ABSTRACT
Low molecular weight gels are formed via the self-assembly of small molecules into fibrous structures. In the case of hydrogels, these networks entrap large volumes of water, yielding soft materials. Such gels tend to have weak mechanical properties and a high permeability for cells, making them particularly appealing for regenerative medicine applications. Ureido-pyrimidinone (UPy) supramolecular gelators are self-assembling systems that have demonstrated excellent capabilities as biomaterials. Here, we combine UPy-gelators with another low molecular weight gelator, the functionalized dipeptide 2NapFF. We have successfully characterized these multicomponent systems on a molecular and bulk scale. The addition of 2NapFF to a crosslinked UPy hydrogel significantly increased hydrogel stiffness from 30 Pa to 1300 Pa. Small-angle X-ray scattering was used to probe the underlying structures of the systems and showed that the mixed UPy and 2NapFF systems resemble the scattering data produced by the pristine UPy systems. However, when a bifunctional UPy-crosslinker was added, the scattering was close to that of the 2NapFF only samples. The results suggest that the crosslinker significantly influences the assembly of the low molecular weight gelators. Finally, we analysed the biocompatibility of the systems using fibroblast cells and found that the cells tended to spread more effectively when the crosslinking species was incorporated. Our results emphasise the need for thorough characterisation at multiple length scales to finely control material properties, which is particularly important for developing novel biomaterials.
ABSTRACT
A long-standing challenge is how to formulate proteins and vaccines to retain function during storage and transport and to remove the burdens of cold-chain management. Any solution must be practical to use, with the protein being released or applied using clinically relevant triggers. Advanced biologic therapies are distributed cold, using substantial energy, limiting equitable distribution in low-resource countries and placing responsibility on the user for correct storage and handling. Cold-chain management is the best solution at present for protein transport but requires substantial infrastructure and energy. For example, in research laboratories, a single freezer at -80 °C consumes as much energy per day as a small household1. Of biological (protein or cell) therapies and all vaccines, 75% require cold-chain management; the cost of cold-chain management in clinical trials has increased by about 20% since 2015, reflecting this complexity. Bespoke formulations and excipients are now required, with trehalose2, sucrose or polymers3 widely used, which stabilize proteins by replacing surface water molecules and thereby make denaturation thermodynamically less likely; this has enabled both freeze-dried proteins and frozen proteins. For example, the human papilloma virus vaccine requires aluminium salt adjuvants to function, but these render it unstable against freeze-thaw4, leading to a very complex and expensive supply chain. Other ideas involve ensilication5 and chemical modification of proteins6. In short, protein stabilization is a challenge with no universal solution7,8. Here we designed a stiff hydrogel that stabilizes proteins against thermal denaturation even at 50 °C, and that can, unlike present technologies, deliver pure, excipient-free protein by mechanically releasing it from a syringe. Macromolecules can be loaded at up to 10 wt% without affecting the mechanism of release. This unique stabilization and excipient-free release synergy offers a practical, scalable and versatile solution to enable the low-cost, cold-chain-free and equitable delivery of therapies worldwide.
Subject(s)
Drug Storage , Hydrogels , Protein Denaturation , Protein Stability , Proteins , Syringes , Humans , Excipients , Freeze Drying , Hydrogels/chemistry , Proteins/administration & dosage , Proteins/chemistry , Proteins/economics , Trehalose , Freezing , Refrigeration , Papillomavirus Vaccines/chemistry , Drug Storage/economics , Drug Storage/methodsABSTRACT
We present the development of time-programmable functional soft materials. The materials undergo reversible phase transitions between lyotropic phases with different topologies and symmetries, which in turn have very different physical properties: viscosity, diffusion, and optical transparency. Here, this behavior is achieved by combining pH-responsive lyotropic phases made from the lipid monoolein doped with 10% oleic acid, with chemical reactions that have well-defined controllable kinetics: autocatalytic urea-urease and methyl formate hydrolysis, which increase and decrease pH, respectively. In this case, we use small-angle X-ray scattering (SAXS) and optical imaging to show temporally controlled transitions between the cloudy hexagonal phase, which is a two-dimensional (2D) array of cylindrical inverse micelles, and the transparent, highly viscous three-dimensional (3D) bicontinuous cubic phases. By combining these into a single reaction mixture where the pH increases and then decreases again, we can induce a sequential transformation cycle from hexagonal to cubic and back to hexagonal over several hours. The sample therefore changes from cloudy to transparent and back again as a proof-of-concept demonstration for a wider range of soft materials with time-programmable changes in physical properties.
