The field of optogenetics has enabled the fundamental understanding of neural circuits and disorders. However, these techniques require invasive surgical procedures to deliver light to target cells due to the low penetration depth of light into tissue. Therefore, ultrasound (US) was used as alternative trigger since US can deeply penetrate tissue with high spatiotemporal control. Our group develops molecular technologies based on polymer mechanochemistry to control the activity of drugs, proteins and nucleic acids by US. While initial efforts relied on low frequency (20 kHz) US that is destructive to cells, our current efforts are dedicated to two technology platforms that allow the activation of bioactive compounds by biocompatible US, i.e. imaging US and low intensity focussed US. The first technology relies on high molecular weight polynucleic acids that are produced by rolling circle amplification or transcription and that encode multiple binding sites for drugs, proteins and nucleic acids. Once these loaded nucleic acid carriers are subjected to US, non-covalent bond cleavage occurs by collapse of US-induced cavitation bubbles leading to activation of the cargoes. In this way, gene knock-down in vitro was achieved by liberating siRNA and immunostimulation was successfully realized in vivo by activating CpG oligonucleotides. Similarly, protein activity can be switched on by US, involving the mechanochemical activation of a protease that subsequently triggers split intein function for controlling the activity of a broad scope of proteins. A second platform technology for low-intensity US activation is mechanophore-incorporated microbubbles that also allow the spatiotemporally controlled release of bioactives.

Single-chain nanoparticles (SCNPs) are polymeric nanoparticles generated by intramolecular collapses and crosslinks of single polymer chains. Conceptually, they mimic the structures of natural enzymes in their dimensions and internal compartmentalizations, making them perfect candidates for numerous applications, especially drug delivery and catalysis.[1] We have previously synthesized amphiphilic, core-shell structured SCNPs (sized < 10 nm) for the covalent encapsulation of various fluorescence and EPR labels. Using spectroscopic methods we could prove the formation of internal compartmentalized structures with multiple labels inside the hydrophobic core of the SCNP.[2, 3]
Additionally, we found that the compartments of lower-critical-solution-temperature- (LCST-) type SCNPs show individual thermoresponsivities, resulting in shrinking SCNPs at medium elevated temperatures by swelling-water depletion. This heat-triggered shrinking behavior can also be triggered using irradiation of near-infrared (NIR) dyes inside the SCNPs, creating a unique contrasting effect for photoacoustic imaging (PAI).[3]
We here present on crosslinked single polymer chains using the polymerization of pyrrole sidechains, resulting in polypyrrole (PPy) crosslinked SCNPs, with PPy as strong absorber, completely transforming irradiating NIR-light into heat via the photothermal effect. This heat can be used in biomedical applications for photothermal therapy, PAI, or both in a theranostic approach. The SCNPs we synthesized are not only applicable for these approaches, but also represent an interesting photo-thermoresponsive effect, as they produce enough heat to trigger their own LCST behavior.[5]

Figure 1. Schematic representation of the photo-thermoresponsivity of the PPy-crosslinked SCNPs, heating up under NIR light irradiation, precipitating upon this heating, and redissolving upon cooling.

A substrate and a conductive material are required to enable electronic devices. Although these two components have distinct roles and different properties, they must function in synergy. Transitioning from solid and inflexible applications to flexible/stretchable ones requires redefining both the substrate and the conductive layer given neither can reversibly withstand the stresses encountered during stretching and bending of the device. The key properties that both the substrate and conductive layer must possess are: reversible stretching and bending while maintaining threshold conductivity. It will be demonstrated that a biopolymer can serve as a flexible and stretchable substrate. The substrate can be transformed from an insulator to a conductor by blending it with an intrinsically conductive and water-soluble polymer.¹

It will be shown that combining both a sustainable biopolymer with a water-soluble conductive polymer can yield an intrinsically conductive substrate for use as a motion sensor. The motion sensor can detect both macro and micromovements, making it ideally suited for tracking a rang of motion and speech detection.² These applications will be demonstrated.

