Micro- and Nanobiomedical Engineering Group

ARTICLES

2023

https://www.sciencedirect.com/science/article/pii/S0956566323003044

@article{LALEH2023115362,
title = {Portable microfluidic impedance biosensor for SARS-CoV-2 detection},
journal = {Biosensors and Bioelectronics},
volume = {236},
pages = {115362},
year = {2023},
issn = {0956-5663},
doi = {https://doi.org/10.1016/j.bios.2023.115362},
url = {https://www.sciencedirect.com/science/article/pii/S0956566323003044},
author = {Soroush Laleh and Bergoi Ibarlucea and Marlena Stadtmüller and Gianaurelio Cuniberti and Mariana Medina-Sánchez},
keywords = {COVID-19 diagnostics, SARS-CoV-2 biosensor, Point-of-care, Electrochemical detection, Electrochemical impedance spectroscopy},
abstract = {Pandemics as the one we are currently facing, where fast-spreading viruses present a threat to humanity, call for simple and reliable methods to perform early diagnosis, enabling detection of very low pathogen loads even before symptoms start showing in the host. So far, standard polymerase chain reaction (PCR) is the most reliable method for doing so, but it is rather slow and needs specialized reagents and trained personnel to operate it. Additionally, it is expensive and not easily accessible. Therefore, developing miniaturized and portable sensors which perform early detection of pathogens with high reliability is necessary to not only prevent the spreading of the disease but also to monitor the effectiveness of the developed vaccines and the appearance of new pathogenic variants. Thus, in this work we develop a sensitive microfluidic impedance biosensor for the direct detection of SARS-CoV-2, towards a mobile point-of-care (POC) platform. The operational parameters are optimized with the aid of design-of-experiment (DoE), for an accurate detection of the viral antigens using electrochemical impedance spectroscopy (EIS). We perform the biodetection of buffer samples spiked with fM concentration levels and validate the biosensor in a clinical context of relevance by analyzing 15 real patient samples up to a Ct value (cycle threshold) of 27. Finally, we demonstrate the versatility of the developed platform using different settings, including a small portable potentiostat, using multiple channels for self-validation, as well as with single biosensors for a smartphone-based readout. This work contributes to the rapid and reliable diagnostics of COVID-19 and can be extended to other infectious diseases, allowing the monitoring of viral load in vaccinated and unvaccinated people to anticipate a potential relapse of the disease.}
}

Micro-and nanorobots have the potential to perform non-invasive drug delivery, sensing, and surgery in living organisms, with the aid of diverse medical imaging techniques. To perform such actions, microrobots require high spatiotemporal resolution tracking with real-time closed-loop feedback. To that end, photoacoustic imaging has appeared as a promising technique for imaging microrobots in deep tissue with higher molecular specificity and contrast. Here, we present different strategies to track magnetically-driven micromotors with improved contrast and specificity using dedicated contrast agents (Au nanorods and nanostars). Furthermore, we discuss the possibility of improving the light absorption properties of the employed nanomaterials considering possible light scattering and coupling to the underlying metal-oxide layers on the micromotor’s surface. For that, 2D COMSOL simulation and experimental results were correlated, confirming that an increased spacing between the Au-nanostructures and the increase of thickness of the underlying oxide layer lead to enhanced light absorption and preservation of the characteristic absorption peak. These characteristics are important when visualizing the micromotors in a complex in vivo environment, to distinguish them from the light absorption properties of the surrounding natural chromophores.

TY - JOUR
AU - Aziz, Azaam
AU - Nauber, Richard
AU - Iglesias, Ana Sánchez
AU - Tang, Min
AU - Ma, Libo
AU - Liz-Marzán, Luis M.
AU - Schmidt, Oliver G.
AU - Medina-Sánchez, Mariana
PY - 2023
DA - 2023/04/22
TI - Nanomaterial-decorated micromotors for enhanced photoacoustic imaging
JO - Journal of Micro-Bio Robotics
AB - Micro-and nanorobots have the potential to perform non-invasive drug delivery, sensing, and surgery in living organisms, with the aid of diverse medical imaging techniques. To perform such actions, microrobots require high spatiotemporal resolution tracking with real-time closed-loop feedback. To that end, photoacoustic imaging has appeared as a promising technique for imaging microrobots in deep tissue with higher molecular specificity and contrast. Here, we present different strategies to track magnetically-driven micromotors with improved contrast and specificity using dedicated contrast agents (Au nanorods and nanostars). Furthermore, we discuss the possibility of improving the light absorption properties of the employed nanomaterials considering possible light scattering and coupling to the underlying metal-oxide layers on the micromotor’s surface. For that, 2D COMSOL simulation and experimental results were correlated, confirming that an increased spacing between the Au-nanostructures and the increase of thickness of the underlying oxide layer lead to enhanced light absorption and preservation of the characteristic absorption peak. These characteristics are important when visualizing the micromotors in a complex in vivo environment, to distinguish them from the light absorption properties of the surrounding natural chromophores.
SN - 2194-6426
UR - https://doi.org/10.1007/s12213-023-00156-7
DO - 10.1007/s12213-023-00156-7
ID - Aziz2023
ER -

Medical microrobots are tiny devices designed to perform diagnostic and/or therapy non-invasively, targeting molecules and cells at their scale. However, they should be designed based on their function and cargo transport requirements. These features are directly related to the microrobots geometry, which varies depending on the size, cargo compliance, adopted locomotion strategy, and their working environment. Geometry also affects the immunological response and the microrobots interaction with their surrounding microenvironment. Here we discuss the influence of a proper microrobot design and material selection when envisioning a biomedical application, giving a particular focus to the optimization of gametes/zygotes microrobotic transport for in-vivo assisted reproduction.

@book{bassani2005encyclopedia,
title={Encyclopedia of Condensed Matter Physics},
author={Bassani, G.F. and Liedl, G.L. and Wyder, P.},
number={v. 1},
isbn={9780122276101},
series={Encyclopedia of Condensed Matter Physics},
url={https://books.google.de/books?id=gRl8MwEACAAJ},
year={2005},
publisher={Academic}
}

Medical microrobotics is an emerging field that aims at non-invasive diagnosis and therapy inside the human body through miniaturized sensors and actuators. Such microrobots can be tethered (e.g., smart microcatheters, microendoscopes) or untethered (e.g., cell-based drug delivery systems). Active motion and multiple functionalities, distinguishing microrobots from mere passive carriers and conventional nanomedicines, can be achieved through external control with physical fields such as magnetism or ultrasound. Here we give an overview of the key challenges in the field of assisted reproduction and how these new technologies could, in the future, enable assisted fertilization in vivo and enhance embryo implantation. As a case study, we describe a potential intervention in the case of recurrent embryo implantation failure, which involves the non-invasive delivery of an early embryo back to the fertilization site using magnetically-controlled microrobots. As the embryo will be in contact with the secretory oviduct fluid, it can develop under natural conditions and in synchrony with the endometrium preparation. We discuss the potential microrobot designs, including a proper selection of materials and processes, envisioning their translation from bench to animal studies and human medicine. Finally, we highlight regulatory and ethical considerations for bringing this technology to the clinic.

TY - JOUR
AU - Nauber, Richard
AU - Goudu, Sandhya R.
AU - Goeckenjan, Maren
AU - Bornhäuser, Martin
AU - Ribeiro, Carla
AU - Medina-Sánchez, Mariana
PY - 2023
DA - 2023/02/09
TI - Medical microrobots in reproductive medicine from the bench to the clinic
JO - Nature Communications
SP - 728
VL - 14
IS - 1
AB - Medical microrobotics is an emerging field that aims at non-invasive diagnosis and therapy inside the human body through miniaturized sensors and actuators. Such microrobots can be tethered (e.g., smart microcatheters, microendoscopes) or untethered (e.g., cell-based drug delivery systems). Active motion and multiple functionalities, distinguishing microrobots from mere passive carriers and conventional nanomedicines, can be achieved through external control with physical fields such as magnetism or ultrasound. Here we give an overview of the key challenges in the field of assisted reproduction and how these new technologies could, in the future, enable assisted fertilization in vivo and enhance embryo implantation. As a case study, we describe a potential intervention in the case of recurrent embryo implantation failure, which involves the non-invasive delivery of an early embryo back to the fertilization site using magnetically-controlled microrobots. As the embryo will be in contact with the secretory oviduct fluid, it can develop under natural conditions and in synchrony with the endometrium preparation. We discuss the potential microrobot designs, including a proper selection of materials and processes, envisioning their translation from bench to animal studies and human medicine. Finally, we highlight regulatory and ethical considerations for bringing this technology to the clinic.
SN - 2041-1723
UR - https://doi.org/10.1038/s41467-023-36215-7
DO - 10.1038/s41467-023-36215-7
ID - Nauber2023
ER -

2022

Experimental Observation of Berry Phases in Optical Moebius-strip Microcavities. J. Wang, S. Valligatla, Y. Yin, L. Schwarz, M. Medina-Sánchez, S. Baunack, C. Hua Lee, R. Thomale, S. Li, V. M. Fomin, L. Ma, O.G. Schmidt. Just accepted in Nat. Photonics. 2022

The Moebius strip, as a fascinating loop structure with one-sided topology, provides a rich playground for manipulating the non-trivial topological behavior of spinning particles, such as electrons, polaritons, and photons in both real and parameter spaces. For photons resonating in a Moebius-strip cavity, the occurrence of an extra phase, known as Berry phase, with purely topological origin is expected due to its non-trivial evolution in the parameter space. However, despite numerous theoretical investigations, characterizing optical Berry phase in a Moebius-strip cavity has remained elusive. Here we report the experimental observation of Berry phase generated in optical Moebius-strip microcavities. In contrast to theoretical predictions in optical, electronic, and magnetic Moebius-topology systems where only Berry phase {pi} occurs, we demonstrate that variable Berry phase smaller than {pi} can be acquired by generating elliptical polarization of resonating light. Moebius-strip microcavities as integrable and Berry-phase-programmable optical systems are of great interest in topological physics and emerging classical or quantum photonic applications.

arXiv:2206.04485 [physics.optics]
(or arXiv:2206.04485v3 [physics.optics] for this version)

https://doi.org/10.48550/arXiv.2206.04485
Focus to learn more

Self-assembled sensor-in-a-tube as versatile tool for label-free EIS viability investigation of cervical cancer cells. E. Ghosh, A. I. Egunov, D. Karnaushenko, M. Medina-Sánchez, O.G. Schmidt. Frequenz, 76, 11-12, 2022.

