In this research project, we are developing microfluidic devices for biphasic biocatalysis on-chip. In biocatalysis, enzymes are used to catalyze chemical reactions in a chemo-, regio- and stereoselective manner. Enzymes are typically less stable in organic media than their native aqueous environment, but chemical and pharmaceutical compounds often tend to be insoluble in water. The use of an aqueous/organic biphasic configuration offers a solution to this problem and has become the reaction medium of choice for numerous biotransformations. Traditionally, two-phase biocatalysis takes place in large flasks and relies on diffusion. However, diffusive mixing on a large scale is a slow process. Microfluidic devices can be used to increase the contact area and contact time between phases, and therefore have the potential to increase biocatalytic efficiency, both in terms of reaction yield and time. For that, we are exploring continuous flow (aqueous and organic phases flow next to each other, reaction takes place at the interphase) and droplet-based (one phase in the droplet and the other surrounding the droplet, reaction takes place at the interphase) microfluidic systems. At the end of the reaction, the two phases are separated allowing the subsequent use of the organic phase containing the product in a further reaction step. The final goal is to create a modular, customizable, plug-and-play system for a cascade of enzymatic and chemical reaction steps. Integrated sensors (e.g. oxygen sensors) along each step will ensure reaction control and reproducibility.
Endothelial cells lining the blood vessel walls are known to change their morphology, function and gene expression according to the mechanobiological stimuli they are experiencing. Such stimuli include shear stress caused by blood flow and the stiffness of the underlying extracellular matrix. However, little is known about the cumulative effects of mechanobiological stimuli over endothelial cell behavior, and even less is known about their role in bacterial infection. In this project, we aim to investigate the mechanobiology of the vascular endothelium in relation to the dissemination of the Lyme disease pathogen, Borrelia burgdoferi, on an organ-on-chip (OoC) platform. The OoC platform will allow precise control over the biomechanical microenvironment endothelial cells are subjected to and will be equipped with integrated sensors for the evaluation of important parameters such as endothelial barrier integrity. Ultimate goal is a correlation between endothelial biomechanics and the mechanisms of Borrelia burgdorferi dissemination.
The human small intestine is an integral interface with the environment, although inside the body. With an area of approximately 30 m2, it is 15 times larger than the area of our skin and it performs several complicated functions including digestion, absorption and nutrients, while providing a basis for intestinal flora and barrier function against pathogens. In this project, we generate small intestine-like structures with the help of a cell-stretching platform. Using cyclic stretching, we stimulate the formation of 3D villi-like structures, which resemble the architecture of the human intestine. The biomimetic nature of this platform allows the generation of organotypic tissue models that are more similar to their in vivo counterparts compared to conventional cell cultures. Therefore, this 3D cell model promises a better transferability of the findings to the human situation without the need for animal models. Using this platform, we aim to study the relation between biomechanics and infection with pathogens (e.g., Listeria monocytogenes and SARS-CoV-2), as well as to test the uptake of orally administered drugs.
In this research project, 3D-printed metastructures are investigated. Special emphasis is placed on lattice structures fabricated using the state-of-the-art Carbon Digital Light Synthesis™ (Carbon DLS™) process. Carbon DLS™ uses digital light projection, oxygen permeable optics, and programmable liquid resins to produce parts with exceptional mechanical properties, resolution, and surface finish. The biggest advantage of this technology is the isotropic mechanical properties of printed parts that make them comparable to injection-molded parts and therefore attractive for industrial applications. We use a combination of experiments and simulations to design, fabricate, and optimize lattice structures, which we then characterize with respect to mechanical behaviour. Of special interest are printed fluidic channels (hollow posts in lattice structure), as these can be used in a variety of applications in academia and industry. 3D printing hollow structures like fluidic channels comes with a special set of challenges, as the un-solidified resin within the channels needs to be removed. Therefore, an additional research focus is placed on channel cleaning strategies as well as optimized geometries for easy resin removal.
To combat infectious diseases, it is important to understand how host cells interact with bacterial pathogens in a milieu dominated by chemical as well as mechanical signals. Currently available biomimetic cell culture platforms which account for the mechanical stretch and fluidic flow are limited in their applicability for comprehensive biomechanical infection assays.