ABSTRACT
Achieving precise control over gelator alignment and morphology is crucial for crafting tailored materials and supramolecular structures with distinct properties. We successfully aligned the self-assembled micelles formed by a functionalized dipeptide 2NapFF into long 1-D "gel noodles" by cross-linking with divalent metal chlorides. We identify the most effective cross-linker for alignment, enhancing mechanical stability, and imparting functional properties. Our study shows that Group 2 metal ions are particularly suited for creating mechanically robust yet flexible gel noodles because of their ionic and nondirectional bonding with carboxylate groups. In contrast, the covalent nature and high directional bonds of d-block metal ions with carboxylates tend to disrupt the self-assembly of 2NapFF. Furthermore, the 2NapFF-Cu noodles demonstrated selective antibacterial activity, indicating that the potent antibacterial property of the copper(II) ion is preserved within the cross-linked system. By merging insights into molecular alignment, gel extrusion processing, and integrating specific functionalities, we illustrate how the versatility of dipeptide-based gels can be utilized in creating next-generation soft materials.
Subject(s)
Anti-Bacterial Agents , Copper , Gels , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Copper/chemistry , Copper/pharmacology , Gels/chemistry , Cross-Linking Reagents/chemistry , Dipeptides/chemistry , Dipeptides/pharmacology , Micelles , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Escherichia coli/drug effectsABSTRACT
Understanding the key parameters that control the self-assembly process is critical to predict self-assembly modes in multi-component systems, which will lead to the development of nanofibrous materials with tuneable properties. Enantiomeric amino acid-based low-molecular-weight gelators (LMWGs) were mixed in polar (polar protic) and aromatic apolar (aromatic) solvents and compared to their individual counterparts to probe the effect of solvent polarity on the self-assembly process. Scanning electron microscopy (SEM) reveals that xerogels of individual components display hollow needles in polar protic solvents, while chiral coils are observed in aromatic solvents. In contrast, the multi-component gel displays hollow needle morphologies in both solvents, indicating similar morphologies in polar protic solvents but an entirely different nanostructure for the individual gel networks in aromatic solvents. PXRD experiments performed on the dried gels showed that the nature of the solvents plays a vital role in the co-assembly process of multi-component gels. The self-assembly modes and the gel state structure of the gels are analysed by wide-angle X-ray diffraction (WAXS) and small-angle neutron diffraction (SANS), which reveals that the mixed gel undergoes different co-assembly modes depending on the nature of the solvent systems. This study shows that different co-assembly modes can be achieved for structurally similar components by varying the solvent polarity, demonstrating the importance of solvent choice in the self-assembly process of multi-component gels.
ABSTRACT
Peptide-based biopolymers have gained increasing attention due to their versatile applications. A naphthalene dipeptide (2NapFF) can form chirality-dependent tubular micelles, leading to supramolecular gels. The precise molecular arrangement within these micelles and the mechanism governing gelation have remained enigmatic. We determined, at near-atomic resolution, cryoelectron microscopy structures of the 2NapFF micelles LL-tube and LD-tube, generated by the stereoisomers (l,l)-2NapFF and (l,d)-2NapFF, respectively. The structures reveal that the fundamental packing of dipeptides is driven by the systematic π-π stacking of aromatic rings and that same-charge repulsion between the carbonyl groups is responsible for the stiffness of both tubes. The structural analysis elucidates how a single residue's altered chirality gives rise to markedly distinct tubular structures and sheds light on the mechanisms underlying the pH-dependent gelation of LL- and LD-tubes. The understanding of dipeptide packing and gelation mechanisms provides insights for the rational design of 2NapFF derivatives, enabling the modulation of micellar dimensions.
