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3D-printed magnetic microfluidics for applications in life sciences

Periodic Reporting for period 1 - microMAGNETOFLUIDICS (3D-printed magnetic microfluidics for applications in life sciences)

Reporting period: 2016-06-01 to 2018-05-31

The field of microfluidics is providing answers to several key questions in biology. Specifically, microfluidic single-cell analysis yields important insights into the heterogeneity of cells that is crucial for cancer research, regenerative medicine and drug development. Microfluidics has also emerged as a powerful tool to study single bacteria and to address questions concerning antibiotic persistence and the role of the microbiome in protecting against modern plagues such as cancer, autoimmune diseases and obesity. Despite its great potential, microfluidic technologies have not been widely adopted in mainstream biomedical research since they require a great deal of external equipment, which is often difficult to operate by untrained personnel.
The aim of this project is to simplify fluid handling and single-cell studies by developing a microfluidic device that includes magnetic microvalves. These microvalves can be wirelessly actuated to generate compartments and isolate single cells. The magnetic microvalves will be integrated by means of a very recently available lithographic tool based on two-photon polymerization (2PP) with sub-diffraction limit resolution, which enables the fabrication of polymer-based 3D micro- and nano-architectures. The microMAGNETOFLUIDICS project is strongly interdisciplinary in nature where physics, materials science, and biology are strongly intertwined. The innovative character of this project is unprecedented since no previous studies have been reported on 3D printed magnetic microvalves operating within a microfluidic channel. The topic of the project is timely because it promotes the use of microfluidics among biologists and bacteriologists for decrypting cellular mechanisms at a single-cell level.
The main scientific and training objectives of the project were:
1. to fabricate a microfluidic network of channels by soft lithography;
2. to fabricate magnetic microvalves by two-photon polymerization (2PP);
3. to isolate single cells, in particular bacterial cells.
In summary, we successfully reported about single bacteria isolation. Moreover, in parallel we developed, for the first time, a new technique to 4D print polymeric structures at the microscale, i.e. 3D print soft structures with an embedded capability of spatiotemporal transformation. This achievement is a step forward in the field of small scale robots and paves the way to the fabrication of soft micro actuators and soft robotic components for future medical devices.
The work carried out per objective during the fellowship has been the following:
1. the wells to trap single cells have been fabricated by soft lithography;
2. the masters replicated by soft lithography have been fabricated by standard lithography as by two-photon polymerization;
3. single bacterial cells have been successfully isolated.
Throughout the project, the fellow had the opportunity to be introduced to the fabrication techniques of micro- and nano- robots. She was involved in the preparation of a review manuscript on small-scale machines driven by external power sources published on Advanced Materials (X. Chen, B. Jang, D. Ahmed, C. Hu, C. De Marco, M. Hoop, F. Mushtaq, B. J. Nelson, S. Pané*, Small‐Scale Machines Driven by External Power Sources Adv. Mater. 2018, 30, 1705061). During her training period, she had also the opportunity to contribute to the preparation of a manuscript on template-assisted electroforming of fully semi-hard-magnetic helical microactuators (G. Chatzipirpiridis, C. de Marco, E. Pellicer, O. Ergeneman, J. Sort, B. J. Nelson, and S. Pané*, Template-Assisted Electroforming of Fully Semi-Hard-Magnetic Helical Microactuators, Adv. Eng. Mater. 2018, 1800179). That led to the conceptualization of the 4D printing technique and to the investigation of 3D shaped shape-memory materials as promising and alternative solutions to fabricate the 3D printed microfluidic valves (C. de Marco, S. Pané, B. J. Nelson*, 4D printing and robotics. Sci. Robot. 3, eaau0449 (2018), 2 publications in preparation). Moreover, the fellow had the opportunity to transfer her know-how about surfaces functionalization and characterization (X. Wang, C. Hu*, L. Schurz, C. De Marco, X. Chen, S. Pané and B. J. Nelson, Surface Chemistry-Mediated Control of Individual Magnetic Helical Microswimmers in a Swarm, ACS Nano, accepted, 1 publication in preparation).
The main scientific achievement was to have a simple tool to isolate single cells, without the need of using complex manipulation techniques such as fluidic force microscopy, optical tweezers, electric tweezers and dielectrophoresis. The here proposed Flip-Chip technique represents a contribution to the state of the art. Nowadays, droplet microfluidics in combination with conventional flow cytometry is the only powerful technique which ensures a high-throughput cellular manipulation in sorting single cells, but the main constrain is that this technology had not yet been used to guide single droplets into individual cells. The technology here presented overcomes this limitation.
Moreover, to show the feasibility of the 4D printing approach, we decided to test it with a commercial biocompatible shape memory polymer (SMP). We focused on SMPs because they can be easily triggered by external stimuli (heat in this case), and their morphological change can function as a valve into a microfluidic channel. As proof of concept, we chose a stent shape, since fabricating stents is one of the most notable application of SMPs.
SEM images of master fabricated by 2PP and single E.Coli bacterium trapped