Exosome-coated oxygen nanobubble-laden hydrogel augments intracellular delivery of exosomes for enhanced wound healing.

Wound healing is an obvious clinical concern that can be hindered by inadequate angiogenesis, inflammation, and chronic hypoxia. While exosomes derived from adipose tissue-derived stem cells have shown promise in accelerating healing by carrying therapeutic growth factors and microRNAs, intracellular cargo delivery is compromised in hypoxic tissues due to activated hypoxia-induced endocytic recycling. To address this challenge, we have developed a strategy to coat oxygen nanobubbles with exosomes and incorporate them into a polyvinyl alcohol/gelatin hybrid hydrogel. This approach not only alleviates wound hypoxia but also offers an efficient means of delivering exosome-coated nanoparticles in hypoxic conditions. The self-healing properties of the hydrogel, along with its component, gelatin, aids in hemostasis, while its crosslinking bonds facilitate hydrogen peroxide decomposition, to ameliorate wound inflammation. Here, we show the potential of this multifunctional hydrogel for enhanced healing, promoting angiogenesis, facilitating exosome delivery, mitigating hypoxia, and inhibiting inflammation in a male rat full-thickness wound model.

Reprocessability in Engineering Thermosets Achieved Through Frontal RingOpening Metathesis Polymerization.

While valued for their durability and exceptional performance, crosslinked thermosets are challenging to recycle and reuse. Here, inherent reprocessability in industrially relevant polyolefin thermosetsis unveiled. Unlike prior methods, this approach eliminates the need to introduce exchangeable functionality to regenerate the material, relying instead on preserving the activity of the metathesis catalyst employed in the curing reaction. Frontal ring-opening metathesis polymerization (FROMP) proves critical to preserving this activity. Conditions controlling catalytic viability are explored to successfully reclaim performance across multiple generations of material, thus demonstrating long-term reprocessability. This straightforward and scalable remolding strategy is poised for widespread adoption. Given the anticipated growth in polyolefin thermosets, these findings represent an important conceptual advance in the pursuit of a fully circular lifecycle for thermoset polymers.

Unraveling Reactivity Differences: Room-Temperature Ring-Opening Metathesis Polymerization (ROMP) versus Frontal ROMP.

In this study, we explore the distinct reactivity patterns between frontal ring-opening metathesis polymerization (FROMP) and room-temperature solventless ring-opening metathesis polymerization (ROMP). Despite their shared mechanism, we find that FROMP is less sensitive to inhibitor concentration than room-temperature ROMP. By increasing the initiator-to-monomer ratio for a fixed inhibitor/initiator quantity, we find reduction in the ROMP background reactivity at room temperature (i.e., increased resin pot life). At elevated temperatures where inhibitor dissociation prevails, accelerated frontal polymerization rates are observed because of the concentrated presence of the initiator. Surprisingly, the strategy of employing higher initiator loading enhances both pot life and front speeds, which leads to FROMP rates exceeding prior reported values by over 5 times. This counterintuitive behavior is attributed to an increase in the proximity of the inhibitor to the initiator within the bulk resin and to whether the temperature favors coordination or dissociation of the inhibitor. A rapid method was developed for assessing resin pot life, and a straightforward model for active initiator behavior was established. Modified resin systems enabled direct ink writing of robust thermoset structures at rates much faster than previously possible.

Nuclear deformation regulates YAP dynamics in cancer associated fibroblasts.

Cells cultured on stiff 2D substrates exert high intracellular force, resulting in mechanical deformation of their nuclei. This nuclear deformation (ND) plays a crucial role in the transport of Yes Associated Protein (YAP) from the cytoplasm to the nucleus. However, cells in vivo are in soft 3D environment with potentially much lower intracellular forces. Whether and how cells may deform their nuclei in 3D for YAP localization remains unclear. Here, by culturing human colon cancer associated fibroblasts (CAFs) on 2D, 2.5D, and 3D substrates, we differentiated the effects of stiffness, force, and ND on YAP localization. We found that nuclear translocation of YAP depends on the degree of ND irrespective of dimensionality, stiffness and total force. ND induced by the perinuclear force, not the total force, and nuclear membrane curvature correlate strongly with YAP activation. Immunostained slices of human tumors further supported the association between ND and YAP nuclear localization, suggesting ND as a potential biomarker for YAP activation in tumors. Additionally, we conducted quantitative analysis of the force dynamics of CAFs on 2D substrates to construct a stochastic model of YAP kinetics. This model revealed that the probability of YAP nuclear translocation, as well as the residence time in the nucleus follow a power law. This study provides valuable insights into the regulatory mechanisms governing YAP dynamics and highlights the significance of threshold activation in YAP localization. STATEMENT OF SIGNIFICANCE: Yes Associated Protein (YAP), a transcription cofactor, has been identified as one of the drivers of cancer progression. High tumor stiffness is attributed to driving YAP to the nucleus, wherein it activates pro-metastatic genes. Here we show, using cancer associated fibroblasts, that YAP translocation to the nucleus depends on the degree of nuclear deformation, irrespective of stiffness. We also identified that perinuclear force induced membrane curvature correlates strongly with YAP nuclear transport. A novel stochastic model of YAP kinetics unveiled a power law relationship between the activation threshold and persistence time of YAP in the nucleus. Overall, this study provides novel insights into the regulatory mechanisms governing YAP dynamics and the probability of activation that is of immense clinical significance.