ABSTRACT
Light can be used to design stimuli-responsive systems. We induce transient changes in the assembly of a low molecular weight gelator solution using a merocyanine photoacid. Through our approach, reversible viscosity changes can be achieved via irradiation, delivering systems where flow can be controlled non-invasively on demand.
ABSTRACT
Correction for 'Multi-layer 3D printed dipeptide-based low molecular weight gels' by Max J. S. Hill et al., Soft Matter, 2022, 18, 5960-5965, https://doi.org/10.1039/D2SM00663D.
ABSTRACT
We outline the effect of imposing spatial constraints during gelation on hydrogels formed by dipeptide-based low molecular weight gelators. The gels were formed via either a solvent switch or a change in pH and formed in different sized vessels to produce gels of different thickness while maintaining the same volume. The different methods of gelation led to gels with different underlying microstructure. Confocal microscopy was used to visualize the resulting microstructures, while the corresponding mechanical properties were probed via cavitation rheology. We show that solvent-switch-triggered gels are sensitive to imposed spatial constraints, in both altered microstructure and mechanical properties, while their pH-triggered equivalents are not. These results are significant because it is often necessary to form gels of different thicknesses for different analytical techniques. Also, gels of different thicknesses are utilized between various applications of these materials. Our data show that it is important to consider the spatial constraints imposed in these situations.
Subject(s)
Dipeptides , Hydrogels , Molecular Weight , Microscopy, Confocal , SolventsABSTRACT
Preparation of multicomponent systems provides a method for changing the properties of low molecular weight gelator (LMWG)-based systems. Here we have prepared a variety of multicomponent systems where both components are N-functionalised dipeptide-based LMWGs that may either co-assemble or self-sort when mixed. We exemplify how varying the concentration ratio of the two components can be used to tune the properties of the multicomponent systems pre-gelation, during gelation and in the gel state using viscosity and rheology measurements, circular dichroism, NMR and small angle neutron scattering. We also investigate the effect of changing the chirality of a single component on the properties of these systems. While predicting the outcome of multicomponent assembly is a challenge, the preparation of a variety of systems allows us to probe the factors affecting their design. This work provides insights into how the properties of multicomponent systems composed of two gelators with the same basic structural design can be tuned by varying the chirality and the concentration ratio of the two components and considering the behaviour of the two components when alone.
ABSTRACT
Self-sorting in functionalized dipeptide systems can be driven by the chirality of a single amino acid, both at a high pH in the micellar state and at a low pH in the gel state. The structures formed are affected to some degree by the relative concentrations of each component showing the complexity of such an approach. The structures underpinning the gel network are predefined by the micellar structures at a high pH. Here, we describe the systems prepared from two dipeptide-based gelators that differ only by the chirality of one of the amino acids. We provide firm evidence for self-sorting in the micellar and gel phases using small-angle neutron scattering and cryo-transmission electron microscopy (cryo-TEM), showing that complete self-sorting occurs across a range of relative concentrations.
Subject(s)
Dipeptides , Micelles , Dipeptides/chemistry , Microscopy, Electron, Transmission , Cryoelectron Microscopy , Amino AcidsABSTRACT
Gels formed using a perylene bisimide (PBI) as a low molecular weight gelator can show the photothermal effect. Formation of the PBI radical anion results in new absorption bands forming, meaning that subsequent irradiation with a wavelength of light overlapping with the new absorption band leads to heating of the gel. This approach can be used to heat the gel, as well as the surrounding milieu. We show how we can use electrochemical methods as well as multicomponent systems to form the radical anion without the need for UV light, and how we can use the photothermal effect to induce phase transitions in the solutions above the gels by exploiting photothermal behavior.
