The Micro- and NanoBiomedical Engineering group (MNBE) aims at designing and developing microtools that interface biological samples at the cellular and molecular levels, for both fundamental studies and healthcare applications, in particular in the field of assisted reproduction and targeted drug delivery. Such microtools range from medical microrobots to smart sensor-actuator systems, made employing cutting-edge microfabrication technologies and functional nanomaterials.
Infertility is a worldwide problem affecting ~11% of the reproductive-age population. Severe cases are currently treated by in vitro fertilization (IVF) and intracytoplasmic injection techniques (ICSI) with high fertilization rates (~95%). However, embryo transfer is still the critical stage with only 32% of the cases resulting in clinical pregnancies. Moreover, the implantation rates per embryo remain very low (~17%) and often the procedure needs to be repeated several times with no success implying a high economic and social cost. Among the different methods used to overcome this issue, zygote intrafallopian transfer seems more promising offering appropriate physiological environment for zygote/embryo development at an optimal synchronization between embryonic and endometrial preparation. However, these methods are invasive and involve surgical procedures and anaesthesia to introduce macroscopic imaging and manipulation tools into the female body, increasing the risk of injury and ectopic pregnancies. The goal of Micro-GIFT is to seek for novel approaches to non-invasively transport and release high-quality gametes/zygotes in the fallopian tube in vivo (mice model). For that multifunctional untethered microrobots (~100 µm size) will be developed making use of smart materials and advanced microtechnologies. However, there are major challenges that need to be overcome to bring this technology close to the clinic, such as the in vivo imaging and control of such microrobots, and their removal after use. The project will also provide deeper insights on the contribution of the fallopian tube on the natural embryo development and implantation, being crucial to create more natural procedures with high success rates. The PI has contributed significantly to the field of sperm-based microbots for assisted fertilization and targeted drug delivery as well as developed a variety of novel microbiosensors for molecular and cellular analysis.
B. Rivkin, C. Becker, B. Singh, A. Aziz, F. Akbar, A. Egunov, D.D. Karnaushenko, R. Naumann, R. Schäfer, M. Medina-Sánchez, D. Karnaushenko, and O.G. Schmidt
Existing electronically integrated catheters rely on the manual assembly of separate components to integrate sensing and actuation capabilities. This strongly impedes their miniaturization and further integration. Here, we report an electronically integrated self-assembled microcatheter. Electronic components for sensing and actuation are embedded into the catheter wall through the self-assembly of photolithographically processed polymer thin films. With a diameter of only about 0.1 mm, the catheter integrates actuated digits for manipulation and a magnetic sensor for navigation and is capable of targeted delivery of liquids. Fundamental functionalities are demonstrated and evaluated with artificial model environments and ex vivo tissue. Using the integrated magnetic sensor, we develop a strategy for the magnetic tracking of medical tools that facilitates basic navigation with a high resolution below 0.1 mm. These highly flexible and microsized integrated catheters might expand the boundary of minimally invasive surgery and lead to new biomedical applications.
A. Aziz, J. Holthof, S. Meyer, O.G. Schmidt, and M. Medina-Sánchez
The fast evolution of medical micro- and nanorobots in the endeavor to perform non-invasive medical operations in living organisms has boosted the use of diverse medical imaging techniques in the last years. Among those techniques, photoacoustic imaging (PAI), considered a functional technique, has shown to be promising for the visualization of micromotors in deep tissue with high spatiotemporal resolution as it possesses the molecular specificity of optical methods and the penetration depth of ultrasound. However, the precise maneuvering and function's control of medical micromotors, in particular in living organisms, require both anatomical and functional imaging feedback. Therefore, herein, the use of high-frequency ultrasound and PAI is reported to obtain anatomical and molecular information, respectively, of magnetically-driven micromotors in vitro and under ex vivo tissues. Furthermore, the steerability of the micromotors is demonstrated by the action of an external magnetic field into the uterus and bladder of living mice in real-time, being able to discriminate the micromotors’ signal from one of the endogenous chromophores by multispectral analysis. Finally, the successful loading and release of a model cargo by the micromotors toward non-invasive in vivo medical interventions is demonstrated.
R. Herzer, A. Gebert, U. Hempel, F. Hebenstreit, S. Oswald, C. Damm, O. G. Schmidt, and M. Medina-Sánchez
Titanium and its alloys are frequently used to replace structural components of the human body due to their high mechanical strength, low stiffness, and biocompatibility. In particular, the use of porous materials has improved implant stabilization and the promotion of bone. However, it remains unclear which material properties and geometrical cues are optimal for a proper osteoinduction and osseointegration. To that end, transparent tubular microscaffolds are fabricated, mimicking the typical pores of structural implants, with the aim of studying early bone formation and cell-material interactions at the single cell level. Here, a β-stabilized alloy Ti-45Nb (wt%) is used for the microscaffold's fabrication due to its elastic modulus close to that of natural bone. Human mesenchymal stem cell migration, adhesion, and osteogenic differentiation is thus investigated, paying particular attention to the CaP formation and cell-body crystallization, both analyzed via optical and electron microscopy. It is demonstrated that the developed platform is suited for the long-term study of living single cells in an appropriate microenvironment, obtaining in the process deeper insights on early bone formation and providing cues to improve the stability and biocompatibility of current structural implants.
L. Schwarz, D.D. Karnaushenko, F. Hebenstreit, R. Naumann, O. G. Schmidt, M. Medina-Sánchez
Embryo transfer (ET) is a decisive step in the in vitro fertilization process. In most cases, the embryo is transferred to the uterus after several days of in vitro culture. Although studies have identified the beneficial effects of ET on proper embryo development in the earlier stages, this strategy is compromised by the necessity to transfer early embryos (zygotes) back to the fallopian tube instead of the uterus, which requires a more invasive, laparoscopic procedure, termed zygote intrafallopian transfer (ZIFT). Magnetic micromotors offer the possibility to mitigate such surgical interventions, as they have the potential to transport and deliver cellular cargo such as zygotes through the uterus and fallopian tube noninvasively, actuated by an externally applied rotating magnetic field. This study presents the capture, transport, and release of bovine and murine zygotes using two types of magnetic micropropellers, helix and spiral. Although helices represent an established micromotor architecture, spirals surpass them in terms of motion performance and with their ability to reliably capture and secure the cargo during both motion and transfer between different environments. Herein, this is demonstrated with murine oocytes/zygotes as the cargo; this is the first step toward the application of noninvasive, magnetic micromotor-assisted ZIFT.
M. Medina-Sánchez, O.G. Schmidt
[…To enter clinical trials, microbots must clear two major hurdles. First, researchers need to be able to see and control them operating inside the body — current imaging techniques have insufficient resolution and sensitivity. Second, the vehicles need to be biocompatible and be removed or stabilized after use. Achieving both aims would set the stage for further improvements — in steering and mobility, materials and capabilities. Microbot researchers need to establish mechanisms for operating microbots, possibly even in swarms, inside the body. For example, ultrasound and magnetic fields could direct them broadly to the right region, from where finer, biochemical sensing would take over. The goal is a microbot that can sense, diagnose and act autonomously, while people monitor it and retain control in case of malfunction...]
last updated 2022-01-24 hs