Advanced microtechnologies offer new opportunities for the development of active implants that go beyond the design of pacemakers and cochlea implants. Examples of future implants include neural and muscular stimulators, implantable drug delivery systems, intracorporal monitoring devices and body fluid control systems. The active microimplants demand a high degree of device miniaturization without compromising on design flexibility and biocompatibility requirements. With the need for integrating various microcomponents for a complex retina stimulator device, we have developed a novel technique for microassembly and high-density interconnects employing flexible, ultra-thin polymer based substrates. Pads for interconnections, conductive lines, and microelectrodes were embedded into the polyimide substrate as thin films. Photolithography and sputtering has been employed to pattern the microstructures. The novel "MicroFlex interconnection (MFI)" technology was developed to achieve chip size package (CSP) dimensions without the requirement of using bumped flip chips (FC). The MFI is based on a rivet like approach that yields an electrical and mechanical contact between the pads on the flexible polyimide substrate and the bare chips or electronic components. Center to center bond pad distances smaller than 100 /spl mu/m were accomplished. The ultra thin substrates and the MFI technology was proven to be biocompatible. Electrical and mechanical tests confirmed that interconnects and assembly of bare chips are reliable and durable. Based on our experience with the retina stimulator implant, we defined design rules regarding the flexible substrate, the bond pads, and the embedded conductive tracks. It is concluded that the MFI opens new venues for a novel generation of active implants with advanced sensing, actuation, and signal processing properties.

A new interconnection technique has been developed that allows versatile multiple strand connections between microsensors, sensor arrays, and chips designed for wire bonding. The new technique has been termed “Microflex interconnection” technique (MFI). Conventional wire bonding technique is commonly restricted to planar interconnects with a limited degree of freedom for placing microsystem components in hybrid assemblies. The MFI technique has overcome this limitation by interconnecting microsystem components through custom designed flexible substrates with embedded metallized conductors, pad arrays for integrated circuits’ assembly and substrate integrated electrodes. Standard CMOS components without additional pad metallization can be used. The integration density of the MFI technique corresponds to one of the flip-chip technology. Special advantages of the MFI technique are three-dimensional interconnects, the flexibility in design and shape, and easy visual inspection of alignment qualities. The method is especially suitable for small volumes of customer specified devices and biomedical implants because all materials used are biocompatible. Within this paper, the MFI technique is introduced, described in detail, and tested according to international standards. The evaluation of the electrical and mechanical properties of the interconnection sites exhibited promising results regarding stability and reliability. First applications in the biomedical field were presented on the example of a neural implant and a sensorized cardiac catheter.

Micromachining technologies were established to fabricate microelectrode arrays and devices for interfacing parts of the central or peripheral nervous system in case of neuronal disorders. The devices were part of a neural prosthesis that allows simultaneous multichannel recording and multisite stimulation of neurons. Overcoming the brittle mechanics of silicon devices and challenging housing demands close to the nerve, we established a process technology to fabricate light-weighted and highly flexible polyimide based devices with integrated interconnects. A new assembling technique-the microflex interconnection (MFI)-has been applied for the connection of the flexible microsystems to silicon microelectronics. In this paper, we present different shapes and applications of the flexible electrodes. The discussion is focused on electrode properties and the hybrid assembly of a fully implantable neural prosthesis

Different research groups are focusing their work on the development of a neural prostheses to aid patients suffering from blindness. A German consortium of 14 partners works on the development of a retina implant system for ganglion cell stimulation. This paper outlines the concept of the authors' system and focuses on the flexible substrate and the assembly of the first implantable retina stimulation systems

For cell biosensors and for studying neural networks using planar electrode substrates, a suitable technique for positioning single cells on electrodes was needed. We reported a new method for fast and efficient positioning of single cells on ring electrodes by controlled suction through holes. We described the microfabrication of electrode substrates with microholes and the cell positioning procedure. L929 cells and Neuro 2A cells could be positioned in parallel without cell damage.

