Bio-MEMS and Medical Microdevices III

We applied electrical impedance spectroscopy analysis for investigation of cardiac cell (H9C2 – rat cardiomyoblast) proliferation after verapamil hydrochloride exposure. For this purpose, two different PDMS/glass microsystems with circular microchamber and longitudinal microchannel integrated with Pt/Al electrodes were used. The microchambers were fabricated in PDMS using photolithography and replica moulding techniques. Pt/Al electrodes were fabricated on a 4-inch glass substrate using Physical Vapor Deposition. Solution of verapamil hydrochloride was introduced into the microsystems with H9C2 cell culture (a flow rate of 1 µl/min) for 96 h continuously. The impedance spectra were recorded from 100 Hz to 1 MHz.

We propose the novel structure of an interferometric biosensor based on multimode interference (MMI) waveguides using eigenmode expansion (EME) method. The MMI structures with a 90 nm Si3N4 core are used as power splitters with 5 outputs. We analyze the coupling efficiency of the laser source with the structure, the excess loss and power imbalance for different compact MMI waveguides with widths ranging from 45 μm to 15 μm. For a laser we achieve a coupling efficiency of 52%. MMI waveguides with tapered channels show excess loss values under 0.5 dB and power imbalance values under 0.08 dB.

In this paper, a sensor system architecture for in-vivo light scattering studies on blood cells is presented. It aims at correlating Mie scattering to compositional and physiological information of blood cells towards a non-invasive blood-cell counting sensor. An overview of previously reported theoretical and experimental data on light scattering from blood cells is presented. State-of-the-art methods such as differential pulse measurements, vessel pressure optimization are employed, to amplify the scattering signal. A prototype sensor system based on a 640-660 nm laser light source and a photo diode array is implemented and programmed to obtain mean amplitude and scattering angle measurements.

In this contribution we present travelling-wave based dielectrophoretic (twDEP) microfluidic devices for the handling of suspended grown cells. Travelling-wave based dielectrophoretic devices rely on a moving electric field gradient, which can be realised by applying phase-shifted AC-voltages between sets of parallel electrodes. The distance between these electrodes can be reduced to a few micrometres. In optimised conditions channels with a height of even hundreds of micrometres are applicable. Two microfluidic devices have been realises to investigate the advantages of travelling wave dielectrophoresis for cell handling.

Establishing a reliable bidirectional communication interface between the nervous system and electronic devices is crucial for exploiting the full potential of neural prostheses. Despite recent advancements, current microelectrode technologies evidence important shortcomings, e.g. challenging high density integration, low signal-to-noise ratio, poor long-term stability, etc. Thus, efforts to explore novel materials are essential for the development of next-generation neural prostheses. Graphene and graphene-based materials possess a rather exclusive set of physicochemical properties holding great potential for biomedical applications, in particular neural prostheses. In this presentation, I will provide an overview on fundamentals and applications of several graphene-based technologies and devices aiming at developing an efficient bidirectional communication with electrogenic cells and nerve tissue. The main goal of this talk is to discuss pros and cons of graphene technologies for bioelectronics and neuroprosthetics, and at the same time to identify the main challenges ahead.

In this paper, a study of the power loss attenuation of the plane wave travelling through the tissue layers, from the outside to the inside of the skull within a cochlear implant, is performed. Different implantation depths of the internal antenna, from 10 to 50 mm are considered. To this purpose, the gain and attenuation in dB are studied. A multilayer tissue model is developed, consisting of mainly skin, mastoid bone and brain. An s-parameter analysis is also carried out, using loop antennas and pork head tissue.

A pressure sensing system is integrated in the tip of a, 2 Fr (0.67mm) outer diameter, catheter to carry out Fractional Flow Reserve (FFR) measurements in the coronary arteries. The catheter has a non-concentric guidewire lumen of 0.43 mm diameter. The pressure sensing system consists of a flexible circuit containing a flip chipped MEMS capacitive pressure sensor and an ASIC chip which are mounted face-down in a cavity, located in the thickest part of the catheter outer wall. The miniaturisation, integration and reliability challenges including the electrical catheter wiring connected to the flexible circuit are reported.

A novel negative-dielectrophoresis based approach for switching of microparticles in microdevices is reported. Two sets of electrodes piercing the microchannel from both sides are used to generate an electric field that controls the location of the microparticles inside the microdevice. The microfluidic device consists of a glass substrate and a PDMS layer. The microfluidic device was fabricated using standard microfabrication. Several parameters that affect the switching of cells were numerically studied using FEM. Experiments were carried out using red blood cells to demonstrate the effectiveness of the microdevice in switching of cells to three sub-channels.

This paper reports on a microfluidic platform with an integrated spin valve giant magneto-resistance (GMR) sensor used for the detection and quantification of single magnetic micromarkers. A microfluidic channel containing the magnetic fluid, microconductors (MCs) for collection of the magnetic markers and a spin valve GMR sensor for detecting the presence of their magnetic stray field were integrated on a single chip. The results show that the sensor is capable of detecting a single magnetic marker with 2.8 µm diameter.

We present a microfluidic chip for an easy setup of a 3D cell culture. The chip is mainly made out of silicon and glass which are highly biocompatible. The chip contains one feeding channel and one gas channel to supply them with fresh culture media and gases like oxygen and carbon dioxide. These channels are located alongside the cell culture. We embedded HaCat-cells in agarose and proved the good viability after 24 hours by staining them with TrypanBlue.

