Periodic Reporting for period 2 - 4D-BIOMAP (Biomechanical Stimulation based on 4D Printed Magneto-Active Polymers)
Période du rapport: 2022-07-01 au 2023-12-31
4D-BIOMAP is a multidisciplinary project that aims at providing cutting-edge solutions to modulate the mechanical properties of cell’s/tissue’s substrate remotely. This mechanical stimulation has an important role on biological structures leading to alterations in functional responses, morphological changes and activation of growth or healing processes. However, there are still important limitations to evaluate these biomechanical effects and apply defined mechanical stimuli. Critical limitations are related to the isolation, combination and remote control of the aimed mechanical environment affecting the biological structure of interest. Current solutions are based on polymeric substrates for cell culture and the direct application of mechanical loading on them. More sophisticated solutions propose the use of photo-activation, but this is limited when opaque bodies are surrounding the target.
To overcome these current limitations preventing advance in this field, we are developing novel heterogeneous (spatial and temporal stiffness gradients) 4D printed structures based on magneto-active polymers. These structures enable for the first time for remote magneto-mechanical stimulation of biological structures and (reversible) evolution of their mechanical surrounding simulating relevant pathological processes.
The anticipated results of the project will offer direct benefits for health purposes by paving the path to model mechanistic-mediated biological processes as well as test and design new therapeutics. In this regard, the specific results expected will contribute to elucidate the role of mechanics on central nervous system cells and tissues, analysing the effect of deformation and stiffness (temporal and spatial) gradients. From a more visionary view, this project will revolutionise the creation of customised mechano-stimulation systems, suitably extended to in vivo applications thanks to the low magnetic permeability of biological tissues.
To overcome these current limitations preventing advance in this field, we are developing novel heterogeneous (spatial and temporal stiffness gradients) 4D printed structures based on magneto-active polymers. These structures enable for the first time for remote magneto-mechanical stimulation of biological structures and (reversible) evolution of their mechanical surrounding simulating relevant pathological processes.
The anticipated results of the project will offer direct benefits for health purposes by paving the path to model mechanistic-mediated biological processes as well as test and design new therapeutics. In this regard, the specific results expected will contribute to elucidate the role of mechanics on central nervous system cells and tissues, analysing the effect of deformation and stiffness (temporal and spatial) gradients. From a more visionary view, this project will revolutionise the creation of customised mechano-stimulation systems, suitably extended to in vivo applications thanks to the low magnetic permeability of biological tissues.
4D-BIOMAP project is articulated in different activities that, combined together, aim at providing a new disruptive technology to open new possibilities in mechanobiological studies. In this regard, we can split the activities conducted to date in three main blocks:
1. The first set of activities has focused on the development of ultra-soft (~1 kPa) magnetorheological elastomers (MREs) and their magneto-mechanical characterisation. We have provided the largest experimental characterisation of these MREs to date analysing their coupled response at microstructural and macrostructural scales. This experimental study has considered different mechanical loading conditions such as uniaxial tensile and compressive loading, shear tests, dynamic mechanical analysis, nanoindentation and cyclic loading. In addition, we have combined these mechanical conditions with controlled external magnetic fields, with a special focus on viscoelastic responses mediated by external magnetic fields. These results have identified new viscous mechanisms driven by magnetic actuation. We discovered that external magnetic actuation leads to important microstructural rearrangements of the particles inducing heterogeneous distributions of viscous deformations that result in synergistic effects leading to significantly larger and more complex viscous relaxations at the macroscopic scale. In addition, we have conceptualised a new class of hybrid MRE. This new MRE class provides enhanced magnetorheological effect (stiffening under magnetic fields) and effective remanent magnetisation than standard soft-magnetic and hard-magnetic MREs at once. Moreover, we have conceptualised a new 3D printing technique and we have developed (from scratch) the hardware and software components of the first prototype. This system allows for printing multidomain ultra-soft MREs using reactive inks without chemical additives.