ABSTRACT
Multicomponent supramolecular systems can be used to achieve different properties and new behaviors compared to their corresponding single component systems. Here, a two-component system is used, showing that a non-gelling component modifies the assembly of the gelling component, allowing access to co-assembled structures that cannot be formed from the gelling component alone. The systems are characterized across multiple length scales, from the molecular level by NMR and CD spectroscopy to the microstructure level by SANS and finally to the material level using nanoindentation and rheology. By exploiting the enhanced mechanical properties achieved through addition of the second component, multicomponent noodles are formed with superior mechanical properties to those formed by the single-component system. Furthermore, the non-gelling component can be triggered to crystallize within the multicomponent noodles, allowing the preparation of new types of hierarchical composite noodles.
ABSTRACT
We use a pH-driven annealing process to convert between co-assembled and self-sorted networks in multicomponent gels. The initially formed gels at low pH are co-assembled, with the two components coexisting within the same self-assembled structures. We use an enzymatic approach to increase the pH, resulting in a gel-to-sol transition, followed by a hydrolysis to lower the pH once again. As the pH decreases, a self-sorted network is formed by a two-stage gelation process determined by the pKa of each component. This approach can be expanded to layered systems to generate many varied systems by changing composition and rates of pH change, adapting their microstructure and so allowing access to a far greater range of morphologies and complexity than can be achieved in single component systems.
Subject(s)
Gels , Gels/chemistry , Rheology , Hydrogen-Ion ConcentrationABSTRACT
Hierarchical self-assembly is an effective means of preparing useful materials. However, control over assembly across length scales is a difficult challenge, often confounded by the perceived need to redesign the molecular building blocks when new material properties are needed. Here, we show that we can treat a simple dipeptide building block as a polyelectrolyte and use polymer physics approaches to explain the self-assembly over a wide concentration range. This allows us to determine how entangled the system is and therefore how it might be best processed, enabling us to prepare interesting analogues to threads and webs, as well as films that lose order on heating and "noodles" which change dimensions on heating, showing that we can transfer micellar-level changes to bulk properties all from a single building block.
ABSTRACT
Correction for 'Fmoc-diphenylalanine hydrogels: understanding the variability in reported mechanical properties' by Jaclyn Raeburn et al., Soft Matter, 2012, 8, 1168-1174, https://doi.org/10.1039/C1SM06929B.
ABSTRACT
Controlling the formation and directional growth of hydrogels is a challenge. In this paper, a new methodology to program the gel formation both over space and time is proposed, using the diffusion and subsequent hydrolysis of 1,1'-carbonyldiimidazole from an immiscible organic solution to the aqueous gel media.
Subject(s)
Hydrogels , Diffusion , Catalysis , RheologyABSTRACT
Using small-angle neutron scattering to investigate the aggregation of self-assembling molecules is well established. Some of these molecules are electrochemically useful, for example, in electrochromic devices. Electrochemistry can also be used in some cases to induce aggregation. Here, we describe an approach whereby electrochemistry can be directly carried out on a sample in the neutron beam, allowing us to monitor changes directly in situ. We exemplify with two examples but highlight that there are many other potential opportunities.
ABSTRACT
We describe the direct 3D printing of dipeptide hydrogels, forming layers from gels prepared from different dipeptides. The dipeptides self-assemble into fibres that lead to very different microstructures letting us differentiate between the gels. We show how the mechanical properties of the overall 3D printed structures are affected by the composition of each of the layers, allowing us to build up structures with different microstructure and stiffness. We also discuss the interface between layers formed from different gelators, showing that the gels remain independent from neighbouring printed material, even when prepared in very close proximity.