In Vivo Polymer Mechanochemistry with Polynucleotides.

Polymer mechanochemistry utilizes mechanical force to activate latent functionalities in macromolecules and widely relies on ultrasonication techniques. Fundamental constraints of frequency and power intensity have prohibited the application of the polymer mechanochemistry principles in a biomedical context up to now, although medical ultrasound is a clinically established modality. Here, a universal polynucleotide framework is presented that allows the binding and release of therapeutic oligonucleotides, both DNA- and RNA-based, as cargo by biocompatible medical imaging ultrasound. It is shown that the high molar mass, colloidal assembly, and a distinct mechanochemical mechanism enable the force-induced release of cargo and subsequent activation of biological function in vitro and in vivo. Thereby, this work introduces a platform for the exploration of biological questions and therapeutics development steered by mechanical force.

Mechanochemical Activation of DNAzyme by Ultrasound.

Controlling the activity of DNAzymes by external triggers is an important task. Here a temporal control over DNAzyme activity through a mechanochemical pathway with the help of ultrasound (US) is demonstrated. The deactivation of the DNAzyme is achieved by hybridization to a complementary strand generated through rolling circle amplification (RCA), an enzymatic polymerization process. Due to the high molar mass of the resulting polynucleic acids, shear force can be applied on the RCA strand through inertial cavitation induced by US. This exerts mechanical force and leads to the cleavage of the base pairing between RCA strand and DNAzyme, resulting in the recovery of DNAzyme activity. This is the first time that this release mechanism is applied for the activation of catalytic nucleic acids, and it has multiple advantages over other stimuli. US has higher penetration depth into tissues compared to light, and it offers a more specific stimulus than heat, which has also limited use in biological systems due to cell damage caused by hyperthermia. This approach is envisioned to improve the control over DNAzyme activity for the development of reliable and specific sensing applications.

Brownian Relaxation Shakes and Breaks Magnetic Iron Oxide-Polymer Nanocomposites to Release Cargo.

Magnetic nanoparticles (NPs) are widely employed for remote controlled molecular release applications using alternating magnetic fields (AMF). Yet, they intrinsically generate heat in the process by Néel relaxation limiting their application scope. In contrast, iron oxide NPs larger than ≈15 nm react to AMF by Brownian relaxation resulting in tumbling and shaking. Here, such iron oxide NPs are combined with polymer shells where the shaking motion mechanically agitates and partially detaches the polymer chains, covalently cleaves a fraction of the polymers, and releases the prototypical cargo molecules doxorubicin and curcumin into solution. This heat-free release mechanism broadens the potential application space of polymer-functionalized magnetic NP composites.

Photoinduced Mechanical Cloaking of Diarylethene-Crosslinked Microgels.

The serial connection of multiple stimuli-responses in polymer architectures enables the logically conjunctive gating of functional material processes on demand. Here, a photoswitchable diarylethene (DAE) acts as a crosslinker in poly(N-vinylcaprolactam) microgels and allows the light-induced shift of the volume phase-transition temperature (VPTT). While swollen microgels below the VPTT are susceptible to force and undergo breakage-aggregation processes, collapsed microgels above the VPTT stay intact in mechanical fields induced by ultrasonication. Within a VPTT shift regime, photoswitching of the DAE transfers microgels from the swollen to the collapsed state and thereby gates their response to force as demonstrated by the light-gated activation of an embedded fluorogenic mechanophore. This photoinduced mechanical cloaking system operates on the polymer topology level and is thereby principally universally applicable.

Polymer Mechanochemistry in Microbubbles.

Polymer mechanochemistry is a promising technology to convert mechanical energy into chemical functionality by breaking covalent and supramolecular bonds site-selectively. Yet, the mechanochemical reaction rates of covalent bonds in typically used ultrasonication setups lead to reasonable conversions only after comparably long sonication times. This can be accelerated by either increasing the reactivity of the mechanoresponsive moiety or by modifying the encompassing polymer topology. Here, a microbubble system with a tailored polymer shell consisting of an N2 gas core and a mechanoresponsive disulfide-containing polymer network is presented. It is found that the mechanochemical activation of the disulfides is greatly accelerated using these microbubbles compared to commensurate solid core particles or capsules filled with liquid. Aided by computational simulations, it is found that low shell thickness, low shell stiffness and crosslink density, and a size-dependent eigenfrequency close to the used ultrasound frequency maximize the mechanochemical yield over the course of the sonication process.

