BioMEMS Devices Research Articles

Special Issue on Bio-MEMS

A Micro Electro-Mechanical System (MEMS) is a micro-sized mechatronic device based on semiconductor integrated-circuit manufacturing technology. MEMS technology is inherently a very powerful tool for researchers to manipulate and measure the microscopic biological components of biological tissues since their basic constituent units, cells and intracellular microstructures, are also micron or even submicron in size. MEMS technology applied to medicine and life sciences is called Bio-MEMS. Many Bio-MEMS devices and technologies have been developed in recent years, including microfluidic devices for cell culture, manipulation, and measurement, as well as lab-on-a-chip devices for chemical reactions and analyses on MEMS devices. This special issue consists of 13 papers: 1 review article, 1 letter, and 11 research papers. These papers include studies on mechanical stress on cells using MEMS devices, the control of cell functions through microfabrication techniques, cell measurement and in vivo microenvironment simulation using microfluidic devices, and basic research on wearable devices and self-assembling microstructures using MEMS technologies. The editorial committee members are confident that this special issue will make a significant contribution to the further development of Bio-MEMS. We sincerely appreciate the excellent contributions of the authors and the time and effort of the reviewers. We would also like to thank the editorial board of the Journal of Robotics and Mechatronics for their support of this special issue.

Bio-MEMS Devices for Medical and Healthcare Measurements from the Body Surface

In the present study, we describe attempts to develop medical/healthcare measurement devices from the body surface using microfabrication technology. These devices can be divided into two types: internal vessel diameter measurement from the body surface using ultrasound to measure blood pressure and vascular tone, and collection and measurement of biological substances and collection of cells from the body surface.

Localized Surface Hydrophilicity Tailoring of Polyimide Film for Flexible Electronics Manufacturing Using an Atmospheric Pressure Ar/H2O Microplasma Jet.

The poor hydrophilicity of polyimide (PI) films limits their applications in flexible electronics, such as in wearable and implantable bio-MEMS devices. In this paper, an atmospheric pressure Ar/H2O microplasma jet (μAPPJ) with a nozzle diameter of 100 μm was utilized to site-selectively tune the surface hydrophilicity of a PI film. The electrical and optical characteristics of the μAPPJ were firstly investigated, and the results showed that multi-spikes occurred during the plasma discharge and that diverse reactive species, such as O atoms and OH radicals, were generated in the plasma plume. The physical and chemical properties of pristine and microplasma-modified PI surfaces were characterized by the water contact angle (WCA), atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). The wettability of the PI surface was significantly enhanced after microplasma modification, and the WCA could be adjusted by varying the applied voltage, water vapor content, plasma treatment time and storage time. The AFM images indicated that the surface roughness increased after the plasma treatment, which partially contributed to an improvement in the surface hydrophilicity. The XPS results showed a reduction in the C content and an increase in the O content, and abundant hydrophilic polar oxygen-containing functional groups were also grafted onto the PI film surface. Finally, the interaction mechanism between the PI molecular chains and the microplasma is discussed. The breaking of C-N and C-O bonds and the grafting of OH radicals were the key pathways to dominate the reaction process.

Biomechanical characterization and modeling of human mesenchymal stem cells under compression

The application of microelectromechanical systems (MEMS) in biomedical devices has expanded vastly over the last few decades, with MEMS devices being developed to measure different characteristics of cells. The study of cell mechanics offers valuable understanding of cell viability and functionality. Cell biomechanics approaches also facilitate the characterization of important cell and tissue behaviors. In particular, understanding of the biological response of cells to their biomechanical environment would enhance the knowledge of how cellular responses correlate to tissue level characteristics and how some diseases, such as cancer, grow in the body. This study focuses on viscoelastic modeling of the behavior of a single suspended human mesenchymal stem cell (hMSC). Mechanical properties of hMSC cells are particularly important in tissue engineering and research for the treatment of cardiovascular diseases. We evaluated the elastic and viscoelastic properties of hMSC cells using a miniaturized custom-made BioMEMS device. Our results were compared to the elastic and viscoelastic properties measured by other methods such as atomic force microscopy (AFM) and micropipette aspiration. Different approaches were applied to model the experimentally obtained force data, including elastic and Standard Linear Solid (SLS) constitutive models, and the corresponding constants were derived. These values were compared to the ones in literature that were based on micropipette aspiration and AFM methods. We then utilized a tensegrity approach to model major parts of the internal structure of the cell and treat the cell as a network of viscoelastic microtubules and microfilaments, as opposed to a simple spherical blob. The results predicted from the tensegrity model were similar to the recorded experimental data.

