Naked-Eye Thiol Analyte Detection via Self-Propagating, Amplified Reaction Cycle.

We present an approach for detecting thiol analytes through a self-propagating amplification cycle that triggers the macroscopic degradation of a hydrogel scaffold. The amplification system consists of an allylic phosphonium salt that upon reaction with the thiol analyte releases a phosphine, which reduces a disulfide to form two thiols, closing the cycle and ultimately resulting in exponential amplification of the thiol input. When integrated in a disulfide cross-linked hydrogel, the amplification process leads to physical degradation of the hydrogel in response to thiol analytes. We developed a numerical model to predict the behavior of the amplification cycle in response to varying concentrations of thiol triggers and validated it with experimental data. Using this system, we were able to detect multiple thiol analytes, including a small molecule probe, glutathione, DNA, and a protein, at concentrations ranging from 132 to 0.132 µM. In addition, we discovered that the self-propagating amplification cycle could be initiated by force-generated molecular scission, enabling damage-triggered hydrogel destruction.

Dynamic Growth of Macroscopically Structured Supramolecular Hydrogels through Orchestrated Reaction-Diffusion.

Living organisms are capable of dynamically changing their structures for adaptive functions through sophisticated reaction-diffusion processes. Here we show how active supramolecular hydrogels with programmable lifetimes and macroscopic structures can be created by relying on a simple reaction-diffusion strategy. Two hydrogel precursors (poly(acrylic acid) PAA/CaCl2 and Na2 CO3 ) diffuse from different locations and generate amorphous calcium carbonate (ACC) nanoparticles at the diffusional fronts, leading to the formation of hydrogel structures driven by electrostatic interactions between PAA and ACC nanoparticles. Interestingly, the formed hydrogels are capable of autonomously disintegrating over time because of a delayed influx of electrostatic-interaction inhibitors (NaCl). The hydrogel growth process is well explained by a reaction-diffusion model which offers a theoretical means to program the dynamic growth of structured hydrogels. Furthermore, we demonstrate a conceptual access to dynamic information storage in soft materials using the developed reaction-diffusion strategy. This work may serve as a starting point for the development of life-like materials with adaptive structures and functionalities.

Design Rules for Binary Bisamide Gelators: toward Gels with Tailor-Made Structures and Properties.

This study intends to develop design rules for binary mixture of gelators that govern their assembly behavior and subsequently explore the impact of their supramolecular assembly patterns on the gels' rheological properties. To achieve these goals, nBA gelators with odd and even parities [n-methylene spacers between the amide groups (n = 5-10) and 17 carbons at each end] were blended at different ratios. Such bisamides with simple structures were selected to study because their different spacer lengths offer the possibility to have matching or non-matching hydrogen bonds. The results show that the assembly behavior of binary mixtures of bisamide gelators is the same in the solid and gel states. Binary mixtures of gelators, which only differ two methylene moieties in the spacer length, form compounds and co-assemble into fibers and sheets observed for (5BA)1(7BA)1 and (6BA)1(8BA)1 mixtures, respectively. Binary gelator mixtures of the same parity and a larger spacer length difference still lead to mixing for the odd parity couple (5BA)1(9BA)1), but to partial phase separation for the even parity mixture (6BA)1(10BA)1. Binary mixtures of gelators of different parities gave complete phase separation in the solid state, and self-sorted gels consisting of discrete fibers and sheets in the gels of (5BA)3(6BA)1 and (5BA)3(10BA)1. The even-even binary gels (20 wt %) consisting of co-assembled sheets show higher G' than odd-odd binary gels (20 wt %) consisting of co-assembled fibers. In general, the self-sorting of odd and even molecules into the separate primary structures results in a dramatic decrease of G' compared to the co-assembled gels (20 wt %), except for (5BA)1(9BA)1 gel (20 wt %). It might be due to larger woven spheres in (5BA)1(9BA)1 gel (20 wt %), which probably have a less entangled gel network.

Supramolecular Arrangement and Rheological Properties of Bisamide Gels.

