Multi-hierarchical self-assembly of a collagen mimetic peptide from triple helix to nanofibre and hydrogel.
TL;DR: A peptide is described that replicates the self-assembly of collagen through each of the same steps as those of natural collagen, propagated into nanofibres with characteristic triple helical packing and lengths with a lower bound of several hundred nanometres.
Abstract: Replicating the multi-hierarchical self-assembly of collagen has long-attracted scientists, from both the perspective of the fundamental science of supramolecular chemistry and that of potential biomedical applications in tissue engineering. Many approaches to drive the self-assembly of synthetic systems through the same steps as those of natural collagen (peptide chain to triple helix to nanofibres and, finally, to a hydrogel) are partially successful, but none simultaneously demonstrate all the levels of structural assembly. Here we describe a peptide that replicates the self-assembly of collagen through each of these steps. The peptide features collagen's characteristic proline-hydroxyproline-glycine repeating unit, complemented by designed salt-bridged hydrogen bonds between lysine and aspartate to stabilize the triple helix in a sticky-ended assembly. This assembly is propagated into nanofibres with characteristic triple helical packing and lengths with a lower bound of several hundred nanometres. These nanofibres form a hydrogel that is degraded by collagenase at a similar rate to that of natural collagen.
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TL;DR: The specific features of supramolecular polymers that can lead to applications in a variety of fields are reviewed, including: materials—in which processability and self-healing properties are of interest; biomedicine— in which the concerns are dynamic functionality and biodegradability; and hierarchical assembly and electronic systems—with an interest in unidirectionality of charge flow.
Abstract: Supramolecular polymers can be random and entangled coils with the mechanical properties of plastics and elastomers, but with great capacity for processability, recycling, and self-healing due to their reversible monomer-to-polymer transitions. At the other extreme, supramolecular polymers can be formed by self-assembly among designed subunits to yield shape-persistent and highly ordered filaments. The use of strong and directional interactions among molecular subunits can achieve not only rich dynamic behavior but also high degrees of internal order that are not known in ordinary polymers. They can resemble, for example, the ordered and dynamic one-dimensional supramolecular assemblies of the cell cytoskeleton and possess useful biological and electronic functions.
2,777 citations
TL;DR: The advances in making hydrogels with improved mechanical strength and greater flexibility for use in a wide range of applications are reviewed, foreseeing opportunities in the further development of more sophisticated fabrication methods that allow better-controlled hydrogel architecture across multiple length scales.
Abstract: BACKGROUND Hydrogels are formed through the cross-linking of hydrophilic polymer chains within an aqueous microenvironment. The gelation can be achieved through a variety of mechanisms, spanning physical entanglement of polymer chains, electrostatic interactions, and covalent chemical cross-linking. The water-rich nature of hydrogels makes them broadly applicable to many areas, including tissue engineering, drug delivery, soft electronics, and actuators. Conventional hydrogels usually possess limited mechanical strength and are prone to permanent breakage. The lack of desired dynamic cues and structural complexity within the hydrogels has further limited their functions. Broadened applications of hydrogels, however, require advanced engineering of parameters such as mechanics and spatiotemporal presentation of active or bioactive moieties, as well as manipulation of multiscale shape, structure, and architecture. ADVANCES Hydrogels with substantially improved physicochemical properties have been enabled by rational design at the molecular level and control over multiscale architecture. For example, formulations that combine permanent polymer networks with reversibly bonding chains for energy dissipation show strong toughness and stretchability. Similar strategies may also substantially enhance the bonding affinity of hydrogels at interfaces with solids by covalently anchoring the polymer networks of tough hydrogels onto solid surfaces. Shear-thinning hydrogels that feature reversible bonds impart a fluidic nature upon application of shear forces and return back to their gel states once the forces are released. Self-healing hydrogels based on nanomaterial hybridization, electrostatic interactions, and slide-ring configurations exhibit excellent abilities in spontaneously healing themselves after damages. Additionally, harnessing techniques that can dynamically and precisely configure hydrogels have resulted in flexibility to regulate their architecture, activity, and functionality. Dynamic modulations of polymer chain physics and chemistry can lead to temporal alteration of hydrogel structures in a programmed manner. Three-dimensional printing enables architectural control of hydrogels at high precision, with a potential to further integrate elements that enable change of hydrogel configurations along prescribed paths. OUTLOOK We envision the continuation of innovation in new bioorthogonal chemistries for making hydrogels, enabling their fabrication in the presence of biological species without impairing cellular or biomolecule functions. We also foresee opportunities in the further development of more sophisticated fabrication methods that allow better-controlled hydrogel architecture across multiple length scales. In addition, technologies that precisely regulate the physicochemical properties of hydrogels in spatiotemporally controlled manners are crucial in controlling their dynamics, such as degradation and dynamic presentation of biomolecules. We believe that the fabrication of hydrogels should be coupled with end applications in a feedback loop in order to achieve optimal designs through iterations. In the end, it is the combination of multiscale constituents and complementary strategies that will enable new applications of this important class of materials.
