[Show abstract][Hide abstract] ABSTRACT: The most fatal outcomes of prostate carcinoma (PCa) result from hormone-refractory variants of the tumor, especially from metastatic spread rather than from primary tumor burden. The goal of the study was to establish and apply rat MAT-Lu prostate cancer tumor models for improved non-invasive live follow up of tumor growth and metastasis by in vivo bioluminescence. We established luciferase transduced MAT-Lu rat PCa cells and studied tumor growth and metastatic processes in an ectopic as well as orthotopic setting. An intravenous bolus treatment with doxorubicin was used to demonstrate the basic applicability of in vivo imaging to follow up therapeutic intervention in these models. In vitro analysis of tissue homogenates confirmed major metastatic spread of subcutaneous tumors into the lung. Our sensitive method, however, for the first time detects metastasis also in lymph node (11/24), spleen (3/24), kidney (4/24), liver (5/24), and bone tissue (femur or spinal cord - 5/20 and 12/20, respectively). Preliminary data of orthotopic implantation (three animals) showed metastatic invasion to investigated organs in all animals but with varying preference (e.g., to lymph nodes). Intravenous bolus treatment of MAT-Lu PCa with doxorubicin reduced subcutaneous tumor growth by about 50% and the number of animals affected by metastatic lesions in lymph nodes (0/4), lung (3/6) or lumbar spine (0/2), as determined by in vivo imaging and in vitro analysis. Additionally, the possible applicability of the luciferase transduced MAT-Lu model(s) to study basic principles of metronomic therapies via jugular vein catheter, using newly established active microport pumping systems, is presented.
[Show abstract][Hide abstract] ABSTRACT: We present the results of our currently completed project “Active Microports”. A miniaturized drug delivery system for metronomic cancer therapy was developed. It has a total weight of only 36g and is able to deliver flowrates between zero and 6 µl/min virtually independent of the backpressure for pressures up to 30 kPa. The feasibility of the approach was demonstrated by a trial on metronomic cancer therapy with doxorubicin on a rat prostate tumor model.
[Show abstract][Hide abstract] ABSTRACT: We present a novel concept of an implantable active microport based on micro technology that incorporates a high-resolution volumetric dosing unit and a drug reservoir into the space of a conventional subcutaneous port. The controlled release of small drug volumes from such an "active microport" is crucial e.g. for innovative methods in cancer treatment or pain therapy. Our microport system delivers a flow rate in the range of 10-1,000 mul/h and enables a patient-specific release profile. The core of our device is a two-stage piezoelectric micropump. It features a backpressure-independent volumetric dosing capability i.e. a stable flow rate is ensured up to a backpressure of 30 kPa. The stroke volume and hence the resolution of the mircopump is voltage controlled and can be preset between 10 and 200 nl. A miniaturized high-performance electronic control unit enables freely programmable dosing profiles. This electronic circuit is optimized for both energy consumption and weight which are both essential for a portable device. The data of an implemented pressure sensor are used to permanently monitor the dosing process and to detect a potential catheter occlusion. A polyurethane soft lithography process is introduced for the fabrication of the prototype. Therewith, a compact multilayer system has been developed which measures only 50 x 35 x 25 mm(3).
[Show abstract][Hide abstract] ABSTRACT: We present for the first time a thermal phase-change micro-actuator that is based on a "conductive" paraffin. The conductive paraffin approach addresses the key challenges in the design of thermal phase-change actuators: The efficiency is increased, the reaction time is reduced and the heating of the surrounding structures is also reduced compared to the standard paraffin actuator design with metal heating resistors. A novel fabrication process for diaphragm actuators has been established and sample actuators have been characterized. It turns out that the conductive paraffin actuator is slightly more efficient than actuators with buried heaters, while the fabrication process is much simpler.
[Show abstract][Hide abstract] ABSTRACT: In this paper we present the state of the art of our artificial sphincter project. A novel silicon micropump has been designed recently for this system that features a four-membrane actuator set-up. The four-membrane micropump can transport fluid bidirectional with a maximum flow rate of 4.1 ml/min and can build up a back pressure of 60 kPa. The total size of the micropump is 30 mm × 12 mm × 1 mm. The novel pump is modeled by a lumped-parameter approach and compared to our three-membrane design. The main advantage of an additional membrane is a reduction of the driving frequency of the micropump while the flow rate remains the same compared to a three-membrane model. Consequently, the power consumption of the micropump can be reduced. A reliability analysis shows that the four-membrane micropump is more reliable then our previous design. The micropump was integrated into the artificial sphincter prosthesis. The first in vivo experiment is described and the measured data of the prosthesis implanted in a mini pig are given.
