Accepted Manuscripts

Technical Brief  
Tomasz Bugajski, Douglas Kondro, Kartikeya Murari and Janet L. Ronsky
J. Med. Devices   doi: 10.1115/1.4041190
Pectus Carinatum (PC) presents itself as a protrusion located on the chest of adolescent individuals. The current treatment for PC is performed with a Pectus Carinatum Orthosis (PCO) that applies a compressive force to the protrusion. While this treatment is widely accepted, the magnitude of compressive forces applied remains unknown leading to conditions of excessive or deficient compression. Although the crucial need for this quantitative data is recognized, no studies reporting the data or methods are available. The purpose of this study was to design an accurate force measurement system (FMS) that could be incorporated into a PCO with minimal bulk. The FMS was effortlessly implemented into the PCO and was able to withstand the applied forces. The system calibration revealed an increase in load cell error with increased magnitude of applied force (mean error of 0.58 V [standard deviation = 0.34 V]). This response was speculated to be attributed to the congruency of the FMS with the surface it resided on. Participants recruited to evaluate the FMS demonstrated reliable forces with smaller standard deviations than those during the calibration. The successful FMS is the foundational component in a wireless, minimalistic sensor system to provide real time force feedback to both the clinician and patient.
TOPICS: Sensors, Bracing (Construction), Flexible manufacturing systems, Errors, Calibration, Compression, Force feedback, Force measurement, Orthotics, Stress, Design
Technical Brief  
Hyung Min Hahn, Kwang Sik Jeong, Bo Young Yoo, Jong Ha Park, Hyun Joo Jung and IL JAE LEE
J. Med. Devices   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 (18.0x105 cells/mL of fat) compared to a conventional bowl (2.3x105 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.
TOPICS: Reliability, Errors, Shapes
Review Article  
Carlos Herrada, Md Alamgir Kabir, Rommel Altamirano and Waseem Asghar
J. Med. Devices   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 foetuses, 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). Limitations of current methods are described, opportunities are highlighted, and potential solutions are discussed.
TOPICS: Surface plasmon resonance, Chain, Biosensors, Diseases, Enzymes, Nervous system, Modal assurance criterion
Hongmei Chen and Zhifeng Zhang
J. Med. Devices   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. CTCs number at different periods could be utilized as a tool to evaluate stages of disease treatment. However, facing the challenge of rareness in blood, the precise enumeration is challenging. In the present research, towards the design of a sensitive physical-based capture of CTCs, we present an inertial- deformability hybrid microfluidic chip through a spiral channel and a trapezoid- circular pillar structure. To clinically validate the device, the microfluidic chip has been tested for whole blood and lysed blood with a small number of CTCs (colorectal and non-small-cell lung cancer) spiked in. The result showed that the capture efficiency could reach approximately to 100% for cancer cell line at 1.5 ml/h with viability over 90%. Finally, we conducted numerical modeling to explain the working principle through Volume of Fluid (VOF) simulation. We believe it is a promising device in the future development of clinical CTC enumeration, evaluating the effectiveness of cancer therapy after chemotherapy and pharmacological responses.
TOPICS: Inertia (Mechanics), Design, Cancer, Microfluidics, Blood, Diseases, Lung, Patient treatment, Tumors, Fluids, Computer simulation, Columns (Structural), Simulation
Tariq Mohana Bahwini, Yongmin Zhong, Chengfan Gu, Zeyad Nasa and Denny Oetomo
J. Med. Devices   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 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 calculates 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.
TOPICS: Atomic force microscopy, Mechanical properties, Brain, Cancer, Young's modulus, Deformation, Fittings, Patient diagnosis, Algorithms, Biomechanics
Guest Editorial  
Yaling Liu
J. Med. Devices   doi: 10.1115/1.4040996
This is the editorial for Special Issue: Microscale Medical Devices
TOPICS: Medical devices, Microscale devices
Hyun-Boo Lee, Shinnosuke Inoue, Jong-Hoon Kim, Minjoong Jeong and Jae-Hyun Chung
J. Med. Devices   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 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.
TOPICS: Electrokinetics, Heat, Electrodes, Equilibrium (Physics), Electroosmosis, Thermal conductivity, Drugs, Physiology, Dielectrophoresis, Electric fields, Electrical conductivity
David A. Prim, Jay Potts and John/F Eberth
J. Med. Devices   doi: 10.1115/1.4040648
Intricate patterns of blood pressure and flow are generated by the cyclic contraction and relaxation of the heart and the coordinated opening and closing of valves. These pulsatile waves are augmented by the resistance, compliance, and inertance properties of the vasculature, resulting in unique hemodynamic characteristics present at distinct anatomically locations. In vivo these hemodynamically generated loads, transduced as physical signals into resident vascular cells, are crucial to the maintenance and preservation of healthy vascular physiology. Failure to recreate biomimetic loading in vitro however, 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 the concept of biomimetic impedances. Here the elements of an incubator-based culture system were formulaically designed to match the vascular impedance of a brachial artery using a 5-element electrohydraulic analog that incorporates both inherent (systemic) and added elements. Using freshly harvested saphenous veins, the relative expression of seven known mechanically sensitive remodeling genes were analyzed using a quantitative polymerase chain reaction (qPCR). 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 after 6 hours in our bioreactor. The analytical approach and biological confirmation provide a framework towards the general design of hemodynamic-mimetic vascular culture systems.