We report a systematic study of the gelation behavior of nBA gelators in xylene, with odd and even n-methylene spacers between the amide groups (n = 5-10) and 17 carbons at each end. The melting temperatures (Tm0) of nBA gels are obtained from fitting our DSCN(T) model to the experimental DSC data. The found Tm0 of nBA gels is about 35 °C lower than Tm0 of the pure nBA gelators. This is reasonably well explained by a simple model combining theories of Flory-Huggins and Gibbs free energy of melting (FHM model). We attribute this depression to an increase in entropy upon melting of the gel due to mixing with the solvent. The odd-even alternation in Tm0 of nBA gels, which was also found for the nBA gelators, indicates that the solid structures inside the gels are somewhat similar. This was studied using XRD: similar 00l reflections were found in the XRD patterns of all nBA gels and their nBA gelators. For even nBA gels, the same reflections in the 19-25° (2θ) region confirm that the sheetlike supramolecular structure of the gels is analogous to the lamellar structure of the solid gelators. For odd nBA gels, a slight difference in the reflections around 20-25° (2θ) implies a somewhat different side-by-side packing of odd nBA gels compared to the solid state. This variation is found for all the odd gels, and indeed, they show distinctly different morphologies compared to the even nBA gels. The possible effect of this on the rheological properties is discussed using some inspiration from the Halpin-Tsai model for composites where nBA gels are considered to be analogous to composite materials. The change of the storage modulus (G') with the shape factor of woven fibers and sheets in nBA gels (20 wt %) indicates that a rheological odd-even effect might indeed be present.

How the Choice of Force-Field Affects the Stability and Self-Assembly Process of Supramolecular CTA Fibers.

In recent years, computational methods have become an essential element of studies focusing on the self-assembly process. Although they provide unique insights, they face challenges, from which two are the most often mentioned in the literature: the temporal and spatial scale of the self-assembly. A less often mentioned issue, but not less important, is the choice of the force-field. The repetitive nature of the supramolecular structure results in many similar interactions. Consequently, even a small deviation in these interactions can lead to significant energy differences in the whole structure. However, studies comparing different force-fields for self-assembling systems are scarce. In this article, we compare molecular dynamics simulations for trifold hydrogen-bonded fibers performed with different force-fields, namely GROMOS, CHARMM General Force Field (CGenFF), CHARMM Drude, General Amber Force-Field (GAFF), Martini, and polarized Martini. Briefly, we tested the force-fields by simulating: (i) spontaneous self-assembly (none form a fiber within 500 ns), (ii) stability of the fiber (observed for CHARMM Drude, GAFF, MartiniP), (iii) dimerization (observed for GROMOS, GAFF, and MartiniP), and (iv) oligomerization (observed for CHARMM Drude and MartiniP). This system shows that knowledge of the force-field behavior regarding interactions in oligomer and larger self-assembled structures is crucial for designing efficient simulation protocols for self-assembling systems.

An Implantable Artificial Atherosclerotic Plaque as a Novel Approach for Drug Transport Studies on Drug-Eluting Stents.

Atherosclerotic arteries are commonly treated using drug-eluting stents (DES). However, it remains unclear whether and how the properties of atherosclerotic plaque affect drug transport in the arterial wall. A limitation of the currently used atherosclerotic animal models to study arterial drug distribution is the unpredictability of plaque size, composition, and location. In the present study, the aim is to create an artificial atherosclerotic plaque-of reproducible and controllable complexity and implantable at specific locations-to enable systematic studies on transport phenomena of drugs in stented atherosclerosis-mimicking arteries. For this purpose, mixtures of relevant lipids at concentrations mimicking atherosclerotic plaque are incorporated in gelatin/alginate hydrogels. Lipid-free (control) and lipid-rich hydrogels (artificial plaque) are created, mounted on DES and successfully implanted in porcine coronary arteries ex-vivo. Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) is used to measure local drug distribution in the arterial wall behind the prepared hydrogels, showing that the lipid-rich hydrogel significantly hampers drug transport as compared to the lipid-free hydrogel. This observation confirms the importance of studying drug transport phenomena in the presence of lipids and of having an experimental model in which lipids and other plaque constituents can be precisely controlled and systematically studied.

