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Microgels are colloidal polymer networks with high molar mass and properties between rigid particles, flexible macromolecules, and micellar aggregates. Their unique stimuli-responsiveness in conjunction with their colloidal phase behavior render them useful for many applications ranging from engineering to biomedicine. In many scenarios either the microgel's mechanical properties or its interactions with mechanical force play an important role. Here, we firstly explain microgel mechanical properties and how these are measured by atomic force microscopy (AFM), then we equip the reader with the synthetic background to understand how specific architectures and chemical functionalities enable these mechanical properties, and eventually we elucidate how the interaction of force with microgels can lead to the activation of latent functionality. Since the interaction of microgels with force is a multiscale and multidisciplinary subject, we introduce and interconnect the different research areas that contribute to the understanding of this emerging field in this Tutorial Review.

The ultrasound-mediated activation of drugs from macromolecular architectures using the principles of polymer mechanochemistry (sonopharmacology) is a promising strategy to gain spatiotemporal control over drug activity. Yet, conceptual challenges limit the applicability of this method. Especially low drug-loading content and low mechanochemical efficiency require the use of high carrier mass concentrations and prolonged exposure to ultrasound. Moreover, the activated drug is generally shielded by the hydrodynamic coil of the attached polymer fragment leading to a decreased drug potency. Here we present a carrier design for the ultrasound-induced activation of vancomycin, which is deactivated with its H-bond-complementary peptide target sequence. We show that the progression from mechanophore-centered linear chains to mechanophore-decorated polymer brushes increases drug-loading content, mechanochemical efficiency, and drug potency. These results may serve as a design guideline for future endeavors in the field of sonopharmacology.

Advanced materials 35(16), 2210052 (2023). doi:10.1002/adma.202210052, Published by Wiley-VCH, Weinheim

Optical force probes (OFPs) are force-responsive molecules that report on mechanically induced transformations by the alteration of their optical properties. Yet, their modular design and incorporation into polymer architectures at desired positions is challenging. Here we report triazole-extended anthracene OFPs that combine two modular ‘click’ reactions in their synthesis potentially allowing their incorporation at desirable positions in complex polymer materials. Importantly, these retain the excellent optical properties of their parent 9-π-extended anthracene OFP counterparts.

A Correction to this paper has been published: https://doi.org/10.1038/s41557-021-00685-3.

Angewandte Chemie / International edition (2022). doi:10.1002/anie.202207557, Published by Wiley-VCH, Weinheim

ACS polymers Au 2(4), 208-212 (2022). doi:10.1021/acspolymersau.2c00029, Published by American Chemical Society, Washington, DC

Journal of polymer science (2022). doi:10.1002/pol.20220342, Published by Wiley, Hoboken, NJ

The regulation of enzyme activity is a method to control biological function. We report two systems enabling the ultrasound‐induced activation of thrombin, which is vital for secondary hemostasis. First, we designed polyaptamers, which can specifically bind to thrombin, inhibiting its catalytic activity. With ultrasound generating inertial cavitation and therapeutic medical focused ultrasound, the interactions between polyaptamer and enzyme are cleaved, restoring the activity to catalyze the conversion of fibrinogen into fibrin. Second, we used split aptamers conjugated to the surface of gold nanoparticles (AuNPs). In the presence of thrombin, these assemble into an aptamer tertiary structure, induce AuNP aggregation, and deactivate the enzyme. By ultrasonication, the AuNP aggregates reversibly disassemble releasing and activating the enzyme. We envision that this approach will be a blueprint to control the function of other proteins by mechanical stimuli in the sonogenetics field., The precise regulation of protein activity is important to understand complex biological signaling networks and to devise new therapeutic approaches. Here, we use either polyaptamers or split aptamer‐conjugated AuNPs to inhibit the activity of thrombin. Mechanical force generated by ultrasound is exploited to activate thrombin, thereby catalyzing the formation of fibrin from fibrinogen.