TOPICS: Biomimetics, Bioreactors, Hemodynamics, Signals, Physiology, Failure, Pressure, Flow (Dynamics), Maintenance, Preservation, Relaxation (Physics), Stress, Waves, Blood, Blood vessels, Chain, Design, Valves
Samuel / A Miller, William / R Heineman, Alison A. Weiss and Rupak K. Banerjee
J. Med. Devices   doi: 10.1115/1.4040563
Efficient detection of pathogens is essential to the development of a reliable point-of-care diagnostic device. Magnetophoretic separation, a technique used in microfluidic platforms, utilizes magnetic microbeads coated with specific antigens to bind and remove targeted biomolecules using an external magnetic field. For better reliability and accuracy in the device, the efficient capture of these magnetic microbeads is important. The aim was to analyze the effect of an electroosmotic flow switching on the capture efficiency of magnetic microbeads in a microfluidic device and demonstrate viability of bacteria capture. This analysis was performed at microbead concentrations of 2x106 and 4x106 beads/mL, electroosmotic flow voltages of 650 and 750 volts, and under constant and switching flow protocols. Images were taken using an inverted fluorescent microscope and the pixel count was analyzed to determine fluorescent intensity. A capture zone was used to distinguish between captured and uncaptured beads. The capture efficiency range was 31% - 42% for constant flow and 71% to 85% for switching flow. Compared to constant flow, the relative percentage increase due to the switching flow was ~2 times (p<0.05). Initial testing using bacteria-bead complexes was also performed in which these complexes were captured under the constant flow to create a calibration curve based on fluorescent pixel count. The calibration curve was linear on a log-log plot (R2 = 0.96). The significant increase in capture efficiency highlights the effectiveness of flow switching for magnetophoretic separation in microfluidic devices and prove its viability in bacterial analysis.
TOPICS: Flow (Dynamics), Microfluidics, Bacteria, Electroosmosis, Calibration, Separation (Technology), Electrical measurement, Magnetic fields, Reliability, Microscopes, Testing
Abhijith Rajiv, Yaxuan Zhou, Jeremy Ridge, Per G. Reinhall and Eric/J Seibel
J. Med. Devices   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 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. 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 98% 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.
TOPICS: Fibers, Testing, Design, Microfabrication, Errors, Etching, Finite element model, Geometry, Imaging, Engineering simulation, Biomedical imaging, Catheters, Diseases, Ducts, Glass fibers, Reliability, Simulation, Resonance
Review Article  
Christopher Uhl, Wentao Shi and Yaling Liu
J. Med. Devices   doi: 10.1115/1.4040272
As a necessary pathway to man-made organs, organ-on-chips which simulate the activities, mechanics and physiological responses of a real organs have attracted plenty of attention over the past decade. As the maturity of 3D cell-culture models and microfluidics advances, the study of organ-on-chips has made significant progress. This review article provides a comprehensive overview and classification of organ-on-chip microfluidics. Specifically, the review focuses on organ-on-chip systems capable of being used in pre-clinical drug screening and development. Additionally, the review highlights the strengths and weaknesses of each organ-on-chip system towards the goal of improved drug development and screening. The various organ-on-chip 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 organ-on-chip systems have been reviewed over the past decade (2007-2017) with focus given mainly to more recent advances and improvements within each organ system. Each organ-on-chip 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 towards 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.
TOPICS: Drugs, Microfluidics, Physiology, Artificial organs, Blood vessels, Liver, Lung, Tumors
Design Innovation Paper  
F. Mark Payne, Tony Connell and Jacob Rice
J. Med. Devices   doi: 10.1115/1.4030812
Background: Tissue expanders are used in breast reconstruction after mastectomy to create a space for placement of permanent breast implants. The AeroForm™ Tissue Expander, developed by AirXpanders™ Inc., utilizes carbon dioxide released from an internal reservoir to inflate the expander. The released gas is contained within a high barrier material pre-formed into a breast shaped shell of the desired volume. During patient travel to higher altitude, a partially inflated expander will increase in volume proportionately to the gas fill volume. At volume levels near full, expansion is governed by the compliance of the inner gas barrier and silicone shell. Therefore, the assessment of the expander performance at altitude consists of the analysis of two operating regimes. The first regime is fill levels < 70% full where the implant, when exposed to cabin pressure, expands without significantly stressing the inner gas barrier. The second is fill levels ~>70% where the response of the inner gas barrier is important, both in terms of structural capability and determination of the volume increase. We assessed the impact of pressurized flight on expander performance in both operating regimes. Findings: The volume increase associated with altitude increase to 8000 feet (maximum cabin altitude per FAA) is typically within the range administered during post-operative fills of saline expanders. Although assessment must be conducted by a clinician, a patient can be typically expected to tolerate the increased volume with some minor discomfort, such as a feeling of tightness. At higher fill levels, the structural capability of shell has been demonstrated to withstand the additional pressure loading. At these fill levels, the expander does not expand as much, due to the structural restraint of the shell. To date, 7 subjects have flown with the expander in situ during clinical trials. All subjects were required to temporarily cease dosing up to two weeks prior. Flight travel was completed uneventfully and they reported discomfort levels ranging from none to moderate. The recommendation to cease dosing two weeks prior to flying was made to allow the expected 1 cc per day of CO2 permeation to occur, which will result in slight deflation to accommodate for the expansion of the CO2 when flying. As expected, subjects reported a sensation of pressure upon ascent which subsided on descent.
TOPICS: Biological tissues, Carbon dioxide, Shells, Pressure, Flight, Reservoirs, Silicones

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