This paper reports on the hybrid integration of a shape memory alloy (SMA) wire into a micromechanical structure to form a thermal drive system with advanced performance. The SMA wire is utilized as a bending actuator driving a suspended shuttle. This approach allows a cyclic movement with large displacements and forces. Depending on the temperature and the mechanical boundary conditions, the actuator provides maximum displacements of 160 µm and maximum forces of about 120 mN. Displacement and force of the drive system are adjustable by design of the return spring stiffness and a geometry-defined offset. The influence of spring stiffness, offset and temperature load on the actuator performance is presented. The proposed actuator system enables new applications, for example chip-based energy autonomous detection and counting of thermal thresholds.

In this paper we present a hybrid microsystem for acquisition and counting of sterilisation cycles. The device includes a micromechanical counter mechanism and a thermal actuator based on a shape memory alloy (SMA). The device is designed to count 100 sterilization cycles. The basic functionality is investigated on a hotplate using a thermal temperature profile with a peak temperature of 135 deg C. In this manner, counting of thermal cycles is demonstrated.

The steam sterilization of reusable medical instruments is a critical process. Standardized treatments with hot, saturated steam at maximum temperatures of up to 138 degrees C often represent a significant thermal load, which is repeated with varying number of cycles depending on the medical device. Until now, there is no possibility for medical device manufacturers to monitor how often a product has been sterilized. However, this is necessary for both safety and warranty issues, since according to the European Medical Device Regulation (EU-MDR), the manufacturer must specify how often a product can be sterilized. In this paper the actuator approach for a micromechanical "sterilization cycle counter" is presented. It is designed to autonomously record, count and store steam sterilizations directly on the instrument by combining silicon micromechanics with shape memory alloy (SMA) actuators. This enables an autonomous operation without additional energy sources such as batteries. During the steam sterilization cycle, a certain temperature limit is exceeded once and detected by the SMA. The system development aims at the heterogeneous integration of standard SMA wires into a silicon microstructure. The transformation temperatures of the SMA is thereby increased to the relevant range by prestressing. In detail, the paper first describes the approach of the counting mechanism and the possibilities and limitations of implementing and pretensioning of SMA wires in silicon microstructures. Based on that, the development of the SMA actuator geometry using an SMA Finite Element Analysis (FEA) model according to the approach of Aurichio is described. The model is validated using an up-scaled test bench of the system, in which various geometric parameters can be varied. Finally, the results will be discussed in particular regarding the MEMS process chain to be carried out in the next step.

Intracortical microprobes allow the precise monitoring of electrical and chemical signaling and are widely used in neuroscience. Microelectromechanical system (MEMS) technologies have greatly enhanced the integration of multifunctional probes by facilitating the combination of multiple recording electrodes and drug delivery channels in a single probe. Depending on the neuroscientific application, various assembly strategies are required in addition to the microprobe fabrication itself. This paper summarizes recent advances in the fabrication and assembly of micromachined silicon probes for drug delivery achieved within the EU-funded research project NeuroProbes. The described fabrication process combines a two-wafer silicon bonding process with deep reactive ion etching, wafer grinding, and thin film patterning and offers a maximum in design flexibility. By applying this process, three general comb-like microprobe designs featuring up to four 8-mm-long shafts, cross sections from 150×200 to 250×250 µm², and different electrode and fluidic channel configurations are realized. Furthermore, we discuss the development and application of different probe assemblies for acute, semichronic, and chronic applications, including comb and array assemblies, floating microprobe arrays, as well as the complete drug delivery system NeuroMedicator for small animal research.

