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Guest Editorial

J. Med. Devices. 2018;12(4):040301-040301-1. doi:10.1115/1.4040996.
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The medical device industry increasingly relies on complex microfluidic, microelectromechanical, and nanoelectromechanical devices as part of modern clinical treatments and diagnostic testing. The benefits of using microdevices are faster results and lower costs. Fundamental and translational research in microscale medical devices has exploded and is rapidly moving toward commercialization in the device, pharmaceutical, biotechnology, and life science industries. Applications for microscale devices include drug discovery, cell growth, disease studies, diagnostics, biologic sensing, mixing, filtration, and many others. For example, organ-on-a chip devices have recently been developed that mimic the biologic and physiologic properties of living systems and can be used for early evaluation of new drugs or devices, as well as to study disease state. Likewise, lab-on-a-chip systems that use microsamples of blood are revolutionizing the diagnostic testing industry.

Commentary by Dr. Valentin Fuster

Review Article

J. Med. Devices. 2018;12(4):040801-040801-14. doi:10.1115/1.4040272.

As a necessary pathway to man-made organs, organ-on-chips (OOC), which simulate the activities, mechanics, and physiological responses of real organs, have attracted plenty of attention over the past decade. As the maturity of three-dimensional (3D) cell-culture models and microfluidics advances, the study of OOCs has made significant progress. This review article provides a comprehensive overview and classification of OOC microfluidics. Specifically, the review focuses on OOC systems capable of being used in preclinical drug screening and development. Additionally, the review highlights the strengths and weaknesses of each OOC system toward the goal of improved drug development and screening. The various OOC systems investigated throughout the review include, blood vessel, lung, liver, and tumor systems and the potential benefits, which each provides to the growing challenge of high-throughput drug screening. Published OOC systems have been reviewed over the past decade (2007–2018) with focus given mainly to more recent advances and improvements within each organ system. Each OOC system has been reviewed on how closely and realistically it is able to mimic its physiological counterpart, the degree of information provided by the system toward the ultimate goal of drug development and screening, how easily each system would be able to transition to large scale high-throughput drug screening, and what further improvements to each system would help to improve the functionality, realistic nature of the platform, and throughput capacity. Finally, a summary is provided of where the broad field of OOCs appears to be headed in the near future along with suggestions on where future efforts should be focused for optimized performance of OOC systems in general.

Commentary by Dr. Valentin Fuster
J. Med. Devices. 2018;12(4):040802-040802-11. doi:10.1115/1.4041086.

The Zika virus (ZIKV) is one of the most infamous mosquito-borne flavivirus on recent memory due to its potential association with high mortality rates in fetuses, microcephaly and neurological impairments in neonates, and autoimmune disorders. The severity of the disease, as well as its fast spread over several continents, has urged the World Health Organization (WHO) to declare ZIKV a global health concern. In consequence, over the past couple of years, there has been a significant effort for the development of ZIKV diagnostic methods, vaccine development, and prevention strategies. This review focuses on the most recent aspects of ZIKV research which includes the outbreaks, genome structure, multiplication and propagation of the virus, and more importantly, the development of serological and molecular detection tools such as Zika IgM antibody capture enzyme-linked immunosorbent assay (Zika MAC-ELISA), plaque reduction neutralization test (PRNT), reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR), reverse transcription-loop mediated isothermal amplification (RT-LAMP), localized surface plasmon resonance (LSPR) biosensors, nucleic acid sequence-based amplification (NASBA), and recombinase polymerase amplification (RPA). Additionally, we discuss the limitations of currently available diagnostic methods, the potential of newly developed sensing technologies, and also provide insight into future areas of research.

Commentary by Dr. Valentin Fuster

Research Papers

J. Med. Devices. 2018;12(4):041001-041001-7. doi:10.1115/1.4041227.

A novel, needle array dry electrode consisting of 10 × 10 array of stainless steel (SS) Microtips was developed for electroencephalography (EEG) monitoring. The developed dry electrode uses commercially available, inexpensive, SS acupuncture needles certified for invasive use, to collect the EEG signal. The microtips of the acupuncture needles project out of a flat Teflon base by approximately 150 μm. Mechanical failure analysis was carried out, with theoretical calculations for individual needles and experimental measurements with a universal testing machine (UTM). The theoretically calculated critical load for failure for individual needle was 0.88 N, while the UTM measurements show the failure occurring at 0.95 N; this difference is probably due to the simplified assumptions used in calculations. The UTM measurements of the individual needle applied against a Silicone elastomer reveal that the force required for the penetration of the needle of the electrode into skin maybe as low as 0.01 N. Needle array insertion into silicone elastomer sheet and its optical inspection was carried out to assess the ability of the microneedles to penetrate the skin. The impedance of the electrode, measured in three electrode configuration in 0.9% NaCl solution, was approximately 6.8KΩ at 20 Hz, which is sufficiently low to fulfill the requirements of biopotential measurement. The construction and characteristics of the developed needle array dry electrode show that they are suitable for penetrating the stratum corneum of the skin and acquire the EEG signal directly from the interstitial fluidic layer underneath. The construction of the electrode and its mechanical and electrical characteristics show that it is a promising dry electrode for long duration EEG Monitoring.

