A monolithic silicon optoelectronic transducer for protein sensing is presented. The device is based on monolithic silicon optocouplers properly bio-functionalized so that signal transduction is induced by the optical coupling deduction due to biomolecular binding. Microfluidic modules made of PDMS are also employed for immobilization of biomolecules onto the optocouplers and sample application. Bioassay results concerning simultaneous real-time monitoring of binding reactions between two different protein analytes and their counterparts immobilized onto adjacent optocouplers are presented.

Biochip-compatible packaging for a DNA monolithic opto-electronic biosensor is presented. The packaging involves coated opto-coupler chips, ceramic carriers, plastic fluidic modules, optical alignment, self-aligned under-fill gluing as well as potting encapsulation. All the steps were implemented without denaturing the bio-molecular probes and without degrading the optical quality of the transducers. Such a packaged optical microchip was successfully employed in SNP detection.

Biomicroelectromechanical systems (bio-MEMS) are MEMS which are designed for medical or biological applications. As with other MEMS, bio-MEMS frequently, have to be packaged to provide an interface to the macroscale world of the user. Bio-MEMS can be roughly divided in two groups. Bio-MEMS can be pure technical systems applied in a biological environment or technical systems which integrate biological materials as one functional component of the system. In both cases, the materials which have intimate contact to biological matter have to be biocompatible to avoid unintentional effects on the biological substances, which in case of medical implants, could harm the patient. In the case of biosensors, the use of nonbiocompatible materials could interfere with the biological subcomponents which would affect the sensor's performance. Bio-MEMS containing biological subcomponents require the use of "biocompatible" technologies for assembly and packaging; e.g., high temperatures occurring, for instance, during thermosonic wire bonding and other thermobonding processes would denature the bioaffinity layers on biosensor chips. This means that the use of selected or alternative packaging and assembly methods, or new strategies, is necessary for a wide range of bio-MEMS applications. This paper provides an overview of some of the strategies, technologies, and applications in the field of bio-MEMS packaging. It includes the following: strategies for the partitioning of subsystems within integrated microsystems for (bio)chemical analysis/synthesis; methods for microassembly of bio-MEMS; technologies for bonding of polymer bio-MEMS components; packaging of miniature medical devices; packaging of biosensors for in vitro applications; packaging of micropumps as a bio-MEMS component. The applications discussed are derived from different fields to demonstrate the plethora of bio-MEMS considerations. In commercial production, packaging is possibly the major cost factor of bio-MEMS-based products, and its development requires special attention.

A bioanalytical microsystem that is based on a monolithic silicon optical transducer and a microfluidic module and it is appropriate for real-time sensing of either DNA or protein analytes is presented. The optical transducer monolithically integrates silicon avalanche diodes as light sources, silicon nitride optical fibers and detectors and efficiently intercouples these optical elements through a self-alignment technique. After hydrophilization and silanization of the transducer surface, the biomolecular probes are immobilized through physical adsorption. Detection is performed through reaction of the immobilized biomolecules with gold nanoparticle labeled counterpart molecules. The binding of these molecules within the evanescent field at the surface of the optical fiber cause attenuated total reflection of the waveguided modes and reduction of the detector photocurrent. Using the developed microsystem, determination of single nucleotide polymorphism (SNP) in the gene of the human phenol sulfotransferase SULT1A1 was achieved. Full-matching hybrid resulted in 4-5 times higher signals compared to the mismatched hybrid after hybridization and dissociation processes. The protein sensing abilities of the developed microsystem were also investigated through a non-competitive assay for the determination of the MB isoform of creatine kinase enzyme (CK-MB) that is a widely used cardiac marker.

An optical real-time affinity biosensor, which is based on a monolithic silicon optoelectronic transducer and a microfluidic module, is described. The transducer monolithically integrates silicon avalanche diodes as light sources, silicon nitride optical fibers, and p/n junction detectors and efficiently intercouples these elements through a self-alignment technique. The transducer surface is hydrophilized by oxygen plasma treatment, silanized with (3-aminopropyl)triethoxysilane and bioactivated through adsorption of the biomolecular probes. The use of a microfluidic module allows real-time monitoring of the binding reaction of the gold nanoparticle-labeled analytes with the immobilized probes. Their binding within the evanescent field at the surface of the optical fiber causes attenuated total reflection of the waveguided modes and reduction of the detector photocurrent. The biotin-streptavidin model assay was used for the evaluation of the analytical potentials of the device developed. Detection limits of 3.8 and 13 pM in terms of gold nanoparticle-labeled streptavidin were achieved for continuous- and stopped-flow assay modes, respectively. The detection sensitivity was improved by silver plating of the immobilized gold nanoparticles, and a detection limit of 20 fM was obtained after 20-min of silver plating. In addition, two different analytes, streptavidin and anti-mouse IgG, were simultaneously assayed on the same chip demonstrating the multianalyte potential of the sensor developed.

