In living systems adaptive regulation requires the presence of nonlinear responses in the underlying chemical networks. Positive feedbacks, for example, can lead to autocatalytic bursts that provide switches between two stable states or to oscillatory dynamics. The stereostructure stabilized by hydrogen bonds provides an enzyme its selectivity, rendering pH regulation essential for its functioning. For effective control, triggers by small concentration changes play roles where the strength of feedback is important. Here we show that the interaction of acid-base equilibria with simple reactions with pH-dependent rate can lead to the emergence of a positive feedback in hydroxide ion concentration during the hydrolysis of some Schiff bases in the physiological pH range. The underlying reaction network can also support bistability in an open system.

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.

We have developed an analytical method to quantitatively analyze differential scanning calorimetry (DSC) experimental data. This method provides accurate determination of thermal properties such as equilibrium melting temperature, latent heat, change of heat capacity which can be performed automatically without intervention of a DSC operator. DSC is one of the best techniques to determine the thermal properties of materials. However, the accuracy of the transition temperature and enthalpy change can be affected by artifacts caused by the instrumentation, sampling, and the DSC analysis methods which are based on graphical constructions. In the present study, an analytical function (DSC_N(T)) has been developed based on an assumed Arrhenius crystal size distribution together with instrumental and sample-related peak broadening. The DSC_N(T) function was successfully applied to fit the experimental data of a substantial number of calibration and new unknown samples, including samples with an obvious asymmetry of the melting peak, yielding the thermal characteristics such as melting and glass transition temperature, and enthalpy and heat capacity change. It also allows very accurate analysis of binary systems with two distinct but severely overlapping peaks and samples that include a cold crystallization before melting.

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.

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 Na₂CO₃) 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.

Safety and efficacy of coronary drug-eluting stents (DES) are often preclinically tested using healthy or minimally diseased swine. These generally show significant fibrotic neointima at follow-up, while in patients, incomplete healing is often observed. The aim of this study was to investigate neointima responses to DES in swine with significant coronary atherosclerosis. Adult familial hypercholesterolemic swine (n = 6) received a high fat diet to develop atherosclerosis. Serial OCT was performed before, directly after, and 28 days after DES implantation (n = 14 stents). Lumen, stent and plaque area, uncovered struts, neointima thickness and neointima type were analyzed for each frame and averaged per stent. Histology was performed to show differences in coronary atherosclerosis. A range of plaque size and severity was found, from healthy segments to lipid-rich plaques. Accordingly, neointima responses ranged from uncovered struts, to minimal neointima, to fibrotic neointima. Lower plaque burden resulted in a fibrotic neointima at follow-up, reminiscent of minimally diseased swine coronary models. In contrast, higher plaque burden resulted in minimal neointima and more uncovered struts at follow-up, similarly to patients’ responses. The presence of lipid-rich plaques resulted in more uncovered struts, which underscores the importance of advanced disease when performing safety and efficacy testing of DES.

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.

The crystal structure and phase behavior of bisamide gelators are investigated using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy, X-ray diffraction (XRD), and molecular modeling, aiming at a better understanding of bisamide gel systems. A homologous series of bisamide model compounds (nBAs) was prepared with the (CH₂)_nspacer between the two amide groups, where n varies from 5 to 10, and with two symmetric C17 alkyl tails. With increasing spacer length, the thermal properties show a clear odd-even effect, which was characterized using our newly developed analytical model DSC_N(T). Using XRD, all studied nBA compounds turn out to have a layer-like structure. The XRD patterns of the odd BA series are very similar but show marked differences compared to the XRD patterns of the even series, which in turn are very similar. The odd-membered 5BA molecules are nearly perpendicular to the stacked layers, as described by a pseudo-orthorhombic unit cell, whereas the even-membered 6BA molecules are tilted at an angle with respect to the layer normal, as described by a triclinic unit cell. In both the odd and even series, the inter-layer interaction is the van der Waals interaction. The 6BA hydrogen bonding scheme is very similar to that of Nylon 6,10 α, unlike the 5BA H bonding scheme. The packing of the C17 alkyl tails in the 5BA layers is similar to polyethylene, and unlike 6BA. The slightly higher crystalline density of 6BA (1.038 g cm^-3) as compared to 5BA (1.018 g cm^-3) explains the higher melting point, higher enthalpy of fusion, and the observed shift of N-H stretch bands to higher wave numbers. The structural differences observed between the odd and even BA series reflect the different structure-directing effect of parallel versus antiparallel amide hydrogen bonding motifs. These differences underlie the observed odd-even effect in the thermal properties of nBA compounds.

Transient materials that function out-of-equilibrium have been of great interest due to their unique properties that are rarely observed in thermodynamically stable occasions. However, the current advances are still limited to supramolecular objects, and the applications using this transient nature remain largely unexplored. Herein we report on chemical fuel powered transient polymer hydrogels for controlled formation and free release of pharmaceutical crystals. The transient polymer hydrogels with highly tunable stiffness and lifetime were created by chemical fuel powered crosslinking, which can be well regenerated without obvious deteriorations by simply refueling. On the basis of these properties, especially the transient nature, these hydrogels can serve as novel reusable platforms to control the pharmaceutical crystallization, more importantly, freely release the obtained crystals, which is inaccessible by conventional static gels. This work is expected to serve as an example to accelerate the development of more advanced out-of-equilibrium materials and exploitations of their high-tech applications.

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.

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.

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.

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.

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.

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.

This work describes a facile approach allowing Dibenzoyl-L-Cystine (DBC) based hydrogel controlled deposition and controlled detachments over a conducting support. The method itself is an electrochemically assisted approach, where the water oxidation at the electrode surface results in a local pH drop inducing DBC gelation and hydrogel formation. We have comprehensively described the possibility of the hydrogel shaping by alternating the anodic deposition potential, DBC concentration and finally the working electrode geometry. The latter includes macro-electrodes in a form of platinum discs having diameter equal to 200 and 500 μm; hexagonal arrays of circular platinum microelectrodes with a diameter of a single electrode equal to 5 or 10 μm and custom made platinum microelectrodes, having the shape of circles, triangles and squares, that are used to shape the microgels. Over the course of our work we were able to define the conditions to form a number of different hydrogel shapes such as: (i) flat and planar deposits; (ii) hemispherical deposits with an oxygen bubble pocket; (iii) spongy hydrogel structures or (iv) hemispherical micro-cups build from radially oriented DBC fibres directionally growing from the support. Furthermore, we were also able to remotely form and then detach the hydrogel deposit in the initial formulation solution using only an electrochemical trigger. Our work represents a solid proof of concept and opens a number of new avenues for the electrochemically assisted soft matter fabrication down to micrometre scale.

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 H₂O₂ 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.

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.

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.

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.