Patients that are blind due to photoreceptor degeneration caused by retinitis pigmentosa or macula degeneration are able to perceive light sensations after localized electrical stimulation. This opens the possibility to restore vision by an artificial implant to some extend. Thirteen groups in the German EPI-RET consortium work on the development of an epiretinal implant for ganglion cell stimulation. Here, we present the development of flexible stimulation devices and the hybrid integration of all components to an implantable system. Micromachining technology has been used to realize 15 micron thin, ultra-light weighted and highly flexible substrates with 25 stimulation electrodes. Polyimide has been used as material for substrate and insulation layers. Gold and platinum or Iridium has been used for integrated conductive lines and electrodes, respectively. Cytotoxicity testing according to ISO and USP has been performed. The polyimide and the metals proved to be non toxic. An assembling technology has been developed to connect the microchips to the thin polyimide substrate. First prototypes exhibit excellent mechanical properties.

A new stacking technology -MicroStack (MS)-for the assembly of multible integrated circuits (IC) and micro devices has been developed. It is based on the MicroFlex-Interconnection- (MFI) and Flip-Chip technology. Microdevices have been assembled on high density thin film flexible multilayer substrates in arrangements that minimize conductor path lengths, adjust to various housing shapes, and improve the thermal management of microdevices by integration of heat sinks. Flexible, 10 mum high-density thin film polyimide multilayer substrates (HDI-F) (Pyralin, PI 2611, DuPont) have been fabricated using micromachining techniques. The polyimide substrate serves for both, mechanical support for handling and electrical interconnection. The MFI (connection of chips through holes in the polyimide with bond balls) was used to assemble standard Ii's onto the polyimide substrates. In a first step, one chip is assembled on the back side of the flexible ribbon cable by the MFI technology. In the second step, a second chip is adjusted face to face to the bond balls onto the topside of the substrate. The ball served as a conductor studs for the Flip-Chip bonding of the top side chip. The polyimide substrate and the ball studs separate both chips with a distance of 20-60 mum. Several microsystem pairs were connected to one substrate. Such assembled substrates can build stacks by faulting. Heal sinks can be integrated by placing heating conductor devices between each chip pair. The MS technique was applied to place micro-devices with high interconnection densities of <150 <mu>m pitch. The chip pairs were flexible to bending and robust to mechanical handling at the same time. The MFI proved to be highly reliable in respect of tests according to MIL 883 1010 C.

For single-cell-biosensor applications and for studying neural networks using planar electrode substrates often the position of cells on detectors is necessary. Here, the authors present a new method for fast placement of single cells on ring electrodes by suction on suction holes. They describe the fabrication of a micromachined planar electrode substrate with suction holes and the placement of L929 cells and Neuro 2A cells on particular positions. The results are discussed regarding the deciding factors for placement. Finally, applications of the authors' cell placement technique to form patterned neural networks are outlined.

This paper describes a new interconnection wire method which allows versatile multiple strand connections between microsensors, sensor arrays and integrated circuits (IC). The interconnection method is termed Micro Flex Interconnects (MFI). One example for this technology is the connection of implantable, highly flexible neural micro devices to electronics for interfacing to the external world. The interconnection technique is based on a novel multilayer process using polyimide (Du Pont PI 2611) [1]. The thickness of the polyimide structure ranges from 5 to 15 mu m including the insulation layers. Several metallization layers can be embedded in the material. This approach exhibits same advantages. The involved material is non-toxic and the IC's do not need any additional bond pad metallization. The MFI technique has been proven long-term stable. The metallization material can be chosen accordingly for electrodes, conducting lines, and connection pads. An commercial ball wedge bonder is the only equipment needed to perform the MFI method.

Micromachining technologies were established to fabricate microelectrode arrays and devices for interfacing parts of the central or peripheral nervous system. The devices were part of a neural prosthesis that allows simultaneous multichannel recording and multisite stimulation of neurons. Overcoming the brittle mechanics of silicon devices and challenging housing demands close to the nerve we established a process technology to fabricate light-weighted and highly flexible polyimide based devices. Platinum and iridium thin-film electrodes were embedded in the polyimide. With reactive ion etching we got the possibility to simply integrate interconnections and to form nearly arbitrary outer shapes of the devices. We designed multichannel devices with up to 24 electrodes in the shape of plates, hooks and cuffs for different applications. In vitro tests exhibited stable electrode properties and no cytotoxicity of the materials and the devices. Sieve electrodes were chronically implanted in rats to interface the regenerating sciatic nerve. After six months, recordings and stimulation of the nerve via electrodes on the micro-device proved functional reinnervation of the limb. Concentric circular structures were designed for a retina implant for the blind. In preliminary studies in rabbits, evoked potentials in the visual cortex corresponded to stimulation sites of the implant.