The advancement of micro and nanotechnology has led to the manufacturing of miniaturized sensors with improved functionalities for highly sensitive point of care devices. This work is particularly focused on analysing cancer cells and the effect of a model drug on their survival rate. To that end, we developed a highly sensitive rolled-up micro-electrochemical impedance spectroscopy sensor, encapsulated into a microfluidic channel. The sensor was built by strain engineering of shapeable materials and with diameters close to the cell size to improve their sensitivity. To demonstrate the platform performance, we first carried out measurements with different electrode geometries using cell medium at different concentrations. We also performed measurements using cancer cell suspensions, obtaining distinct signals from single cells, cell clusters and cellular debris. Finally, cancer cells were treated with an anticancer drug (Camptothecin), at different concentrations, over the same period, and further analysed using the developed platform.

@article{GhoshEgunovKarnaushenkoMedinaSánchezSchmidt+2022+729+740,
url = {https://doi.org/10.1515/freq-2022-0090},
title = {Self-assembled sensor-in-a-tube as a versatile tool for label-free EIS viability investigation of cervical cancer cells},
title = {},
author = {Eashika Ghosh and Aleksandr I. Egunov and Daniil Karnaushenko and Mariana Medina-Sánchez and Oliver G. Schmidt},
pages = {729--740},
volume = {76},
number = {11-12},
journal = {Frequenz},
doi = {doi:10.1515/freq-2022-0090},
year = {2022},
lastchecked = {2022-12-01}
}

Multifunctional 4D-printed sperm-hybrid microcarriers for assisted reproduction. F. Rajabasadi, S. Moreno, K. Fichna, A. Aziz, D. Appelhans, O.G. Schmidt, M. Medina-Sánchez. Adv. Mater. Just accepted. 2022

Remotely controllable microrobots are appealing for various biomedical in vivo applications. In particular, in recent years, our group has focused on developing sperm-microcarriers to assist sperm cells with motion deficiencies or low sperm count (two of the most prominent male infertility problems) to reach the oocyte toward in-vivo-assisted fertilization. Different sperm carriers, considering their motion in realistic media and confined environments, have been optimized. However, the already-reported sperm carriers have been mainly designed to transport single sperm cell, with limited functionality. Thus, to take a step forward, here, the development of a 4D-printed multi-functional microcarrier containing soft and smart materials is reported. These microcarriers can not only transport and deliver multiple motile sperm cells, but also release heparin and mediate local enzymatic reactions by hyaluro-nidase-loaded polymersomes (HYAL-Psomes). These multifunctional facets enable in situ sperm capacitation/hyperactivation, and the local degradation of the cumulus complex that surrounds the oocyte, both to facilitate the sperm–oocyte interaction for the ultimate goal of in vivo assisted fertilization.

@article{https://doi.org/10.1002/adma.202204257,
author = {Rajabasadi, Fatemeh and Moreno, Silvia and Fichna, Kristin and Aziz, Azaam and Appelhans, Dietmar and Schmidt, Oliver G. and Medina-Sánchez, Mariana},
title = {Multifunctional 4D-Printed Sperm-Hybrid Microcarriers for Assisted Reproduction},
journal = {Advanced Materials},
volume = {n/a},
number = {n/a},
pages = {2204257},
keywords = {4D-printing lithography, assisted fertilization, biohybrid micromotors, enzyme-loaded polymersomes, multifunctional sperm-hybrid microcarriers, targeted cargo-delivery},
doi = {https://doi.org/10.1002/adma.202204257},
url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/adma.202204257},
eprint = {https://onlinelibrary.wiley.com/doi/pdf/10.1002/adma.202204257},
abstract = {Abstract Remotely controllable microrobots are appealing for various biomedical in vivo applications. In particular, in recent years, our group has focused on developing sperm-microcarriers to assist sperm cells with motion deficiencies or low sperm count (two of the most prominent male infertility problems) to reach the oocyte toward in-vivo-assisted fertilization. Different sperm carriers, considering their motion in realistic media and confined environments, have been optimized. However, the already-reported sperm carriers have been mainly designed to transport single sperm cell, with limited functionality. Thus, to take a step forward, here, the development of a 4D-printed multifunctional microcarrier containing soft and smart materials is reported. These microcarriers can not only transport and deliver multiple motile sperm cells, but also release heparin and mediate local enzymatic reactions by hyaluronidase-loaded polymersomes (HYAL-Psomes). These multifunctional facets enable in situ sperm capacitation/hyperactivation, and the local degradation of the cumulus complex that surrounds the oocyte, both to facilitate the sperm–oocyte interaction for the ultimate goal of in vivo assisted fertilization.}
}

Imaging and control of nanomaterial-decorated micromotors, A. Aziz, R. Nauber, A. Sánchez-Iglesias, L. M. Marzán, O.G. Schmidt, and M. Medina-Sánchez. International Conference on Manipulation, Automation, and Robotics at Small Scales, pp. 1-6, doi: 10.1109/MARSS55884.2022.9870252.

Micro-and nanorobots have the potential to perform non-invasive drug delivery, sensing, and surgery in living organisms with the aid of diverse medical imaging techniques. To perform such actions with microrobots require high spatiotemporal resolution tracking methods with real-time closed-loop feedback. Photoacoustic imaging (PAI) has appeared to be promising for the imaging of microrobots in deep tissue with better contrast. The precise maneuvering and function control of micromotors demands the combination of both deeptissue imaging and their control. Here, we show the motion behavior of the micromotors in a parametric study using closedloop control with optical feedback. We also present different strategies to overcome the current limitations of PAI to track micromotors with improved contrast by the use of dedicated contrast agents (Au nanorods (AuNRs) and Au nanostars (AuNSs)) and the proper selection of the transducer according to the penetration depth, and finally, we discuss the possibility to employ trans-illumination settings.

@INPROCEEDINGS{9870252,
author={Aziz, Azaam and Nauber, Richard and Iglesias, Ana Sánchez and Liz-Marzán, Luis M. and Schmidt, Oliver G. and Medina-Sánchez, Mariana},
booktitle={2022 International Conference on Manipulation, Automation and Robotics at Small Scales (MARSS)},
title={Imaging and control of nanomaterial-decorated micromotors},
year={2022},
volume={},
number={},
pages={1-6},
doi={10.1109/MARSS55884.2022.9870252}}

Small Scale Propulsion: How Systematic Studies of Low Reynolds Number Physics Can Bring Micro/Nanomachines to New Horizons, P. Wrede, M. Medina-Sánchez, and V.M. Fomin. Journal of Nanotechnology and Nanomaterials, 2022, 3,1.

Micromachines are small-scale human-made machines with remarkable potential for medical treatments, microrobotics and environmental
remediation applications. However, meaningful real-world applications are missing. This is mainly caused by their small size leading to
unintuitive physics of motion. Motivated by the aim of understanding the fundamental physics at the micrometer scale and thereby overcoming
resulting challenges, we discuss the importance of robust models supported by experimental data. Our previously performed study on the
switching in propulsion mechanisms for conical tubular catalytic micromotors will be summarized and serve as an example for discussion. We
emphasize on the need for systematic experimental studies to enable the design of highly application-oriented micromachines, which can
be translated into real-world scenarios.

@article{wrede2022small,
title={Small Scale Propulsion: How Systematic Studies of Low Reynolds Number Physics Can Bring Micro/Nanomachines to New Horizons},
author={Wrede, Paul and Medina-S{\'a}nchez, Mariana and Fomin, Vladimir M},
year={2022}
}

Real-Time Tracking of Individual Droplets in Multiphase Microfluidics. B. Ibarlucea, J. Schütt, L. Baraban, D. Makarov, M. Medina-Sánchez, and G. Cuniberti. Book: Microfluidics and Nanofluidics - Fundamentals and Applications. DOI: 10.5772/intechopen. 106796, 2022.

Multiphase microfluidics enables the high-throughput manipulation of droplets for multitude of applications, from the confined fabrication of nano- and micro-objects to the parallelization of chemical reactions of biomedical or biological interest. While the standard methods to follow droplets on a chip are represented by a visual observation through either optical or fluorescence microscopy, the conjunction of microfluidic platforms with miniaturized transduction mechanisms opens new ways towards the real-time and individual tracking of each independent reactor. Here we provide an overview of the most recent droplet sensing techniques, with a special focus on those based on electrical signals for an optics-less analysis.

@incollection{Ibarlucea22,
author = {Bergoi Ibarlucea and Julian Schütt and Larysa Baraban and Denys Makarov and Mariana Medina Sanchez and Gianaurelio Cuniberti},
title = {Real-Time Tracking of Individual Droplets in Multiphase Microfluidics},
booktitle = {Microfluidics and Nanofluidics - Fundamentals and Applications},
publisher = {IntechOpen},
address = {Rijeka},
year = {2022},
editor = {Prof. Mingzhou Yu},
chapter = {6},
doi = {10.5772/intechopen.106796},
url = {https://doi.org/10.5772/intechopen.106796}
}

Continuous monitoring of molecular biomarkers in microfluidic devices, A. Idili, H. Montón, M. Medina-Sánchez, B. Ibarlucea, G. Cuniberti, O.G. Schmidt, K. W. Plaxco, C. Parolo. Progress in Molecular Biology and Translational Science, 187, 1.

The ability to monitor molecular targets is crucial in fields ranging from healthcare to industrial processing to environmental protection. Devices employing biomolecules to achieve this goal are called biosensors. Over the last half century researchers have developed dozens of different biosensor approaches. In this chapter we analyze recent advances in the biosensing field aiming at adapting these to the problem of continuous molecular monitoring in complex sample streams, and how the merging of these sensors with lab-on-a-chip technologies would be beneficial to both. To do so we discuss (1) the components that comprise a biosensor, (2) the challenges associated with continuous molecular monitoring in complex sample streams, (3) how different sensing strategies deal with (or fail to deal with) these challenges, and (4) the implementation of these technologies into lab-on-a-chip architectures.