Fur ein miniaturisiertes osmotisches Medikamen- tendosiersystem, das als austauschbare Kartusche in einer Zahnteilprothese getragen wird, wurden mogliche Einbau- verfahren evaluiert, welche sich durch die Vermessung und Betrachtung des verfugbaren Platzes im Prothesenkorper in 200 Zahnpatientenfallen ergaben. Hierbei wurde beruck- sichtigt, dass einerseits der Wirkstoff in ausreichender Men- ge in der Kartusche gespeichert werden kann, andererseits die ursprunglichen Funktionsfahigkeiten der Prothese, d.h. die Stabilitat, Langlebigkeit und Okklusion erhalten bleiben. In Abhangigkeit der Einbauhohe zwischen Kieferkamm- Mitte und der tiefsten Stelle der Zentralfissur des entspre- chenden Zahnes, kann die Kartusche entweder bei ausrei- chenden Platzverhaltnissen in einem standardisierten Ein- baukasten oder bei unzureichenden Platzverhaltnissen in einer individuell gefertigte Prothese in 183 der 200 betrach- teten Falle eingebaut werden.

Microinfusions of drugs directly into the central nervous system of awake animals represent a widely used means of unravelling brain functions related to behaviour. However, current approaches generally use tethered liquid infusion systems and a syringe pump to deliver drugs into the brain, which often interfere with behaviour. We address this shortfall with a miniaturised electronically-controlled drug delivery system (20 × 17.5 × 5 mm3) designed to be skull-mounted in rats. The device features a micropump connected to two 8-mm-long silicon microprobes with a cross section of 250 × 250 μm2 and integrated fluid microchannels. Using an external electronic control unit, the device allows infusion of 16 metered doses (0.25 μL each, 8 per silicon shaft). Each dosage requires 3.375 Ws of electrical power making the device additionally compatible with state-of-the-art wireless headstages. A dosage precision of 0.25 ± 0.01 μL was determined in vitro before in vivo tests were carried out in awake rats. No passive leakage from the loaded devices into the brain could be detected using methylene blue dye. Finally, the device was used to investigate the effects of the NMDA-receptor antagonist 3-((R)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid, (R)-CPP, administered directly into the prefrontal cortex of rats during performance on a task to assess visual attention and impulsivity. In agreement with previous findings using conventional tethered infusion systems, acute (R)-CPP administration produced a marked increase in impulsivity.

This paper reviews miniaturized drug delivery systems applying osmotic principles for pumping. Osmotic micropumps require no electrical energy and consequently enable drug delivery systems of smallest size for a broad field of new applications. In contrast to common tablets, these pumps provide constant (zero-order) drug release rates. This facilitates systems for long term use not limited by gastrointestinal transit time and first-pass metabolism. The review focuses on parenteral routes of administration targeting drug delivery either in a site-specific or systemic way. Osmotic pumps consist of three building blocks: osmotic agent, solvent, and drug. This is used to categorize pumps into (i) single compartment systems using water from body fluids as solvent and the drug itself as the osmotic agent, (ii) two compartment systems employing a separate osmotic agent, and (iii) multi-compartment architectures employing solvent, drug and osmotic agent separately. In parallel to the micropumps, relevant applications and therapies are discussed.

The NeuroMedicator is a micropump integrated with application-specific silicon microprobes aimed for drug delivery in neural research with small animals. The micropump has outer dimensions of 11 × 15 × 3 mm3 and contains 16 reservoirs each having a capacity of 0.25 µL. Thereby, the reservoirs are interconnected in a pearl-chain-like manner and are connected to two 8 mm long silicon microprobes. Each microprobe has a cross-sectional area of 250 × 250 µm2 and features an integrated drug delivery channel of 50 × 50 µm2 with an outlet of 25 µm in diameter. The drug is loaded to the micropump prior to implantation. After implantation, individual 0.25 µL portions of drug can be sequentially released by short heating pulses applied to a polydimethylsiloxane (PDMS) layer containing Expancel® microspheres. Due to local, irreversible thermal expansion of the elastic composite material, the drug is displaced from the reservoirs and released through the microprobe outlet directly to the neural tissue. While implanted, leakage of drug by diffusion occurs due to the open microprobe outlets. The maximum leakage within the first three days after implantation is calculated to be equivalent to 0.06 µL of drug solution.

This paper reports on the drug release mechanisms of silicone structures with embedded steroids applied in pacing leads. Different derivatives of the steroid dexamethasone, which is associated with the reduction of acute stimulation thresholds, were evaluated together with different matrix based release control mechanisms with the target to potentially match optimal drug release rates during the first month after implantation. By incorporating dexamethasone-21-dihydrogen phosphate in silicone matrices in combination with release rate adaption layers, almost continuous release rates were obtained under physiological test settings.