Towards Green 3D-Microfabrication of Bio-MEMS Devices Using ADEX Dry Film Photoresists

Current trends in miniaturized diagnostics indicate an increasing demand for large quantities of mobile devices for health monitoring and point-of-care diagnostics. This comes along with a need for rapid but preferably also green microfabrication. Dry film photoresists (DFPs) promise low-cost and greener microfabrication and can partly or fully replace conventional silicon-technologies being associated with high-energy demands and the intense use of toxic and climate-active chemicals. Due to their mechanical stability and superior film thickness homogeneity, DFPs outperform conventional spin-on photoresists, such as SU-8, especially when three-dimensional architectures are required for micro-analytical devices (e.g. microfluidics). In this study, we utilize the commercial epoxy-based DFP ADEX to demonstrate various application scenarios ranging from the direct modification of microcantilever beams via the assembly of microfluidic channels to lamination-free patterning of DFPs, which employs the DFP directly as a substrate material. Finally, kinked, bottom-up grown silicon nanowires were integrated in this manner as prospective ion-sensitive field-effect transistors in a bio-probe architecture directly on ADEX substrates. Hence, we have developed the required set of microfabrication protocols for such an assembly comprising metal thin film deposition, direct burn-in of lithography alignment markers, and polymer patterning on top of the DFP.

In Vitro Cytocompatibility Assessment of Ti-Modified, Silicon-oxycarbide-Based, Polymer-Derived, Ceramic-Implantable Electrodes under Pacing Conditions.

Polymer-derived ceramics (PDC) have recently gained increased interest in the field of bioceramics. Among PDC's, carbon-rich silicon oxycarbide ceramics (SiOC) possess good combined electrical and mechanical properties. Their durability in aggressive environments and proposed cytocompatibility makes them an attractive material for fabrication of bio-MEMS devices such as pacemaker electrodes. The aim of the present study is to demonstrate the remarkable mechanical and electrical properties, biological response of PDCs modified with titanium (Ti) and their potential for application as pacemaker electrodes. Therefore, a new type of SiOC modified with Ti fillers was synthesized via PDC route using a Pt-catalyzed hydrosilylation reaction. Preceramic green bodies were pyrolyzed at 1000 °C under an argon atmosphere to achieve amorphous ceramics. Electrical and mechanical characterization of SiCxO2(1-x)/TiOxCy ceramics revealed a maximum electrical conductivity of 10 S cm-1 and a flexural strength of maximal 1 GPa, which is acceptable for pacemaker applications. Ti incorporation is found to be beneficial for enhancing the electrical conductivity of SiOC ceramics and the conductivity values were increased with Ti doping and reached a maximum for the composition with 30 wt % Ti precursor. Cytocompatibility was demonstrated for the PDC SiOC ceramics as well as SiOC ceramics modified with Ti fillers. Cytocompatibility was also demonstrated for SiTiOC20 electrodes under pacing conditions by monitoring of cells in an in vitro 3D environment. Collectively, these data demonstrate the great potential of polymer-derived SiOC ceramics to be used as pacemaker electrodes.

Development of a bio-MEMS device for electrical and mechanical conditioning and characterization of cell sheets for myocardial repair.

Here we propose a bio-MEMS device designed to evaluate contractile force and conduction velocity of cell sheets in response to mechanical and electrical stimulation of the cell source as it grows to form a cellular sheet. Moreover, the design allows for the incorporation of patient-specific data and cell sources. An optimized device would allow cell sheets to be cultured, characterized, and conditioned to be compatible with a specific patient's cardiac environment in vitro, before implantation. This design draws upon existing methods in the literature but makes an important advance by combining the mechanical and electrical stimulation into a single system for optimized cell sheet growth. The device has been designed to achieve cellular alignment, electrical stimulation, mechanical stimulation, conduction velocity readout, contraction force readout, and eventually cell sheet release. The platform is a set of comb electrical contacts consisting of three-dimensional walls made of polydimethylsiloxane and coated with electrically conductive metals on the tops of the walls. Not only do the walls serve as a method for stimulating cells that are attached to the top, but their geometry is tailored such that they are flexible enough to be bent by the cells and used to measure force. The platform can be stretched via a linear actuator setup, allowing for simultaneous electrical and mechanical stimulation that can be derived from patient-specific clinical data.