Transformative Materials for Interfacial Drug Delivery.

Drug delivery systems (DDS) are designed to temporally and spatially control drug availability and activity. They assist in improving the balance between on-target therapeutic efficacy and off-target toxic side effects. DDS aid in overcoming biological barriers encountered by drug molecules upon applying them via various routes of administration. They are furthermore increasingly explored for modulating the interface between implanted (bio)medical materials and host tissue. Herein, an overview of the biological barriers and host-material interfaces encountered by DDS upon oral, intravenous, and local administration is provided, and material engineering advances at different time and space scales to exemplify how current and future DDS can contribute to improved disease treatment are highlighted.

Fracture Detection in Bio-Glues with Fluorescent-Protein-Based Optical Force Probes.

Glues are being used to bond, seal, and repair in industry and biomedicine. The improvement of gluing performance is hence important for the development of new glues with better and balanced property spaces, which in turn necessitates a mechanistic understanding of their mechanical failure. Optical force probes (OFPs) allow the observation of mechanical material damage in polymers from the macro- down to the microscale, yet have never been employed in glues. Here, the development of a series of ratiometric OFPs based on fluorescent-protein-dye and protein-protein conjugates and their incorporation into genetically engineered bio-glues is reported. The OFPs are designed to efficiently modulate Förster resonance energy transfer upon force application thereby reporting on force-induced molecular alterations independent of concentration and fluorescence intensity both spectrally and through their fluorescence lifetime. By fluorescence spectroscopy in solution and in the solid state and by fluorescence lifetime imaging microscopy, stress concentrations are visualized and adhesive and cohesive failure in the fracture zone is differentiated.

Mechanoresponsive Metal-Organic Cage-Crosslinked Polymer Hydrogels.

We report the formation of metal-organic cage-crosslinked polymer hydrogels. To enable crosslinking of the cages and subsequent network formation, we used homodifunctionalized poly(ethylene glycol) (PEG) chains terminally substituted with bipyridines as ligands for the Pd6 L4 corners. The encapsulation of guest molecules into supramolecular self-assembled metal-organic cage-crosslinked hydrogels, as well as ultrasound-induced disassembly of the cages with release of their cargo, is presented in addition to their characterization by nuclear magnetic resonance (NMR) techniques, rheology, and comprehensive small-angle X-ray scattering (SAXS) experiments. The constrained geometries simulating external force (CoGEF) method and barriers using a force-modified potential energy surface (FMPES) suggest that the cage-opening mechanism starts with the dissociation of one pyridine ligand at around 0.5 nN. We show the efficient sonochemical activation of the hydrogels HG3 -6 , increasing the non-covalent guest-loading of completely unmodified drugs available for release by a factor of ten in comparison to non-crosslinked, star-shaped assemblies in solution.

Sonopharmacology: controlling pharmacotherapy and diagnosis by ultrasound-induced polymer mechanochemistry.

Active pharmaceutical ingredients are the most consequential and widely employed treatment in medicine although they suffer from many systematic limitations, particularly off-target activity and toxicity. To mitigate these effects, stimuli-responsive controlled delivery and release strategies for drugs are being developed. Fueled by the field of polymer mechanochemistry, recently new molecular technologies enabled the emergence of force as an unprecedented stimulus for this purpose by using ultrasound. In this research area, termed sonopharmacology, mechanophores bearing drug molecules are incorporated within biocompatible macromolecular scaffolds as preprogrammed, latent moieties. This review presents the novelties in controlling drug activation, monitoring, and release by ultrasound, while discussing the limitations and challenges for future developments.

Mechanoresponsive diselenide-crosslinked microgels with programmed ultrasound-triggered degradation and radical scavenging ability for protein protection.

In the context of controlled delivery and release, proteins constitute a delicate class of cargo requiring advanced delivery platforms and protection. We here show that mechanoresponsive diselenide-crosslinked microgels undergo controlled ultrasound-triggered degradation in aqueous solution for the release of proteins. Simultaneously, the proteins are protected from chemical and conformational damage by the microgels, which disintegrate to water-soluble polymer chains upon sonication. The degradation process is controlled by the amount of diselenide crosslinks, the temperature, and the sonication amplitude. We demonstrate that the ultrasound-mediated cleavage of diselenide bonds in these microgels facilitates the release and activates latent functionality preventing the oxidation and denaturation of the encapsulated proteins (cytochrome C and myoglobin) opening new application possibilities in the targeted delivery of biomacromolecules.