We report on a miniaturized, exchangeable drug delivery cartridge for Parkinson's Disease which is integrated in a partial removable prosthesis. An osmotic pumping principle uses saliva to release constantly a separately stored drug to the buccal mucosa, thus avoiding first pass metabolism and drug plasma level fluctuations. Therapeutic relevant information and fill level of the cartridge can be determined before and after usage with an external readout station. The selected material combinations of the cartridge fulfill both, functional and regulatory aspects as well as requirements for assembly and packaging, e.g. thermal fusion bonding, solvent bonding and capillary stop bonding. By using the cartridge, highly precise release rates over 97% of its storage capacity with a rate deviation of only 1.1% can be achieved.

A parameter based approach for selecting hybrid thermoplastic material combinations for solvent bonding by applying the supposed Hansen Solubility Parameter (HSP) model is demonstrated. This new method allows identification of (i) appropriate material combinations as well as (ii) less harmful or more cost effective solvents to replace potentially toxic combinations. The required number of experimental trials is minimized with respect to conventional selection techniques in both cases. Exemplary, the HSP model was successfully applied to select the polymer material of a flexible membrane as well as a suitable solvent mixture for bonding with a rigid cyclic olefin copolymer (COC). The rigid/flexible material bond is the integral part of a miniaturized microfluidic drug delivery device based on osmotic pumping. Characterizations of the bond quality in the assembled device confirmed the predictions of the model as a promising engineering tool.

This paper reports on silicon-based microprobes, 8 mm long and 250 µm × 250 µm cross-section, comprising four recessed biosensor microelectrodes (50 µm × 150 µm) per probe shank coated with an enzymatic layer for the selective detection of choline at multiple sites in brain tissue. Integrated in the same probe shank are up to two microfluidic channels for controlled local liquid delivery at a defined distance from the biosensor microelectrodes. State-of-the-art silicon micromachining processing was applied for reproducible fabrication of these experiment-tailored multi-functional probe arrays. Reliable electric and fluidic interconnections to the microprobes are guaranteed by a custom-made holder. The reversible packaging method implemented in this holder significantly reduces cost and assembly time and simplifies storage of the biosensor probes between consecutive experiments. The functionalization of the electrodes is carried out using electrochemically aided adsorption. This spatially controlled deposition technique enables a parallel deposition of membranes and is especially useful when working with microelectrode arrays. The achieved biosensors show adequate characteristics to detect choline in physiologically relevant concentrations at sufficient temporal and spatial resolution for brain research. Sensitivity to choline better than 10 pA µm−1, detection limit below 1 µM and response time of 2 s were obtained. The proposed combination of biosensors and microfluidic injectors on the same microprobe allows simultaneous chemical stimulation and recording as demonstrated in an agarose gel-based brain phantom.

Body sensor networks (BSN) promise to enhance quality of life in common human habitats. The very next and natural step towards the improvement of the already valuable applications based on BSN is the incorporation of body actuator devices which adapt its actuation dynamically based on the information provided by the body sensors, thus forming Body Sensor and Actuator Networks (BS&AN). This paper shows how BS&AN can be exploited to create an innovative system to support the treatment of patients affected by Parkinson's Disease (PD). The combination of clinical and technological knowledge in BS&AN allows to significantly improve the quality of life of patients suffering from PD.

This paper reports on the design, fabrication, assembly and characterization of a three-dimensional silicon-based floating microprobe array for localized drug delivery to be applied in neuroscience research. The microprobe array is composed of a silicon platform into which up to four silicon probe combs with needle-like probe shafts can be inserted. Two dedicated positions in the array allow the integration of combs for drug delivery. The implemented comb variants feature 8 mm long probe shafts with two individually addressable microchannels incorporated in a single shaft or distributed to two shafts. Liquid supply to the array is realized by a highly flexible 250 mu m thick multi-lumen microfluidic cable made from polydimethylsiloxane (PDMS). The specific design concept of the slim-base platform enables floating implantation of the array in the small space between brain and skull. In turn, the flexible cable mechanically decouples the array from any microfluidic interface rigidly fixed to the skull. After assembly of the array, full functionality is demonstrated and characterized at infusion rates from 1 to 5 mu L min(-1). Further, the effect of a parylene-C coating on the water vapour and osmotic liquid water transport through the PDMS cable walls is experimentally evaluated by determining the respective transmission rates including the water vapour permeability of the used PDMS type.