The aim of this project is to develop a platform which is then applied in infection assays of Listeria Monocytogenes (LM) bacteria. This platform has to allow for:
combination of cell stretching / shear flow
multiple stretch patterns
access from top for infection assays
live-cell time-lapse microscopy
conduction of cellular biomechanical measurements
The project is a collaboration with the University of Tübingen, which is applying the system in bio-chemo-mechanical infection studies.
At IMT, we apply 3D-printing and PDMS molding/spinning techniques to manufacture cell culture systems with stretchable membranes. We characterize the developed systems by applying the finite elment method to model the strain in the membrane and validate the outcomes by microscopy and image correlation.
Microfluidic organ-on-chip (OoC) platforms are increasingly utilized in biomedical research and development as a replacement for traditional static cell cultures and animal experiments. In this project, we aim to develop a miniaturized electrical impedance tomographer (EIT) and integrate it into an organ-on-chip platform for label-free cell and tissue characterization. EIT is a commonly used, non-invasive, and radiation-free type of medical imaging. Beyond the well-known medical applications, EIT can be used to reconstruct the impedance distribution of samples placed within an electrode array, given variations in conductivity across the sample. The resolution of the acquired “electrical images” depends on many parameters such as the size of the sampling volume, the geometry of the electrode array, the parameters used during measurement and the algorithms used for image reconstruction. In addition to the standard regularization technique, the reconstruction of the "electrical image" can be improved by using deep learning methods to achieve high resolution and fast computation for real-time imaging. Our aim is to reduce the sampling volume through miniaturization, and optimize all other important parameters in order to acquire impedance maps with cellular resolution (10-20 µm). This will allow us to observe localized events taking place across cellular monolayers cultured under biomimetic conditions.
Project period: 02/2019 - 02/2022
Funding organization: SMART BIOTECS - Land Niedersachsen
With the BM=x^3 project, we not only want to bring professional training in micro- & nanotechnology to the forefront of society, but also bring the type of training up to date. More flexible and dynamic learning and further education are in the focus here. For this we want to create a new platform to connect the present and the virtual world.
Project period: 2021-2024
Funding organization: Bundesinstitut für Berufsbildung
By combining controllable microfluidic nanoparticle generation from the Institute for Microtechnology (IMT) at the TU Braunschweig with the DLS System developed at the Fraunhofer Institute for Microtechnology and Microsystems (IMM) in Mainz, a feedback-regulated nanoparticle reactor is to be realized with which the size, size distribution and shape of the generated particles can be precisely controlled and can be sure about the stability of the process for a long time. A new type of microfluidic precipitation system is to be developed on the basis of existing prototypes of microfluidic systems from IMT, which, together with the existing flowDLS system from Fraunhofer IMM (IMM), allows direct online measurement of the generated nanoparticles in the microfluidic channel. The application partner ConSenxus GmbH comes from the field of instrument engineering and has decades of expertise in the field of particle analysis methods. Also, ConSenxus has useful contacts as well as the necessary special knowledge to adapt the system to the needs of potential users
In the embedded sensors project, a curing monitoring system for CFRP components is to be developed in order to control the curing process even more precisely. This is to be integrated directly within the laminate and provide real-time data during curing in the autoclave as well as material data for health monitoring during subsequent operation in order to detect component failure at an early stage. A sensor package with capacitors (interdigital structures), strain and temperature sensors will be structured on a carrier film, which will chemically bond with the epoxy resin so that the sensor itself causes as little structural weakening as possible. The sensor structures will be produced in three different ways, photolithographically, by selective laser ablation and by the LIFT process, the direct printing of metallic gold pixels.
Goal of the project is to fabricate an ultra-thin, stretchable, flexible bending sensor array that can be attached at the belly of a premature baby. All the bending sensors consist of strain gauges, which are integrated into both sides of a polyimide film. Every two upper und two lower strain gauges are connected through the polyimide film by using the vertical interconnect accesses (i. e. vias) into a Wheatstone bridge, so they can measure the shape change of the premature infant belly and feed it back by an electrical signal. During breathing the belly of the premature baby becomes periodic larger and smaller which will cause a vibration of the electrical signal. For the baby's health, only the following materials can be used to produce the bending sensor array: gold, titan, Polyimide, PDMS and copper.