2. The second set of activities has focused on the constitutive and computational modelling of the magneto-mechanical behaviour of ultra-soft MREs. We have significantly contributed to the constitutive and computational modelling of these materials, highlighting the consideration of viscoelastic effects driven by external magnetic fields. It is worth to mention that we have addressed the modelling of the multi-physical problem from all angles considering: micromechanical based approaches following lattice-based models; micromechanical based approaches following homogenisation techniques; and phenomenological approaches at the continuum/structural scale.
3. The last set of activities relates to the major achievement to date, which consists in the development of a new technology and the associated experimental-computational platform to conduct novel research in mechanobiology. This technology allows to control complex dynamic deformations on cellular substrates, which are then transmitted to biological systems simulating physiologically and pathologically relevant scenarios. This has been obtained thanks to the conceptualisation of the ultra-soft MREs, that allow for non-invasive, remote, dynamic and reversible mechanical stimulation of cells via external magnetic actuation. This framework also incorporates a comprehensive computational framework to guide the experimental design of biological studies.
Overall, the results obtained during this ERC project have been published in several international journals and presented in different conferences and invited lectures. In addition, the research outcomes of the project have led to patents and open-source codes published in ZENODO.
1. The first set of activities has focused on the development of ultra-soft (~1 kPa) magnetorheological elastomers (MREs) and their magneto-mechanical characterisation. We have provided the largest experimental characterisation of these MREs to date analysing their coupled response at microstructural and macrostructural scales. This experimental study has considered different mechanical loading conditions such as uniaxial tensile and compressive loading, shear tests, dynamic mechanical analysis, nanoindentation and cyclic loading. In addition, we have combined these mechanical conditions with controlled external magnetic fields, with a special focus on viscoelastic responses mediated by external magnetic fields. These results have identified new viscous mechanisms driven by magnetic actuation. We discovered that external magnetic actuation leads to important microstructural rearrangements of the particles inducing heterogeneous distributions of viscous deformations that result in synergistic effects leading to significantly larger and more complex viscous relaxations at the macroscopic scale. In addition, we have conceptualised a new class of hybrid MRE. This new MRE class provides enhanced magnetorheological effect (stiffening under magnetic fields) and effective remanent magnetisation than standard soft-magnetic and hard-magnetic MREs at once. Moreover, we have conceptualised a new 3D printing technique and we have developed (from scratch) the hardware and software components of the first prototype. This system allows for printing multidomain ultra-soft MREs using reactive inks without chemical additives.
2. The second set of activities has focused on the constitutive and computational modelling of the magneto-mechanical behaviour of ultra-soft MREs. We have significantly contributed to the constitutive and computational modelling of these materials, highlighting the consideration of viscoelastic effects driven by external magnetic fields. It is worth to mention that we have addressed the modelling of the multi-physical problem from all angles considering: micromechanical based approaches following lattice-based models; micromechanical based approaches following homogenisation techniques; and phenomenological approaches at the continuum/structural scale.
3. The last set of activities relates to the major achievement to date, which consists in the development of a new technology and the associated experimental-computational platform to conduct novel research in mechanobiology. This technology allows to control complex dynamic deformations on cellular substrates, which are then transmitted to biological systems simulating physiologically and pathologically relevant scenarios. This has been obtained thanks to the conceptualisation of the ultra-soft MREs, that allow for non-invasive, remote, dynamic and reversible mechanical stimulation of cells via external magnetic actuation. This framework also incorporates a comprehensive computational framework to guide the experimental design of biological studies.
Overall, the results obtained during this ERC project have been published in several international journals and presented in different conferences and invited lectures. In addition, the research outcomes of the project have led to patents and open-source codes published in ZENODO.
We consider that the 4D-BIOMAP project has provided two significant breakthroughs to date that wil contribute to advance in research fields significantly beyond the state of the art:
1. Magneto-mechanical system to reproduce and quantify complex strain patterns in biological materials: Before this system, all mechanobiological research efforts were focused on static mechanical environments or mechanical actuating conditions limited to very simple deformation modes (i.e. uniaxial or biaxial); which could rarely be combined. With our magneto-mechanical system we push these studies significantly forward by enabling the on-the-fly control of complex heterogeneous deformation patterns via a remote, non-invasive, temporally-dynamic and reversible fashion. Some ongoing efforts are allowing us to couple our system to other mechanobiological instrumentation to enable for the first time the evaluation of mechanical properties changes within cells over time under evolving mechanical boundary conditions. In addition, we have started multiple collaborations with renown international groups in the field who want to adapt our technology to their studies.