We report on a novel disposable drug delivery system for neural research which allows to infuse 16 discrete liquid portions of 0.25 µL directly into neural cell tissue. The system comprises an 11×14.5×3 mm3 fluidic chip with a pluggable electrical micro connector and two 8-mm-long micromachined silicon fluidic microprobes with a cross-sectional area of 250×250 µm2. A pearl chain-like fluidic structure with spherical segments was developed which stores and predefines the required drug liquid portions for the whole time of operation. The micropump principle for liquid delivery is based on the local, irreversible thermal expansion of microspheres embedded into polydimethylsiloxane (PDMS).

This paper reports on the design, fabrication and characterization of silicon-based microprobes for simultaneous neural recording and drug delivery. The fabrication technology is based on two-stage deep reactive ion etching combined with silicon wafer bonding and grinding to realize channel structures integrated in needle-like probe shafts. Liquids can be supplied to microfluidic devices via in-plane and out-of-plane ports. The liquid is dispensed at circular out-of-plane ports with a diameter of 25 µm and rectangular in-plane ports with dimensions of 50 × 50 µm2. Two-shaft probes with a pitch between shafts of 1.0 and 1.5 mm were realized. The probe shafts have a length of 8 mm and rectangular cross-sections of w × h (w = 250 µm and h = 200 or 250 µm). Each shaft contains one or two fluidic channels with a cross-section of 50 × 50 µm2. In addition, each probe shaft comprises four recording sites with diameters of 20 µm close to the outlet ports. Mechanical and fluidic characterization demonstrated the functionality of the probes. Typical infusion rates of 1.5 µL min−1 are achieved at a differential pressure of 1 kPa. The Pt-gray electrodes have an average electrode impedance of 260 ± 59 kΩ at 1 kHz.

Neural drug delivery by microprobes is considered to be one of the most promising methods for treating brain related diseases since the drug liquid can be directly infused into a specific brain region. However, this requires in turn knowledge on the liquid distribution during infusion. This work evaluates the liquid distribution in agarose gel of micro-fabricated silicon probes with two different outlet styles in comparison to a conventional stainless steel capillary. The optical liquid distributions for infusion rates of 0.2, 0.5, and 1.2 μL/min are determined in a special experimental setup which allows in parallel the measurement of pressure and flow during infusion. Flexible fluidic interfacing to the silicon probes is achieved by small o-rings for easy interchangeability. Since the actual pressure and flow conditions at the outlets of the inserted microprobes cannot be directly measured, a system model of the experimental setup is derived which allows to determine these values. Information on the predominant liquid distributions for the different probe types and infusion rates is qualitatively provided. Finally, actual pressure and flow conditions as well as backflow heights are exemplary presented for an infusion rate of 0.2 μL/min.

This paper reports on novel robust microprobe systems for simultaneous neural recording and drug delivery. The systems comprise needle-shaped silicon probes with microfluidic channels and recording electrodes integrated into a robust polyetheretherketone (PEEK) packaging. The microprobes are fabricated using deep reactive ion etching (DRIE) of silicon combined with silicon wafer bonding, wafer grinding, and thin film processing. An integrated system assembly with mechanical, fluidic and electrical interfaces is developed for easy handling and robustness during operation. This enables the microprobe systems to be used in acute as well as chronic applications. The assembly process includes a dead volume free fluidic interconnection technology which attaches polytetrafluoroethylene (PTFE) tubing to the probes by using heat shrinkable tubing. Furthermore, the novel approach of system integration is characterized with respect to its mechanical, fluidic, and electrical properties. Finally, the operation of the microprobe systems is verified in acute in-vivo experiments in which liquid delivery and recording of neural signals is successfully demonstrated.