No preview · Article · Sep 2007 · Sensors and Actuators A Physical
[Show abstract][Hide abstract] ABSTRACT: We present the design, simulation, and complete characterization of an active piezo-driven silicon microvalve as applied in silicon micropumps. Therefore, the piezo-membrane actuator was studied in detail. Various test actuators were fabricated and evaluated regarding their deflection and pressure behavior. The results were compared to numerical simulations. Moreover, the fluid flow through the valve and the resulting pressure drop are modeled, simulated and experimentally analyzed with fabricated fluid flow test chips. The given data can be used to estimate, model, and design piezo-membrane actuators and microvalves.
No preview · Article · May 2007 · Microelectronic Engineering
[Show abstract][Hide abstract] ABSTRACT: A novel design of a piezoelectric silicon micropump is proposed, which provides a constant flow rate over a wide backpressure range of up to 30 kPa. This highly appreciable feature is based on a new serial arrangement of two active valves and relies on both an appropriate electrical actuation sequence of the piezo-actuators and an immanent limitation of the membrane deflection by the valve seats. The design is optimized for the low flow regime ranging from 0.1 to 50 µl min −1 . A detailed lumped-parameter model is derived in order to reveal the physics behind this pumping principle and to identify the optimum control scheme. For the fabrication of our device, a comparably simple and robust 2-wafer process is utilized. A thorough experimental investigation demonstrates the high performance of the micropump. The backpressure independence of the flow rate enables high-resolution volumetric dosing within the aforementioned flow range. The stroke volume and hence the resolution of the micropump is adjustable via the upstroke voltage of the actuator between 50 and 200 nl. Depending on this setting typical actuation frequencies range from 0.05 to 5 Hz and the flow rate scales proportional to the frequency within that frequency range.
Full-text · Article · May 2007 · Journal of Micromechanics and Microengineering
[Show abstract][Hide abstract] ABSTRACT: For biomedical applications the encapsulation of devices is a nontrivial task which has to meet ambitious specifications such as biocompatibility, mechanical and chemical stability, fluidic sealing or electrical isolation. Especially for microsystems the packaging is considered as a key process since it has to provide the interface between the microchips and the outer world. For life science applications polydimethylsiloxane (PDMS) has been widely employed, particularly for the formation of multilayer stacks. In our concept the multilayer approach is employed to design a multilayered housing for an active microport with embedded functional structures. In addition to PDMS, we explored polyurethane (PU) as a suitable material for the multilayer technique. Compared to PDMS it excels by an even better transparency and a slightly higher mechanical stability. Moreover, a large number of glues work with PU whereas adhesives for PDMS are rarely found. For our application the bond strength is an extremely critical parameter due to the demand of an absolutely reliable sealing. Several bonding techniques such as adhesion, annealing, mixing ratio variation and adhesive layers have been compared considering the reversibility of the bond type and the bond strength. An experimental setup has been developed which applies a load to the bond interface and determines the maximum applicable force.
[Show abstract][Hide abstract] ABSTRACT: This paper reports on significant progress in the development of an implantable active microport system for an automated administration of aqueous drug suspensions. A novel piezoelectric two-stage micropump ensures the controlled release of minute amounts of fluid with flow rates between 0.1 μl/min and 50 μl/min. A modification of the chamber design reduces the detrimental effect of entrapped air bubbles. The absence of air bubbles in the pump chamber yields a significantly enhanced accuracy of the delivered fluid volumes. An optimized actuation scheme referred to as gas pumping mode is proposed for the transport of gas. For alternate gas and liquid pumping a critical compression ratio is analytically derived which is determined by the capillary pressure drop of a gas–liquid interface trapped in the pump chamber. Due to an increased compression ratio of the new pump chamber design the micropump has now a full capability to pump both gas and liquid which enables a reliable self-priming.
No preview · Article · Jan 2007 · Sensors and Actuators A Physical
[Show abstract][Hide abstract] ABSTRACT: We present - for the first time - a novel design of a micropump which enables a backpressure-independent flow rate up to 20 kPa within the low flow regime required for drug delivery systems. Our concept, based on two piezoelectrically actuated diaphragms, allows an accurate dosing in the range of 1 - 50 µ l/min with freely programmable release profiles and offers the potential to minimize chip size and power consumption in comparison to 3-actuator peristaltic micropumps. The stroke volume is adjustable between 50 - 200 nl by means of voltage control which enables a high resolution volumetric dosing. Within the relevant frequency range below 2 Hz the flow rate is proportional to the frequency. Our design also excels in its comparably simple and robust 2-layer fabrication process.