Peripheral nerve lesions lead to nerve degeneration and flaccid paralysis. The first objective in functional rehabilitation of these diseases should be the preservation of the neuro-muscular junction by biological means and following functional electrical stimulation (FES) may restore some function of the paralyzed limb. The combination of biological cells and technical microdevices to biohybrid systems might become a new approach in neural prosthetics research to preserve skeletal muscle function. In this paper, a microdevice for a biohybrid system to interface peripheral nerves after traumatic lesions is presented. The development of the microprobe design and the fabrication technology is described and first experimental results are given and afterwards discussed. The technical microprobe is designed in a way that meets the most important technical requirements: adaptation to the distal nerve stump, suitability to combine the microstructure with a containment for cells, and integrated microelectrodes as information transducers for cell stimulation and monitoring. Micromachining technologies were applied to fabricate a polyimide-based sieve-like microprobe with 19 substrate-integrated ring electrodes and a distributed counter electrode. Monolithic integration of fixation flaps and a three-dimensional shaping technology led to a device that might be adapted to nerve stumps with neurosurgical sutures in the epineurium. First experimental results of the durability of the shaping technology and electrochemical electrode properties were investigated. The three-dimensional shape remained quite stable after sterilization in an autoclave and chronic implantation. Electrode impedance was below 200 kΩ at 1 kHz which ought to permit recording of signals from nerves sprouting through the sieve holes.

Peripheral nerves have been previously interfaced with multi-electrode structures including sieve-shaped designs for regeneration of peripheral nerve axons through the sieve and cuff-shaped microelectrodes for interfacing intact peripheral nerve bundles. Both approaches assume intact motor neurons and neuromuscular junctions for excitation of skeletal muscle. An innovative biohybrid microdevice has been developed for housing gene manipulated nerve cell complexes on the microprobe. The microprobe is designed for implantation and for subsequent out-sprouting of probe based neural cells, generating a biological junction with the targeted skeletal muscle. Polymer micromachining technology has been applied to microfabricate 3-D flexible polymer structures with embedded microelectrodes. Adherence and growth of gene manipulated OLN-93 nerve cells on the probes have been investigated. Microprobes without cells have been implanted into the proximal stump of the sciatic nerve in the rat. Results demonstrate that the new design of 3-D biohybrid microprobes is well suited for implantation into the peripheral nervous system. OLN-93 nerve cells could adhere and grow on the microprobes under in-vitro conditions. The microprobes remained biostable and fixed at the original sites of the sciatic nerve 11 month after implantation

Article MINIATURISIERTE SIEB-ELEKTRODEN ALS SCHNITTSTELLE ZU NERVENSTÜMPFEN NACH AMPUTATION UND PERIPHERER LÄHMUNG was published on January 1, 2001 in the journal Biomedical Engineering / Biomedizinische Technik (volume 46, issue s1).

In cell-based biosensors which are used in test systems it is advantageous to position cells in array structures. Here, cells are positioned by hydrodynamic flow in microfabricated array structures on suction micro-holes with ring electrodes. The electrode impedance is measured to investigate if the positioning of cells can be electrically monitored. It is shown that hydrodynamic positioning of cells can be monitored by impedance measurement

To fulfill the need for rapid, cost-effective and sensitive methods for the detection of bacteria in medical diagnostics, food technology, biotechnology and environmental monitoring, a development of a bacterial sensor was initiated. Our approach of a biosensor for E. coli is based on an acousto-gravimetric flexural plate wave (FPW) transducer (gravimetric detection limit of less than 6 ng in a 32 microns thick sensitive layer in aqueous media), and an immunoaffinity layer on the transducer membrane for the molecular recognition of the target bacteria. An intermediate layer of covalently coupled poly (acrylic acid) yielded a major reduction of the non-specific binding to the metal surface. Such a biosensor, using antibodies against E. coli K12 and E. coli 15 outer surface antigens, yielded a detection range of 3.0 x 10(5) to 6.2 x 10(7) cells/ml for samples with the corresponding bacteria. To increase the sensitivity further, an amplification method using microspheres coupled with antibodies against E. coli was tested as a sandwich assay, and up to now a five-fold amplification of the signal has been achieved.