Slipping hydrodynamics of Powell–Eyring fluid in a cylindrical microchannel under electrical double layer phenomenon

The electroosmotic flow of a Powell–Eyring fluid through a cylindrical microchannel activated by an electric field, taking the interfacial slip into account is presented. The study employs an analytical framework of homotopy perturbation method to obtain the underlying flow dynamics of Powell–Eyring fluid over interfacial scales. The rich physical interaction between the fluid rheology, interfacial slip and electrical forces uncovers alteration in the flow dynamics and shear stress profile for Powell–Eyring fluid. Different regimes of flow enhancement in the cylindrical microchannel, triggered by the combined effects of slipping dynamics and electrical double layer phenomena are established through the study. The present analytical framework is canonical with the numerical results for all the cases as considered in this study. The inferences obtained from the present analysis may improve the design of bio-MEMS and microfluidic devices applied for medical diagnostics and transportation of biofluids.

Chemisorption of Water on the Surface of Silicon Microparticles Measured by Dynamic Nuclear Polarization Enhanced NMR

We use dynamic nuclear polarization (DNP) enhanced nuclear magnetic resonance (NMR) at liquid helium temperatures to directly detect hydrogen attached to the surface of silicon microparticles. The proton NMR spectrum from a dry sample of polycrystalline silicon powder (1-5 $\mu$m) shows a distinctively narrow Lorentzian-shaped resonance with a width of 6.2 kHz, indicative of a very sparse distribution of protons attached to the silicon surface. These protons are within a few atomic monolayers of the silicon surface. The high sensitivity NMR detection of surface protons from low surface area ($0.26 - 1.3 \: m^2/g$) particles is enabled by an overall signal enhancement of 4150 over the room temperature NMR signal at the same field. When the particles were suspended in a solvent with 80% H2O and 20% D2O, the narrow peak was observed to grow in intensity over time, indicating growth of the sparse surface proton layer. However, when the particles were suspended in a solvent with 20% H2O and 80% D2O, the narrow bound-proton peak was observed to shrink due to exchange between the surface protons and the deuterium in solution. This decrease was accompanied by a concomitant growth in the intensity of the frozen solvent peak, as the relative proton concentration of the solvent increased. When the particles were suspended in the organic solvent hexane, the proton NMR spectra remained unchanged over time. These results are consistent with the known chemisorption of water on the silicon surface resulting in the formation of hydride and hydroxyl species. Low-temperature DNP NMR can thus be used as a non-destructive probe of surface corrosion for silicon in aqueous environments. This is important in the context of using silicon MEMS and bioMEMS devices in such environments, for silicon micro- and nano-particle MRI imaging agents, and the use of nanosilicon for splitting water in fuel cells.

Slip-driven electroosmotic transport through porous media.

We investigate the slip-driven transport of a Newtonian fluid through porous media under electrical double layer effect. We employ a semianalytical framework to obtain the underlying electrohydrodynamics for different configurations of porous media. We bring out an alteration in flow dynamics, stemming from interplay among the geometrical feature of the models and the interfacial slip as modulated by the electrical forcing. Further, we show the consequent effects of the underlying flow dynamics on the volumetric transport rate through different models. Also, we show the inception of reverse flow in the region close to the wall, resulting from the induced pressure gradient due to the convection of co-ions in the opposite direction to flow and pinpoint its effect of the flow rate variation under the influence of interfacial slip. We believe that the inferences obtained from the present analysis may improve the design of bio-MEMS (microelectromechanical systems) and microfluidic devices, which are used for in-situ bioremediation.

Effects of thermal boundary conditions on the joule heating of electrolyte in a microchannel

Joule heating effects on a slit microchannel filled with electrolytes are comprehensively investigated with emphasis on the thermal boundary conditions. An accurate analytical expression is proposed for the electrical field and the temperature distributions due to Joule heating are numerically obtained from the energy balance equation. The results show that a thermal design based on the average electric potential difference between electrodes can cause severe underestimation of Joule heating. In addition, the parametric study of thermal boundary conditions gives us an insight into the best cooling scenario for microfluidic devices. Other significant thermal characteristics, including Nusselt number, thermophoretic force, and entropy generation, are discussed as well. This study will provide useful information for the optimization of a bioMEMS device in relation to the thermal aspect.