In vivo biosensing agents are emerging as a novel platform for continuous monitoring, especially in the context of therapeutic drug management and critical care scenarios. While electrochemical approaches have been established with superb temporal resolution and promising biocompatibility [1], these lack the spatial resolution typical of imaging modalities. Ultrasound is one of the most commonly used medical imaging techniques, with advantages of portability and wide-spread availability, however to our knowledge there have not been significant focus employed on developing analyte-responsive contrast agents. Photoacoustic imaging is also emerging clinically, adding additional capability around endogenous molecular contrast (e.g. for oxygen monitoring). Current clinical contrast agents are micron-sized gas bubbles, which generate a high degree of echogenicity and are employed clinically for a variety of ultrasound imaging investigations. However, these agents are short-lived in vivo and are not amenable to continuous monitoring applications.

In this study, we produced a pH-sensitive ultrasound contrast agent for pre-clinical animal applications. We employed a scaffold of a silica nanoparticles containing a pH-sensitive polymer as the dynamic component, observing a novel pH-specific echogenic effect [2]. After confirming pH-specific ultrasound imaging in vitro, we extended to monitoring dynamic pH changes in a simple in vivo mouse model, demonstrating compelling proof of concept for continuous monitoring applications. We recently expanded this concept to employ photoacoustic imaging for continuous pH monitoring, further confirming the novel echogenic effects. The nanomaterial design, synthesis, characterisation and biological application results will be presented for discussion.

Chemotherapeutic drug discovery takes 10-13 years on average, with only 5% of potential candidates reaching the market.1 This high attrition rate can be explained by the lack of reliable in vitro models causing the pre-clinical candidates to fail when starting the clinical trials. To bridge this translational gap, 3D cellular models arise to emulate physiological conditions with higher fidelity than 2D conventional systems. These 3D constructs require from highly sensitive and non-invasive analytical techniques able to overcome the limitations that conventional imaging techniques and cell assays show when having multi-layered matrices. In this sense, surface-enhanced Raman spectroscopy (SERS), allow for the detection of low concentrated metabolites when located next to metallic nanostructures.2 These nanostructures can be incorporated into hydrogel-based matrices to obtain bioinks that allow to print multi-functional 3D scaffolds in which cells can be cultured and the biomarkers they produce can be detected in situ by SERS. 3 In here, we developed a library of plasmonic hydrogels by combining alginate, gelatin and carboxymethyl cellulose (CMC) modified with complementary functional groups that enable thiol-ene orthogonal photo-crosslinking. Then, different properties of these materials were evaluated including rheology, swelling, degradation or biocompatibility. Finally, we assessed the influence of hydrogel composition on the SERS sensitivity for sensing different analytes, including chemotherapeutics (pemetrexed or doxorubicin) and cancer-related biomarkers (adenine). In these studies, we found key hydrogel features linked to their SERS performance and selectivity, which provide insights for the rational design of plasmonic hydrogels for the obtention and study of 3D cancer models.

Diseases or injuries to the nervous system often lead to severe sensory, motor, and autonomic dysfunctions. In 2021, these conditions were the leading cause of disability-adjusted life-years (DALYs) globally, impacting 3.40 billion individuals. Because of these staggering statistics, solving this problem has become urgent. Tissue engineering approaches with neuronal cell-transplanted scaffolds are one of the strategies to repair damaged nervous tissues and restore functionality. However, challenges remain in designing them to achieve intricate forms, adequate mechanical properties, and balanced ionic conductivity to ensure structural integrity and proper neuron signaling.

Our research presents a 3D-printable hydrogel, featuring non-toxic crosslinkers, specifically crafted for neuronal scaffolds that mimic the extracellular matrix (ECM) of the central nervous system. This hydrogel consists of poly(vinyl alcohol) (PVA), gelatin (Gel), κ-carrageenan (κ-Car), and cellulose nanocrystals (CNCs), and is manufactured using direct ink writing (DIW) at room temperature. By utilizing dual physical-ionic non-covalent crosslink bonding between the polymer and CNC-induced aligned microstructure, we achieve excellent ionic conductivity (2 S/m) and a highly porous structure (>600% swelling).

Compared to the traditional freeze-thawing (FT) method, our post-printing treatment, incorporating salting-out using Hofmeister ions (K+ and OH-), significantly enhances the compressive modulus (60 kPa), extends the degradation period (<2% weight loss per week), and improves sterilizability in ethanol. In vitro tests also confirm that the hydrogel is biocompatible and supports cell attachment. This innovative approach successfully combines 3D-printability and mechanical robustness with ionic conductivity, making it a promising solution for creating transplantable neural scaffolds.