@incollection{IDILI2022295,
title = {Chapter Eleven - Continuous monitoring of molecular biomarkers in microfluidic devices},
editor = {Alok Pandya and Vijai Singh},
series = {Progress in Molecular Biology and Translational Science},
publisher = {Academic Press},
volume = {187},
number = {1},
pages = {295-333},
year = {2022},
booktitle = {Micro/Nanofluidics and Lab-on-Chip Based Emerging Technologies for Biomedical and Translational Research Applications - Part B},
issn = {1877-1173},
doi = {https://doi.org/10.1016/bs.pmbts.2021.07.027},
url = {https://www.sciencedirect.com/science/article/pii/S1877117321001678},
author = {Andrea Idili and Helena Montón and Mariana Medina-Sánchez and Bergoi Ibarlucea and Gianaurelio Cuniberti and Oliver G. Schmidt and Kevin W. Plaxco and Claudio Parolo},
keywords = {Continuous sensing, Real-time sensing, Biosensors, Analytical devices, Diagnostics},
abstract = {The ability to monitor molecular targets is crucial in fields ranging from healthcare to industrial processing to environmental protection. Devices employing biomolecules to achieve this goal are called biosensors. Over the last half century researchers have developed dozens of different biosensor approaches. In this chapter we analyze recent advances in the biosensing field aiming at adapting these to the problem of continuous molecular monitoring in complex sample streams, and how the merging of these sensors with lab-on-a-chip technologies would be beneficial to both. To do so we discuss (1) the components that comprise a biosensor, (2) the challenges associated with continuous molecular monitoring in complex sample streams, (3) how different sensing strategies deal with (or fail to deal with) these challenges, and (4) the implementation of these technologies into lab-on-a-chip architectures.}
}

2021

Electronically integrated microcatheters based on self-assembling polymer films. 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, Science Advances. 2021. 7(51), eabl5408.

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.

@article{rivkin2021electronically, title={Electronically integrated microcatheters based on self-assembling polymer films}, author={Rivkin, Boris and Becker, Christian and Singh, Balram and Aziz, Azaam and Akbar, Farzin and Egunov, Aleksandr and Karnaushenko, Dmitriy D and Naumann, Ronald and Schafer, Rudolf and Medina-Sanchez, Mariana and others}, journal={Science advances}, volume={7}, number={51}, pages={eabl5408}, year={2021}, publisher={American Association for the Advancement of Science}}

Self-sufficient self-oscillating microsystem driven by low power at low Reynolds numbers, F. Akbar, B. Rivkin, A. Aziz, C. Becker, D. D. Karnaushenko, M. Medina-Sánchez, D. Karnaushenko, and O. G. Schmidt, Science Advances. 2021, 7, eabj0767

Oscillations at several hertz are a key feature of dynamic behavior of various biological entities, such as the pulsating heart, firing neurons, or the sperm-beating flagellum. Inspired by nature’s fundamental self-oscillations, we use electroactive polymer microactuators and three-dimensional microswitches to create a synthetic electromechanical parametric relaxation oscillator (EMPRO) that relies on the shape change of micropatterned polypyrrole and generates a rhythmic motion at biologically relevant stroke frequencies of up to ~95 Hz. We incorporate an Ag-Mg electrochemical battery into the EMPRO for autonomous operation in a nontoxic environment. Such a self-sufficient self-oscillating microsystem offers new opportunities for artificial life at low Reynolds numbers by, for instance, mimicking and replacing nature’s propulsion and pumping units.

@article{
doi:10.1126/sciadv.abj0767,
author = {Farzin Akbar and Boris Rivkin and Azaam Aziz and Christian Becker and Dmitriy D. Karnaushenko and Mariana Medina-Sánchez and Daniil Karnaushenko and Oliver G. Schmidt },
title = {Self-sufficient self-oscillating microsystem driven by low power at low Reynolds numbers},
journal = {Science Advances},
volume = {7},
number = {44},
pages = {eabj0767},
year = {2021},
doi = {10.1126/sciadv.abj0767},
URL = {https://www.science.org/doi/abs/10.1126/sciadv.abj0767},
eprint = {https://www.science.org/doi/pdf/10.1126/sciadv.abj0767},
abstract = {Fast autonomous rhythmic motion is achieved in water for an artificial microsystem inspired by biologically relevant frequencies. Oscillations at several hertz are a key feature of dynamic behavior of various biological entities, such as the pulsating heart, firing neurons, or the sperm-beating flagellum. Inspired by nature’s fundamental self-oscillations, we use electroactive polymer microactuators and three-dimensional microswitches to create a synthetic electromechanical parametric relaxation oscillator (EMPRO) that relies on the shape change of micropatterned polypyrrole and generates a rhythmic motion at biologically relevant stroke frequencies of up to ~95 Hz. We incorporate an Ag-Mg electrochemical battery into the EMPRO for autonomous operation in a nontoxic environment. Such a self-sufficient self-oscillating microsystem offers new opportunities for artificial life at low Reynolds numbers by, for instance, mimicking and replacing nature’s propulsion and pumping units.}}

Nano-biosupercapacitors enable autarkic sensor operation in blood, Y. Lee, V.K. Bandari, Z. Li, M. Medina-Sánchez, M.F. Maitz, D. Karnaushenko, M. V. Tsurkan, D.D. Karnaushenko, and O.G. Schmidt, Nature Communications. 12, 4967 (2021).

Mariana Medina-Sánchez 3, Manfred F. Maitz 4, Daniil Karnaushenko3, Mikhail V. Tsurkan 4, Dmitriy D. Karnaushenko 3 & Oliver G. Schmidt

Today’s smallest energy storage devices for in-vivo applications are larger than 3 mm3 and lack the ability to continuously drive the complex functions of smart dust electronic and microrobotic systems. Here, we create a tubular biosupercapacitor occupying a mere volume of 1/1000 mm3 (=1 nanoliter), yet delivering up to 1.6 V in blood. The tubular geometry of this nano-biosupercapacitor provides efficient self-protection against external forces from pulsating blood or muscle contraction. Redox enzymes and living cells, naturally present in blood boost the performance of the device by 40% and help to solve the self-discharging problem persistently encountered by miniaturized supercapacitors. At full capacity, the nano-biosupercapacitors drive a complex integrated sensor system to measure the pH-value in blood. This demonstration opens up opportunities for next generation intravascular implants and microrobotic systems operating in hard-to-reach small spaces deep inside the human body.

TY - JOUR
AU - Lee, Yeji
AU - Bandari, Vineeth Kumar
AU - Li, Zhe
AU - Medina-Sánchez, Mariana
AU - Maitz, Manfred F.
AU - Karnaushenko, Daniil
AU - Tsurkan, Mikhail V.
AU - Karnaushenko, Dmitriy D.
AU - Schmidt, Oliver G.
PY - 2021
DA - 2021/08/23
TI - Nano-biosupercapacitors enable autarkic sensor operation in blood
JO - Nature Communications
SP - 4967
VL - 12
IS - 1
AB - Today’s smallest energy storage devices for in-vivo applications are larger than 3 mm3 and lack the ability to continuously drive the complex functions of smart dust electronic and microrobotic systems. Here, we create a tubular biosupercapacitor occupying a mere volume of 1/1000 mm3 (=1 nanoliter), yet delivering up to 1.6 V in blood. The tubular geometry of this nano-biosupercapacitor provides efficient self-protection against external forces from pulsating blood or muscle contraction. Redox enzymes and living cells, naturally present in blood boost the performance of the device by 40% and help to solve the self-discharging problem persistently encountered by miniaturized supercapacitors. At full capacity, the nano-biosupercapacitors drive a complex integrated sensor system to measure the pH-value in blood. This demonstration opens up opportunities for next generation intravascular implants and microrobotic systems operating in hard-to-reach small spaces deep inside the human body.
SN - 2041-1723
UR - https://doi.org/10.1038/s41467-021-24863-6
DO - 10.1038/s41467-021-24863-6
ID - Lee2021
ER -

Continuous monitoring of molecular biomarkers in microfluidic devices, A. Idili A, H. Montón, M. Medina-Sánchez, B. Ibarlucea, G. Cuniberti, O.G. Schmidt, K. W. Plaxco, and C. Parolo. Progress in Molecular Biology and Translational Science. 2022, 87(1), 295-333.

The ability to monitor molecular targets is crucial in fields ranging from healthcare to industrial processing to environmental protection. Devices employing biomolecules to achieve this goal are called biosensors. Over the last half century researchers have developed dozens of different biosensor approaches. In this chapter we analyze recent advances in the biosensing field aiming at adapting these to the problem of continuous molecular monitoring in complex sample streams, and how the merging of these sensors with lab-on-a-chip technologies would be beneficial to both. To do so we discuss (1) the components that comprise a biosensor, (2) the challenges associated with continuous molecular monitoring in complex sample streams, (3) how different sensing strategies deal with (or fail to deal with) these challenges, and (4) the implementation of these technologies into lab-on-a-chip architectures.

@article {PMID:35094779,
Title = {Continuous monitoring of molecular biomarkers in microfluidic devices},
Author = {Idili, Andrea and Montón, Helena and Medina-Sánchez, Mariana and Ibarlucea, Bergoi and Cuniberti, Gianaurelio and Schmidt, Oliver G and Plaxco, Kevin W and Parolo, Claudio},
DOI = {10.1016/bs.pmbts.2021.07.027},
Number = {1},
Volume = {187},
Year = {2022},
Journal = {Progress in molecular biology and translational science},
ISSN = {1877-1173},
Pages = {295—333},
Abstract = {The ability to monitor molecular targets is crucial in fields ranging from healthcare to industrial processing to environmental protection. Devices employing biomolecules to achieve this goal are called biosensors. Over the last half century researchers have developed dozens of different biosensor approaches. In this chapter we analyze recent advances in the biosensing field aiming at adapting these to the problem of continuous molecular monitoring in complex sample streams, and how the merging of these sensors with lab-on-a-chip technologies would be beneficial to both. To do so we discuss (1) the components that comprise a biosensor, (2) the challenges associated with continuous molecular monitoring in complex sample streams, (3) how different sensing strategies deal with (or fail to deal with) these challenges, and (4) the implementation of these technologies into lab-on-a-chip architectures.},
URL = {https://doi.org/10.1016/bs.pmbts.2021.07.027},
}

Dual Ultrasound and Photoacoustic Tracking of Magnetically Driven Micromotors: From In Vitro to In Vivo, A. Aziz, J. Holthof, S. Meyer, O.G. Schmidt, and M. Medina-Sánchez. Advanced Healthcare Materials. 2021, 10, 2101077.

