Every year, 7 million people die due to inhalation of particulate matter in air pollution causing severe chronic-inflammation-related diseases, including pulmonary fibrosis, and blood coagulation disorders. With increasing amounts of man-made nanoparticles introduced to the market and into the environment, inhalation hazard is constantly increasing. To mitigate the risk, efficient nanotoxicological assessment solutions are required.
Efficient prediction of chronic-inflammation-related diseases is currently hindered by the lack of mechanistic understanding and current toxicological assessment framework. Recently, 200 man-years have been spent in our discovery of a mechanism responsible for triggering chronic inflammation. To understand the development of even more complex diseases in a much shorter time, a paradigm shift in mechanism discovery, in an animal-free fashion, is absolutely necessary.
The uttermost goal of the proposed project is to develop the paradigm-shifting concept of high-throughput identification of the causally connected network of molecular key events and validate it in the case of nanomaterial-induced fibrosis and initiation of blood coagulation.
To foster mechanistic discoveries of disease development, we propose a novel uCellnNet concept, by which we aim to disentangle a response of a natively complex tissue with an entangled network of interactions and overwhelming molecular events among multiple cell types into a network of pairs of individual cell types that exhibit different modes of interactions. For high-throughput monitoring of the latter in real-time, the glass-chip cell-populated device with microscale features - uCellnNet Interaction Mode Inspector - will be developed. Finally, we will validate the here proposed uCellnNet concept on a hypothetical pathway of initiation of blood coagulation and the development of fibrosis, involving the three key cell types (pulmonary epithelial cells, macrophages, and fibroblasts).
To achieve such an ambitious goal we gathered a multidisciplinary team that has previously already contributed to the discovery of a mechanism of nanoparticle-induced chronic inflammation, published in the prestigious journal Advanced Materials (IF 27). The team consists of top-level experts in advanced high-resolution live-cell imaging, toxicology of inhaled nanomaterials, systems biology, lipid regulation of coagulation enzymes, artificial intelligence guided image analysis, and microscale glass substrate prototyping, thus assuring the project feasibility.
Impact (scientific, social, economic)
If successful, this project will directly impact the understanding of the development of fibrosis. In addition, uCellnNet concept can certainly boost mechanistic research of early molecular events and their causal connections in the development of nanoparticle-induced diseases and chronic diseases in general, which can be implemented in future regulatory frameworks much faster. This can in turn facilitate high-throughput animal-free toxicological assessment and prediction of nanomaterial safety. Thus, this project directly supports the safe introduction of various powders, microscale materials, and nanomaterials into the everyday market, affecting chemical, nanotech, and electronic industry sectors.
The development of soft flexible materials with morphing and shape-programmable abilities is essential for technological progress of soft robotics, biomechanics, and flexible electronics. However, morph-on-demand materials remain a rather elusive class of smart materials. Shape-programmable matter capable of transforming between three-dimensional shapes in response to external stimuli such as light, heat, electric and magnetic fields is a class of active materials whose geometry can be controlled for performing tasks beyond the operational scope of conventional machines or robots.
In this project, we are proposing the development of a method to produce a new generation of 3D-printable soft material with anisotropic response. The material will be based on the recently developed polymer dispersed liquid crystal elastomers (PDLCE). Such composite material consists of thermomechanically active liquid single crystal elastomer (LSCE) microparticles, dispersed and oriented in a crosslinked polymer matrix. The particle orientation can be spatially modulated using an external magnetic alignment field over the composite volume, resulting in custom-tailored, temperature responsive shape changes of the specimen. We have recently devised a method of producing a suspension of anisotropically shaped LSCE microparticles with their liquid crystal ordering and consequently, direction of thermomechanical actuation, aligned along the particle’s longer axis. Anisotropically shaped LSCE particles can thus be oriented using simple laminar flow, present during deposition while 3D printing the material. The use of the state-of-the-art robotic hand with a mounted polymer dispensing unit, will enable us to precisely control the imprinted thermomechanical anisotropy, by exploiting the robotic hand’s six degrees of freedom of movement in order to deposit PDLCE voxels at arbitrary angles. The developed 3D printable ink will be used to print a tube capable of peristaltic movement, triggered by consecutive heating and cooling of the specimen via incorporated heating wires or by UV/
microwave irradiation absorbing nanostructures additionally functionalizing the LSCE composite.
The realization of a 3D printed peristaltic tube will demonstrate the applicative advantages of our printing method and of the PDLCE 3D printable ink, by producing a specimen with complex morphing abilities that cannot be achieved by any of the currently developed additive manufacturing technologies.
preparation of polydomain LSCE bulk materials (temperature-controlled crosslinking of the mixture of commercially available chemicals);
preparation of polydomain LSCE bulk materials with deuterium labelled constituents (for characterization purposes);
synthesis of MoS2 nanotubes by sulphurization of Mo6S4I6 nanowires at 1073 K in a reactive gas composed of 98 vol% Ar, 1 vol % of H2S and 1vol % of H2 for 1h;
preparation of PDLCE resin by freeze-fracturing of bulk LCE and frozen matrix material in a cryogenic planetary ball mill;
preparation of PDLCE printable ink by pre-shearing the PDLCE resin using custom-build rotational parallel plates inside a temperature controlled chamber;
determination of liquid crystal ordering inside deformed PDLCE microparticles of a PDLCE printable ink via quadrupole-perturbed deuteron NMR spectroscopy;
determination of LSCE microparticles orientational order and its associated order parameter Q in PDLCEs via quadrupole-perturbed deuteron NMR spectroscopy;
determination of bulk LSCE, matrix elastomer, and PDLCE thermomechanical coefficient λ in a temperature-controlled extensometer;
preparation of PDLCE composite material and peristaltic tube by fused layer deposition of flow-oriented PDLCE printable ink, deposited by a robotic arm with a mounted polymer dispense unit;
characterization of peristaltic tube performance by analysis of the flow velocity, pressure and volume of expelled liquids using flow and pressure sensors;
physical modelling of the PDLCE peristaltic tube performance based on mechanical and thermomechanical properties of the PDLCE material, imprinted spatial alignment of PDLCE microparticles and tube’s geometrical constraints.