Gelation Kinetics-Structure Analysis of pH-triggered Low Molecular Weight Hydrogelators.

Properties such as shear modulus, gelation time, structure of supramolecular hydrogels are strongly dependent on self-assembly, gelation triggering mechanism and processes used to form the gel. In our work we extend reported rheology analysis methodologies to pH-triggered supramolecular gels to understand structural insight using a model system based on N-N' Dibenzoyl-L-Cystine pH-triggered hydrogelator and Glucono-δ-Lactone as the trigger. We observed that Avrami growth model when applied to time-sweep rheological data of gels formed at lower trigger concentrations provide estimates of fractal dimension which agree well compared with visualization of the microstructure as seen via Confocal Laser Scanning Microscopy, for a range of gelator concentrations.

Tuneable Control of Organocatalytic Activity through Host-Guest Chemistry.

Dynamic regulation of chemical reactivity is important in many complex chemical reaction networks, such as cascade reactions and signal transduction processes. Signal responsive catalysts could play a crucial role in regulating these reaction pathways. Recently, supramolecular encapsulation was reported to regulate the activities of artificial catalysts. We present a host-guest chemistry strategy to modulate the activity of commercially available synthetic organocatalysts. The molecular container cucurbit[7]uril was successfully applied to change the activity of four different organocatalysts and one initiator, enabling up- or down-regulation of the reaction rates of four different classes of chemical reactions. In most cases CB[7] encapsulation results in catalyst inhibition, however in one case catalyst activation by binding to CB[7] was observed. The mechanism behind this unexpected behavior was explored by NMR binding studies and pKa measurements. The catalytic activity can be instantaneously switched during operation, by addition of either supramolecular host or competitive binding molecules, and the reaction rate can be predicted with a kinetic model. Overall, this signal responsive system proves a promising tool to control catalytic activity.

Transient supramolecular hydrogels formed by catalytic control over molecular self-assembly.

The present work shows how transient supramolecular hydrogels can be formed by catalytically controlled molecular self-assembly. Catalysis formation of molecular gelators leads the self-assembly along a kinetically favored pathway, resulting in transient hydrogels. This work demonstrates an effective approach towards pathway-dependent supramolecular materials.

Interfacial Microcompartmentalization by Kinetic Control of Selective Interfacial Accumulation.

Reported here is a 2D, interfacial microcompartmentalization strategy governed by 3D phase separation. In aqueous polyethylene glycol (PEG) solutions doped with biotinylated polymers, the polymers spontaneously accumulate in the interfacial layer between the oil-surfactant-water interface and the adjacent polymer phase. In aqueous two-phase systems, these polymers first accumulated in the interfacial layer separating two polymer solutions and then selectively migrated to the oil-PEG interfacial layer. By using polymers with varying photopolymerizable groups and crosslinking rates, kinetic control and capture of spatial organisation in a variety of compartmentalized macroscopic structures, without the need of creating barrier layers, was achieved. This selective interfacial accumulation provides an extension of 3D phase separation towards synthetic compartmentalization, and is also relevant for understanding intracellular organisation.

Dual-Functionalized Crescent Microgels for Selectively Capturing and Killing Cancer Cells.

In cancer therapy, the selective targeting of cancer cells while avoiding side effects to normal cells is still full of challenges. Here, we developed dual-functionalized crescent microgels, which selectively captured and killed lung cancer cells in situ without killing other cells. Crescent microgels with the inner surface of the cavity functionalized with antibody and containing glucose oxidase (GOX) in the gel matrix have been produced in a microfluidic device. These microgels presented high affinity and good selectivity to lung cancer cells and retained them inside the cavities for extended periods of time. Exposing the crescent hydrogels to physiological concentrations of glucose leads to the production of a locally high concentration of H2 O2 inside the microgels' cavities, due to the catalytic action by GOX inside the gel matrix, which selectively killed 90 % cancer cells entrapped in the microgel cavities without killing the cells outside. Our strategy to create synergy between different functions by incorporating them in a single microgel presents a novel approach to therapeutic systems, with potentially broad applications in smart materials, bioengineering and biomedical fields.