[Show abstract][Hide abstract] ABSTRACT: This paper deals with the theory, fabrication and characterization of micro diaphragm pumps with active valves. Three types of micropumps with piezoelectric actuation are presented. Special emphasis is given on the accordance of theory and experiment. The theory is based on a lumped-element approach that is reduced to its basics to enable a reasonable accuracy with a minimized set of conceptional parameters. The experimental results fit well to the theory. The fabrication technology of the micropumps comprises of a silicon bulk micromechanics process in combination with a back-end gluing process of piezoelectric PZT-disks (PZT lead-circonat-titanat) to the silicon diaphragms. The micropumps were developed for different applications. The three- and the four-diaphragm micropumps were designed as high performance drivers for an artificial sphincter prosthesis. They show a maximum flowrate of 4 ml/min and a maximum sustainable backpressure of up to 70 kPa. The two-diaphragm micropump was engineered for an implantable drug delivery device and features a pressure independent dosing for backpressures up to 20 kPa.
[Show abstract][Hide abstract] ABSTRACT: We present two novel fluidic concepts to drastically accelerate the process of mixing in batch-mode (stopped-flow) on centrifugal microfluidic platforms. The core of our simple and robust setup exhibits a microstructured disk with a round mixing chamber rotating on a macroscopic drive unit. In the first approach, magnetic beads which are prefilled into the mixing chamber are periodically deflected by a set of permanent magnets equidistantly aligned at spatially fixed positions in the lab-frame. Their radial positions alternatingly deviate by a slight positive and negative offset from the mean orbit of the chamber to periodically deflect the beads inbound and outbound during rotation. Advection is induced by the relative motion of the beads with respect to the liquid which results from the magnetic and centrifugal forces, as well as inertia. In a second approach--without magnetic beads--the disk is spun upon periodic changes in the sense of rotation. This way, inertia effects induce stirring of the liquids. As a result, both strategies accelerate mixing from about 7 minutes for mere diffusion to less than five seconds. Combining both effects, an ultimate mixing time of less than one second could be achieved.
[Show abstract][Hide abstract] ABSTRACT: For the first time, we present a simple and robust optical concept to enable precise and sensitive read-out of colorimetric assays in flat lab-on-a-chip devices. The optical guidance of the probe beam through an incorporated measurement chamber to the detector is based on the total internal reflection at V-grooves in the polymer chip. This way, the optical path length through the flat measurement chamber and thus the performance of the measurements are massively enhanced compared to direct (perpendicular) beam incidence. This is demonstrated by a chip-based, colorimetric glucose-assay on serum. Outstanding features are an excellent reproducibility (CV= 1.91 %), a competitive lower limit of detection (c<sub>min</sub> = 124 μM), and a high degree of linearity (R<sup>2</sup> = 0.998) within a working range extending over nearly three orders of magnitude.
[Show abstract][Hide abstract] ABSTRACT: To realize a highly parallel optical detection in bead-based bioanalytical assays, we investigate the hydrodynamic aggregation of bead suspensions in a hexagonally periodical monolayer by a pressure-driven flow through a microfluidic structure. This device consists of one inlet channel connected to a shallow chamber with a depth that only slightly exceeds the diameter of the beads. To enforce the aggregation of the beads, the flow leaves the chamber via outlet channels possessing a depth smaller than a bead diameter. This way the outlets act as barriers to the beads and force them to accumulate in the chamber. Benchmarking different chamber and outlet designs we found an optimum filling behavior for a rhombus-like aggregation chamber connected to a single outlet channel at the same width as the chamber. Here, the aperture angle of 60° fosters hexagonal aggregation patterns which leads to the highest packaging density. Reproducible filling ratios of more than 94 % have been achieved. The rhombus-like chamber also shows the smallest increase of the hydrodynamic resistance during filling and the best rinsing behavior which allows to minimize the volume of washing detergents used for a bioassay. Zones of accumulated beads redistribute the hydrodynamic flow through the device during the filling process. CFD-simulations, embedded in an iterative master-routine, are carried out to describe the complete process of filling and to assist the process of design optimization. INTRODUCTION Miniaturization of assay formats is a major goal for medical diagnostics. This development is driven by the demand for fast analysis with low consumption of reagents . Bead-based analytical methods are favorable in terms of enhanced reaction kinetics.
[Show abstract][Hide abstract] ABSTRACT: This work presents the investigation of hydrodynamic filling of beads into flat microfluidic devices. A periodical hexagonal monolayer as aggregation pattern is favorable for parallel optical detection. Several microfluidic devices for bead-based analyses were designed. Each microfluidic device consists of one inlet channel, one flat aggregation chamber for the beads and several outlet channels. Suspensions of beads with 180 µm in diameter are loaded into a flat chamber measuring 190 µm in depth by a pressure driven flow. With the depth smaller than a bead diameter, the outlets act as barriers to the beads and force them to accumulate in the chamber. Therefore, the decisive impact parameters are the geometry, the particle concentration of suspension, and the inlet pressure. Reproducible filling ratios of more than 94 % have been achieved.