Scale-Dependent Rheology of Synovial Fluid Lubricating Macromolecules.

Synovial fluid (SF) is the complex biofluid that facilitates the exceptional lubrication of articular cartilage in joints. Its primary lubricating macromolecules, the linear polysaccharide hyaluronic acid (HA) and the mucin-like glycoprotein proteoglycan 4 (PRG4 or lubricin), interact synergistically to reduce boundary friction. However, the precise manner in which these molecules influence the rheological properties of SF remains unclear. This study aimed to elucidate this by employing confocal microscopy and multiscale rheometry to examine the microstructure and rheology of solutions containing recombinant human PRG4 (rhPRG4) and HA. Contrary to previous assumptions of an extensive HA-rhPRG4 network, it is discovered that rhPRG4 primarily forms stiff, gel-like aggregates. The properties of these aggregates, including their size and stiffness, are found to be influenced by the viscoelastic characteristics of the surrounding HA matrix. Consequently, the rheology of this system is not governed by a single length scale, but instead responds as a disordered, hierarchical network with solid-like rhPRG4 aggregates distributed throughout the continuous HA phase. These findings provide new insights into the biomechanical function of PRG4 in cartilage lubrication and may have implications in the development of HA-based therapies for joint diseases like osteoarthritis.

Soft glassy materials with tunable extensibility.

Extensibility is beyond the paradigm of classical soft glassy materials, and more broadly, yield-stress fluids. Recently, model yield-stress fluids with significant extensibility have been designed by adding polymeric phases to classically viscoplastic dispersions [Nelson et al., J. Rheol., 2018, 62, 357; Nelson et al., Curr. Opin. Solid State Mater. Sci., 2019, 23, 100758; Dekker et al., J. Non-Newtonian Fluid Mech., 2022, 310, 104938]. However, fundamental questions remain about the design of and coupling between the shear and extensional rheology of such systems. In this work, we propose a model material, a mixture of soft glassy microgels and solutions of high molecular weight linear polymers. We establish systematic criteria for the design and thorough rheological characterization of such systems, in both shear and extension. Using our material, we show that it is possible to dramatically change the behavior in extension with minimal change in the shear yield stress and elastic modulus, thus enabling applications that exploit orthogonal modulation of shear and extensional material properties.

Secondary Bubble Entrainment via Primary Bubble Bursting at a Viscoelastic Surface.

Bubble bursting at liquid surfaces is ubiquitous and plays a key role for the mass transfer across interfaces, impacting global climate and human health. Here, we document an unexpected phenomenon that when a bubble bursts at a viscoelastic surface of a bovine serum albumin solution, a secondary (daughter) bubble is entrapped with no subsequent jet drop ejection, contrary to the counterpart experimentally observed at a Newtonian surface. We show that the strong surface dilatational elastic stress from the viscoelastic surface retards the cavity collapse and efficiently damps out the precursor waves, thus facilitating the dominant wave focusing above the cavity nadir. The onset of daughter bubble entrainment is well predicted by an interfacial elastocapillary number comparing the effects of surface dilatational elasticity and surface tension. Our Letter highlights the important role of surface rheology on free surface flows and may find important implications in bubble dynamics with a contaminated interface exhibiting complex surface rheology.

Reversible Reactions, Mesh Size, and Segmental Dynamics Control Penetrant Diffusion in Ethylene Vitrimers.

