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31-10-2010, 08:40 PM


.docx   SMART OPTICAL CMOS ARRAY DETECTOR.docx (Size: 553.27 KB / Downloads: 55)


This report gives a very brief overview of micromechanical sensors, a field which is relatively new but has already filled bookshelves with meters of journal and conference papers and which has attracted great activity in the past 10-15 years.A microfluidic system for cancer diagnosis based around a core MEMS biosensor technology is presented in this paper. The principle of the MEMS biosensor is introduced and the functionalisation strategy for cancer marker recognition is described. In addition, the successful packaging and integration of functional MEMS biosensor devices are reported herein. This ongoing work represents one of the first hybrid systems to integrate a PCB packaged silicon MEMS device into a disposable microfluidic cartridge. Micromechanical sensors have become possible due to the development of micromachining echnologies and many of the concepts and principles on which the sensors rely can only be used courtesy of this technology. That is why a substantial part of this report is dedicated to this technology. Just not to leave the reader completely in the dark, at the end a extensive list of references is included for further reading.



Cancer diagnosis at its early stages has a profound impact on successful disease treatment. Such early detection in clinical diagnostics is now being realised through advances in analytical systems and instrumentation miniaturisation . The more recent introduction of microfluidic technologies has shown that there is great potential to take this positive impact even further by enabling the development of point of care systems . This has the important potential of significantly reducing the cost of health care. The SmartHEALTH Integrated Project consortium is funded by the European Commission to address these issues . The system presented in this paper is part of the clinical diagnostics instrument being developed within the smartHEALTH project and implimentation and its main aim is to address the necessity for accurate and early detection of several types of cancer
One aspect of micromechanical sensors is that they are made by micromachining technology which basically has been adopted from microelectronics. As such, the field of micromechanical sensor research and fabrication forms a part of a wider field called Micro System Technology (MST) (mostly used in Europe) or Micro Electro-Mechanical Systems (MEMS). Although in the field of MEMS there is no driving force to constantly reduce feature sizes, the efforts made in this direction in the field of microelectronics are used beneficially. It offers MEMS researchers and engineers a toolbox increasingly meeting their requirements in terms of accuracy and feature size.
If one had to give an indication of the feature sizes of MEMS devices one could say that these roughly have dimensions on the order of one micrometer to one millimetre, albeit that this is no
restricting definition. Although these dimensions may look modestly small in respect of today’s advent of nanotechnology, there is still a huge transition going from "macro-sensors" to micro-sensors which is related to various scaling laws. This may be easily appreciated looking at a unit-cell in the form of a cube with (linear) unit dimension l. Since the volume, and hence the mass, are proportional to l3, and the surface is proportional to l2, the ratio of body to surface forces will be proportional to l. In other words, scaling down a "macro-sensor" from 1 cm to 10 micrometer, means that the surface forces will play a 1000-fold more important role. This is for example reflected in the
fact that gravity normally does not play an important role in micromechanical sensors2 (nor do inertial forces) except when sensors are especially aimed at measuring these effects3. Looking at diffusion, be it particles or fluxes (e.g. heat), diffusion times scale with l2. Hence, thermal processes will be 100 times faster when one reduces a system by a factor of 10.


Micromechanical sensors form a class of sensors which we here loosely define as sensors which are sensistive in one way or another to mechanical properties and which are made by micromachining technology (disregarding the actual size of the sensors). The diagnostic system being developed relies on a circular diaphragm resonator (CDR), MEMS mass sensor, as the central theme. This type of sensor is attractive as a new platform technology in the first instance due to the sensitivity it yields compared to current state of the art mass sensors. The published mass sensitivity being 100pg cm-2 Hz. As an introduction to the principles of the core technology the CDR device takes advantage of the degenerate mode resonant mass sensor principle [5]. In short, this principle consists of a vibrating circular diaphragm, which supports a- pair of spatially independent modes of vibration sharing a common natural frequency. By functionalising the area corresponding to one of these modes with a biological capture species e.g. an antibody, but ensuring the remaining area remains inert, a biosensor is created. In basic terms, target molecules bind to the functionalised area creating a split in the resonant frequency of the two modes, which is proportional to a change in mass at the surface and, ultimately, analyte concentration. This type of structure presents the intrinsic advantage of having a reference frequency, to compensate for non-specific effects, within the same structure as the functional device thus improving the sensitivity of detection. The fact that a reference sensor is not required to compensate for pressure and temperature fluctuations is a significant advantage. 

In the above response we can see that, the difference in mass on the patterned and non-patterned sections creates a frequency split that can be measured. Supplementary addition of mass when the target analyte is captured further increases the frequency split. The fact that the sample and reference sectors are on the same sensor will auto-compensate for temperature and pressure fluctuations maintaining the relative frequency split value.

There is an important aspect of microsensors: being small, and generally producing small signals, they do not trivially interface with the macro-world. Therefore, micromechanical sensors cannot be viewed as separate entities but they should actually be considered as microsystems involving not only the sensing microstructure but the interfacing and packaging as well. Hence, the design and development-process of microsensors should simultaneously include the interfacing and packaging aspects in order to successfully come to a working micro-sensor-system. In some cases, where one cannot rely on standard technology (i.e. in the form of foundry-processes4), it may be even necessary to design the microfabrication processes hand in hand with the microsystems. The foregoing also reveals the multi-disciplinary nature of microsensorsystems; not only are the mechanical properties of structures important, but generally all the physical domains that take part in the transduction of the measurand to the eventual signal. This may involve such things as mechanics, for the actual response of the sensor (i.e. a bending membrane), optics (for read-out of a displacement), opto-electronic conversion and electronics for further signal processing. Moreover,the sensorsystem needs to be packaged. Although packaging of electronic integrated circuits is not a trivial thing, packaging a microsensor may even be more challenging by the very sole reason that a sensor should somehow "be open" to the environment in order to measure the measurand. This means, that apart from an electrical interconnection, it needs at least one other physical connection.
Also from this point of view, the design and development of microsensorsystems requires multidisciplinary teams and system approaches, rather than sole monodisciplinary depth.