Supramolecular coordination cages show a wide range of useful properties including, but not limited to, complex molecular machine‐like operations, confined space catalysis, and rich host–guest chemistries. Here we report the uptake and release of non‐covalently encapsulated, pharmaceutically‐active cargo from an octahedral Pd cage bearing polymer chains on each vertex. Six poly(ethylene glycol)‐decorated bipyridine ligands are used to assemble an octahedral PdII 6(TPT)4 cage. The supramolecular container encapsulates progesterone and ibuprofen within its hydrophobic nanocavity and is activated by shear force produced by ultrasonication in aqueous solution entailing complete cargo release upon rupture, as shown by NMR and GPC analyses., An octahedral PdII 6(TPT)4 cage with polymer chains on each vertex is activated by shear force from ultrasonication in aqueous solution. The metal–organic cage encapsulates progesterone or ibuprofen within its hydrophobic nanocavity and shows complete cargo release upon rupture.

Advanced science 10, 2104004 (2022). doi:10.1002/advs.202104004, Published by Wiley-VCH, Weinheim

Mechanical force applied by ultrasound in solution leads to the dissociation of DNA metallo-base-pair interactions when these motifs are functionalized with oligodeoxynucleotide sequences of sufficient length. The annealing and force-induced denaturing process is followed by the attachment of distance-sensitive fluorescent probes and is found to be reversible.

Traditional pharmacotherapy suffers from multiple drawbacks that hamper patient treatment, such as the buildup of antibiotic resistances or low drug selectivity and toxicity during systemic application. To overcome these challenges, drug activity can be controlled by employing delivery, targeting, or release solutions that mostly rely on the response to external physicochemical stimuli. Due to various technical limitations, mechanical force as a stimulus in the context of polymer mechanochemistry has so far not been used for this purpose, yet it has been proven to be a convenient and robust method to site-selectively rearrange or cleave bonds with submolecular precision in the realm of materials chemistry. Here, we present an unprecedented mechanochemically responsive system capable of successively releasing small furan-containing molecules, including the furylated fluorophore dansyl and the drugs furosemide as well as furylated doxorubicin, by ultrasound-induced selective scission of disulfide-centered polymers in solution. We show that mechanochemically generated thiol-terminated polymers undergo a Michael-type addition to Diels-Alder (DA) adducts of furylated drugs and acetylenedicarboxylate derivatives, initiating the downstream release of the small molecule drug by a retro DA reaction. We believe that this method can serve as a blueprint for the activation of many other small molecules.

The design and manipulation of (multi)functional materials at the nanoscale holds the promise of fuelling tomorrow's major technological advances. In the realm of macromolecular nanosystems, the incorporation of force-responsive groups, so called mechanophores, has resulted in unprecedented access to responsive behaviours and enabled sophisticated functions of the resulting structures and advanced materials. Among the diverse force-activated motifs, the on-demand release or activation of compounds, such as catalysts, drugs, or monomers for self-healing, are sought-after since they enable triggering pristine small molecule function from macromolecular frameworks. Here, we highlight examples of molecular cargo release systems from polymer-based architectures in solution by means of sonochemical activation by ultrasound (ultrasound-induced mechanochemistry). Important design concepts of these advanced materials are discussed, as well as their syntheses and applications.

Chemical science 13(38), 11304-11311 (2022). doi:10.1039/D2SC03153A, Published by RSC, Cambridge

Stiffening due to internal stress generation is of paramount importance in living systems and is the foundation for many biomechanical processes. For example, cells stiffen their surrounding matrix by pulling on collagen and fibrin fibers. At the subcellular level, molecular motors prompt fluidization and actively stiffen the cytoskeleton by sliding polar actin filaments in opposite directions. Here, we demonstrate that chemical cross-linking of a fibrous matrix of synthetic semiflexible polymers with thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) produces internal stress by induction of a coil-to-globule transition upon crossing the lower critical solution temperature of PNIPAM, resulting in a macroscopic stiffening response that spans more than 3 orders of magnitude in modulus. The forces generated through collapsing PNIPAM are sufficient to drive a fluid material into a stiff gel within a few seconds. Moreover, rigidified networks dramatically stiffen in response to applied shear stress featuring power law rheology with exponents that match those of reconstituted collagen and actomyosin networks prestressed by molecular motors. This concept holds potential for the rational design of synthetic materials that are fluid at room temperature and rapidly rigidify at body temperature to form hydrogels mechanically and structurally akin to cells and tissues.

