This PDF file contains the front matter associated with SPIE Proceedings Volume 8765, including the Title Page, Copyright Information, Table of Contents, and the Conference Committee listing.

The WIMAGINE platform was developed as a proof of concept and first functional prototype of an implantable device for recording ECoG signals on a large number of electrodes. The designed system provides the means of recording wirelessly up to 64 ECoG channels. Two ASIC CINESIC32 ensure the amplification and digitization of the neurosignals which are then transmitted to a PC using a ZL70102 transceiver in the MICS band. An MSP430 handles the communication protocol, configures the ASICs and gives access to various sensor information. The electronics are packaged hermetically in a biocompatible titanium housing encapsulated medical grade silicone. The whole device is powered remotely over an inductive link at 13.56MHz and complies with the regulations applicable to class III AIMD.

This paper reports a 64-channel inductively powered neural recording sensor array. Neural signals are acquired, filtered, digitized and compressed in the channels. Additionally, each channel implements a local auto-calibration mechanism which configures the transfer characteristics of the recording site. The system has two operation modes; in one case the information captured by the channels is sent as uncompressed raw data; in the other, feature vectors extracted from the detected neural spikes are transmitted. Data streams coming from the channels are serialized by an embedded digital processor and transferred to the outside by means of the same inductive link used for powering the system. Simulation results show that the power consumption of the complete system is 377uW.

The analysis of the mechanical properties of cells is a field of great interest both in medicine and biology because it becomes fundamental each time it is necessary to recognize and prevent some diseases causing alterations in cellular behaviour and resistance. Biological Micro Electro-Mechanical Systems (Bio-MEMS) allow the application of extremely small and precise forces increasing, as a consequence, the number of results possible per experiment and the number of experiments that can be performed simultaneously. The aim of our work is to present a microgripper for single-cell manipulation and to detect the best structure design for keeping the cell and the integrated strategy for its actuation. Specifications and targets impose several limitations and difficulties in micro manipulators design and these obstacles are even more important when the target of microgripping are biological particles (e.g. living cells). The main parameters that have to be taken into account while designing a cell micromanipulator are, aside from its actuation principle, its kinematics, its fingertips shape, its releasing strategy and its material biocompatibility. Both thermal and piezoelectric actuation strategies are investigated in order to understand their main advantages and limitations related, for example, to motion range, hysteresis, thermal stability and insulation, high temperature and high voltage; all these parameters have to be considered to ensure the cell’s integrity during its micromanipulation.

While most actual micropumps use piezoelectric based actuators, we present an original approach based on bimetallic effect for deflecting a flexible silicon membranes. We have simulated, fabricated and characterized fully integrated thermally actuated membranes. Analytical and numerical models have been used to simulate and optimize the performance of the actuated diaphragm. It predicts the deflection behavior under definite power actuation and pressure. In particular, heat transfer analysis is conducted to evaluate temperature field distribution within the device. High displacements (~80μm) where obtained under low driving power. Our results show a very good fit between experiments under pressure and theoretical predictions.

Sample preparation is a key issue of modern analytical methods for in vitro diagnostics of diseases with microbiological origins: methods to separate bacteria from other elements of the complex biological samples are of great importance. In the present study, we investigated the DEP force as a way to perform such a de-complexification of the sample by extracting micro-organisms from a complex biological sample under a highly non-uniform electric field in a micro-system based on an interdigitated electrodes array. Different parameters were investigated to optimize the capture efficiency, such as the size of the gap between the electrodes and the height of the capture channel. These parameters are decisive for the distribution of the electric field inside the separation chamber. To optimize these relevant parameters, we performed numerical simulations using COMSOL Multiphysics and correlated them with experimental results. The optimization of the capture efficiency of the device has first been tested on micro-organisms solution but was also investigated on human blood samples spiked with micro-organisms, thereby mimicking real biological samples.

Cardiovascular diseases are the leading causes of illness and death in Europe, having a major impact on healthcare costs. An intelligent stent (e-stent), capable of obtaining and transmitting measurements of physiological parameters, can be a useful tool for real-time monitorization of arterial blockage without patient hospitalization. In this paper, a behavioral model of a pressure sensing-based e-stent is proposed and simulated under several restenosis conditions. Special attention has been given to the need of an accurate fault model, obtained from realistic finite-element simulations, to ensure long-term reliability; particularly for those faults whose behavior cannot be described by usual analytical models.

