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Circulating tumor cells are of utmost importance among various biomarkers in liquid biopsies as a prognosis indicator of metastasis as well as in chemotherapeutic monitoring. This study introduces an efficient tool composed of soft nano/hybrid immune microgels for magnetic isolation of targeted tumor cells. The development process involves the in situ synthesis of magnetic nanoparticles within the three-dimensional matrix of thermoresponsive microgels. Surface modification and anti-EpCAM conjugation are adjusted by changing the temperature, and a conjugation efficiency of around 70% is achieved by using a protein G linker. Anti-EpCAM-conjugated nano/hybrid magnetic microgels are used to isolate EpCAM-expressing breast adenocarcinoma MCF-7 cells from culture media and whole blood with an efficiency of 75 and 70%, respectively. Furthermore, we demonstrate the ability of the hybrid microgels to isolate cancer cells with a purity of 65% and culture the cells post-isolation for further drug studies. The multifunctional hybrid microcarriers reported in this work can be potentially used for continuous monitoring of cancers and in personalized medicine.

Several biomedical analyses are performed on particular types of cells present in body samples or using functionalized microparticles. Success in such analyses depends on the ability to separate or isolate the target cells or microparticles from the rest of the sample. In conventional procedures, multiple pieces of equipment, such as centrifuges, magnets, and macroscale filters, are used for such purposes, which are time-consuming, associated with human error, and require several operational steps. In the past two decades, there has been a tendency to develop microfluidic techniques, so-called lab-on-a-chip, to miniaturize and automate these procedures. The processes used for the separation and isolation of the cells and microparticles are scaled down into a small microfluidic chip, requiring very small amounts of sample. Differences in the physical and biological properties of the target cells from the other components present in the sample are the key to the development of such microfluidic techniques. These techniques are categorized as filtration-, hydrodynamic-, dielectrophoretic-, acoustic- and magnetic-based methods. Here we review the microfluidic techniques developed for sorting, separation, and isolation of cells and microparticles for biomedical applications. The mechanisms behind such techniques are thoroughly explained and the applications in which these techniques have been adopted are reviewed.

Glioblastoma multiforme (GBM) is a rapidly progressive and deadly form of brain tumor with a median survival rate of ~15 months. GBMs are hard to treat and significantly affect the patient's physical and cognitive abilities and quality of life. Temozolomide (TMZ)&mdash, an alkylating agent that causes DNA damage&mdash, is the only chemotherapy choice for the treatment of GBM. However, TMZ also induces autophagy and causes tumor cell resistance and thus fails to improve the survival rate among patients. Here, we studied the drug-induced programmed cell death and invasion inhibition capacity of TMZ and a mevalonate cascade inhibitor, simvastatin (Simva), in a three-dimensional (3D) microfluidic model of GBM. We elucidate the role of autophagy in apoptotic cell death by comparing apoptosis in autophagy knockdown cells (Atg7 KD) against their scrambled counterparts. Our results show that the cells were significantly less sensitive to drugs in the 3D model as compared to monolayer culture systems. An immunofluorescence analysis confirmed that apoptosis is the mechanism of cell death in TMZ- and Simva-treated glioma cells. However, the induction of apoptosis in the 3D model is significantly lower than in monolayer cultures. We have also shown that autophagy inhibition (Atg7 KD) did not change TMZ and Simva-induced apoptosis in the 3D microfluidic model. Overall, for the first time in this study we have established the simultaneous detection of drug induced apoptosis and autophagy in a 3D microfluidic model of GBM. Our study presents a potential ex vivo platform for developing novel therapeutic strategies tailored toward disrupting key molecular pathways involved in programmed cell death and tumor invasion in glioblastoma.

Cryptosporidium is a critical waterborne protozoan pathogen found in water resources that have been a major cause of death and serious illnesses worldwide, costing millions of dollars annually for its detection and treatment. Over the past several decades, substantial efforts have been made towards developing techniques for the detection of Cryptosporidium. Early diagnostic techniques were established based on the existing tools in laboratories, such as microscopes. Advancements in fluorescence microscopy, immunological, and molecular techniques have led to the development of several kits for the detection of Cryptosporidium spp. However, these methods have several limitations, such as long processing times, large sample volumes, the requirement for bulky and expensive laboratory tools, and the high cost of reagents. There is an urgent need to improve these existing techniques and develop low-cost, portable and rapid detection tools for applications in the water quality industry. In this review, we compare recent advances in nanotechnology, biosensing and microfluidics that have facilitated the development of sophisticated tools for the detection of Cryptosporidium spp.Finally, we highlight the advantages and disadvantages, of these state-of-the-art detection methods compared to current analytical methodologies and discuss the need for future developments to improve such methods for detecting Cryptosporidium in the water supply chain to enable real-time and on-site monitoring in water resources and remote areas.