Tuning the resonator quality is a long established technique for inorganic lasers giving access to extremely short or temporally precise laser pulses. However, this so-called q-switching, where the resonator can be “on” and sustain lasing or be switched “off” and inhibit lasing is widely unknown for conjugated polymer lasers. Here, we admix thermally stable photochromic dithienylethenes with conjugated polymer laser gain materials on 1D and 2D diffractive feedback gratings, which are generated by two-photon laser writing. By irradiation with differently colored light, the thermally bistable dithienylethenes reversibly modulate the refractive index of and exhibit competing absorption with the gain medium, effectively suppressing laser emission in the one state and allowing low threshold (2.15 mJ/cm2) laser emission in the other state.

Angewandte Chemie 133(3), 1515-1519 (2020). doi:10.1002/ange.202010324, Published by Wiley-VCH, Weinheim

The covalent attachment of cargo molecules (e.g., drugs and fluorophores) in β-position to a disulfide moiety through carbamate and carbonate bonds finds many applications in responsive release systems. Recently, we showed that the combination of this release process with polymer mechanochemistry-induced disulfide scission enabled the remote-controlled release of small molecule drugs and fluorophores from their inactive parent macromolecules using ultrasound. The nature of the linker bond largely governed the subsequent release kinetics, an aspect that has not been investigated so far. To compare the differences, we here employ disulfide-centered polymers releasing either hydroxyl- or amino-naphthalimides from their respective β-carbonate or -carbamate linkers by force-induced intramolecular 5-exo-trig cyclization. We present the synthesis, characterization, and cell imaging evaluation of three naphthalimides featuring colorimetric and green fluorescence turn-on upon release, allowing monitoring of the release process. We believe that the insights gained from these experiments would advance the tailoring of release rates for force-induced pharmacotherapy.

Light‐responsive materials have been extensively studied due to the attractive possibility of manipulating their properties with high spatiotemporal control in a non‐invasive fashion. This stimulated the development of a series of photo‐deformable smart devices. However, it remained a challenge to reversibly modulate the stiffness and toughness of bulk materials. Here, we present bioengineered protein fibers and their optomechanical manipulation by employing electrostatic interactions between supercharged polypeptides (SUPs) and an azobenzene (Azo)‐based surfactant. Photo‐isomerization of the Azo moiety from the E‐ to Z‐form reversibly triggered the modulation of tensile strength, stiffness, and toughness of the bulk protein fiber. Specifically, the photo‐induced rearrangement into the Z‐form of Azo possibly strengthened cation–π interactions within the fiber material, resulting in an around twofold increase in the fiber's mechanical performance. The outstanding mechanical and responsive properties open a path towards the development of SUP‐Azo fibers as smart stimuli‐responsive mechano‐biomaterials., Bioengineered protein fibers were prepared through electrostatic complexation of a positively charged polypeptide and a negatively charged azobenzene‐based surfactant. The photo‐isomerization of the azobenzene moiety from E‐ to Z‐isomer reversibly triggered a modulation of the bulk protein fiber's mechanical performance.

Chemistry - a European journal 27(64), 15889-15897 (2021). doi:10.1002/chem.202102938, Published by Wiley-VCH, Weinheim

DNA-based gels are attractive materials as they allow intuitive rational design, respond to external physicochemical stimuli, and show great potential for biomedical applications. However, their relatively poor mechanical properties currently limit their technological application considerably as the latter requires mechanical integrity and tunability. With this work, a DNA organogel is reported that gels through supramolecular interactions, which induce mesophase ordering, and that exhibits exceptional stretchability, deformability, plasticity, and biocompatibility. Moreover, the nature of the supramolecular bond enables complete self-healing within 3 s. Most importantly, the DNA-based liquid crystalline organogels exhibit impressive ultimate tensile strengths above 1 MPa, stiffness higher than 20 MPa, and toughness up to 18 MJ m−3, rendering these materials the strongest among reported DNA networks. In addition, the facile access is demonstrated to composite DNA materials by blending magnetic nanoparticles with the organogel matrix giving access to magnetic field induced actuation. It is believed that these findings contribute significantly to the advancement of DNA gels for their use in smart materials and biomedical applications.