Imaging-assisted hydrogel formation for single cell isolation.

We report a flexible single-cell isolation method by imaging-assisted hydrogel formation. Our approach consists of imaging-aided selective capture of cells of interest by encasing them into a polymeric hydrogel, followed by removal of unwanted cells and subsequent release of isolated cells by enzymatic hydrogel degradation, thus offering an opportunity for further analysis or cultivation of selected cells. We achieved high sorting efficiency and observed excellent viability rates (>98%) for NIH/3T3 fibroblasts and A549 carcinoma cells isolated using this procedure. The method presented here offers a mask-free, cost-efficient and easy-to-use alternative to many currently existing surface-based cell-sorting techniques, and has the potential to impact the field of cell culturing and isolation, e.g. single cell genomics and proteomics, investigation of cellular heterogeneity and isolation of best performing mutants for developing new cell lines.

Transient Supramolecular Hydrogels Formed by Aging-Induced Seeded Self-Assembly of Molecular Hydrogelators.

Here, transient supramolecular hydrogels that are formed through simple aging-induced seeded self-assembly of molecular gelators are reported. In the involved molecular self-assembly system, multicomponent gelators are formed from a mixture of precursor molecules and, typically, can spontaneously self-assemble into thermodynamically more stable hydrogels through a multilevel self-sorting process. In the present work, it is surprisingly found that one of the precursor molecules is capable of self-assembling into nano-sized aggregates upon a gentle aging treatment. Importantly, these tiny aggregates can serve as seeds to force the self-assembly of gelators along a kinetically controlled pathway, leading to transient hydrogels that eventually spontaneously convert into thermodynamically more stable hydrogels over time. Such an aging-induced seeded self-assembly process is not only a new route toward synthetic out-of-equilibrium supramolecular systems, but also suggests the necessity of reporting the age of self-assembling building block solutions in other self-assembly systems.

Spatial Manipulation and Integration of Supramolecular Filaments on Hydrogel Substrates towards Advanced Soft Devices.

Supramolecular assemblies are promising building blocks for the fabrication of functional soft devices for high-tech applications. However, there is a lack of effective methods for large-scale manipulation and integration of nano-sized supramolecular structures on soft substrate. Now, functional soft devices composed of micellar filaments and hydrogels can be created through a versatile approach involving guided dewetting, transfer-printing, and laser-assisted patterning. Such an approach enables unprecedented control over the location and alignment of the micellar filaments on hydrogel substrates. As examples, freely suspended micellar fishnets immobilized on hydrogels are formed, showing the capability of trapping and releasing micro-objects and the piconewton force sensitivity. By incorporating responsive moieties into hydrogels, shape-morphing actuators with micelle-controlled rolling directionality are constructed.

Biomimetic Strain-Stiffening Self-Assembled Hydrogels.

Supramolecular structures with strain-stiffening properties are ubiquitous in nature but remain rare in the lab. Herein, we report on strain-stiffening supramolecular hydrogels that are entirely produced through the self-assembly of synthetic molecular gelators. The involved gelators self-assemble into semi-flexible fibers, which thereby crosslink into hydrogels. Interestingly, these hydrogels are capable of stiffening in response to applied stress, resembling biological intermediate filaments system. Furthermore, strain-stiffening hydrogel networks embedded with liposomes are constructed through orthogonal self-assembly of gelators and phospholipids, mimicking biological tissues in both architecture and mechanical properties. This work furthers the development of biomimetic soft materials with mechanical responsiveness and presents potentially enticing applications in diverse fields, such as tissue engineering, artificial life, and strain sensors.

Locally pH controlled and directed growth of supramolecular gel microshapes using electrocatalytic nanoparticles.

Controlled localization of platinum nanoparticles (Pt NPs) at a solid support assisted by a polarized liquid-liquid interface is reported. Electrocatalytic water oxidation resulted in local pH modulation followed by the directed self-assembly of a dibenzoyl-l-cystine hydrogelator forming a structured hydrogel retaining the shape of the Pt NP deposit.