The aim of the Research Unit FOR3022 is to gain a profound understanding of an integrated Structural Health Monitoring in Fiber Metal Laminates using guided ultrasonic waves. The group at IMT investigates microfabricated and structure integrable acceleration sensors, which monitor the adhesive boundary layer within fiber metal laminates. Using glass and silicon as sensor materials, the acoustic impedance of the sensor resembles that of the structure, yielding functional compliance.
The number of heart failure patients is continuously rising in Europe (currently about 15 million). Every third patient dies in the first year after diagnosing the disease since a worsening of the condition can only be detected by external symptoms. However, latest studies show that a worsening can be diagnosed several weeks afore due to an often increased left ventricular end-diastolic pressure (LVEDP). The current method of monitoring LVEDP is associated with considerable side effects and complications for the patient as well as high costs for health care due to multiple invasive operations. The BMBF funded research project "ForMat-CARDIO" is focused on the development of pressure sensors as the basis for long-term cardiovascular implants. The solution will be a telemetric pressure sensor that is permanently implanted in the left ventricle and monitors the vital functions of the left heart. The chronic implants will be made of highly biocompatible medical-grade materials with high pressure sensitivity in combination with nanosensor technology (Nanogranular Tunneling Resistor (NTR)). The small dimensions of the NTR sensors in combination with their excellent sensitivity allow a high degree of miniaturization of the implants (< 2 mm).
The applicability of the liver surgery, as an effective therapeutic strategy against liver cancer, is limited by liver ischemia-reperfusion (I-R) injury. The underlying mechanism is still unclear but this injury is observed in a number of clinical settings, including hepatic resectional surgery, liver transplantation, trauma and hemorrhagic shock with fluid resuscitation . Therefore, the research of the I-R injury is believed to have a significant meaning for the surgical success rate and effectiveness. For the necessary improvements of surgery procedures and pharmaceutical measures against I-R injury, (Organ-on-a-Chip) OOC technology could provide an extremely effective and efficient tool. The aim of the proposed PhD project is therefore to develop a novel in vitro human liver-on-chip system for automated long-term continuous in situ monitoring in an on-chip micro-environment mimicking the human liver to be used in Liver Ischemia-Reperfusion (I-R) Injury research. Necessary sensors will be integrated into a Si based organ on chip system with nano-porous membrane (e.g. Si3N4 nanosieves), in order to manipulate and monitor multi micro environmental parameters.
 Lentsch, A. B.; Kato, A.; Yoshidome, H.; McMasters, K. M.; Edwards, M. J. (2000): Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury. In Hepatology (Baltimore, Md.) 32 (2), pp. 169–173. DOI: 10.1053/jhep.2000.9323
Membranes fulfill numerous technical functions and are excellently suited for separating compartments while ensuring mass transfer. The properties in mass transfer and exchange as well as microfluidics and hydrodynamic pore flow are of highest interest for many applications in the biomedical field. The joining technology for a damage-free insertion of membrane in organ-on-a-chip systems, as well as the manufacturing technology, such as injection molding, represent a major challenge in this context. The membrane itself is usually a porous film with specific properties that require prudent handling to avoid membrane damage prior to use. In view of the serial manufacturing process using injection molding, the joining of the membrane with complex microcomponents, in particular, presents a complex challenge due to minimal joining areas and geometric/process/application-specific conditions.
The joint project goal is to develop a joining technology for these challenges in conjunction with the manufacturing technology, variothermal micro injection molding. As part of this development, a permeation chip for a blood-brain barrier cell model will be designed by the IMT to optimally combine membrane functionalities and process requirements. The dynamic organ-on-chip system creates shear forces on the cultivated cells to improve their growth and the formation of dense paracellular tight-junctions. In this context, the processes and the respective biomedical application as well as the required sterilization have to be implemented in such a way that an optimal efficiency in combination with the manufacturing capabilities can be achieved. The technology development of joining technology also expands the range of manufacturing technologies in tool manufacturing and series production in injection molding.
The aim of the project “Micro reactors for biopharmaceutical applications” is to develop a novel micro bioreactor (MBR) in glass that can be used for biopharmaceutical screening applications. These reactors are open at the top so that they can be filled using a liquid handling system. In addition, all necessary sensors for process monitoring are integrated directly into the reactor. For manufacturing fs-laser direct writing in glass (Foturan® or fused silica) is used. This enables the production of real 3D microstructures on wafer level. Besides manufacturing, further work packages include the integration of sensors such as a 3D micro structured impedance electrode to measure biomass and the integration of waveguides by fs-laser direct writing to do optical sensing of e.g. dissolved oxygen and glucose. Furthermore, a new mixing technique of the MBR, using capillary surface waves is developed and evaluated by micro particle image velocimetry.