Ultrasound (US) produces cavitation‐induced mechanical forces stretching and breaking polymer chains in solution. This type of polymer mechanochemistry is widely used for synthetic polymers, but not biomacromolecules, even though US is biocompatible and commonly used for medical therapy as well as in vivo imaging. The ability to control protein activity by US would thus be a major stepping‐stone for these disciplines. Here, we provide the first examples of selective protein activation and deactivation by means of US. Using GFP as a model system, we engineer US sensitivity into proteins by design. The incorporation of long and highly charged domains enables the efficient transfer of force to the protein structure. We then use this principle to activate the catalytic activity of trypsin by inducing the release of its inhibitor. We expect that this concept to switch “on” and “off” protein activity by US will serve as a blueprint to remotely control other bioactive molecules., Proteins are genetically engineered and equipped with long supercharged polypeptide handles, rendering them susceptible to ultrasound. The concept is demonstrated by designing ultrasound‐responsive GFP derivatives the fluorescence of which can be switched “off,” while the activation of catalytic activity is switched “on” by ultrasound using trypsin in conjunction with a protein inhibitor.

The biomedical application of nanoparticles (NPs) for diagnosis and therapy is considerably stalled by their inefficient cellular internalization. Many strategies to overcome this obstacle have been developed but are not generally applicable to different NP systems, consequently underlining the need for a universal method that enhances NP entry into cells. Here we describe a method to increase NP cellular uptake via strand hybridization between DNA-functionalized NPs and cells that bear the respective complementary sequence incorporated into the membrane. By this, the NPs bind efficiently to the cellular surface enhancing internalization of three completely different NP types: DNA tetrahedrons, gold (Au) NPs, and polystyrene (PS) NPs. We show that our approach is a simple and generalizable strategy that can be applied to virtually every functionalizable NP system.

Fluorescent proteins are investigated extensively as markers for the imaging of cells and tissues that are treated by gene transfection. However, limited transfection efficiency and lack of targeting restrict the clinical application of this method rooted in the challenging development of robust fluorescent proteins for in vivo bioimaging. To address this, a new type of near-infrared (NIR) fluorescent protein assemblies manufactured by genetic engineering is presented. Due to the formation of well-defined nanoparticles and spectral operation within the phototherapeutic window, the NIR protein aggregates allow stable and specific tumor imaging via simple exogenous injection. Importantly, in vivo tumor metastases are tracked and this overcomes the limitations of in vivo imaging that can only be implemented relying on the gene transfection of fluorescent proteins. Concomitantly, the efficient loading of hydrophobic drugs into the protein nanoparticles is demonstrated facilitating the therapy of tumors in a mouse model. It is believed that these theranostic NIR fluorescent protein assemblies, hence, show great potential for the in vivo detection and therapy of cancer.

We here performed an in-depth investigation of the behavior of microgels (mu gels) and their associated physicochemical transformations under shear force. Thermo- and mechanoresponsive poly(N-vinylcaprolactam) (PVCL) mu gels (d similar to 400 nm) cross-linked with a force-responsive mechanofluorophore in different crosslinking degrees were synthesized and examined. Fluorescence spectroscopy (FS), confocal laser scanning microscopy (CLSM), dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryoTEM), high-resolution magic-angle sample spinning (HRMAS) nuclear magnetic resonance (NMR), Fourier-transform infrared (FTIR), and X-ray photoelectron spectroscopy (XPS) are used to characterize the mu gels before, during, and after shearing with different shear rates and intensities. The obtained results suggest nonuniform structural features consisting of a softer outer "corona" and a harder particle "core" (cross-linker-rich). Upon shearing, the mu gels rapidly lose their corona and the cores agglomerate altering mu gel functionality. Surprisingly, mu gels degrade promptly, even when subjected to low shear forces, such as the extrusion through a needle. This has potential implications for all applications in which shear forces in solution are expected, including extrusion, injection, and filtration processes involving colloidal mu gel solutions as well as circulation within the bloodstream of living organisms.