Commentary by Dr. Valentin Fuster
J. Med. Devices. 2018;12(4):041002-041002-10. doi:10.1115/1.4040648.

Pulsatile waves of blood pressure and flow are continuously augmented by the resistance, compliance, and inertance properties of the vasculature, resulting in unique wave characteristics at distinct anatomical locations. Hemodynamically generated loads, transduced as physical signals into resident vascular cells, are crucial to the maintenance and preservation of a healthy vascular physiology; thus, failure to recreate biomimetic loading in vitro can lead to pathological gene expression and aberrant remodeling. As a generalized approach to improve native and engineered blood vessels, we have designed, built, and tested a pulsatile perfusion bioreactor based on biomimetic impedances and a novel five-element electrohydraulic analog. Here, the elements of an incubator-based culture system were formulaically designed to match the vascular impedance of a brachial artery by incorporating both the inherent (systemic) and added elements of the physical system into the theoretical approach. Freshly harvested porcine saphenous veins were perfused within a physiological culture chamber for 6 h and the relative expression of seven known mechanically sensitive remodeling genes analyzed using the quantitative polymerase chain reaction (qPCR) method. Of these, we found plasminogen activator inhibitor-1 (SERPINE1) and fibronectin-1 (FN1) to be highly sensitive to differences between arterial- and venous-like culture conditions. The analytical approach and biological confirmation provide a framework toward the general design of long-term hemodynamic-mimetic vascular culture systems.

Commentary by Dr. Valentin Fuster
J. Med. Devices. 2018;12(4):041003-041003-8. doi:10.1115/1.4040271.

Forward-viewing catheters and scopes for diagnosing disease and guiding interventions in small ducts (less than 3 mm diameter) require wide-field high-quality imaging since scope tip bending is difficult and ineffective. A high-fidelity electromechanically coupled finite element (FE) model of a piezoelectric actuated resonant fiber scanner is presented, which enables improvement on the general design of fiber-optic scanner geometry to increase scan frequency and field of view (FOV). Using the proposed model, parametric sweeps on the specific design variables achieved by acid etching of glass fiber are analyzed to identify their effect on scanner performance and to choose improved designs. The resulting complex fiber scanner design requires development of unique microfabrication techniques. Comparison of three model simulations and their experimental testing show that our proposed coupled model has prediction error of ≤12% with respect to experimental data, while other uncoupled models have up to 39% error. The model and microfabrication techniques presented in this paper have significance for fiber scanning-based systems in that they demonstrate reliability for model-driven design and also flexibility for fiber scanner design of complex geometries, allowing for improvement on medical imaging performance.

Commentary by Dr. Valentin Fuster
J. Med. Devices. 2018;12(4):041004-041004-6. doi:10.1115/1.4040986.

Detection and capture of circulating tumor cells (CTCs) with microfluidic chips hold significance in cancer prognosis, diagnosis, and anti-cancer treatment. The counting of CTCs provides potential tools to evaluate cancer stages as well as treatment progress. However, facing the challenge of rareness in blood, the precise enumeration of CTCs is challenging. In the present research, we designed an inertial-deformability hybrid microfluidic chip using a long spiral channel with trapezoid-circular pillars and a capture zone. To clinically validate the device, the microfluidic chip has been tested for the whole blood and lysed blood with a small number of CTCs (colorectal and nonsmall-cell lung cancer) spiked in. The capture efficiency reaches over 90% for three types of cancer cell lines at the flow rate of 1.5 mL/h. Following numerical modeling was conducted to explain the working principle and working condition (Reynolds number below 10 and Dean number around 1). This design extended the effective capture length, improved the capture efficiency, and made the CTC enumeration much easier. We believe that this hybrid chip is promising clinically in the CTCs enumeration, evaluation of cancer therapy, and pharmacological responses.

Commentary by Dr. Valentin Fuster
J. Med. Devices. 2018;12(4):041005-041005-6. doi:10.1115/1.4040563.