Millions of patients worldwide are receiving anticoagulant therapy to treat hypercoagulable diseases. While standard testing is still performed in the central laboratory, point-of-care (POC) diagnostics are being developed due to the increasing number of patients requiring long-term anticoagulation and with a need for more personalized and targeted therapy. Many POC devices on the market focus on clot measurement, a technique which is limited in terms of variability, highlighting the need for more reliable assays of anticoagulant status. The anti-Xa assay, a factor specific optical assay, was developed to measure the extent to which exogenous factor Xa (FXa) is inhibited by heparinantithrombin complexes. We have developed a novel microfluidic device and assay for monitoring the effect of heparin anticoagulant therapy at the point-of-care. The assay which was also developed in our institute is based on the anti-Xa assay principle but uses fluorescence as the method of detection. Our device is a disposable laminate microfluidic strip, fabricated from the cyclic polyolefin (COP), Zeonor®, which is extremely suitable for application to fluorescent device platforms. We present data on the execution of the anti-Xa assay in this microfluidic format, demonstrating that the assay can be used to measure heparin in human plasma samples from 0 to 0.8 U/ml, with average assay reproducibility of 8% and a rapid result obtained within 60 seconds. Results indicate that with further development, the fluorogenic anti-Xa assay and device could become a successful method for monitoring anticoagulant therapy.

The possibility to engineer bio-nanomaterials with programmed synthesis and controlled immobilization of biomolecules through biomimetic molecular evolution approach has been demonstrated. Material specific peptides with exquisite molecular recognition function were used as a linker for the attachment of biomolecules. Exploring the origin of peptide material specificity not only opens up rational design approach with precise control over biomimetic bio-sensor design, but more importantly provides a new route of functionalizing for various material surfaces with enhanced sensitivity over classical grafting chemistry. To study the fine prints of experimentally obtained peptides, theoretical understanding of surface interactions may serve as important clues for further refinement. By taking advantage of classical molecular dynamics (MD) simulations and density functional theory (DFT), we investigated the origin of this smart recognition function through the strength of interaction of experimentally selected 12mer peptides revealing high binding affinity towards n+-Si(100). Here, we attempt for the very first time to model the interaction of the peptides (in buffer solution) with semiconductors and we calculate their binding energies at the atomic level, enabling thereby linking direct evidence to our experimental evidence. Several peptide conformations have been taken into account simultaneously upon the surface. Our studies demonstrate that the peptides possess certain recognition function and their high interaction energy with the surface makes them unique among the populations. Our work is a step towards the understanding of the interactions between peptides and semiconductor surfaces that is a highly relevant challenge in the development of novel devices with a high degree of biocompatibility as well.

Cell behavior (i.e. attachment, proliferation, etc.) on nanostructured surfaces is currently a hot topic throughout the scientific community. However, studies often show diverging results due to differences in cells, local surface chemistry, and nanotopography fabrication methods. In this study, we use Oxygen plasma etching to both randomly nanotexture a PMMA surface and change its surface chemistry. We find that 3T3 cells behave quite differently on flat PMMA surfaces as compared to nanotextured ones, showing an on-off attachment behavior. Work is under progress to exploit this effect allowing selective cell capturing, and creation of cell arrays in adjacent plasma-nanotextured/smooth areas using a stencil mask during etching.

This study presents a wireless power and data transmission system to overcome the problems in intracranial epilepsy monitoring associated with transcutaneous wires. Firstly, a wireless power transfer link based on inductive coupling is implemented and a power management unit for the implant is designed. 4-coil resonant inductive link scheme is exploited since it exhibits a high efficiency and optimal load flexibility. Power management unit consists of an active rectifier, a low drop-out voltage regulator which is biased internally with a supply independent current source; all implemented as integrated circuit. Wireless power link provides 10 mW under 1.8 V dc to the load, more specifically the electrodes and read-out electronics. Wireless data communication is realized using the same frequency, 8.4 MHz, as the power link. Load shift keying is performed for uplink (from implant to external) communication by switching an integrated modulator which, in fact, detunes the resonance. Modulated signal is recovered on the external device by means of an integrated self-referenced ASK demodulator. Data rate is adapted for a fast ripple ( < 500 Hz) detection system which requires 300 kbps communication. The measurements show that the system works at 36% power transfer efficiency without communication link and the efficiency drops to 33% with 300 kbps uplink data transfer. Finally, in-vitro tests that emulate the real operation scenario are performed thanks to the two-polymer packaging and almost the same power transfer efficiency is achieved under same operation conditions.