The diffusion of two aromatic dyes with nearly identical sizes was measured in ethylene vitrimers with precise linker lengths and borate ester cross-links using fluorescence recovery after photobleaching (FRAP). One dye possessed a reactive hydroxyl group, while the second was inert. The reaction of the hydroxyl group with the network is slow relative to the hopping times of the dye, resulting in a large slowdown by a factor of 50 for a reactive probe molecule. A kinetic model was fit to the fluorescence intensity data to determine rate constants for the reversible reaction of the dye from the network, which confirms the role of slow reaction kinetics. A second network cross-linker was also investigated with a substituted boronic ester showing ∼10,000 times faster exchange kinetics. In this system, the two dyes show the same diffusion coefficient, as the reaction is no longer the rate-limiting step. The role of dense meshes on small and large dyes is also discussed in the context of the existing theories. These results highlight the potential of dynamic networks to control penetrant transport through synergistic effects of the mesh size, dynamic bond kinetics, and penetrant-network interactions.

Mechanisms of gill-clogging by hagfish slime.

Hagfishes defend themselves from gill-breathing predators by producing large volumes of fibrous slime when attacked. The slime's effectiveness comes from its ability to clog predators' gills, but the mechanisms by which hagfish slime clogs are uncertain, especially given its remarkably dilute concentration of solids. We quantified the clogging performance of hagfish slime over a range of concentrations, measured the contributions of its mucous and thread components, and measured the effect of turbulent mixing on clogging. To assess the porous structure of hagfish slime, we used a custom device to measure its Darcy permeability. We show that hagfish slime clogs at extremely dilute concentrations like those found in native hagfish slime and displays clogging performance that is superior to three thickening agents. We report an extremely low Darcy permeability for hagfish slime, and an effective pore size of 10-300 nm. We also show that the mucous and thread components play distinct yet crucial roles, with mucus being responsible for effective clogging and low permeability and the threads imparting mechanical strength and retaining clogging function over time. Our results provide new insights into the mechanisms by which hagfish slime clogs gills and may inspire the development of ultra-soft materials with novel properties.

Concentration-dependent Cycling of Phenothiazine-based Electrolytes in Nonaqueous Redox Flow Cells.

Increasing redox-active species concentrations can improve viability for organic redox flow batteries by enabling higher energy densities, but the required concentrated solutions can become viscous and less conductive, leading to inefficient electrochemical cycling and low material utilization at higher current densities. To better understand these tradeoffs in a model system, we study a highly soluble and stable redox-active couple, N-(2-(2-methoxyethoxy)ethyl)phenothiazine (MEEPT), and its bis(trifluoromethanesulfonyl)imide radical cation salt (MEEPT-TFSI). We measure the physicochemical properties of electrolytes containing 0.2-1 M active species and connect these to symmetric cell cycling behavior, achieving robust cycling performance. Specifically, for a 1 M electrolyte concentration, we demonstrate 94% materials utilization, 89% capacity retention, and 99.8% average coulombic efficiency over 435 h (100 full cycles). This demonstration helps to establish potential for high-performing, concentrated nonaqueous electrolytes and highlights possible failure modes in such systems.

Softening by charging: how collective modes of ionic association in concentrated redoxmer/electrolyte solutions define the structural and dynamic properties in different states of charge.

Understanding the physical and chemical processes occurring in concentrated electrolyte solutions is required to achieve redox flow batteries with high energy density. Highly concentrated electrolyte solutions are often studied in which collective crowded interactions between molecules and ions become predominant. Herein, experimental and computational methods were used to examine non-aqueous electrolyte solutions in two different states of charge as a function of redoxmer concentration. As the latter increases and the ionic association strengthens, the electric conductivity passes through a maximum and the solution increasingly gels, which is seen through a rapid non-linear increase in viscosity. We establish that the structural rigidity of ionic networks is closely connected with this loss of fluidity and show that charging generally yields softer ionic assemblies with weaker attractive forces and improved dynamical properties.

Gelation under stress: impact of shear flow on the formation and mechanical properties of methylcellulose hydrogels.

We demonstrate that small unidirectional applied-stresses during temperature-induced gelation dramatically change the gel temperature and the resulting mechanical properties and structure of aqueous methylcellulose (MC), a material that forms a brittle gel with a fibrillar microstructure at elevated temperatures. Applied stress makes gelation more difficult, evidenced by an increased gelation temperature, and weakens mechanical properties of the hot gel, evidenced by a decreased elastic modulus and decreased apparent failure stress. In extreme cases, formation of a fully percolated polymer network is inhibited and a soft granular yield-stress fluid is formed. We quantify the effects of the applied stress using a filament-based mechanical model to relate the measured properties to the structural features of the fibril network. The dramatic changes in the gel temperature and hot gel properties give more design freedom to processing-dependent rheology, but could be detrimental to coating applications where gravitational stress during gelation is unavoidable.