An effective treatment of human diseases using regenerative medicine and cell therapy approaches requires a large number of cells. Cultivation of cells on microcarriers is a promising approach due to the high surface-to-volume ratios that these microcarriers offer. Here, multifunctional temperature-responsive microcarriers (cytoGel) made of an interpenetrating hydrogel network composed of poly(N-isopropylacrylamide) (PNIPAM), poly(ethylene glycol) diacrylate (PEGDA), and gelatin methacryloyl (GelMA) are developed. A flow-focusing microfluidic chip is used to produce microcarriers with diameters in the range of 100-300 μm and uniform size distribution (polydispersity index of ≈0.08). The mechanical properties and cells adhesion properties of cytoGel are adjusted by changing the composition hydrogel composition. Notably, GelMA regulates the temperature response and enhances microcarrier stiffness. Human-derived glioma cells (U87) are grown on cytoGel in static and dynamic culture conditions with cell viabilities greater than 90%. Enzyme-free cell detachment is achieved at room temperature with up to 70% detachment efficiency. Controlled release of bioactive molecules from cytoGel is accomplished for over a week to showcase the potential use of microcarriers for localized delivery of growth factors to cell surfaces. These microcarriers hold great promise for the efficient expansion of cells for the industrial-scale culture of therapeutic cells.

A continuous nonlinear full-state time-delayed feedback control scheme is designed within the framework of geometric mechanics to stabilize the rigid body attitude motion, which is subject to an unknown constant time delay in feedback measurement. The attitude kinematics is globally described on the matrix Lie group S O ( 3 ) of rigid body rotations. A Morse–Lyapunov–Krasovskii functional is utilized to guarantee the asymptotic stability of the system, which yields the control gain matrices via linear matrix inequality stability conditions. In light of this result, a delayed feedback control scheme is also designed for the planar rotational motion to examine the almost global asymptotic stability of the system in the presence of an unknown time delay in feedback measurement. Simulations are performed for the proposed control schemes based on the discretized models of the controlled systems and the performance of the proposed controllers are evaluated by employing large maneuvers.

In this article, we present a method for cell culture on a digital microfluidic (DMF) platform. Dielectrophoresis is used for trapping and patterning cells encapsulated within a 3D gelatin methacrylate (GelMA) hydrogel. In this method, planar traps are patterned within the electrodes on the DMF chip. Dispersed HEK 293 cells in GelMA solution are used to show negative dielectrophoresis when subject to a voltage at 20 kHz. The effects of the cell concentration, trap area, and trap spacing are analyzed. The rise time for patterning cells is shown to be rapid, from 8.5 seconds to 198.3 seconds for 50 μm and 500 μm diameter traps, respectively. The number of cells trapped was significantly influenced by the trap diameter and cell concentration. Live/dead assayed cells under a fluorescence microscope indicated that clusters of HEK 293 cells are 66% viable after 4 days of culturing. Certain trap designs were 78% viable on average after 4 days. This platform can be applied to execute quantitative, automated cell behavior studies and drug tests on the array of cells in vitro.

Following the development of microfluidic systems, there has been a high tendency towards developing lab-on-a-chip devices for biochemical applications. A great deal of effort has been devoted to improve and advance these devices with the goal of performing complete sets of biochemical assays on the device and possibly developing portable platforms for point of care applications. Among the different microfluidic systems used for such a purpose, digital microfluidics (DMF) shows high flexibility and capability of performing multiplex and parallel biochemical operations, and hence, has been considered as a suitable candidate for lab-on-a-chip applications. In this review, we discuss the most recent advances in the DMF platforms, and evaluate the feasibility of developing multifunctional packages for performing complete sets of processes of biochemical assays, particularly for point-of-care applications. The progress in the development of DMF systems is reviewed from eight different aspects, including device fabrication, basic fluidic operations, automation, manipulation of biological samples, advanced operations, detection, biological applications, and finally, packaging and portability of the DMF devices. Success in developing the lab-on-a-chip DMF devices will be concluded based on the advances achieved in each of these aspects.