Out-of-plane single-mode photonic microcantilevers for integrated nanomechanical sensing platform

We have studied the optomechanical performance of optical microcantilevers fabricated with integrated waveguides for the on-chip and real-time detection of biorecognition events. The nanomechanical photonic device consists of an optical microcantilever with on-chip integrated waveguides for both coupling the light and detecting the microcantilever response. The photonic device was designed to reach a high sensitivity with a low deflection noise density (DND) of only 0.13fm/Hz. The BioMEMS transducer is embedded into a proper designed PMMA/PDMS microfluidic header and connected to a flow delivery system to study the response of the fully-integrated device under physiological conditions. As a proof of concept, we have studied the photonic microcantilever bending during consecutive formation of ultrathin polyelectrolyte multilayer films (electrostatic binding) and during biofunctionalization and biorecognition of the human growth hormone. The read-out platform was developed based on a single laser-single acquisition channel. To avoid the effect of external factors such as device positioning or temperature fluctuations, an automatized light coupling system keeps on tracking the laser beam focused into an input waveguide, increasing the required reproducibility needed for BioMEMS devices and paving the way for a potential portable multichannel sensor platform.

Joule heating in low-voltage electroosmotic with electrolyte containing nano-bubble mixtures through microchannel rectangular orifice

Joule heating effects on a rectangular orifice in microchannel filled with electrolyte containing nanobubbles are comprehensively investigated with emphasis on the thermal boundary conditions. Numerical studies are performed for the velocity and temperature fields to show the various aspects of fluid flow and thermal design in rectangular shaped microchannels. Furthermore the correlations for the maximum temperature increase were presented for several geometry parameters and thermal boundary conditions which gives us an insight to the best cooling scenario of microfluidic rectangular orifices. This study will provide useful information for the optimization of a bioMEMS device in thermal aspect and benefits of nano-bubble injection for temperature control. It is shown that the cooling from the side is superior in reducing the peak temperature of the micro-orifice.

Switching the Biointerface of Displaceable Poly-p-xylylene Coatings.

A new class of functionalized poly-p-xylyene coating has been synthesized to provide switchable and displaceable surface properties for biomaterials. The switchability is achieved through a mechanism for detaching/attaching biomolecules and/or a mechanism through which the programmed restoration of functions or their replacement by other functions can be carried out. This advanced version of poly-p-xylylene comprises an integrated disulfide moiety within the functional side group, and the switching phenomenon between the immobilized functional molecules is triggered by the redox thiol-disulfide interchange reaction. These dynamically well-defined molecules on the surfaces respond simultaneously to altered biological properties and controlled biointerfacial functions, for example, switching wettability or reversibly altered cell adhesion activity. Poly-p-xylylenes are a key player in controlling surface properties for many important applications, such as medical implants, biosensors, bioMEMS devices, and microfluidics. The introduction of this new facet of poly-p-xylylenes enables the dynamic mimicry of biological functions relevant to the design of new biomaterials.

Development of a bio-microelectromechanical system device for axonal extension evaluation by PC12D patterning using a dielectrophoresis method

We developed a bio-microelectromechanical system (bio-MEMS) device by combining the dielectrophoresis (DEP) method and MEMS technology that to trap a single PC12D (rat phenocromocytoma cell) for cell pattern formation to measure the axonal extension function. Our device could trap PC12Ds to assign bicells, with designed distances between two cells of 100, 200, and 300 μm. PC12Ds were injected into our bio-MEMS device using a micropipette. We observed the axonal extension using a time-lapse microscope to study the effect of the bicell distance on the axonal extension and connection ability. An alternative electric field (frequency: 10 MHz, voltage: 5 Vp−p) was applied for the PC12D DEP patterning. To keep the patterned PC12Ds on the electrode holes, water was injected using a microsyringe to sweep out excess cells, which remained outside the holes. An average single PC12D pattern ratio of 89.3% was achieved. The axonal extension ability was affected by the cell distance. PC12D bicell distances of 100 and 200 μm showed good connection ratios of 86.7% and 91.7%, respectively, where as a bicell distance of 300 μm showed a low-connection ratio of about 40.0%. We confirmed the applicability of our bio-MEMS device to bicell patterning and evaluated the cell extension function.

Electrically Conducting PDMS Nanocompsite Using in-Situ Reduction of Gold Nanostructures and Mechanical Stimulation of Carbon Nanotubes

Electrically conducting nanocomposite has numerous application potential in flexible MEMS and wearable electronics. Polydimethylsiloxane (PDMS) has been identified as an attractive candidate for the fabrication of Bio-MEMS devices due to its several benefits such as biocompatibility, good optical properties, easy and low-cost fabrication using soft-lithography, etc. In this work, an electrically conducting PDMS nanocomposite is synthesized using a novel combined process of in-situ reduction by curing agent of PDMS from aqueous gold chloride solution, and mechanical stimulation of multi-wall carbon nanotubes. The electrical and thermal properties of the nanocomposite is characterized for various concentration of gold chloride solution and conducting fillers in the PDMS matrix. Further, the nanocomposite is micropatterned to fabricate heating elements and electrical signal routing lines in flexible PDMS sheets.