Future work will face parallelization of the MBRs to use them for testing pharmaceutical active ingredients on living cells. This results in new challenges in the field of liquid supply and the parallelization of the inserted sensors
This project aims to develop a micro-optical gyroscope prototype, funded by Deutsches Zentrum für Luft- und Raumfahrt (DLR). Inertial measurement units (IMUs), which are vastly used in many applications for navigation, are essential components in modern world. A complete IMU consists of three accelerometers for detecting the translational motion and three gyroscopes for detecting the rotational motion for each spatial dimensions, thus, any motion can be fully tracked. The operating principle of an optical gyroscope is based on the Sagnac effect, which occurs in rotating systems where two light beams circulate in opposite directions. The circulating light beams experience different path lengths in the presence of rotation; shortened against the direction of rotation, extended in other direction. The rotational movement is then determined by measuring the phase difference between the two propagating light beams. Our miniaturized gyroscope consists of a triangular passive ring resonator in which light beams circulate through reflection on three silicon mirrors. The two of mirrors having angles with the surface of 54.74° are monolithically produced through the KOH etching of a (100) silicon wafer. The use of passive resonator provides some advantages over conventional ring laser gyroscopes (RLG) and interferometric gyroscopes (IFOG), such as the elimination of the lock-in effect for small rotation rates mostly occurring in RLGs and high sensitivity compared to IFOGs.
The aim of this project is to investigate a multifunctional bondline, which is capable of joining two adherents made from carbon fiber reinforced polymer. This is intended to improve the reliability of bonds between lightweight components. The specially designed bondline shall slow or stop crack propagation and monitor its own structural health. Therefore integrated thin foil sensors, fabricated by means of lithography measure the gradient of stress inside the bond without degrading its mechanical properties. Metallic thin film sensors are structured directly on a PVDF substrate, which becomes a part of the crack stopping mechanism when embedded into the carbon fiber matrix. The epoxy resin, which is carrying the major portion of the loads inside the bond, remains completely undisturbed. With suitable algorithms the sensor signals shall be analysed to reliably detect cracks within the bondline. This new way of integrating sensors will lead to a higher level of structural compliance in comparison to sensors being integrated into the epoxy resin layer.
Before a promising pharmaceutical drug candidate can be approved, complex test series have to be carried out using animal experiments in which the efficacy and toxicity as well as the permeability through the biological barriers are examined. However, the results obtained are ethically questionable and scientifically controversial due to the physiological structure of the animal. In order to avoid animal experiments and to improve the informative value of the tests, membrane-based Organ-on-a-Chip systems are currently developed, which enable three-dimensional cell cultivation to reproduce basic organ functions. In detail, the BMBF funded Blood-Brain-Barrier-on-Chip project is concerned with the microtechnical reproduction of the blood-brain barrier, a natural barrier responsible for the homeostasis of the central nervous system. By separating two microchannels by a thin, porous membrane, the physical structure of the barrier can be mimicked. The colonization with specific cell types and the application of the shear stress emulates furthermore the functionality of the blood-brain barrier. This organotypical model is then suitable for permeation studies of active substances that only take effect at the brain navel. In a similar constellation, the Nasal-Mucosa-on-Chip project deals with a microfluidic system for permeability studies of the nasal mucosa for the future administration of drugs.
The aim of the study is to develop a novel miniature device – termed NeuroExaminer – by structured microfabrication of glass that enables a stable and highly reproducible positioning of both zebrafish larvae and juveniles within a system with perfected optical properties for whole brain light-sheet microscopy at the subsecond time-scale. Furthermore, the NeuroExaminer will contain microchannels for precisely controlled compound application with subsecond resolution and steep concentration gradient formation.
This will allow to reveal the pharmacokinetics and neuromodulatory functions of any water soluble compound. In the course of the project we will develop a proof of concept by using the NeuroExaminer to investigate brain-wide alterations induced by two different psychostimulant substances through continuously monitoring neuronal activity at cellular resolution over at least one hour. This will demonstrate that the NeuroExaminer is a powerful novel instrument to reveal the specific neural activity of drugs, including their lag time until neuromodulation is achieved together with circuit activation or repression in a time-dependent manner.