The delayed feedback stabilization of rigid spacecraft attitude dynamics in the presence of an unknown time-varying delay in the measurement is addressed. The attitude representation is parameterized using minimal attitude coordinates. The time-varying delay and its derivative are assumed to be bounded. By employing a linear state feedback controller via a Lyapunov–Krasovskii functional, a general delay-dependent stability condition is characterized for the closed-loop parameterized system in terms of a linear matrix inequality (LMI) whose solution gives the suitable controller gains. An estimate of the region of attraction of the controlled system is also obtained, inside which the asymptotic stability of parameterized system is guaranteed.

In the present study, a hydrodynamic particle manipulation method for digital microfluidic platforms is introduced to separate and concentrate non-buoyant particles in micro-droplets. The proposed method utilizes the combined effects of the gravitational forces and the fluid flow inside the droplet, and it depends only on the hydrodynamic properties of the system without the need of external electrical or magnetic modules. The desired hydrodynamic effect is created by manipulating the droplet in a controlled fashion on a circular pattern of electrodes using the electrowetting-on-dielectric technique. Two successful electrode designs (Star Design and Square Design) are presented. To investigate the feasibility of the proposed particle separation technique, suspensions of silica and polystyrene beads are tested. The fabricated devices successfully focus the non-buoyant silica beads of 1 μm and 5 μm and polystyrene beads of 15 μm in a region on the central electrode; whereas the focusing behavior is not observed for the polystyrene beads of 5 μm. A capturing efficiency of 86% and 94% is achieved for the 5 μm silica particles and 15 μm polystyrene particles, respectively. A parametric study is conducted to investigate the dependency of the focusing regimes on the particle size and density, the droplet size and the electrode geometry, and the actuation scheme. To understand the focusing mechanism, the fluid flow inside the droplet is simulated numerically, and the observed time scales are verified through analytical calculations. Finally, the application of the current particle focusing technique is illustrated for detection of the presence of a low concentration of DNA (18 μg mL−1).

In this paper, a numerical approach is developed for the stability analysis of linear stochastic delay differential equations (SDDEs) in the parameter space based on the Chebyshev Spectral Continuous Time Approximation (CSCTA) technique. The CSCTA method is used to approximate an infinite-dimensional linear SDDE as a set of linear stochastic differential equations (SDEs). The mean and mean-square stability concepts are employed for the stochastic stability analysis of the resulting SDE. For this purpose, a set of linear deterministic differential equations for both the first and second moments are obtained using the Ito differential rule. Two examples are provided: a first order SDDE with multiplicative stochastic excitation and a second order SDDE with both additive and multiplicative stochastic excitation. In both examples the stability charts obtained from the proposed approach match those obtained using the stochastic semi-discretization method as described by Elbeyli et al. (Commun Nonlinear Sci Numer Simul 10(1):85–94, 2005). In the first example the stability results obtained from both numerical approaches are found to be less conservative than the Lyapunov-based stability region obtained by Samiei et al. (Int J Dyn Control 1(1):64–80, 2013).

In this paper, we obtain an analytical Lyapunov- based stability conditions for scalar linear and nonlinear stochastic systems with discrete time-delay. The Lyapunov–Krasovskii and Lyapunov–Razumikhin methods are applied with techniques from stochastic calculus to obtain the regions of mean square asymptotic stability in the parameter space. Both delay-independent and delay-dependent stability conditions are analyzed corresponding to both additive and multiplicative stochastic Brownian motion excitation in the Ito form. It is also shown that the derived sufficient conditions are less conservative in comparison with other numerical LMI-based Lyapunov approaches. A range of different stability charts are obtained based on the derived Lyapunov-based stability criteria, which are also compared with numerical first and second moment stability boundaries computed using the stochastic semidiscretization method. A Lipschitz condition is used to treat nonlinear functions of the current and delayed states.

In the present study the effects of surface tension on the growth and collapse stages of cavitation bubbles are studied individually for both spherical and nonspherical bubbles. The Gilmore equation is used to simulate the spherical bubble dynamics by considering mass diffusion and heat transfer. For the collapse stage near a rigid boundary, the Navier–Stokes and energy equations are used to simulate the flow domain, and the VOF method is adopted to track the interface between the gas and the liquid phases. Simulations are divided into two cases. In the first case, the collapse stage alone is considered in both spherical and nonspherical situations with different conditions of bubble radius and surface tension. According to the results, surface tension has no significant effects on the flow pattern and collapse rate. In the second case, both the growth and collapse stages of bubbles with different initial radii and surface tensions are considered. In this case surface tension affects the growth stage considerably and, as a result, the jet velocity and collapse time decrease with increasing surface tension coefficient. This effect is more significant for bubbles with smaller radii.