Electrically Conducting PDMS Nanocomposite Using In Situ Reduction of Gold Nanostructures and Mechanical Stimulation of Carbon Nanotubes and Silver Nanoparticles

Electrically conducting nanocomposite has numerous application potential in flexible MEMS and wearable electronics. Polydimethylsiloxane (PDMS) has been identified as an attractive candidate for the fabrication of Bio-MEMS devices due to several benefits such as biocompatibility, good optical properties, easy and low-cost fabrication using soft-lithography, etc. Until now, the synthesis of electrically conducting nanocomposite is proposed only by mechanical stimulation of electrically conducting nano materials such as carbon nanotubes, gold or silver nanoparticles in polymer matrix. In this work, an electrically conducting PDMS nanocomposite is synthesized using a novel combined process of in situ reduction by curing agent of PDMS from aqueous gold chloride solution, and mechanical stimulation of multi-wall carbon nanotubes and silver nanoparticles. The optical, electrical and thermal properties of the PDMS- nanocomposite are characterized. Further, the nanocomposite is micro patterned to fabricate heating elements and electrical signal routing lines in flexible PDMS sheets. The resistivity of the nanocomposite is measured as 3.5 × 10−3 Ω.m, which is much lower than the previously reported value of 1 Ω.m.

Development of microarray device for functional evaluation of PC12D cell axonal extension ability

In this study, we developed a microarray bio-MEMS device that could trap PC12D (rat pheochromocytoma cells) cells to examine the intercellular interaction effect on the cell activation and the axonal extension ability. This is needed to assign particular patterns of PC12D cells to establish a cell functional evaluation technique. This experimental observation-based technique can be used for design of the cell sheet and scaffold for peripheral and central nerve regeneration. We have fabricated a micropillar-array bio-MEMS device, whose diameter was approximately 10 μm, by using thick photoresist SU-8 on the glass slide substrate. A maximum trapped PC12D cell ratio, 48.5%, was achieved. Through experimental observation of patterned PC12D “bi-cells” activation, we obtained the following results. Most of the PC12D “bi-cells” which had distances between 40 and 100 μm were connected after 24 h with a high probability. On the other hand, “bi-cells” which had distances between 110 and 200 μm were not connected. In addition, we measured axonal extension velocities in cases where the intercellular distance was between 40 and 100 μm. A maximum axonal extension velocity, 86.4 μm/h, was obtained at the intercellular distance of 40 μm.

Solution processing of microcavity for BioMEMS application

Compared to the conventional silicon-based technology, the solution process appears to be a revolution in the field of micro/nanofabrication due to its advantages of high efficiency in material and energy consumption and the use of low cost material. In this paper, we introduce a new approach to fabricate BioMEMS devices using this novel technology to make microcavity. Zirconium oxide patterns were formed on the silicon substrate simply by spin coating its precursor and thermal imprinting technique. We used poly-propylene carbonate (PPC) for the sacrificial material due to its unique pyrolysis property. The PPC was coated on the ZrO patterns and excess film was etched by oxygen plasma but retaining PPC structure between the lines of ZrO pattern. Then another ZrO layer was coated to encapsulate the PPC. The final microcavity structures were obtained by just baking the substrate by pyrolyzing the PPC. The obtained results show the approach’s prospect of becoming an ideal alternative for the current BioMEMS micro/nanofabrication technologies

Particle Transport in Therapeutic Magnetic Fields

Iron oxide magnetic nanoparticles, in ferrofluids or as magnetic microspheres, offer magnetic maneuverability, biochemical surface functionalization, and magnetic relaxation under the influence of an alternating field. The use of these properties for clinical applications requires an understanding of particles, forces, and scalar transport at various length scales. This review explains the behavior of magnetic nano- and microparticles during magnetic drug targeting and magnetic fluid hyperthermia, and the microfluidic transport of these particles in bioMEMS (biomedical microelectromechanical systems) devices for ex vivo therapeutic and diagnostic applications. Magnetic particle transport, the momentum interaction of these particles with a host fluid in a flow, and thermal transport in a particle-infused tissue are characterized through the governing electrodynamic, hydrodynamic, and scalar transport equations.