The use of paper test strips for illness detection and monitoring is gaining importance in the last years, as they offer fast and low cost results that can be obtained not only by medical personal, but also by normal users at home (“Anywhere care”). The objective of this work is to design a self-calibrating platform that enables the detection and quantification of small analytes for on-line blood monitoring, in order to be used in Therapeutic Drug-Monitoring (TDM), but also in fast tests for water quality assurance in swimming pools.
The challenges involving this project are the calibration of the system (issues like age depence results or batch-to-batch variations) and the results evaluation with the camera of a smart-phone. The approaches proposed to solve these problems are strips with more channels for better reproducibility, channels with controlled flow velocity and the implementation of new assays.
The aim of the project is to characterize application-related properties of dispersed micro- and nanoparticles with the highest possible accuracy by separating the nanoparticles and characterizing single particle properties in micro- or nanofluidic systems. To achieve this goal, model systems with highest control of particle-particle and particle-wall interactions are defined. For the production of such model systems, the latest fabrication technologies in the areas of 2-photon polymerization and femtosecond laser processing are used. By isolating individual particles in a volume of only a few femtoliters, the characterization and counting of individual nanoparticles by means of electronic and optical precision technology is possible and background interference signals can be greatly reduced.
Project period: 11/2016 - 10/2021
Funding organization: Ministerium für Wissenschaft und Kultur des Bundeslandes Niedersachsen
Every 10th newborn baby is a premature birth, worldwide. Progress in the care of very immature premature babies has led to a rate of healthy survival of over 90% today, compared to marginal survival rates 40 years ago. One of the key building blocks has been the improvement of ventilation. Studies have shown that ventilation triggered by self-breathing leads to significantly better long-term results than ventilation modes used in the past. In order to further increase the rate of healthy survival, it is therefore necessary to further develop ventilation in such a way that the ventilator is triggered by the child's own breathing using an easy-to-use sensor system.
The goal of smartNIV is the development of an intelligent non-invasive ventilation system for premature infants, which is controlled by a highly elastic multi-sensor patch. This patch is applied to the skin at the transition between chest and abdomen to measure the typical deformations of the thorax caused by breathing and to provide the ventilator with a control signal.
The multi-sensor concept offers the advantage that the failure of even several sensors does not lead to the failure of the entire system. In addition, the flat patch is intended to increase the tolerance against positional inaccuracies to such an extent that simple but reliable application by medical personnel is guaranteed. Furthermore, the patch can be easily resized and is therefore also suitable for very small premature babies. In addition to the novel, highly elastic sensor hardware, the innovation lies in the evaluation software based on artificial intelligence, which will adapt automatically and in real time to the ventilation situation. Conventional systems are hard-coded and therefore very susceptible to interference compared to e.g. unexpected child movements.
All in all, this new medical technology should not only enable triggered respiratory support, but also the recording of the entire respiratory curve, i.e. not only the beginning of inhalation, but also the beginning of exhalation and the intensity of the breathing effort in between. For the first time ever, non-invasive, gentle ventilation would be able to support the breathing effort of a premature infant to the nearest millisecond, which is currently only available for invasive ventilation. It is expected that this will not only relieve the financial burden on the healthcare system, but will also give premature and newborn babies significantly better chances of surviving healthy.
In order to exploit the results, the project consortium aims at a downstream development of the demonstrator into an approved medical device. The supply of the hardware and software as well as the final production and marketing of the entire system should be handled within the consortium.
During the fabrication of pharmaceutical core-shell particles a defined size and drug loading is required for optimal efficacy. Other applications of the project include the recycling of mining wastes separating ore particles. Therefore, a fractionation not only by size but also by other material parameters is desired. In the first funding period, the systems were sequentially designed so that a size separation is followed by a material dependent separation. As method for size dependent fractionation, we choose deterministic lateral displacement (DLD) consisting of an array of tilted micro-posts due to its high range and selectivity of particle sizes. DLD fractionation relies only on flow effects such as Reynolds number and geometry of the array. For material dependent fractionation, we choose dielectrophoresis and magnetophoresis using an external magnetic or electric field.