DIagnosis tOol Based on the measurement of molecular interactions

The result is one or several silicon chips, which include an array of piezoresistive cantilevers. These cantilevers have submicron thickness, a length between 100 and 300 micrometers and lateral dimensions in the range one to ten micrometers. The cantilevers are connected in a Wheatstone bridge or a half-bridge configuration and can provide an electrical voltage output proportional to the differential deflection between cantilevers. The cantilever structures, with a flat tip, are suitable for the measurement of intermolecular forces when binding is achieved between a functionalised cantilever and a differently functionalised surface. Modified piezoresistive cantilevers with sharp tips can be used for AFM applications in suitably adapted AFM instruments. Fabrication of cantilevers with on-chip integrated CMOS amplifier circuits has also been demonstrated. Devices such as those described are not commercially available. The flat tip cantilever devices are intended for in vitro diagnostics in healthcare, and may allow developing instruments for near-patient testing, such as the high-sensitivity instrument defined within BioFinger. In vitro diagnostics based on low-concentration protein detection have important application scenarios in human healthcare. The modified cantilevers with sharp tips can be used in AFM applications, and may allow developing all electrical AFM instruments. CNM has the capability of producing small and medium quantities of nanocantilever array chips in its clean room, through its commercial spin-off company D+T Microelectrónica. If required, production can be later transferred to a commercial MEMS foundry. Nanotec can commercialise the chips for external users.

The fictionalisation method can be used to perform localised fictionalisation of single cantilevers lined up in an array on a microchip. Applications like multi-analyte detection and schemes with dedicated reference cantilevers require that specific biomolecular recognition elements can be immobilised on a cantilever without affecting the neighbouring ones. Apart from providing local confinement of the probe solution used for immobilisation, the tool has to allow fast and simple alignment with the cantilever chip and has to be compatible with the chemistry used to carry out the binding procedure. To comply with these requirements, a fictionalisation tool based on surface-tension confinement has been designed. Deposition is carried out by wetting the cantilever with a small drop of probe solution formed at the tip of a polyether ether ketone (PEEK) capillary. The drop is created by applying a minute pressure to the solution in the capillary by controlled warming of the supply vial. The hydrophobicity of the PEEK material assures a high contact angle, and therefore good confinement, of the drop. The capillary array is aligned with the on-chip cantilevers by alignment guides machined into the capillary holder.

The CMOS-integrated four-channel static cantilever system is composed of four piezoresistive cantilevers, analog signal conditioning circuitry and an I2C interface and associated converters, monolithically integrated on the same chip. The size of the chip is 5 x 3 mm2. The chip presents a novel platform for the detection of surface-stress changes. The system benefits from standard, industrial CMOS technology to integrate the sensor elements. The four sensor cantilevers are combined with on-chip electronic circuitry to achieve low-noise performance a high degree of flexibility. Various configurations of sensing layers and reference cantilevers have been implemented, including fully symmetric Wheatstone bridges for reduced sensor offset. The system is targeted for "biosensing"- the detection of specific biomolecules, but can also be used for a variety of related surface-stress experiments, such as humidity or gas-sensing. The system is fabricated and fully tested. An upgrade to a larger sensor array is possible. The sensor is fabricated in a standard 0.8µm CMOS process and the cantilevers are released with dedicated post-CMOS micromachining. A special chip package based on the casting of poly(dimethylsiloxane) (PDMS) was developed, which allows the operation of the cantilever chip in liquid environments. Furthermore, the PDMS casting technology allows for the integration of microfluidic components, such as pumps and filters, which were implemented in the form a novel single-stroke micropump ans a blood filtration unit.

The four-channel resonant cantilever system features an array of four equally-spaced cantilevers with a pitch of 500 µm. The actuation, as well as the read out scheme is integrated on the cantilevers, which allows fully autonomous operation. Hence, no external read out equipment, such as a laser setup is needed. The cantilevers are electromagnetically actuated using the Lorentz force acting on an integrated current path in a static external magnetic field. The cantilever vibration is read out by a transistor-based Wheatstone bridge, which is located at the clamped edge of the cantilever. Monolithically integrated on the same chip are a multiplexer, an analog feedback circuit and a digital I2C bus interface. All four cantilevers can be sequentially connected via the multiplexer to the analog feedback circuit, thus serving as frequency-determining element in an oscillator configuration. The chip size is 4.8×2.6 mm2. With the integrated multiplexer it is possible to operate and read-out all four cantilevers sequentially. This allows, for instance, to quantify multiple analytes simultaneously in a sample. An upgrade to a larger sensor array is possible. The sensor is fabricated in a standard 0.8-µm CMOS process and the cantilevers are released with dedicated post-CMOS micromachining. A special chip package based on the casting of poly(dimethylsiloxane) (PDMS) was developed, which allows the operation of the cantilever chip in liquid environments. The sensor has been used to detect prostate specific antigen (PSA) levels as low as 10 ng/ml in sample fluids.

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