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.

@article{https://doi.org/10.1002/adhm.202101077,
author = {Aziz, Azaam and Holthof, Joost and Meyer, Sandra and Schmidt, Oliver G. and Medina-Sánchez, Mariana},
title = {Dual Ultrasound and Photoacoustic Tracking of Magnetically Driven Micromotors: From In Vitro to In Vivo},
journal = {Advanced Healthcare Materials},
volume = {10},
number = {22},
pages = {2101077},
keywords = {dual in vivo imaging, medical tracking, micromotors, photoacoustics, ultrasound},
doi = {https://doi.org/10.1002/adhm.202101077},
url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/adhm.202101077},
eprint = {https://onlinelibrary.wiley.com/doi/pdf/10.1002/adhm.202101077},
abstract = {Abstract 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.},
year = {2021}
}

Micromotor-mediated sperm constrictions for improved swimming performance, F. Striggow, L. Nadporozhskaia, B. M. Friedrich, O.G. Schmidt, and M. Medina-Sánchez, The European Physical Journal E, 2021, 44(67), 1-15.

Sperm-driven micromotors, consisting of a single sperm cell captured in a microcap, utilize the strong propulsion generated by the flagellar beat of motile spermatozoa for locomotion. It enables the movement of such micromotors in biological media, while being steered remotely by means of an external magnetic field. The substantial decrease in swimming speed, caused by the additional hydrodynamic load of the microcap, limits the applicability of sperm-based micromotors. Therefore, to improve the performance of such micromotors, we first investigate the effects of additional cargo on the flagellar beat of spermatozoa. We designed two different kinds of microcaps, which each result in different load responses of the flagellar beat. As an additional design feature, we constrain rotational degrees of freedom of the cell’s motion by modifying the inner cavity of the cap. Particularly, cell rolling is substantially reduced by tightly locking the sperm head inside the microcap. Likewise, cell yawing is decreased by aligning the micromotors under an external static magnetic field. The observed differences in swimming speed of different micromotors are not so much a direct consequence of hydrodynamic effects, but rather stem from changes in flagellar bending waves, hence are an indirect effect. Our work serves as proof-of-principle that the optimal design of microcaps is key for the development of efficient sperm-driven micromotors.

@article {Striggow2021Micromotor-mediated, title={Micromotor-mediated sperm constrictions for improved swimming performance}, author={Friedrich Striggow, Lidiia Nadporozhskaia, Benjamin M. Friedrich, Oliver Schmidt, Mariana Medina-Sánchez}, journal={The European Physical Journal E}, volume={44}, number={67}, pages={1-15}, year={2021}, publisher={Springer}

3D and 4D Lithography of Untethered Microrobots, F. Rajabasadi, L. Schwarz, M. Medina-Sánchez, and O.G. Schmidt. Progress in Material Science, 2021, 120, 1-32.

In the last decades, additive manufacturing (AM), also called three-dimensional (3D) printing, has advanced micro/nano-fabrication technologies, especially in applications like lightweight engineering, optics, energy, and biomedicine. Among these 3D printing technologies, two-photon polymerization (TPP) is the technique which offers the highest resolution (even at the nanometric scale), reproducibility and the possibility to create monolithically 3D complex structures with a variety of materials (e.g. organic and inorganic, passive and active). Such active materials change their shape upon an applied stimulus or degrade over time at certain conditions making them dynamic and reconfigurable (also called 4D printing). This is particularly interesting in the field of medical microrobotics as complex functions such as gentle interactions with biological samples, adaptability when moving in small capillaries, controlled …

@article{Rajabasadi20213Dand4D, title={3D and 4D lithography of untethered microrobots}, author={Fatemeh Rajabasadi, Lukas Schwarz, Mariana Medina-Sánchez, O.G. Schmidt}, journal={Progress in Material Science}, volume={120}, pages={1-32}, year={2021}, publisher={Elsevier}

Rolled-Up Metal Oxide Microscaffolds to Study Early Bone Formation at Single Cell Resolution, R. Herzer, A. Gebert, U. Hempel, F. Hebenstreit, S. Oswald, C.Damm, O.G. Schmidt, and M. Medina‐Sánchez, Small. 2021, 17(12), 2170053.

Transparent Ti-45Nb 3D microstructures offer an elegant way to study single bone cell-implant material interactions and pore size effects in vitro. In article number 2005527, Mariana Medina-Sánchez and co-workers present this technology as an excellent tool to live monitor cell migration and adhesion behavior changes deriving from highly constricted microenvironments, while also providing deeper insights on cell death related bone mineralization processes in low nutrition conditions.

@article{Herzer2021Bone, title={Bone Formation: Rolled-Up Metal Oxide Microscaffolds to Study Early Bone Formation at Single Cell Resolution }, author={Raffael Herzer, Annett Gebert, Ute Hempel, Franziska Hebenstreit, Steffen Oswald, Christine Damm, Oliver G Schmidt, Mariana Medina‐Sánchez}, journal={Small}, Volume={17}, number={12}, Pages={2170053}, year={2021}, publisher={Wiley Online Library}

Switching Propulsion Mechanisms of Tubular Catalytic Micromotors. P. Wrede, M. Medina‐Sánchez, V.M. Fomin, and O.G. Schmidt, Small, 2021. 17(12), 2006449.

Different propulsion mechanisms have been suggested for describing the motion of a variety of chemical micromotors, which have attracted great attention in the last decades due to their high efficiency and thrust force, enabling several applications in the fields of environmental remediation and biomedicine. Bubble‐recoil based motion, in particular, has been modeled by three different phenomena: capillary forces, bubble growth, and bubble expulsion. However, these models have been suggested independently based on a single influencing factor (i.e., viscosity), limiting the understanding of the overall micromotor performance. Therefore, the combined effect of medium viscosity, surface tension, and fuel concentration is analyzed on the micromotor swimming ability, and the dominant propulsion mechanisms that describe its motion more accurately are identified. Using statistically relevant experimental data, a holistic theoretical model is proposed for bubble‐propelled tubular catalytic micromotors that includes all three above‐mentioned phenomena and provides deeper insights into their propulsion physics toward optimized geometries and experimental conditions.

@article{wrede2021catalytic, title={Switching Propulsion Mechanisms of Tubular Catalytic Micromotors}, author={Wrede, Paul and Medina-S{'a}nchez, Mariana and Fomin, Vladimir M. and Schmidt, Oliver G.}, journal={Small}, volume={17}, number={12}, pages={2006449}, year={2021}, publisher={Wiley Online Library} }

Shape-Controlled Flexible Microelectronics Facilitated by Integrated Sensors and Conductive Polymer Actuators. B. Rivkin, C. Becker, F. Akbar, R. Ravishankar, D.D. Karnaushenko, R. Naumann, A. Mirhajivarzaneh, M. Medina-Sánchez, D. Karnaushenko, and O.G. Schmidt, Advanced Intelligent Systems. 2021, 3(6), 2000238.

The next generation of biomedical tools requires reshapeable electronics to closely interface with biological tissues. This will offer unique mechanical properties and the ability to conform to irregular geometries while being robust and lightweight. Such devices can be achieved with soft materials and thin-film structures that are able to reshape on demand. However, reshaping at the submillimeter scale remains a challenging task. Herein, shape-controlled microscale devices are demonstrated that integrate electronic sensors and electroactive polymer actuators. The fast and biocompatible actuators are capable of actively reshaping the device into flat or curved geometries. The curvature and position of the devices are monitored with strain or magnetic sensors. The sensor signals are used in a closed feedback loop to control the actuators. The devices are wafer-scale microfabricated resulting in multiple functional units capable of grasping, holding, and releasing biological tissues, as demonstrated with a neuronal bundle.

@article{rivkin2021shape, title={Shape-Controlled Flexible Microelectronics Facilitated by Integrated Sensors and Conductive Polymer Actuators}, author={Rivkin, Boris and Becker, Christian and Akbar, Farzin and Ravishankar, Rachappa and Karnaushenko, Dmitriy D and Naumann, Ronald and Mirhajivarzaneh, Alaleh and Medina-Sanchez, Mariana and Karnaushenko, Daniil and Schmidt, Oliver G}, journal={Advanced Intelligent Systems}, pages={2000238}, year={2021}, publisher={Wiley Online Library}}

Impedimetric Microfluidic Sensor-in-a-Tube for Label-Free Immune Cell Analysis. A. Egunov, Z. Dou, D.D. Karnaushenko, F. Hebenstreit, N. Kretschmann, K. Akgün, T. Ziemssen, D. Karnaushenko, M. Medina-Sánchez, and O.G. Schmidt, Small, 2021, 17(5), 2002549.

Analytical platforms based on impedance spectroscopy are promising for non-invasive and label-free analysis of single cells as well as of their extracellular matrix, being essential to understand cell function in the presence of certain diseases. Here, an innovative rolled-up impedimetric microfulidic sensor, called sensor-in-a-tube, is introduced for the simultaneous analysis of single human monocytes CD14+ and their extracellular medium upon liposaccharides (LPS)-mediated activation. In particular, rolled-up platinum microelectrodes are integrated within for the static and dynamic (in-flow) detection of cells and their surrounding medium (containing expressed cytokines) over an excitation frequency range from 102 to 5 × 106 Hz. The correspondence between cell activation stages and the electrical properties of the cell surrounding medium have been detected by electrical impedance spectroscopy in dynamic mode without employing electrode surface functionalization or labeling. The designed sensor-in-a-tube platform is shown as a sensitive and reliable tool for precise single cell analysis toward immune-deficient diseases diagnosis.

Egunov, A. I., Dou, Z., Karnaushenko, D. D., Hebenstreit, F., Kretschmann, N., Akgün, K., Ziemssen, T., Karnaushenko, D., Medina-Sánchez, M., Schmidt, O. G., Impedimetric Microfluidic Sensor-in-a-Tube for Label-Free Immune Cell Analysis. Small 2021, 17, 2002549. https://doi.org/10.1002/smll.202002549

2020

Engineering microrobots for targeted cancer therapies from a medical perspective. C. Schmidt, M. Medina-Sánchez, R.J. Edmondson, and O.G. Schmidt, Nature Communications, 2020. 11(1), 1-18.