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.

A new interconnection technique has been developed that allows versatile multiple strand connections between microsensors, sensor arrays, and chips designed for wire bonding. The new technique has been termed 'microflex interconnects' (MFI).Conventional wire bonding technique is commonly restricted to planar interconnects with a limited degree of freedom for placing microsystem components. The MFI technique has overcome this limitation by interconnecting microsystem components through custom designed flexible foils with embedded metallized conductors. The MFI foils may also serve as circuit substrates. This basic foil material is polyimide (Du Pont PI 2611)(1) or BCB2 which are patterned photolithographically. Platinum, gold or either conductive metals are sputtered or evaporated on the foil and patterned using lift-off technique. Several metallization layers can be embedded in the material. Pitch and shape of the MFI contact pads correspond to the one of the chips to be interconnected. A via hole is placed in the center of the MFI contact pads. MFI pads and chip pads are adjusted. Metal balls or wedges generate the electrical and mechanical contact through the vias between the chips and the MFI substrate. An commercial wire bonder is the only equipment needed to perform, the MFI method.The MFI technique was applied to bond standard CMOS integrated circuit (IC) bond pads with a width of 30 mu m and a pitch of 70 mu m to a 10 mu m thick MFI foil. The integration density of the MFI technique correspond to one of the flip-chip technology(3). Special advantages of the MFI technique are three-dimensional interconnects, the flexibility in design and shape, and easy visual inspection of alignment qualities. The MFI method is also suited for biomedical applications because all materials used are biocompatible.

Article Flexible Multikanal-Mikroelektroden mit integrierten Zuleitungen zum Einsatz in der Neuroprothetik was published on January 1, 1997 in the journal Biomedical Engineering / Biomedizinische Technik (volume 42, issue s2).

It has been shown previously that peripheral nerve axons regenerate through microvias in silicon devices, A major challenge in the design of a biocompatible interface is to establish a reliable electrical and mechanical interconnection to signal-processing and transmission electronics which allows simultaneous multichannel recordings or stimulation of nerves, This paper describes the on-going work of developing a new generation of flexible and extremely light-weight electrode arrays with integrated cables. A process technology has been established to fabricate a multilayer device with micromachining methods, which overcomes the 'classical' separation of substrate and insulation layers, The micromachined electrodes exhibit promising mechanical stability and high insulation resistance.

Different research groups are focusing their work on the development of a neural prostheses to aid patients suffering from blindness. In some diseases (retinitis pigmentosa or macula degeneration), degeneration of the photoreceptors often leaves the ganglion cell layer and the central vision system largely intact. This paper outlines the authors' approach of interfacing the retina with flexible multielectrode structures for ganglion cell stimulation. Results are given on the material selection for substrate materials and the design for flexible stimulation devices. By means of cytotoxicity testing, in a first step of an evaluation procedure, the biocompatibility of different substrate and coating materials has been investigated. The methods were sensitive to such a degree that even the influence of changes in process technology on the material was detected. Different geometric test structures have been created that led to the design of flexible, light-weighted stimulation devices with integrated cables. The devices were fabricated using micromachining technology. The authors used polyimide as substrate and insulation layers and platinum as electrode and interconnect metallization layers. The first structures were distributed to the partners for acute and chronic implantation in animal models.

It has been shown previously that peripheral nerve axons are regenerating through microvias in silicon devices. A major challenge is the design of a biocompatible integrated neural connector allowing simultaneous, multi-site recordings or stimulation of axons in nerve bundles and to establish a reliable mechanical and electrical connection. This paper describes on-going research in the framework of an European project aimed to develop an implantable neural microsystem comprising various designs of perforated dices, multiple electrodes with on-chip integrated preprocessing circuitry, functional guidance channels for support and fixation of regenerating axons, and interconnection assemblies for bi-directional nervous signal transmission. Special emphasis is given on a light-weight design of the device and on the biocompatible integration and packaging of the chip. In this paper, we report about the microfabrication of the perforated dices, their incorporation into biocompatible guidance channels, and about in vitro and in vivo biocompatibility testing of materials applied.