Linear and nonlinear viscoelasticity of concentrated thermoresponsive microgel suspensions.

We present an integrated experimental and theoretical study of the dynamics and rheology of self-crosslinked, slightly charged, temperature responsive soft poly(N-isopropylacrylamide) (pNIPAM) microgels over a wide range of concentration and temperature spanning the sharp change in particle size and intermolecular interactions across the lower critical solution temperature (LCST). Dramatic, non-monotonic changes in viscoelasticity are observed as a function of temperature, with distinct concentration dependence in the dense fluid, glassy, and soft-jammed regimes. Motivated by our experimental observations, we formulate a minimalistic model for the size dependence of a single microgel particle and the change of the interparticle interaction from purely repulsive to attractive upon heating. Using microscopic equilibrium and time-dependent statistical mechanical theories, theoretical predictions are quantitatively compared with experimental measurements of the shear modulus. Good agreement is found for the nonmonotonic temperature behavior that originates as a consequence of the competition between reduced microgel packing fraction and increasing interparticle attractions. Testable predictions are made for nonlinear rheological properties such as the yield stress and strain. To our knowledge, this is the first attempt to quantitatively understand in a unified manner the viscoelasticity of dense, temperature-responsive microgel suspensions spanning a wide range of temperatures and concentrations.

Self-Assembled Solute Networks in Crowded Electrolyte Solutions and Nanoconfinement of Charged Redoxmer Molecules.

Redoxmers are electrochemically active organic molecules storing charge and energy in electrolyte fluids circulating through redox flow batteries (RFBs). Such molecules typically have solvent-repelling cores and solvent-attracting pendant groups introduced to increase solubility in liquid electrolytes. These two features can facilitate nanoscale aggregation of the redoxmer molecules in crowded solutions. In some cases, this aggregation leads to the emergence of continuous networks of solute molecules in contact, and the solution becomes microscopically heterogeneous. Here, we use small-angle X-ray scattering (SAXS) and molecular dynamics modeling to demonstrate formation of such networks and examine structural factors controlling this self-assembly. We also show that salt ions become excluded from these solute aggregates into small pockets of electrolytes, where these ions strongly associate. This confinement by exclusion is also likely to occur to charged redoxmer molecules in a "sea" of neutral precursors coexisting in the same solution. Here, we demonstrate that the decay lifetime of the confined charged molecules in such solutions can increase several fold compared to dilute solutions. We attribute this behavior to a "microreactor effect" on reverse reactions of the confined species during their decomposition.

Base-triggered self-amplifying degradable polyurethanes with the ability to translate local stimulation to continuous long-range degradation.

A new type of base-triggered self-amplifying degradable polyurethane is reported that degrades under mild conditions, with the release of increasing amounts of amine product leading to self-amplified degradation. The polymer incorporates a base-sensitive Fmoc-derivative into every repeating unit to enable highly sensitive amine amplified degradation. A sigmoidal degradation curve for the linear polymer was observed consistent with a self-amplifying degradation mechanism. An analogous cross-linked polyurethane gel was prepared and also found to undergo amplified breakdown. In this case, a trace amount of localized base initiates the degradation, which in turn propagates through the material in an amplified manner. The results demonstrate the potential utility of these new generation polyurethanes in enhanced disposability and as stimuli responsive materials.

Exploiting Nonlinear Elasticity for Anomalous Magnetoresponsive Stiffening.

A paradigm for enhanced magnetorheological elastic materials is introduced and experimentally established. We show that a nonlinearly stiffening polymer matrix can be exploited to achieve anomalous magneto-elastomer stiffening exceeding standard magneto-elastomer theory and experiment in terms of percentage stiffness change and sensitivity to applied magnetic flux. Using a model system of a semiflexible fibrin network embedded with micron sized carbonyl iron particles, we demonstrate that even at a modest particle volume fraction (0.5-4%), a coupling between the magnetically interacting dipoles and a strain-stiffening polymer mesh provides previously unexplored opportunities for material design. Our experiments indicate that confined particles within the fibrin network internally tension and stiffen the polymer mesh when an external field is applied, resulting in a field-dependent stiffening response from the polymer mesh that superposes with the magnetic interparticle interactions.

Unravelling hagfish slime.