Systemic chemotherapy remains the backbone of many cancer treatments. Due to its untargeted nature and the severe side effects it can cause, numerous nanomedicine approaches have been developed to overcome these issues. However, targeted delivery of therapeutics remains challenging. Engineering microrobots is increasingly receiving attention in this regard. Their functionalities, particularly their motility, allow microrobots to penetrate tissues and reach cancers more efficiently. Here, we highlight how different microrobots, ranging from tailor-made motile bacteria and tiny bubble-propelled microengines to hybrid spermbots, can be engineered to integrate sophisticated features optimised for precision-targeting of a wide range of cancers. Towards this, we highlight the importance of integrating clinicians, the public and cancer patients early on in the development of these novel technologies.

@article{schmidt2020engineering, title={Engineering microrobots for targeted cancer therapies from a medical perspective}, author={Schmidt, Christine K and Medina-Sánchez, Mariana and Edmondson, Richard J and Schmidt, Oliver G}, journal={Nature Communications}, volume={11}, number={1}, pages={1--18}, year={2020}, publisher={Nature Publishing Group} }

Human spermbots for patient-representative 3D ovarian cancer cell treatment. H. Xu, M. Medina-Sánchez, W. Zhang, M.P. Seaton, D.R. Brison, R.J, Edmondson, O.G. Schmidt, et al. Nanoscale, 2020, 12(39), 20467-20481.

Cellular micromotors are attractive for locally delivering high concentrations of drug, and targeting hard-to-reach disease sites such as cervical cancer and early ovarian cancer lesions by non-invasive means. Spermatozoa are highly efficient micromotors perfectly adapted to traveling up the female reproductive system. Indeed, bovine sperm-based micromotors have shown potential to carry drugs toward gynecological cancers. However, due to major differences in the molecular make-up of bovine and human sperm, a key translational bottleneck for bringing this technology closer to the clinic is to transfer this concept to human material. Here, we successfully load human sperm with Doxorubicin (DOX) and perform treatment of 3D cervical cancer and patient-representative ovarian cancer cell cultures, resulting in strong anticancer cell effects. Additionally, we define the subcellular localization of the chemotherapeutic drug within human sperm, using high-resolution optical microscopy. We also assess drug effects on sperm motility and viability over time, employing sperm samples from healthy donors as well as assisted reproduction patients. Finally, we demonstrate guidance and release of human drug-loaded sperm onto cancer tissues using magnetic microcaps, and show the sperm microcap loaded with a second anticancer drug, camptothecin (CPT), which unlike DOX is not suitable for directly loading into sperm due to its hydrophobic nature. This co-drug delivery approach opens up novel targeted combinatorial drug therapies for future applications.

@article{xu2020human, title={Human spermbots for patient-representative 3D ovarian cancer cell treatment}, author={Xu, Haifeng and Medina-S{\'a}nchez, Mariana and Zhang, Wunan and Seaton, Melanie PH and Brison, Daniel R and Edmondson, Richard J and Taylor, Stephen S and Nelson, Louisa and Zeng, Kang and Bagley, Steven and others}, journal={Nanoscale}, volume={12}, number={39}, pages={20467--20481}, year={2020}, publisher={Royal Society of Chemistry} }

Medical Imaging of Microrobots: Toward In Vivo Applications. A. Aziz, S. Pane, V. Iacovacci, N. Koukourakis, J. Czarske, A. Menciassi, M. Medina-Sánchez, and O.G. Schmidt, ACS Nano, 2020, 14(9), 10865-10893.

Medical microrobots (MRs) have been demonstrated for a variety of non-invasive biomedical applications, such as tissue engineering, drug delivery, and assisted fertilization, among others. However, most of these demonstrations have been carried out in in vitro settings and under optical microscopy, being significantly different from the clinical practice. Thus, medical imaging techniques are required for localizing and tracking such tiny therapeutic machines when used in medical-relevant applications. This review aims at analyzing the state of the art of microrobots imaging by critically discussing the potentialities and limitations of the techniques employed in this field. Moreover, the physics and the working principle behind each analyzed imaging strategy, the spatiotemporal resolution, and the penetration depth are thoroughly discussed. The paper deals with the suitability of each imaging technique for tracking single or swarms of MRs and discusses the scenarios where contrast or imaging agent’s inclusion is required, either to absorb, emit, or reflect a determined physical signal detected by an external system. Finally, the review highlights the existing challenges and perspective solutions which could be promising for future in vivo applications.

@article{aziz2020review, title={Medical Imaging of Microrobots: Toward In Vivo Applications}, author={Aziz, Azam and Pane, Stefano and Iacovacci, Veronica and Koukourakis Nektarios and Czarke, Jürgen and Menciassi, Arianna and Medina-S{'a}nchez, Mariana and Schmidt, Oliver G.}, journal={ACS Nano}, volume={14}, number={9}, pages={10865--10893}, year={2020}, publisher={ACS Publications} }

A rotating spiral micromotor for noninvasive zygote transfer. L. Schwarz, D.D. Karnaushenko, F. Hebenstreit,R. Naumann, O.G. Schmidt, and M. Medina‐Sánchez, Advanced Science, 2020, 7(18), 2000843.

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.

@article{schwarz2020rotating, title={A rotating spiral micromotor for noninvasive zygote transfer}, author={Schwarz, Lukas and Karnaushenko, Dmitriy D and Hebenstreit, Franziska and Naumann, Ronald and Schmidt, Oliver G and Medina-S{\'a}nchez, Mariana}, journal={Advanced Science}, volume={7}, number={18}, pages={2000843}, year={2020}, publisher={Wiley Online Library} }

IRONSperm: Sperm-templated soft magnetic microrobots, V. Magdanz, I. S. M. Khalil, J. Simmchen, G.P. Furtado, S.Mohanty, J. Gebauer, H. Xu, A. Klingner, A. Aziz, M.Medina-Sánchez, O.G. Schmidt, and S. Misra, Science Advances, 2020, 6(eaba5855) 1-15.

We develop biohybrid magnetic microrobots by electrostatic self-assembly of nonmotile sperm cells and magnetic nanoparticles. Incorporating a biological entity into microrobots entails many functional advantages beyond shape templating, such as the facile uptake of chemotherapeutic agents to achieve targeted drug delivery. We present a single-step electrostatic self-assembly technique to fabricate IRONSperms, soft magnetic microswimmers that emulate the motion of motile sperm cells. Our experiments and theoretical predictions show that the swimming speed of IRONSperms exceeds 0.2 body length/s (6.8 ± 4.1 µm/s) at an actuation frequency of 8 Hz and precision angle of 45°. We demonstrate that the nanoparticle coating increases the acoustic impedance of the sperm cells and enables localization of clusters of IRONSperm using ultrasound feedback. We also confirm the biocompatibility and drug loading …

@ article{Magdanz2020IRONSperm, title={IRONSperm: Sperm-templated soft magnetic microrobots}, author={Veronika Magdanz, Islam S. M. Khalil, Juliane Simmchen, Guilherme P. Furtado, Sumit Mohanty, Johannes Gebauer, Haifeng Xu, Anke Klingner, Azaam Aziz, Mariana Medina-Sánchez, Oliver G. Schmidt Schmidt, Sarthak Misra}, journal={Science Advances}, number={eaba5855}, pages={1-15}, year={2020}, publisher={AAAS}}

Sperm‐Driven Micromotors Moving in Oviduct Fluid and Viscoelastic Media. F. Striggow, M. Medina‐Sánchez, G.K. Auernhammer, V. Magdanz, B.M. Friedrich, and O.G. Schmidt, Small, 2020, 16(24), 2000213.

Biohybrid micromotors propelled by motile cells are fascinating entities for autonomous biomedical operations on the microscale. Their operation under physiological conditions, including highly viscous environments, is an essential prerequisite to be translated to in vivo settings. In this work, a sperm‐driven microswimmer, referred to as a spermbot, is demonstrated to operate in oviduct fluid in vitro. The viscoelastic properties of bovine oviduct fluid (BOF), one of the fluids that sperm cells encounter on their way to the oocyte, are first characterized using passive microrheology. This allows to design an artificial oviduct fluid to match the rheological properties of oviduct fluid for further experiments. Sperm motion is analyzed and it is confirmed that kinetic parameters match in real and artificial oviduct fluids, respectively. It is demonstrated that sperm cells can efficiently couple to magnetic microtubes and propel them forward in media of different viscosities and in BOF. The flagellar beat pattern of coupled as well as of free sperm cells is investigated, revealing an alteration on the regular flagellar beat, presenting an on–off behavior caused by the additional load of the microtube. Finally, a new microcap design is proposed to improve the overall performance of the spermbot in complex biofluids.

@article{striggow2020sperm, title={Sperm-Driven Micromotors Moving in Oviduct Fluid and Viscoelastic Media}, author={Striggow, Friedrich and Medina-S{\'a}nchez, Mariana and Auernhammer, G{\"u}nter K and Magdanz, Veronika and Friedrich, Benjamin M and Schmidt, Oliver G}, journal={Small}, volume={16}, number={24}, pages={2000213}, year={2020}, publisher={Wiley Online Library} }

Magnetic Miromotors for Multiple Motile Sperm Cells Capture, Transport, and Enzymatic Release. H. Xu, M. Medina-Sánchez, and O.G. Schmidt, Angewandte Chemie International Edition, 2020, 59(35), 15029-15037.

An integrated system combining a magnetically‐driven micromotor and a synthetized protein‐based hyaluronic acid (HA) microflake is presented for the in situ selection and transport of multiple motile sperm cells (ca. 50). The system appeals for targeted sperm delivery in the reproductive system to assist fertilization or to deliver drugs. The binding mechanism between the HA microflake and sperm relies on the interactions between HA and the corresponding sperm HA receptors. Once sperm are captured within the HA microflake, the assembly is trapped and transported by a magnetically‐driven helical microcarrier. The trapping of the sperm‐microflake occurs by a local vortex induced by the microcarrier during rotation‐translation under a rotating magnetic field. After transport, the microflake is enzymatically hydrolyzed by local proteases, allowing sperm to escape and finally reach the target location. This cargo‐delivery system represents a new concept to transport not only multiple motile sperm but also other actively moving biological cargoes.