Efficient detection of pathogens is essential for the development of a reliable point-of-care diagnostic device. Magnetophoretic separation, a technique used in microfluidic platforms, utilizes magnetic microbeads (mMBs) coated with specific antigens to bind and remove targeted biomolecules using an external magnetic field. In order to assure reliability and accuracy in the device, the efficient capture of these mMBs is extremely important. The aim of this study was to analyze the effect of an electroosmotic flow (EOF) switching device on the capture efficiency (CE) of mMBs in a microfluidic device and demonstrate viability of bacteria capture. This analysis was performed at microbead concentrations of 2 × 106 beads/mL and 4 × 106 beads/mL, EOF voltages of 650 V and 750 V, and under constant flow and switching flow protocols. Images were taken using an inverted fluorescent microscope and the pixel count was analyzed to determine to fluorescent intensity. A capture zone was used to distinguish which beads were captured versus uncaptured. Under the steady-state flow protocol, CE was determined to range from 31% to 42%, while the switching flow protocol exhibited a CE of 71–85%. The relative percentage increase due to the utilization of the switching protocol was determined to be around two times the CE, with p < 0.05 for all cases. Initial testing using bacteria-bead complexes was also performed in which these complexes were captured under the constant flow protocol to create a calibration curve based on fluorescent pixel count. The calibration curve was linear on a log-log plot, with R2-value of 0.96. The significant increase in CE highlights the effectiveness of flow switching for magnetophoretic separation in microfluidic devices and prove its viability in bacterial analysis.

Commentary by Dr. Valentin Fuster
J. Med. Devices. 2018;12(4):041006-041006-9. doi:10.1115/1.4040677.

Dielectrophoresis (DEP) can be an effective tool to show the physiological change of bacterial cells. The behavior of bacterial cells under an electric field is complicated due to the combined effects of electrokinetic phenomena. This paper presents the study of the electrokinetic behavior of heat-treated Mycobacterium bovis Bacillus Calmette-Guérin (BCG) cells for a cell counting method. Through numerical and experimental study, heat-treated BCG cells are compared with control BCG cells. At various frequencies with the medium conductivity of 0.07 S/m, the equilibrium positions of both control- and heat-treated cells are analyzed in the combined fields of DEP and AC electroosmosis (ACEO). As DEP changes from negative to positive in electroosmotic flow, the equilibrium position of cells is bifurcated from the upper center between two electrodes onto the edges of both electrodes. It was found that the cells floating on electrodes should not be counted as attracted cells because the floating was resulted from the combined effect of the negative DEP and ACEO. According to the analysis, an optimum frequency is proposed to differentiate control cells from heat-treated cells using a cell counting method. The presented study will offer physical insight for the cell counting to differentiate live and dead Mycobacterium bovis BCG cells treated with heat and drugs.

Commentary by Dr. Valentin Fuster
J. Med. Devices. 2018;12(4):041007-041007-12. doi:10.1115/1.4040995.

Characterization of cell mechanical properties plays an important role in disease diagnoses and treatments. This paper uses advanced atomic force microscopy (AFM) to measure the geometrical and mechanical properties of two different human brain normal HNC-2 and cancer U87 MG cells. Based on experimental measurement, it measures the cell deformation and indentation force to characterize cell mechanical properties. A fitting algorithm is developed to generate the force-loading curves from experimental data. An inverse Hertzian method is also established to identify Young's moduli for HNC-2 and U87 MG cells. The results demonstrate that Young's modulus of cancer cells is different from that of normal cells, which can help us to differentiate normal and cancer cells from the biomechanical viewpoint.

Commentary by Dr. Valentin Fuster

Technical Brief

J. Med. Devices. 2018;12(4):044501-044501-5. doi:10.1115/1.4041191.

The enzymatic digestion of lipoaspirate is used to isolate the heterogeneous stromal vascular fraction (SVF) that contains the adipose-derived stromal cells (ASCs). Several automated SVF isolation systems are used to operate standard technical procedures and avoid human errors. However, the yield of isolated cells and the residual collagenase activities of the SVF samples obtained from automated systems are not satisfactory compared to those from manual isolation methods. In this study, we evaluated the efficiency and the reliability of a new automated SVF isolation system in which the bowl was designed in the shape of a radial protrusion at each angle (a top-type bowl). The viability and yield of cells and the residual collagenase activities of SVFs obtained in a top-type bowl were compared with the SVFs obtained in a conventional bowl. We achieved a significantly higher yield of cells and decreased residual collagenase activity in the SVFs obtained from a top-type bowl (18.0 × 105 cells/mL of fat) compared to a conventional bowl (2.3 × 105 cells/mL). There was no significant difference in the cell viability between the two groups. These results suggest that the automated SVF isolation system with an improved bowl structure will potentially yield higher numbers of nucleated cells and decreased residual collagenase activity compared to conventional automated systems in cell-based clinical trials.

Commentary by Dr. Valentin Fuster

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