Hagfish slime is a unique predator defence material containing a network of long fibrous threads each ∼10 cm in length. Hagfish release the threads in a condensed coiled state known as skeins (∼100 µm), which must unravel within a fraction of a second to thwart a predator attack. Here we consider the hypothesis that viscous hydrodynamics can be responsible for this rapid unravelling, as opposed to chemical reaction kinetics alone. Our main conclusion is that, under reasonable physiological conditions, unravelling due to viscous drag can occur within a few hundred milliseconds, and is accelerated if the skein is pinned at a surface such as the mouth of a predator. We model a single skein unspooling as the fibre peels away due to viscous drag. We capture essential features by considering simplified cases of physiologically relevant flows and one-dimensional scenarios where the fibre is aligned with streamlines in either uniform or uniaxial extensional flow. The peeling resistance is modelled with a power-law dependence on peeling velocity. A dimensionless ratio of viscous drag to peeling resistance appears in the dynamical equations and determines the unraveling time scale. Our modelling approach is general and can be refined with future experimental measurements of peel strength for skein unravelling. It provides key insights into the unravelling process, offers potential answers to lingering questions about slime formation from threads and mucous vesicles, and will aid the growing interest in engineering similar bioinspired material systems.

Linear and nonlinear rheology and structural relaxation in dense glassy and jammed soft repulsive pNIPAM microgel suspensions.

We present an integrated experimental and quantitative theoretical study of the mechanics of self-crosslinked, slightly charged, repulsive pNIPAM microgel suspensions over a very wide range of concentrations (c) that span the fluid, glassy and putative "soft jammed" regimes. In the glassy regime we measure a linear elastic dynamic shear modulus over 3 decades which follows an apparent power law concentration dependence G' ∼ c5.64, a variation that appears distinct from prior studies of crosslinked ionic microgel suspensions. At very high concentrations there is a sharp crossover to a nearly linear growth of the modulus. To theoretically understand these observations, we formulate an approach to address all three regimes within a single conceptual Brownian dynamics framework. A minimalist single particle description is constructed that allows microgel size to vary with concentration due to steric de-swelling effects. Using a Hertzian repulsion interparticle potential and a suite of statistical mechanical theories, quantitative predictions under quiescent conditions of microgel collective structure, dynamic localization length, elastic modulus, and the structural relaxation time are made. Based on a constant inter-particle repulsion strength parameter which is determined by requiring the theory to reproduce the linear elastic shear modulus over the entire concentration regime, we demonstrate good agreement between theory and experiment. Testable predictions are then made. We also measured nonlinear rheological properties with a focus on the yield stress and strain. A theoretical analysis with no adjustable parameters predicts how the quiescent structural relaxation time changes under deformation, and how the yield stress and strain change as a function of concentration. Reasonable agreement with our observations is obtained. To the best of our knowledge, this is the first attempt to quantitatively understand structure, quiescent relaxation and shear elasticity, and nonlinear yielding of dense microgel suspensions using microscopic force based theoretical methods that include activated hopping processes. We expect our approach will be useful for other soft polymeric particle suspensions in the core-shell family.

Modulating Noncovalent Cross-links with Molecular Switches.

Spiropyran molecular switches, in conjunction with transition metal ions, are shown to operate as reversible polymer cross-linkers. Solutions containing a spiropyran-functionalized polymer and transition metal ions underwent reversible thermally triggered (light-triggered) transient network formation (disruption) driven by the association (dissociation) of metal-ligand cross-links. Heat triggers metal-ion-mediated cross-linking via thermal isomerization of spiropyran to its open, merocyanine form, and exposure to visible light triggers dissociation of polymer cross-links. Cross-linking is found to depend on both the valence of the ion as well as the molar ratio of spiropyran to metal salt. We envision this to be a starting point for the design of many types of reversible, stimuli-responsive polymers, utilizing the fact that spiropyrans have been shown to respond to a variety of stimuli including heat, light, pH, and mechanical force.

Acid-Triggered, Acid-Generating, and Self-Amplifying Degradable Polymers.

We describe the 3-iodopropyl acetal moiety as a simple cleavable unit that undergoes acid catalyzed hydrolysis to liberate HI (p Ka ∼ -10) and acrolein stoichiometrically. Integrating this unit into linear and network polymers gives a class of macromolecules that undergo a new mechanism of degradation with an acid amplified, sigmoidal rate. This trigger-responsive self-amplified degradable polymer undergoes accelerated rate of degradation and agent release.