ZnO nanostructures were explored as templates for the development of topography-mediated neuronal cultures. Nanostructures of varying features were produced on 4” Si substrates via a rapid, facile and low-cost technique that allows the systematic investigation of nanotopographically-mediated formation of neuronal cultures. The developed ZnO-nanowire based templates were seeded with Neuro-2A mouse neuroblastoma cells and their viability over the course of 1 to 4 days was assessed. Our studies demonstrate that the ZnO-templates can support neuronal cell growth and proliferation suggesting that ZnO substrate can be used for the development of neuronal cell-based platform technologies.

Despite the advances in optical biosensors, the existing technological approaches still face two major challenges: the inherent inability of most sensors to integrate the optical source in the transducer chip, and the need to specifically design the optical transducer per application. In this work, the development of a radical optoelectronic platform is demonstrated based on a monolithic optocoupler array fabricated by standard Si-technology and suitable for multi-analyte detection. The platform has been specifically designed biochemical sensing. In the all-silicon array of transducers, each optocoupler has its own excitation source, while the entire array share a common detector. The light emitting devices (LEDs) are silicon avalanche diodes biased beyond their breakdown voltage and emit in the VIS-NIR part of the spectrum. The LEDs are coupled to individually functionalized optical transducers that converge to a single detector for multiplexed operation. The integrated nature of the basic biosensor scheme and the ability to functionalize each transducer independently allows for the development of miniaturized optical transducers tailored towards multi-analyte tests. The monolithic arrays can be used for a plethora of bio/chemical interactions becoming thus a versatile analytical tool. The platform has been successfully applied in bioassays and binding in a real-time and label-free format and is currently being applied to ultra-sensitive food safety applications.

We report the first demonstration of real-time biosensing in free standing macroporous alumina membranes. The membranes with their 200 nm diameter pores are ideal candidates for biosensing applications where fast response times for small sample volumes are needed as they allow analytes to flow through the pores close to the bioreceptors immobilized on the pores walls. A bulk refractive index sensitivity of 5.2x10^-6 refractive index units was obtained from signal responses to different concentrations of NaCl solutions flowing through the pores. Finally, after functionalizing the alumina pore surfaces with an epoxysilane and then spotting it with β-Lactoglobulin protein, the interactions between the β-lactoglobulin and rabbit anti-β-lactoglobulin, as well as the interaction between the rabbit anti-β-lactoglobulin and a secondary antibody anti-rabbit Immunoglobulin G were monitored in real-time.

Single cell analysis techniques provide a unique opportunity of determining the intercellular heterogeneity in a cell population, which due to genotype variations and different physiological states of the cells i.e. size, shape and age, cannot be retrieved from averaged cell population values. In order to obtain high-value quantitative data from single-cell experiments it is important to have experimental platforms enabling high-throughput studies. Here, we present a microfluidic chip, which is capable of capturing individual cells in suspension inside separate traps. The device consists of three adjacent microchannels with separate inlets and outlets, laterally connected through the V-shaped traps. Vshaped traps, with openings smaller than the size of a single cell, are fabricated in the middle (main) channel perpendicular to the flow direction. Cells are guided into the wells by streamlines of the flows and are kept still at the bottom of the traps. Cells can then be exposed to extracellular stimuli either in the main or the side channels. Microchannels and traps of different sizes can be fabricated in polydimethylsiloxane (PDMS), offering the possibility of independent studies on cellular responses with different cell types and different extracellular environmental changes. We believe that this versatile high-throughput cell trapping approach will contribute to further development of the current knowledge and information acquired from single-cell studies and provide valuable statistical experimental data required for systems biology.