@article{xu2020flake, title={Magnetic Miromotors for Multiple Motile Sperm Cells Capture, Transport, and Enzymatic Release}, author={Xu, Haifeng and Medina-Sánchez, Mariana and Schmidt, Oliver G}, journal={Angewandte Chemie International Edition}, volume={59}, number={35}, pages={15029--15037}, year={2020}, publisher={Wiley Online Library} }

Silicon‐Based Integrated Label‐Free Optofluidic Biosensors: Latest Advances and Roadmap, J. Wang, M. Medina-Sánchez, Y. Yin, L. Ma, R. Herzer, and O.G. Schmidt, Advanced Materials Technologies, 2020, 5 (1901138) 1-24.

By virtue of the well‐developed micro‐ and nanofabrication technologies and rapidly progressing surface functionalization strategies, silicon‐based devices have been widely recognized as a highly promising platform for the next‐generation lab‐on‐a‐chip bioanalytical systems with a great potential for point‐of‐care medical diagnostics. Herein, an overview of the latest advances in silicon‐based integrated optofluidic label‐free biosensing technologies relying on the efficient interactions between the evanescent light field at the functionalized surface and specifically bound analytes is presented. State‐of‐the‐art technologies demonstrating label‐free evanescent wave‐based biomarker detection mainly encompass three device configurations, including on‐chip waveguide‐based interferometers, microring resonators, and photonic‐crystal‐based cavities. Moreover, up‐to‐date strategies for elevating the …

@article{Wang2020Silicon-Based, title={Silicon‐Based Integrated Label‐Free Optofluidic Biosensors: Latest Advances and Roadmap}, authors={Jiawei Wang, Mariana Medina-Sánchez, Yin Yin, Libo Ma, Raffael Herzer, O.G. Schmidt}, Journal={Advanced Materials Technologies}, volume={5}, Number={1901138}, pages={1-24}, year={2020}, publisher={Wiley}}

A flexible microsystem capable of controlled motion and actuation by wireless power transfer, V. Kumar Bandari, Y. Nan, D. Karnaushenko, Y. Hong, B. Sun, F. Striggow, D. D. Karnaushenko, C. Becker, M. Faghih, M. Medina-Sánchez, F. Zhu, and O. G. Schmidt. Nature Electronics, 2020, 3 (3), 172-180.

Microscale systems that can combine multiple functionalities, such as untethered motion, actuation and communication, could be of use in a variety of applications from robotics to drug delivery. However, these systems require both rigid and flexible components—including microelectronic circuits, engines, actuators, sensors, controllers and power supplies—to be integrated on a single platform. Here, we report a flexible microsystem that is capable of controlled locomotion and actuation, and is driven by wireless power transfer. The microsystem uses two tube-shaped catalytic micro-engines that are connected via a flat polymeric structure. A square coil is integrated into the platform, which enables wireless energy transfer via inductive coupling. As a result, the catalytic engines can be locally heated and the direction of motion controlled. Our platform can also integrate light-emitting diodes and a thermoresponsive micro-arm that can be used to perform grasp and release tasks.

@article{Bandari2020Aflexible, title={A flexible microsystem capable of controlled motion and actuation by wireless power transfer}, author={Vineeth Kumar Bandari, Yang Nan, Daniil Karnaushenko, Yu Hong, Bingkun Sun, Friedrich Striggow, Dmitriy D Karnaushenko, Christian Becker, Maryam Faghih, Mariana Medina-Sánchez, Feng Zhu, Oliver G Schmidt}, journal={Nature Electronics}, Volume={3}, number={3}, pages={172-180}, year={2020}, publisher={Nature Publishing Group}}

Sperm Micromotors for Cargo Delivery through Flowing Blood, H. Xu, M. Medina-Sánchez, M. F. Maitz, C. Werner, and O.G. Schmidt, ACS Nano, 2020 14 (3), 2982-2993.

Micromotors are recognized as promising candidates for untethered micromanipulation and targeted cargo delivery in complex biological environments. However, their feasibility in the circulatory system has been limited due to the low thrust force exhibited by many of the reported synthetic micromotors, which is not sufficient to overcome the high flow and complex composition of blood. Here we present a hybrid sperm micromotor that can actively swim against flowing blood (continuous and pulsatile) and perform the function of heparin cargo delivery. In this biohybrid system, the sperm flagellum provides a high propulsion force while the synthetic microstructure serves for magnetic guidance and cargo transport. Moreover, single sperm micromotors can assemble into a train-like carrier after magnetization, allowing the transport of multiple sperm or medical cargoes to the area of interest, serving as potential anticoagulant agents to treat blood clots or other diseases in the circulatory system.

@article{doi:10.1021/acsnano.9b07851,
author = {Xu, Haifeng and Medina-Sánchez, Mariana and Maitz, Manfred F. and Werner, Carsten and Schmidt, Oliver G.},
title = {Sperm Micromotors for Cargo Delivery through Flowing Blood},
journal = {ACS Nano},
volume = {14},
number = {3},
pages = {2982-2993},
year = {2020},
doi = {10.1021/acsnano.9b07851},
note ={PMID: 32096976},

URL = {
https://doi.org/10.1021/acsnano.9b07851

},
eprint = {
https://doi.org/10.1021/acsnano.9b07851

}

}

Sperm-hybrid micromotors: on-board assistance for nature’s bustling swimmers, L. Schwarz, M. Medina-Sánchez, and O.G. Schmidt, Reproduction, 2020, 159(2), 83-96.

Sperm cells that cannot swim and orient properly compromise male fertility. Such defects are responsible for male infertility regardless of the actual quality of the most important content, the sperm’s DNA. Synthetic micromotors are engineered devices that are able to swim in (body) fluids and microscopic environments, similar to flagellated cells like sperm. Coupled together, a sperm-hybrid micromotor embodies the concept of bringing the sperm cell together with artificial components that assist or replace defective functions of the cell, helping it to pursue its goal without interfering with its health, enabling the process of assisted fertilization and further embryo development all inside the body. Non-invasive, remote-controlled in vivo applicability is the key quality of such hybrid microdevices. Assisted reproduction with the help of micromotors is in the focus of this review, although other biomedical applications that arise from the powerful combination of sperm cell and synthetic enhancement are also discussed and summarized. Details are provided about different fabrication processes and cell-material coupling strategies, and the way from proof-of-concept studies to in vivo experiments in animals is outlined.

@article { Spermhybridmicromotorsonboardassistancefornaturesbustlingswimmers,
author = "Lukas Schwarz and Mariana Medina-Sánchez and Oliver G Schmidt",
title = "Sperm-hybrid micromotors: on-board assistance for nature’s bustling swimmers",
journal = "Reproduction",
year = "2020",
publisher = "Bioscientifica Ltd",
address = "Bristol, UK",
volume = "159",
number = "2",
doi = "10.1530/REP-19-0096",
pages= "R83 - R96",
url = "https://rep.bioscientifica.com/view/journals/rep/159/2/REP-19-0096.xml"
}

2019

Advanced Hybrid GaN/ZnO Nanoarchitectured Microtubes for Fluorescent Micromotors Driven by UV Light, N. Wolff, V. Ciobanu, M.Enachi, M. Kamp, T. Braniste, V. Duppel, S. Shree, S.Raevschi, M. Medina-Sánchez, R. Adelung, O.G Schmidt, L. Kienle, and I. Tiginyanu, Small, 2019, 16(1905141) 1-10.

The development of functional microstructures with designed hierarchical and complex morphologies and large free active surfaces offers new potential for improvement of the pristine microstructures properties by the synergistic combination of microscopic as well as nanoscopic effects. In this contribution, dedicated methods of transmission electron microscopy (TEM) including tomography are used to characterize the complex hierarchically structured hybrid GaN/ZnO:Au microtubes containing a dense nanowire network on their interior. The presence of an epitaxially stabilized and chemically extremely stable ultrathin layer of ZnO on the inner wall of the produced GaN microtubes is evidenced. Gold nanoparticles initially trigger the catalytic growth of solid solution phase (Ga1–xZnx)(N1–xOx) nanowires into the interior space of the microtube, which are found to be terminated by AuGa‐alloy nanodots coated in a …

@article(Wolff2019Advanced, title={Advanced Hybrid GaN/ZnO Nanoarchitectured Microtubes for Fluorescent Micromotors Driven by UV Light}, author={Niklas Wolff, Vladimir Ciobanu, Mihai Enachi, Marius Kamp, Tudor Braniste, Viola Duppel, Sindu Shree, Simion Raevschi, Mariana Medina-Sánchez, Rainer Adelung, Oliver G Schmidt, Lorenz Kienle, Ion Tiginyanu}, journal={Small}, Volume={16}, number={1905141}, pages={1-10}, year={2019}, publisher={Wiley}}

Blood platelet enrichment in mass-producible surface acoustic wave (SAW) driven microfluidic chips, C. Richard, A. Fakhfouri, M. Colditz, F. Striggow, R. Kronstein-Wiedemann, T. Tonn, M. Medina-Sánchez, O.G. Schmidt, T. Gemming, and A. Winkler, Lab on a Chip, 2019, 19,4043-4051.

The ability to separate specific biological components from cell suspensions is indispensable for liquid biopsies, and for personalized diagnostics and therapy. This paper describes an advanced surface acoustic wave (SAW) based device designed for the enrichment of platelets (PLTs) from a dispersion of PLTs and red blood cells (RBCs) at whole blood concentrations, opening new possibilities for diverse applications involving cell manipulation with high throughput. The device is made of patterned SU-8 photoresist that is lithographically defined on the wafer scale with a new proposed methodology. The blood cells are initially focused and subsequently separated by an acoustic radiation force (ARF) applied through standing SAWs (SSAWs). By means of flow cytometric analysis, the PLT concentration factor was found to be 7.7, and it was proven that the PLTs maintain their initial state. A substantially higher cell throughput and considerably lower applied powers than comparable devices from literature were achieved. In addition, fully coupled 3D numerical simulations based on SAW wave field measurements were carried out to anticipate the coupling of the wave field into the fluid, and to obtain the resulting pressure field. A comparison to the acoustically simpler case of PDMS channel walls is given. The simulated results show an ideal match to the experimental observations and offer the first insights into the acoustic behavior of SU-8 as channel wall material. The proposed device is compatible with current (Lab-on-a-Chip) microfabrication techniques allowing for mass-scale, reproducible chip manufacturing which is crucial to push the technology from lab-based to real-world applications.