Control over the formation of supramolecular material objects using reaction-diffusion.

Controlled diffusion, reaction and assembly of hydrogelator precursors can be used to create soft hydrogel objects of defined shape and size. In this study we show that controlling local reaction kinetics by means of pH, diffusion length and the concentrations of reactants allows control over the dimensions of formed supramolecular structures. By correlating a reaction diffusion model to experimental results, we show that the influence of all these control parameters can be unified using the Damköhler number, thus providing an easy-to-use relation between experimental parameters and structure dimensions. Finally, our study suggests that control over concentration gradients and chemical reactivity in combination with supramolecular chemistry is a promising platform for the design of soft matter objects of defined sizes, a concept that has received little attention up until now.

Tuning gelled lyotropic liquid crystals (LLCs) - probing the influence of different low molecular weight gelators on the phase diagram of the system H2O/NaCl-Genapol LA070.

Gelled lyotropic liquid crystals (LLCs) are highly tunable multi-component materials. By studying a selection of low molecular weight gelators (LMWGs), we find gelators that form self-assembled gels in LLCs without influencing their phase boundaries. We studied the system H2O/NaCl-Genapol LA070 in the presence of (a) the organogelators 12-hydroxyoctadecanoic acid (12-HOA) and 1,3:2,4-dibenzylidene-d-sorbitol (DBS) and (b) the hydrogelators N,N'-dibenzoyl-l-cystine (DBC) and a tris-amido-cyclohexane derivative (HG1). Visual phase studies and oscillation shear frequency sweeps confirmed that 12-HOA acts as co-surfactant (stabilizing the lamellar Lα phase and destabilizing the hexagonal H1 phase), thus preventing gelation. Conversely, DBS was a potent gelator for LLCs, with the phase boundaries un-influenced by the presence of DBS; gelled lamellar Lα, and softly-gelled hexagonal H1 phases are formed. For the hydrogelator DBC, the LLC phase boundaries were only slightly altered, but no gelled LLCs were formed. For the hydrogelator HG1, however, the phase boundaries were unaffected while gelled lamellar Lα and softly-gelled hexagonal H1 phases were formed. Temperature-dependent rheology measurements demonstrated that by changing the DBS or the HG1 concentration, the sol-gel transition temperature of the gelled lamellar Lα phase can be adjusted such that (a) Tsol-gel is below the Lα-isotropic phase transition (DBS, HG1 mass fraction η = 0.0075) and (b) Tsol-gel is above the gelled Lα-isotropic phase transition (DBS, HG1 η = 0.015). This opens the possibility of temporal materials control by addressing phase transitions in different orders. As this system contains oil and water, both the organogelator DBS and the hydrogelator HG1 can gel these LLCs, but this clearly does not apply to all organogelators/hydrogelators. The study indicates that careful optimization of LMWGs is required to avoid interaction with the surfactant layer and to optimize the Tsol-gel value, which is important for the application of LMWGs in gelled LLCs.

Silk Fluorescence Collimator for Ultrasensitive Humidity Sensing and Light-Harvesting in Semitransparent Dye-Sensitized Solar Cells.

This work examines the self-collimation effect of silk materials on fluorescence emission/detection. A macroscopic regulation strategy, coupled with meso-reconstruction and meso-functionalization, is adopted to amplify the fluorescence emission of organic fluorescent dyes (i.e., Rhodamine 6G (R6G)) using silk photonic crystal (PC) films. The fluorescence emission can be linearly enhanced or inhibited by a PC as a result of the photonic bandgap coupling with the excitation light and/or emission light. Depending on the design of the silk fluorescence collimator, the emission can reach 49.37 times higher than the control. The silk fluorescence collimator can be applied to achieve significant benefits: for instance, as a humidity sensor, it provides good reproducibility and a sensitivity of 28.50 a.u./% relative humidity, which is 80.78 times higher than the sensitivity of the control, and as a novel curtain, it raises the energy conversion efficiency of the semitransparent dye-sensitized solar cells (DSSCs) by 16%.