2. Autonomous self-healing elastomers: Mechanically soft magnetorheological elastomers (MREs) (~1 kPa stiffness) that contain pre-magnetized magnetic particles during the manufacturing process. After mechanical rupture, these MREs are capable of withstanding large cyclic deformations. Additionally, they offer self-repairing capability during infinite cycles, where the breaking threshold value can be programmed based on the balance between magnetic interactions among particles and the stiffness of the polymer matrix. This advancement allows the design of a new generation of mechanical sensors with binary responses to kinematic thresholds, capable of adhering to biological tissues and accommodating large cyclic deformations.
The following steps of the project will face relevant challenges to substitute elastomeric substrates by hydrogel-based substrates. These materials are introducing diffusion-like processes that add an extra complexity in the understanding and controlled of rate-dependent effects. In addition, their integration within our magneto-mechanical technology is very challenging yet. However, when reaching this objective, we will enable to extend the mechanobiology technology to 3D biological systems. This achievement would constitute a clear breakthrough in the field as it would allow for the first time to dynamically control the mechanical environment of biological 3D systems, such as cancer spheroids or different organoids simulation relevant physiological and pathological processes.
Another potential breakthrough is the integration of the current technology with other mechanobiological instrumentation such as nanoindenters. This achievement would open the possibility of evaluating dynamic changes in mechanical properties of cells that are temporally subjected to different mechanical environmental conditions. In addition, the future application of these technological systems is expected to provide important insights into the mechano-functional response of astrocytes and neurons undergoing stroke, tumour growth or traumatic brain injury processes.
1. Magneto-mechanical system to reproduce and quantify complex strain patterns in biological materials: Before this system, all mechanobiological research efforts were focused on static mechanical environments or mechanical actuating conditions limited to very simple deformation modes (i.e. uniaxial or biaxial); which could rarely be combined. With our magneto-mechanical system we push these studies significantly forward by enabling the on-the-fly control of complex heterogeneous deformation patterns via a remote, non-invasive, temporally-dynamic and reversible fashion. Some ongoing efforts are allowing us to couple our system to other mechanobiological instrumentation to enable for the first time the evaluation of mechanical properties changes within cells over time under evolving mechanical boundary conditions. In addition, we have started multiple collaborations with renown international groups in the field who want to adapt our technology to their studies.
2. Autonomous self-healing elastomers: Mechanically soft magnetorheological elastomers (MREs) (~1 kPa stiffness) that contain pre-magnetized magnetic particles during the manufacturing process. After mechanical rupture, these MREs are capable of withstanding large cyclic deformations. Additionally, they offer self-repairing capability during infinite cycles, where the breaking threshold value can be programmed based on the balance between magnetic interactions among particles and the stiffness of the polymer matrix. This advancement allows the design of a new generation of mechanical sensors with binary responses to kinematic thresholds, capable of adhering to biological tissues and accommodating large cyclic deformations.
The following steps of the project will face relevant challenges to substitute elastomeric substrates by hydrogel-based substrates. These materials are introducing diffusion-like processes that add an extra complexity in the understanding and controlled of rate-dependent effects. In addition, their integration within our magneto-mechanical technology is very challenging yet. However, when reaching this objective, we will enable to extend the mechanobiology technology to 3D biological systems. This achievement would constitute a clear breakthrough in the field as it would allow for the first time to dynamically control the mechanical environment of biological 3D systems, such as cancer spheroids or different organoids simulation relevant physiological and pathological processes.
Another potential breakthrough is the integration of the current technology with other mechanobiological instrumentation such as nanoindenters. This achievement would open the possibility of evaluating dynamic changes in mechanical properties of cells that are temporally subjected to different mechanical environmental conditions. In addition, the future application of these technological systems is expected to provide important insights into the mechano-functional response of astrocytes and neurons undergoing stroke, tumour growth or traumatic brain injury processes.