@article{Richard2019Blood, title={Blood platelet enrichment in mass-producible surface acoustic wave (SAW) driven microfluidic chips}, author={Cynthia Richard, Armaghan Fakhfouri, Melanie Colditz, Friedrich Striggow, Romy Kronstein-Wiedemann, Torsten Tonn, Mariana Medina-Sánchez, Oliver G. Schmidt, Andreas Gemming, Thomas, and Winkler}, journal={Lab on a Chip}, volume={19}, pages={4043-4051}, year={2019}, publisher={Royal Society of Chemistry}}

Real‐Time IR Tracking of Single Reflective Micromotors through Scattering Tissues. A. Aziz, M. Medina-Sánchez, N. Koukourakis, J. Wang, R. Kuschmierz, H. Radner, J.W. Czarke, and O.G. Schmidt, Advanced Functional Materials, 2019, 29(51), 1905272.

Medical micromotors have the potential to lead to a paradigm shift in future biomedicine, as they may perform active drug delivery, microsurgery, tissue engineering, or assisted fertilization in a minimally invasive manner. However, the translation to clinical treatment is challenging, as many applications of single or few micromotors require real‐time tracking and control at high spatiotemporal resolution in deep tissue. Although optical techniques are a popular choice for this task, absorption and strong light scattering lead to a pronounced decrease of the signal‐to‐noise ratio with increasing penetration depth. Here, a highly reflective micromotor is introduced which reflects more than tenfold the light intensity of simple gold particles and can be precisely navigated by external magnetic fields. A customized optical IR imaging setup and an image correlation technique are implemented to track single micromotors in real‐time and label‐free underneath phantom and ex vivo mouse skull tissues. As a potential application, the micromotors speed is recorded when moving through different viscous fluids to determine the viscosity of diverse physiological fluids toward remote cardiovascular disease diagnosis. Moreover, the micromotors are loaded with a model drug to demonstrate their cargo‐transport capability. The proposed reflective micromotor is suitable as theranostic tool for sub‐skin or organ‐on‐a‐chip applications.

@article{aziz2019IR, title={Real‐Time IR Tracking of Single Reflective Micromotors through Scattering Tissues}, author={Aziz, Azaam and Medina-S{'a}nchez, Mariana and Koukourakis, Nektarios and Wang, Jiawei and Kuschmierz, Robert and Radner, Hannes and Czarke, Jr{"}gen W and Schmidt, Oliver G }, journal={Advanced Functional Materials}, volume={29}, number={51}, pages={1905272}, year={2019}, publisher={Wiley Online Library} }

Real-time optoacoustic tracking of single moving micro-objects in deep phantom and ex vivo tissues. A. Aziz, M. Medina-Sánchez, J. Claussen, and O.G. Schmidt, Nano Letters, 2019, 19(9), 6612-6620.

Medical imaging plays an important role in diagnosis and treatment of multiple diseases. It is a field which seeks for improved sensitivity and spatiotemporal resolution to allow the dynamic monitoring of diverse biological processes that occur at the micro- and nanoscale. Emerging technologies for targeted diagnosis and therapy such as nanotherapeutics, microimplants, catheters, and small medical tools also need to be precisely located and monitored while performing their function inside the human body. In this work, we show for the first time the real-time tracking of moving single micro-objects below centimeter thick phantom tissue and ex vivo chicken breast, using multispectral optoacoustic tomography (MSOT). This technique combines the advantages of ultrasound imaging regarding depth and resolution with the molecular specificity of optical methods, thereby facilitating the discrimination between the spectral signatures of the micro-objects from those of intrinsic tissue molecules. The resulting MSOT signal is further improved in terms of contrast and specificity by coating the micro-objects’ surface with gold nanorods, possessing a unique absorption spectrum, which facilitate their discrimination from surrounding biological tissues when translated to future in vivo settings.

@article{aziz2020OAimaging, title={Real-time optoacoustic tracking of single moving micro-objects in deep phantom and ex vivo tissues}, author={Aziz, Azam and Medina-S{'a}nchez, Mariana and Claussen, Jing and Schmidt, Oliver G.}, journal={Nano Letters}, volume={19}, number={9}, pages={6612--6620}, year={2019}, publisher={ACS Publications} }

Modeling of Spermbots in a Viscous Colloidal Suspension, I.S.M. Khalil, A. Klingner, V.Magdanz, F. Striggow, M. Medina‐Sánchez, O.G. Schmidt, and S. Misra. Advanced theory and simulations, 2019, 2 (1900072) 1-11.

Spermbots are biohybrid micromachines consisting of single sperm cells captured in artificial magnetic microstructures, and have the potential to act as autonomous tools for minimally invasive medicines and in diverse in vivo applications. This work investigates the hydrodynamic effects of the spermbots in a heterogeneous viscous medium similar to environments encountered in vivo. The propulsion of the spermbots is simulated using a numerical model based on the method of regularized Stokeslets for computing Stokes flows in the presence of immersed obstacles. It is shown that the concentration and size of these obstacles create a pressure gradient along the propulsion axis of the spermbot; hence they influence its effective net motion. In particular, the simulation results herein suggest that the forward and lateral swimming speeds of the spermbot increase with the concentration of the immersed obstacles and …

@article{Khalil2019Modeling, title={Modeling of Spermbots in a Viscous Colloidal Suspension}, author={Islam SM Khalil, Anke Klingner, Veronika Magdanz, Friedrich Striggow, Mariana Medina‐Sánchez, Oliver G Schmidt, Sarthak Misra}, journal={Advanced Theory and Simulations}, volume={2}, number={1900072}, pages={1-11}, year={2019}, publisher={Wiley}}

Three-Dimensional Microtubular Devices for Lab-on-a-Chip Sensing Applications, J. Wang, D. Karnaushenko, M. Medina-Sánchez, Y. Yin, L. Ma, and O.G. Schmidt, ACS Sensors, 2019, 4 (6), 1476-1496.

The rapid advance of micro-/nanofabrication technologies opens up new opportunities for miniaturized sensing devices based on novel three-dimensional (3D) architectures. Notably, microtubular geometry exhibits natural advantages for sensing applications due to its unique properties including the hollow sensing channel, high surface–volume ratio, well-controlled shape parameters and compatibility to on-chip integration. Here the state-of-the-art sensing techniques based on microtubular devices are reviewed. The developed microtubular sensors cover microcapillaries, rolled-up nanomembranes, chemically synthesized tubular arrays, and photoresist-based tubular structures via 3D printing. Various types of microtubular sensors working in optical, electrical, and magnetic principles exhibit an extremely broad scope of sensing targets including liquids, biomolecules, micrometer-sized/nanosized objects, and gases. Moreover, they have also been applied for the detection of mechanical, acoustic, and magnetic fields as well as fluorescence signals in labeling-based analyses. At last, a comprehensive outlook of future research on microtubular sensors is discussed on pushing the detection limit, extending the functionality, and taking a step forward to a compact and integrable core module in a lab-on-a-chip analytical system for understanding fundamental biological events or performing accurate point-of-care diagnostics.

@article{doi:10.1021/acssensors.9b00681,
author = {Wang, Jiawei and Karnaushenko, Daniil and Medina-Sánchez, Mariana and Yin, Yin and Ma, Libo and Schmidt, Oliver G.},
title = {Three-Dimensional Microtubular Devices for Lab-on-a-Chip Sensing Applications},
journal = {ACS Sensors},
volume = {4},
number = {6},
pages = {1476-1496},
year = {2019},
doi = {10.1021/acssensors.9b00681},
note ={PMID: 31132252},

URL = {
https://doi.org/10.1021/acssensors.9b00681

},
eprint = {
https://doi.org/10.1021/acssensors.9b00681

}

}

2018

Sperm-hybrid micromotor for targeted drug delivery. H. Xu, M. Medina-Sánchez, V. Magdanz, L. Schwarz, F. Hebenstreit, and O.G. Schmidt, ACS Nano, 2018, 12(1), 327-337.

A sperm-driven micromotor is presented as a targeted drug delivery system, which is appealing to potentially treat diseases in the female reproductive tract. This system is demonstrated to be an efficient drug delivery vehicle by first loading a motile sperm cell with an anticancer drug (doxorubicin hydrochloride), guiding it magnetically, to an in vitro cultured tumor spheroid, and finally freeing the sperm cell to deliver the drug locally. The sperm release mechanism is designed to liberate the sperm when the biohybrid micromotor hits the tumor walls, allowing it to swim into the tumor and deliver the drug through the sperm–cancer cell membrane fusion. In our experiments, the sperm cells exhibited a high drug encapsulation capability and drug carrying stability, conveniently minimizing toxic side effects and unwanted drug accumulation in healthy tissues. Overall, sperm cells are excellent candidates to operate in physiological environments, as they neither express pathogenic proteins nor proliferate to form undesirable colonies, unlike other cells or microorganisms. This sperm-hybrid micromotor is a biocompatible platform with potential application in gynecological healthcare, treating or detecting cancer or other diseases in the female reproductive system.

@article{xu2018sperm, title={Sperm-hybrid micromotor for targeted drug delivery}, author={Xu, Haifeng and Medina-S{'a}nchez, Mariana and Magdanz, Veronika and Schwarz, Lukas and Hebenstreit, Franziska and Schmidt, Oliver G.}, journal={ACS Nano}, volume={12}, number={1}, pages={327-337}, year={2018}, publisher={ACS Publishing} }

Swimming microrobots: Soft, reconfigurable, and smart. M. Medina-Sánchez, V. Magdanz, M. Guix, V.M. Fomin, and O.G. Schmidt, Advanced Functional Materials, 2018, 28(25), 1707228.

Using materials with properties similar to those of cells and microorganisms together with innovative fabrication methods, soft and smart microrobots can be developed, with increased adaptability and flexibility toward in vivo applications. These tiny robots are designed to carry out difficult tasks such as noninvasive microsurgery, diagnosis and therapy in complex environments, including viscous media and intricate channels. Moreover, the novel property of the soft materials to respond to stimuli has paved the way for the creation of reconfigurable and smart microrobots with both actuation and function (e.g., sensing, drug delivery) capabilities. This feature article aims to give an overview of the different soft and smart swimming microrobots (less than 1 mm in all dimensions), highlighting some aspects of new materials, their development and the challenges in their processing to obtain highly functional microrobots.