Pharmaceutical drug therapy is often hindered by issues caused by poor drug selectivity, including unwanted side effects and drug resistance. Spatial and temporal control over drug activation in response to stimuli is a promising strategy to attenuate and circumvent these problems. Here we use ultrasound to activate drugs from inactive macromolecules or nano-assemblies through the controlled scission of mechanochemically labile covalent bonds and weak non-covalent bonds. We show that a polymer with a disulfide motif at the centre of the main chain releases an alkaloid-based anticancer drug from its β-carbonate linker by a force-induced intramolecular 5-exo-trig cyclization. Second, aminoglycoside antibiotics complexed by a multi-aptamer RNA structure are activated by the mechanochemical opening and scission of the nucleic acid backbone. Lastly, nanoparticle–polymer and nanoparticle–nanoparticle assemblies held together by hydrogen bonds between the peptide antibiotic vancomycin and its complementary peptide target are activated by force-induced scission of hydrogen bonds. This work demonstrates the potential of ultrasound to activate mechanoresponsive prodrug systems. [Figure not available: see fulltext.].

Due to their soft and brittle nature, the mechanical characterization of polymer hydrogels is a difficult task employing traditional testing equipment. Here, we endowed poly(N-isopropyl acrylamide) (PNIPAAm) hydrogel networks with Diels–Alder adducts of π-extended anthracenes as mechanofluorophore crosslinkers. After swelling the networks with varying amounts of water and subjecting them to force, we visualized the subsequent fluorescence caused by covalent bond scission with confocal laser scanning microscopy (CLSM) and related the intensities to the macroscopic fracture mechanics and the elastic moduli recorded with traditional uniaxial compression. The sensitivity of the mechanofluorophores allowed the analysis of low levels of mechanical stress produced via a hand-induced needle-puncturing process and, thus, is an alternative to conventional force application methods. The detection and precise localization of covalent bond scission via CLSM helps elucidating the interrelationship between molecular structure and the macroscopic properties of chemically crosslinked polymeric hydrogels. We believe that this micro-scale mechanophore-assisted fractography can establish a new paradigm for the mechanical analysis of soft matter in fields covering traditional polymer and life sciences.

Over the past decades, it became clear that next to heat and light, pericyclic reactions can be induced mechanochemically when the reacting motifs are embedded as latent force-responsive groups (mechanophores) into polymer architectures. Not only does this enable a variety of functions and applications on a material level, but moreover grants access to symmetry-forbidden reaction products with respect to the Woodward–Hoffmann rules. The latter indicates that polymer mechanochemistry follows its own set of rules that, however, regarding underlying mechanisms and design rationales is far from being holistically understood. Here we review the existing body of literature and identify common structural features and substitution prerequisites to the polymer framework shining light on the differences between polymer mechanochemical pericyclic reactions and their traditional counterparts. By this, we believe to contribute to the major challenge of not only retrospectively describing force-induced reactivity but eventually finding a common molecular design guideline.

In-line electrolyte monitoring during hemodialysis treatment is an important step towards personalized treatment, for optimization of clinical blood pressure management and minimization of cardiovascular complications and bone-mineral disease. But how to achieve such in-line measurement? We propose a real-time electrolyte measurement system based on a molecular fluorescence “on-off” switching mechanism. We have fabricated a disposable polymeric micro-optofluidic device in polydimethylsiloxane (PDMS) with integrated optical fibers to enable in-line electrolyte monitoring. The sensing principle is based on photoinduced electron transfer (PET) that ion-selectively quenches the fluorescence of a molecular optical probe. The PET molecules are covalently immobilized onto the PDMS microchannel walls. As a proof-of-concept, we determine sodium concentration in a flowing medium. A clear relation between fluorescence intensity and sodium concentration is observed. The PET principle can also be applied to many other ion types.

This chapter discusses recent approaches towards the optical detection of stress and deformation in polymeric materials, an important tool in monitoring material integrity and in the study of failure mechanisms of polymeric materials. Optical sensing has specific advantages based on the ease of detection, high sensitivity and spectral resolution of light. In this chapter, a classification of sensing mechanisms is used that distinguishes between the molecular phenomena of isomerization, bond scission, change in conjugation and collective phenomena such as changes in chromophore aggregation and photonic band gap tuning. Molecular mechanisms are discussed that have been used to obtain stress-induced changes in absorption and fluorescence properties and recent work is presented in which the chain scission of dioxetanes is used to produce a luminescent signal with high detectability. Pi-conjugated systems play an important role in optical detection of stress and damage in polymers because their optical properties are very sensitive to changes in conformation and aggregation state. Finally, photonic band gap polymers and cholesteric liquid crystals are discussed, in which the periodic organization of structural features at the scale of the wavelength of light leads to strain-dependent reflection and absorption bands.