Selective bio-sensors that exploit the key-lock principle of enzymes have demonstrated a considerable potential for diagnostic and therapeutic applications. Increasingly complex interactions between drugs and natural substances motivate the development of selective bio-sensors. The metabolisation of 30% of the clinically prescribed drugs is carried out by the isoenzyme P450 CYP2D6. Thus, a bio-sensor based on this enzyme would enable measurements targeting individual interferences between medical drugs and natural substances. An ink-jet printed bio-sensor with a CNT layer functionalised using a CYP2D6 enzymes has been developed and characterised to confirm the considerable potential of enzymatic bio-sensors for smart health applications.

A small size bioanalytical system encompassing all the electronic and fluidic components for the performance of label-free immunochemical determinations using chips with arrays of Mach-Zehnder interferometers integrated on silicon is presented. The chips are manufactured by standard microelectronics processing so as to include on a less than 40-mm2 footprint arrays of ten LEDs connected to their respective waveguides patterned as Mach-Zehnder interferometers. The sensor chip is paired with an appropriately designed microfluidic module to allow for short response times. Each sensor on the array is individually biofunctionalized with recognition biomolecules providing the ability for multi-analyte determinations in a single run.

This work reports a low area, low power, integer-based neural digital processor for the calculation of phase synchronization between two neural signals. The processor calculates the phase-frequency content of a signal by identifying the specific time periods associated with two consecutive minima. The simplicity of this phase-frequency content identifier allows for the digital processor to utilize only basic digital blocks, such as registers, counters, adders and subtractors, without incorporating any complex multiplication and or division algorithms. The low area and power consumptions make the processor an extremely scalable device which would work well in closed loop neural prosthesis for the treatment of neural diseases.

In this paper, a high-resolution bio-optical sensor is developed for brain activity measurement. The aim is to develop an optical sensor with enough sensitivity to detect small electric field perturbations caused by neuronal action potential. The sensing element is a polymeric dielectric micro-resonator fabricated in a spherical shape with a few hundred microns in diameter. They are made of optical quality polymers that are soft which make them mechanically compatible with tissue. The sensors are attached to or embedded in optical fibers which serve as input/output conduits for the sensors. Hundreds or even thousands of spheres can be attached to a single fiber to detect and transmit signals at different locations. The high quality factor for the optical resonator makes it significantly used in such bio-medical applications. The sensing phenomena is based on whispering gallery modes (WGM) shifts of the optical sensor. To mimic the brain signals, the spherical resonator is immersed in a homogeneous electrical field that is created by applying potential difference across two metallic plates. One of the plates has a variable voltage while the volt on the other plate kept fixed. Any small perturbations of the potential difference (voltage) leads to change in the electric field intensity. In turn the sensor morphology will be affected due to the change in the electrostriction force acting on it causing change in its WGM. By tracking these WGM shift on the transmission spectrum, the induced potential difference (voltage change) could be measured. Results of a mathematical model simulation agree well with the preliminary experiments. Also, the results show that the brain activity could be measured using this principle.

In this paper we demonstrate a dark field video imaging system for the detection and size characterization of individual magnetic micromarkers suspended in liquid. The system is convenient to follow dynamic processes and interactions of moving micro/nano objects close to or below the optical resolution limit, and is especially suitable for small sample volumes. The principle can be used to obtain clinical information about liquid contents when an additional biological protocol is provided, i.e., binding of microorganisms to specific magnetic markers. Advantages of the method are the increased sizing precision in the micro- and nano-range as well as the setup’s simplicity. Hence the introduced method is applicable for miniaturized devices and measurements can be carried out in a quick, inexpensive, and compact manner. A minor limitation is that the concentration range of micromarkers in a liquid sample needs to be adjusted such that the number of individual particles in the microscope’s field of view is sufficient.

A rapid, simple and cost-effective minimally invasive technique as a screening method for colitis is described here. The technique includes the testing of serum using Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy detecting the colitis-induced increased presence of mannose and glucose. Another signature, namely the alpha helix to beta sheet ratio of the protein secondary structure further discriminates colitic from non-colitic and other controls. The same signature was also used to monitor remission resulting from targeted treatment. Further spectral markers were identified based on statistical significance analysis by performing second derivative spectral deconvolution of the absorbance spectra.

In this paper, we present a new fabrication method for the whispering gallery mode (WGM) micro-sphere based electric field sensor based which allows for longer time periods of sensitivity. Recently, a WGM-based photonic electric field sensor was proposed using a coupled dielectric microsphere-beam. The external electric field imposes an electrtrostriction force on the dielectric beam, deflecting it. The beam, in turn compresses the sphere causing a shift in its WGM. As part of the fabrication process, the PDMS micro-beams and the spheres are curied at high-temperature (100oC) and subsequently poled by exposing to strong external electric field (~8 MV/m) for two hours. The poling process allows for the deposition of surface charges thereby increasing the electrostriction effect. This methodology is called curing-then-poling (CTP). Although the sensors do become sufficiently sensitive to electric field, they start de-poling after a short period (within ~ 10 minutes) after poling, hence losing sensitivity. In an attempt to mitigate this problem and to lock the polarization for a longer period, we use an alternate methodology whereby the beam is poled and cured simultaneously (curing-while-poling or CWP). The new fabrication method allows for the retention of polarization (and hence, sensitivity to electric field) longer (~ 1500 minutes). An analysis is carried out along with preliminary experiments. Results show that electric fields as small as ~ 100 V/m can be detected with a 300 m diameter sphere sensor a day after poling.