@article{sanchez2018softreview, title={Swimming microrobots: Soft, reconfigurable, and smart}, author={Medina-S{'a}nchez, Mariana and MAgdanz, Veronika and Guix, Maria and Fomin, Vladimir M. and Schmidt, Oliver G.}, journal={Advanced Functional Materials}, volume={28}, number={25}, pages={1707228}, year={2018}, publisher={Wiley Online Library} }

Micro- and nano-motors: the new generation of drug carriers. M. Medina-Sánchez, H. Xu, and O.G. Schmidt, Therapeutic Delivery, 2018, 9(4), 303-316.

Micro- and nano-motors are emerging as novel drug delivery platforms, offering advantages such as rapid drug transport, high tissue penetration and motion controllability. They can be propelled and/or guided by endogenous (i.e., chemotaxis) or exogenous stimuli (e.g., ultrasound, magnetic fields, light) toward the area of interest. Moreover, such stimuli can be used to trigger the release of a therapeutic payload when the motor reaches certain location in order to improve the drug targeting. In this review article, we highlight medically oriented micro-/nano-motors, in particular the ones created for targeted drug delivery, and discuss their current limitations and possibilities toward in vivo applications.

@article{sanchez2018drugreview, title={Micro- and nano-motors: the new generation of drug carriers}, author={Medina-S{'a}nchez, Mariana and Xu, Haifeng and Schmidt, Oliver G.}, journal={Therapeutic Delivery}, volume={9}, number={4}, pages={303--316}, year={2018}, publisher={Future Science Ltd} }

Self-Propelled Micro/Nanoparticle Motors. M. Guix, S.M. Weiz, O.G. Schmidt, and M. Medina-Sánchez, Particle & Particle Systems Characterization, 2018, 35(2), 1700382.

The growing interest in the design and fabrication of novel autonomous micro‐ and nanoparticles is motivated by the vast advances in their motion efficiency and their further implementation in both biomedical and environmental fields. The present review covers the motion principle and fabrication procedures of synthetic and hybrid particle‐like micromotors reported to date to give a comprehensive view of the key design parameters and different approaches for optimal motor guidance. The applications of self‐propelled micro‐ and nanoparticles in different fields are classified accordingly to clarify not only the latest advances but also the current challenges and constraints in the field. This review aims to provide clues to develop more efficient and biocompatible autonomous microparticles in the future, with advanced multitasking and sensing capabilities while being able to perform cooperative work.

@article{guix2018motorsreview, title={Self-Propelled Micro/Nanoparticle Motors}, author={Guix, Maria and Weiz, Sonja M. and Schmidt, Oliver G. and Medina-S{'a}nchez, Mariana}, journal={Particle & Particle Systems Characterization}, volume={35}, number={2}, pages={1700382}, year={2018}, publisher={Wiley Online Library} }

2017

Microsystems for Single-Cell analysis. S.M. Weiz, M. Medina-Sánchez, O.G. Schmidt, and O.G., Advanced Biosystems, 2018, 2(2), 1700193.

Due to the heterogeneity that exists even between cells of the same tissue, it is essential to use techniques and devices able to resolve the characteristics of single biological cells, such as morphology, metabolism, or response to drugs. To that end, different structures with sizes similar to that of individual cells have been developed in recent years, which allow single‐cell studies with high sensitivity and high resolution. By employing a variety of sensing strategies, one can obtain complementary information about individual cells, and thus create a complete picture of cellular properties. This review aims to provide an overview of microscale single‐cell sensors. The progress in micrometer‐sized sensing probes as well as microfluidic and micropatterned devices is described, showing the capabilities of the available systems. In addition, a comprehensive compendium of systems based on rolled‐up microtubes, which have the potential to advance and improve the single‐cell analysis microsystem field, is comprised.

@article{weiz2018microsystems, title={Microsystems for Single-Cell analysis}, author={Weiz, Sonja M. and Medina-S{'a}nchez, Mariana and Schmidt, Oliver G.}, journal={Advanced Biosystems}, volume={2}, number={2}, pages={1700193}, year={2018}, publisher={Wiley Online Library} }

Hybrid BioMicromotors, L. Schwarz, M. Medina-Sánchez, and O.G. Schmidt, Applied Physics Reviews, 2017, 4, 031301.

Micromotors are devices that operate at the microscale and convert energy to motion. Many micromotors are microswimmers, i.e., devices that can move freely in a liquid at a low Reynolds number, where viscous drag dominates over inertia. Hybrid biomicromotors are microswimmers that consist of both biological and artificial components, i.e., one or several living microorganisms combined with one or many synthetic attachments. Initially, living microbes were used as motor units to transport synthetic cargo at the microscale, but this simple allocation has been altered and extended gradually, especially considering hybrid biomicromotors for biomedical in vivo applications, i.e., for non-invasive microscale operations in the body. This review focuses on these applications, where other properties of the microbial component, for example, the capability of chemotaxis, biosensing, and cell-cell interactions, have been exploited in order to realize tasks like localized diagnosis, drug delivery, or assisted fertilization in vivo. In the biohybrid approach, biological and artificially imposed functionalities act jointly through a microrobotic device that can be controlled or supervised externally. We review the development and state-of-the-art of such systems and discuss the mastery of current and future challenges in order to evolve hybrid biomicromotors from apt swimmers to adapted in vivo operators.

@article{doi:10.1063/1.4993441,
author = {Schwarz,Lukas and Medina-Sánchez,Mariana and Schmidt,Oliver G. },
title = {Hybrid BioMicromotors},
journal = {Applied Physics Reviews},
volume = {4},
number = {3},
pages = {031301},
year = {2017},
doi = {10.1063/1.4993441},

URL = {
https://doi.org/10.1063/1.4993441

},
eprint = {
https://doi.org/10.1063/1.4993441

}

}

Medical microbots need better imaging and control M. Medina-Sánchez, O.G. Schmidt, Nature, 2017, 545, 406-408.

There are three types of micromotors. They can be categorized according to their main propulsion mode: chemical, physical or biological (see ‘Three micromotor prototypes’). Each has pros and cons. Chemical micromotors transform fuel energy into motion1. Often, a catalyst (such as platinum, silver or palladium) within the micromotor reacts with liquid surrounding it (usually hydrogen peroxide or organic compounds). These motors are hard to control. Some move by expelling gas bubbles from one end of an asymmetrical tube. Others are made of two metals (usually gold and platinum) and propelled by differences in, for instance, tension, fuel consumption or light absorption rates between their faces. They may be guided by chemical or thermal gradients in their surroundings, or by applying magnetic fields, light or ultrasound. Outside the body, micromotors can be based on poisonous fuels. For example, they could …

@article{Sanchez2017Medical, title={Medical microbots need better imaging and control}, author={Mariana Medina-Sánchez, Oliver G Schmidt}, journal={Nature}, volume={545}, pages={406-408}, year={2017}}

Spermatozoa as Functional Components of Robotic Microswimmers. V. Magdanz, M. Medina-Sánchez, L. Schwarz, H. Xu, J. Elgeti, and O.G. Schmidt, Advanced Materials, 2017, 29, 1606301.

In recent years, the combination of synthetic micro- and nanomaterials with spermatozoa as functional components has led to the development of tubular and helical spermbots – microrobotic devices with potential applications in the biomedical and nanotechnological field. Here, the initial advances in this field are discussed and the use of spermatozoa as functional parts in microdevices elaborated. Besides the potential uses of these hybrid robotic microswimmers, the obstacles along the way are discussed, with suggestions for solutions of the encountered challenges also given.

@article{https://doi.org/10.1002/adma.201606301,
author = {Magdanz, Veronika and Medina-Sánchez, Mariana and Schwarz, Lukas and Xu, Haifeng and Elgeti, Jens and Schmidt, Oliver G.},
title = {Spermatozoa as Functional Components of Robotic Microswimmers},
journal = {Advanced Materials},
volume = {29},
number = {24},
pages = {1606301},
keywords = {microswimmers, microrobotics, microtubes, microhelixes, spermatozoa},
doi = {https://doi.org/10.1002/adma.201606301},
url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/adma.201606301},
eprint = {https://onlinelibrary.wiley.com/doi/pdf/10.1002/adma.201606301},
abstract = {In recent years, the combination of synthetic micro- and nanomaterials with spermatozoa as functional components has led to the development of tubular and helical spermbots – microrobotic devices with potential applications in the biomedical and nanotechnological field. Here, the initial advances in this field are discussed and the use of spermatozoa as functional parts in microdevices elaborated. Besides the potential uses of these hybrid robotic microswimmers, the obstacles along the way are discussed, with suggestions for solutions of the encountered challenges also given.},
year = {2017}
}

2016

Cellular Cargo Delivery: Toward Assisted Fertilization by Sperm-Carrying Micromotors. M. Medina-Sánchez, L. Schwarz, A. K. Meyer, F. Hebenstreit, and O.G. Schmidt, Nano Letters, 2016, 16 (1), 555-561.

We present artificially motorized sperm cells, a novel type of hybrid micromotor, where customized microhelices serve as motors for transporting sperm cells with motion deficiencies to help them carry out their natural function. Our results indicate that metal-coated polymer microhelices are suitable for this task due to potent, controllable, and nonharmful 3D motion behavior. We manage to capture, transport, and release single immotile live sperm cells in fluidic channels that allow mimicking physiological conditions. Important steps toward fertilization are addressed by employing proper means of sperm selection and oocyte culturing. Despite the fact that there still remain some challenges on the way to achieve successful fertilization with artificially motorized sperms, we believe that the potential of this novel approach toward assisted reproduction can be already put into perspective with the present work.

@article{doi:10.1021/acs.nanolett.5b04221,
author = {Medina-Sánchez, Mariana and Schwarz, Lukas and Meyer, Anne K. and Hebenstreit, Franziska and Schmidt, Oliver G.},
title = {Cellular Cargo Delivery: Toward Assisted Fertilization by Sperm-Carrying Micromotors},
journal = {Nano Letters},
volume = {16},
number = {1},
pages = {555-561},
year = {2016},
doi = {10.1021/acs.nanolett.5b04221},
note ={PMID: 26699202},

URL = {
https://doi.org/10.1021/acs.nanolett.5b04221

},
eprint = {
https://doi.org/10.1021/acs.nanolett.5b04221

}

}

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