nematode, displays a rich variety of body shapes and trajectories during its undulatory locomotion in complex environments. Here we show that the individual body postures and entire trails of C. elegans have a simple analytical description in curvature representation. Our model is based on the assumption that the curvature wave is generated in the head segment of the worm body and propagates backwards. We have found that a simple harmonic function for the curvature can capture multiple worm shapes during the undulatory movement. The worm body trajectories can be well represented in terms of piecewise sinusoidal curvature with abrupt changes in amplitude, wavevector, and phase.