Mechanoresponsive Carbamoyloximes for the Activation of Secondary Amines in Polymers.

Mechanophores are molecular moieties that are incorporated into polymers and respond to force with constitutional, configurational, or conformational bond rearrangements to enable functionality. Up to today, several chemically latent motifs have been activated by polymer mechanochemical methods, but the generation of secondary amines remains elusive. Here we report carbamoyloximes as mechanochemical protecting groups for secondary amines. We show that carbamoyloximes undergo force-induced homolytic bond scission at the N-O oxime bond in polymers thus producing the free amine, as the reaction proceeds via the carbamoyloxyl and aminyl radicals, analogously to its photochemical counterpart. Eventually, we apply the carbamoyloxime motif in a force-activated organocatalytic Knoevenagel reaction. We believe that this protecting strategy can be universally applied for many other secondary and primary amines in polymer materials.

Activation of Antibiotic-Grafted Polymer Brushes by Ultrasound.

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.

Microgels react to force: mechanical properties, syntheses, and force-activated functions.

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.

Mechano-Nanoswitches for Ultrasound-Controlled Drug Activation.

Current pharmacotherapy is challenged by side effects and drug resistance issues due to the lack of drug selectivity. Mechanochemistry-based strategies provide new avenues to overcome the related problems by improving drug selectivity. It is recently shown that sonomechanical bond scission enables the remote-controlled drug release from their inactive parent macromolecules using ultrasound (US). To further expand the scope of the US-controlled drug activation strategy, herein a mechano-responsive nanoswitch for the selective activation of doxorubicin (DOX) to inhibit cancer cell proliferation is constructed. As a proof-of-concept, the synthesis, characterization, and US-responsive drug activation evaluation of the mechano-nanoswitch, which provides a blueprint for tailoring nanosystems for force-induced pharmacotherapy is presented.

Mechanically Resistant Poly(N-vinylcaprolactam) Microgels with Sacrificial Supramolecular Catechin Hydrogen Bonds.

Microgels (µgels) swiftly undergo structural and functional degradation when they are exposed to shear forces, which potentially limit their applicability in, e.g., biomedicine and engineering. Here, poly(N-vinylcaprolactam) µgels that resist mechanical disruption through supramolecular hydrogen bonds provided by (+)-catechin hydrate (+C) are synthesized. When +C is added to the microgel structure, an increased resistance against shear force exerted by ultrasonication is observed compared to µgels crosslinked by covalent bonds. While covalently crosslinked µgels degrade already after a few seconds, it is found that µgels having both supramolecular interchain interactions and covalent crosslinks show the highest mechanical durability. By the incorporation of optical force probes, it is found that the covalent bonds of the µgels are not stressed beyond their scission threshold and mechanical energy is dissipated by the force-induced reversible dissociation of the sacrificial +C bonds for at least 20 min of ultrasonication. Additionally, +C renders the µgels pH-sensitive and introduces multiresponsivity. The µgels are extensively characterized using Fourier-transform infrared, Raman and quantitative nuclear magnetic resonance spectroscopy, dynamic light scattering, and cryogenic transmission electron microscopy. These results may serve as blueprint for the preparation of many mechanically durable µgels.

The Mechanochemical Synthesis and Activation of Carbon-Rich π-Conjugated Materials.

Mechanochemistry uses mechanical force to break, form, and manipulate chemical bonds to achieve functional transformations and syntheses. Over the last years, many innovative applications of mechanochemistry have been developed. Specifically for the synthesis and activation of carbon-rich π-conjugated materials, mechanochemistry offers reaction pathways that either are inaccessible with other stimuli, such as light and heat, or improve reaction yields, energy consumption, and substrate scope. Therefore, this review summarizes the recent advances in this research field combining the viewpoints of polymer and trituration mechanochemistry. The highlighted mechanochemical transformations include π-conjugated materials as optical force probes, the force-induced release of small dye molecules, and the mechanochemical synthesis of polyacetylene, carbon allotropes, and other π-conjugated materials.

Highly Stiff and Stretchable DNA Liquid Crystalline Organogels with Super Plasticity, Ultrafast Self-Healing, and Magnetic Response Behaviors.

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.

Release of Molecular Cargo from Polymer Systems by Mechanochemistry.

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.