Responding to an increasing demand for LoC devices to perform bioanalytical protocols for disease diagnostics, the development of an integrated LoC device consisting of a μPCR module integrated with resistive microheaters and a biosensor array for disease diagnostics is presented. The LoC is built on a Printed Circuit Board (PCB) platform, implementing both the amplification of DNA samples and DNA detection/identification on-chip. The resistive microheaters for PCR and the wirings for the sensor read-out are fabricated by means of standard PCB technology. The microfluidic network is continuous-flow, designed to perform 30 PCR cycles with heated zones at constant temperatures, and is built onto the PCB utilizing commercial photopatternable polyimide layers. Following DNA amplification, the product is driven in a chamber where a Si-based biosensor array is placed for DNA detection through hybridization. The sensor array is tested for the detection of mutations of the KRAS gene, responsible for colon cancer.

We present herein a microfluidic system based on passive effects for continuously separate a diphasic fluid-particles flow. Initially developed as a portable blood fragmentation device, its ability to operate passively, on several kinds of objects – organic or inorganic – opens the way to environmental applications, such as water cleaning or analysis. This technology can be implemented as a SamplePrep system, first step of an on-site analysis protocol. In addition, its low-cost and reliable manufacturing, compact size, low weight and ease of use make this technology a possible support for the deployment of health policies in developing countries.

The controlled delivery of drugs and biologicals (proteins, antibodies, DNA and derivatives) is a growing need to take the full benefit of new therapeutic strategies. However these new molecules or biomolecules display solubility issues, or high degradation rates once injected. Therefore, both suitable delivery materials for their encapsulation and protection from the surrounding environment, and smart delivery devices (such as micro-needles or implanted pumps) are necessary to achieve controlled delivery of these precious therapeutic agents. We have developed bio-inspired gel materials, based on lipid nanoparticles which act as reservoirs for lipophilic drugs. The lipid nanoparticles, termed lipidots™, are biocompatible, colloidally stable, non-immunogenic, and obtained from a cheap and simple solvent-free process. The particles can be assembled to form physical or chemical gels, with tunable rheological properties. Physico-chemical studies have been carried out to determine the limits of the stability domains for colloidal and gel formulations (choice of surfactants for nanoparticle surface, and composition ratios of lipids, surfactants and co-surfactants). In particular, it is demonstrated that lipid nanoparticles keep their integrity in the gels. Gels of lipidots™ could therefore constitute biocompatible materials for the efficient encapsulation and tuned delivery of lipophilic drugs and biomolecules.

A 13 x 13 square millimetre tri-axial taxel is presented which is suitable for some medical applications, for instance in assistive robotics that involves contact with humans or in prosthetics. Finite Element Analysis is carried out to determine what structure is the best to obtain a uniform distribution of pressure on the sensing areas underneath the structure. This structure has been fabricated in plastic with a 3D printer and a commercial tactile sensor has been used to implement the sensing areas. A three axis linear motorized translation stage with a tri-axial precision force sensor is used to find the parameters of the linear regression model and characterize the proposed taxel. The results are analysed to see to what extent the goal has been reached in this specific implementation.

Fibrinogen has been identified as a major risk factor in cardiovascular disorders. Fibrinogen (340 kDa) is a soluble dimeric glycoprotein found in plasma and is a major component of the coagulation cascade. It has been identified as a major risk factor in cardiovascular disorders. The time taken for its conversion to fibrin is usually used as an “endpoint” in most clot-based assays, without any information on dynamic changes in physical properties or kinetics of a forming clot. A global coagulation profile as measured by Thromboelastography® (TEG®) provides information on both the time and kinetics of changes in physical property of the forming clot. In this work, Quartz crystal microbalance (QCM), which is a piezoelectric resonator has been used to study coagulation of plasma and compared with TEG. The changes in resonant frequency (Δf) and half width at half maximum (HWHM or ΔΓ) were used to evaluate effect of fibrinogen concentration. It has been shown that TEG is less sensitive to low concentrations of fibrinogen and dilution while QCM is able to monitor clot formation in both the circumstances.

Dean forces have been consistently used in microfluidic mixing units and recently also have been utilized to separate particles in inertial force driven systems by secondary flows. Microfluidic separation systems using inertial forces created by curved asymmetric channels have already been established in the literature. In the present work, we propose a centrifugal lab-on-a-disc platform, which can provide focusing of particles of 21μm diameter size and high separation of two different density types of particles (polystyrene and silica) using of both the inertial focusing forces and sedimentation forces. This comprises the primary advantage of the proposed platform compared to a pump-driven system. This platform can be utilized for the separation of different types of cells bound to specifically-functionalized particles of different densities.