Living organisms teach us how to design material structures that can move autonomously. Such motility is not restricted to animated organisms but can also originate from local differences t expansion coefficients in ligneous compounds. This challenges the design of micro-objects that can perform mechanical work and undergo locomotion. Irrespective of the specific material, three fundamental tasks must be solved: (i) to fuel the material for the actuation; (ii) to control the morphing of the object in time and space; and (iii) to establish a feed-back mechanism that enables timing of a sequence of steps. The later refers to an integrated clock function in order to pulse the energy input for distinct mechanical strokes. Within JELLYCLOCK, we address all three questions at the example of light driven hydrogel micro-objects. We have developed light sensitive microgels that change their shape within milliseconds. IR-irradiation of gold nanorods, entrapped in a thermosensitive hydrogel, is used to heat the gel from inside and enable a gradated spatial and temporal control of its swelling and shrinking. The water-based actuation will be directed to generate a non-reciprocal deformation as required for locomotion at low Reynolds numbers. So far, a directed cyclic deformation action relies on the outside modulation of the irradiation. We will extent this concept by introducing self-oscillating absorption efficiency, so that a stepwise body deformation becomes feasible under continuous irradiation. The project comprises (1) the advanced design of hydrogel based actuators driven by modulated light, (2) achievement of a precise control of the deformation in time and space , and as the actual disruptive step, (3) the realization of a self-sustaining pulsation under continuous near IR irradiation. Such soft micro engines strike a new path to micro-robotics for biomedical or biomechanical applications, or to create micro devices that could mix, sort and circulate fluid.

The limitations of current in vitro tissue models pose a significant challenge in drug discovery and personalized medicine, leading to inefficiencies and unreliability in preclinical testing. These shortcomings result in high costs and prolonged timelines for drug development, straining resources and delaying patient access to innovative treatments. This is mainly due to the currently available cell and tissue models based on flat petri dishes and isotropic hydrogels, which fail to accurately represent the anisotropic structures found in native tissues leading to unreliable preclinical results. Animal models, although considered the gold standard, raises ethical concerns and introduces significant differences compared to human tissues. To address these shortcomings, we have developed a hydrogel system that can be used to fabricate 3D culture models with oriented structures using AnisoPlate. The AnisoPlate is a handheld magnetic device for providing the required external magnetic field in culture plates for the orientation of the rods. The hydrogel system consists of rod-shape elements that are made magneto-responsive by encapsulating superparamagnetic iron oxide nanoparticles (SPIONs). When exposed to low external magnetic fields (in the millitesla range) provided by the AnisoPlate, these rods align in the direction of the field and can be assembled into 3D macroporous oriented constructs mimicking the anisotropic architecture of human tissues. Our solution holds promise not only for researchers in drug discovery, tissue engineering, and regenerative medicine but also for pharmaceutical industries seeking physiologically relevant in vitro models for more accurate preclinical studies, contract research organizations (CROs) aiming to enhance their efficacy in high-throughput screening, and ultimately patients who stand to benefit from accelerated and improved drug development processes leading to innovative treatments.

This project will engineer an injectable biomaterial that forms an anisotropic microheterogeneous structure in vivo. Injectable hydrogels enable a minimal invasive in situ generation of matrices for the regeneration of tissues and organs, but currently lack structural organization and unidirectional orientation. The anisotropic, injectable hydrogels to be developed will mimic local extracellular matrix architectures that cells encounter in complex tissues (e.g. nerves, muscles). This project aims for the development of a biomimetic scaffold for spinal cord regeneration. To realize such a major breakthrough, my group will focus on three research objectives. i) Poly(ethylene glycol) microgel-in-hydrogel matrices will be fabricated with the ability to create macroscopic order due to microgel shape anisotropy and magnetic alignment. Barrel-like microgels will be prepared using an in-mold polymerization technique. Their ability to self-assemble will be investigated in function of their dimensions, aspect ratio, crosslinking density, and volume fraction. Superparamagnetic nanoparticles will be included into the microgels to enable unidirectional orientation by means of a magnetic field. Subsequently, the oriented microgels will be interlocked within a master hydrogel. ii) The microgel-in-hydrogel matrices will be equipped with (bio)functional properties for spinal cord regeneration, i.e., to control and optimize mechanical anisotropy and biological signaling by in vitro cell growth experiments. iii) Selected hydrogel composites will be injected after rat spinal cord injury and directional tissue growth and animal functional behavior will be analyzed. Succesful fabrication of the proposed microgel-in-hydrogel matrix will provide a new type of biomaterial, which enables investigating the effect of an anisotropic structure on physiological and pathological processes in vivo. This is a decisive step towards creating a clinical healing matrix for anisotropic tissue repair.

To date, light has been employed as a widespread trigger to achieve control over the activity of drugs and protein function establishing the fields of photopharmacology and optogenetics, respectively. Both techniques led to promising new therapies, the elucidation of brain function or understanding of neural disorders. However, serious limitations resulting from the low penetration depth of light into tissues are severely hampering progress in these fields. In contrast to photons, ultrasound deeply penetrates tissue and can be applied with sub-millimeter resolution and consequently has been widely established in the clinic over many decades for therapy and diagnostics. In this ERC Advanced Grant, I will develop a radically new approach to control the activity of drugs, proteins and genes by biocompatible ultrasound. Polynucleic acid carriers, which can bind a wide variety of bioactive payloads, will be designed to be sensitive to different ultrasound sources, which can be applied in clinical settings and do not harm cells or tissues. Upon ultrasound irradiation, these carriers liberate their bioactive payloads by mechanochemical principles to switch on drugs and control cellular functions. To achieve this aim, I will: investigate the effect of ultrasound (US) on nucleic acid architectures; study the loading of polynucleic acids with different payloads and their release by US; develop a technology platform to activate small molecule drugs, proteins and oligonucleotides; and showcase the huge potential of these technologies for cancer immunotherapy, diabetes research and tissue engineering. This project will boost sonopharmacology and sonogenetics. Its outcomes will enable spatiotemporal control of drug action to minimize side effects in pharmacotherapy like cancer. The remote controlled orchestration of protein and gene function by US will strongly advance medicine and the life sciences by answering fundamental questions in these fields.

Today’s materials research in the field of synthetic membranes gives access to highly permeable and extremely selective membranes. However, their potential will remain ineffective as high and selective transport rates always go along with resistances emerging at the membrane fluid interface in the form diffusion limitations in the laminary boundary layers. In order to make full use of the very many new materials, also new means to control and minimize such fluid based resistances need to be developed. Yet another phenomena disturbs the full potential use of membranes: retained solutes, colloids and biological matter accumulates at the membrane interface and causes irreversible fouling and scaling. The proposed research aims to develop a rigorous translational methodology to control and improve mass transport through the fluid/membrane interface. ConFluReM will establish Strategic Tools and New Instruments to: (1) comprehend and quantify the prevalent mass transport resistances in representative membrane separation processes, (2) synthesize and fabricate new nano-, micro- and mesoscale material and device systems as instruments to control and overcome the limitations of concentration polarization and fouling, Strategic Tools are experimental and simulation methods to quantify and engineer the mass transport and hydrodynamical properties of the new membrane systems. These encompass flow imaging (flowMRI, microPIV and microfluidic transport studies) as well as computational fluidic dynamics (CFD and CFDEM). New Instruments are synthetic and fabrication means as well as process condition means to improve mixing at the membrane/fluid interface. These encompass (a) lateral patterning of chemical topology of the membrane surface by printing and stamping, (b) shaping the 3D geometry of channels using additive manufacturing techniques and (c) imposing dynamical gradients to destablize fluid side resistances.