The hybrid microfluidic cartridge realisation can be split into three
strands. A. Microfabrication of the Si/glass CDR device. B. Surface functionalisation of the CDR device. C. Packaging the CDR onto a custom designed PCB and integration of the downstream components into a polymer microfluidic platform.

A. MEMS device fabrication
In the current fabrication process the cavity underneath the diaphragm was created by reactive ion etching 2μm
into a 4μm device silicon layer of a SOI wafer. As the diaphragm
and the cavity walls are made of the same material, the diaphragm is perfectly clamped thus ensuring that the flexural displacement of the diaphragm at the outer edge is fully constrained - essential for the correct performance of the device. This step has been introduced to reduce quality issues encountered in earlier manufacturing runs,which were created during Si and glass bonding.
B. Device functionalisation
A hydrophilic polymer was developed
as the basis for biological functionalisation .Using novel
conditions for deposition, APTES was shown to form a porous
polymeric capture network covalently linked to silicon surfaces. Hydrophilic nature of the polymer helps to maintain the 3-D structure of biomolecules and therefore improves functionality at the sensor
interface. Secondly, and most importantly, the polymer has
demonstrated the ability to absorb biomolecules, which should
increase the dynamic range of the sensor. Finally, the optimised
chemistry on CDR patterns demonstrated that the immobilisation
strategy produces highly site-specific and reproducible surfaces for
both CEA antigen / HPV DNA target recognition.
C. Packaging and integration of the device into a microfluidic
During sensor chip integration and packaging, standard operating
procedures were developed such that the mechanical stability of the
diaphragm was not compromised and the functionalising polymer
was not contaminated. In this process, the first step was to mount the
MEMS devices onto a recess of a rigid-flex PCB and then establish
electrical connections for the screening and drive/sense electrodes.
The CDR sensor was then electrically connected to the PCB using
microflex, the proprietary interconnection technology of IBMT (Fig.
6), resulting in a flat surface. The CDR loaded PCB was then
encapsulated with a biocompatible epoxy layer, whilst leaving the
functionalised diaphragm area uncoveredThe packaging procedure, was completed when the CDR loaded PCB was sandwiched, using a shell and insert principle, into a milled polycarbonate microfluidic network that handles reagents and delivers the sample to the biosensor.


Ultimate aim of the SmartHEALTH project and implimentation is tomdevelop an instrument, which achieves an electronic readout of the signal, the preliminary tests of the CDR biosensor have been carried out using electrical stimulation and optical detection. The laser Doppler vibrometry test station used has been described previously . For the purpose of optical access, a window was incorporated into the development prototype cartridge. It is worthy of note that the development of the electronic readout is in progress and will produce a viable signal amplifier and digital signal processing board. In the first instance the fully packaged CDR devices (not functionalised) were mechanically tested. These tests were carried out in the fluidic reaction chamber under vacuum (0.2mbar). Under these conditions, it was found that an unexpected attenuation was observed. This attenuation was attributed to the presence of air in the device cavity (cavity separating the diaphragm from the electrodes). Air was trapped because the epoxy embedding of the die was carried out at atmospheric pressure. As the embedding epoxy covers the electrical bond pads, the channels above the metal lines were sealed (channels result from the glass etch previous to the gold deposition). This effectively locks air inside the chamber underneath the diaphragm, making it impossible to evacuate the cavity when the air is pumped out of the rest of the fluidic network. In order to confirm this, a CDR was packaged without embedding the contact pads in epoxy and then tested at PCB level under vacuum (0.2mbar) and at atmospheric pressure. This resulted in a clear contrast in the amplitude of the resonance peak as can be seen in Fig.

. This was in accordance with what was previously observed
during characterization of large die devices, in which severe
vibrational damping was present in devices tested at atmospheric
pressure .


Fabrication of a new generation of MEMS mass sensor devices based on the CDR principle and their subsequent packaging and integration onto a disposable microfluidic cartridge has been achieved. This hybrid assemblage of PCB packaged silicon MEMS and polymer microfluidics represents one of the first of its kind. The successful deposition of a bio-functionalizing polymer has also been achieved on the MEMS device thus converting it to a biosensor, which will be capable of detecting cancer markers at lowlevels. This will allow the SmartHEALTH project and implimentation to proceed to proof of concept assays in the coming months.

[1] L.J. Kircka “Miniaiturization of analytical systems”
[2] T.H. Schulte, R.L. Bardell and B.H. Weigl “Microfluidic technologies in clinical diagnostics”
[3] A.J. Tudos “Trends in miniaturized analytical systems for point-of-care testing in clinical chemistry”
[4] A.K. Ismail ‘‘The principle of a circular diaphragm mass sensor’’
[5] A.K. Ismail “The fabrication, characterisation
and testing of a circular diaphragm mass sensor”
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