1,588 citations
TL;DR: The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.
Abstract: The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.
1,003 citations
TL;DR: The analysis of the state of the art in the field reveals the presence of innovative techniques for scaffold and material manufacturing that are currently opening the way to the preparation of biomimetic substrates that modulate cell interaction for improved substitution, restoration, retention or enhancement of bone tissue function.
665 citations
Cites background from "Multi-hierarchical self-assembly of..."
...More complex strategies for mimicking natural collagen’s hierarchical structure and composition involve the synthesis of collagen-mimetic peptides (CMPs) that replicate collagen’s characteristic repetitive unit glycine–proline– hydroxyproline and its hierarchical assembly with the characteristic triple-helical packing and length [132]....
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TL;DR: A review of the structure and molecular interactions of collagen in vivo can be found in this article, where the recent use of natural collagen in sponges, injectables, films and membranes, dressings, and skin grafts; and the ongoing development of synthetic collagen mimetic peptides as pylons to anchor cytoactive agents in wound beds.
Abstract: With its wide distribution in soft and hard connective tissues, collagen is the most abundant of animal proteins. In vitro, natural collagen can be formed into highly organized, three-dimensional scaffolds that are intrinsically biocompatible, biodegradable, nontoxic upon exogenous application, and endowed with high tensile strength. These attributes make collagen the material of choice for wound healing and tissue engineering applications. In this article, we review the structure and molecular interactions of collagen in vivo; the recent use of natural collagen in sponges, injectables, films and membranes, dressings, and skin grafts; and the on-going development of synthetic collagen mimetic peptides as pylons to anchor cytoactive agents in wound beds.
633 citations
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TL;DR: The structure of a protein triple helix has been determined by x-ray crystallographic studies of a collagen-like peptide containing a single substitution of the consensus sequence, which adopts a triple-helical structure that confirms the basic features determined from fiber diffraction studies on collagen.
Abstract: The structure of a protein triple helix has been determined at 1.9 angstrom resolution by x-ray crystallographic studies of a collagen-like peptide containing a single substitution of the consensus sequence. This peptide adopts a triple-helical structure that confirms the basic features determined from fiber diffraction studies on collagen: supercoiling of polyproline II helices and interchain hydrogen bonding that follows the model II of Rich and Crick. In addition, the structure provides new information concerning the nature of this protein fold. Each triple helix is surrounded by a cylinder of hydration, with an extensive hydrogen bonding network between water molecules and peptide acceptor groups. Hydroxyproline residues have a critical role in this water network. The interaxial spacing of triple helices in the crystal is similar to that in collagen fibrils, and the water networks linking adjacent triple helices in the crystal structure are likely to be present in connective tissues. The breaking of the repeating (X-Y-Gly)n pattern by a Gly-->Ala substitution results in a subtle alteration of the conformation, with a local untwisting of the triple helix. At the substitution site, direct interchain hydrogen bonds are replaced with interstitial water bridges between the peptide groups. Similar conformational changes may occur in Gly-->X mutated collagens responsible for the diseases osteogenesis imperfecta, chondrodysplasias, and Ehlers-Danlos syndrome IV.
994 citations
TL;DR: A demonstration that, given certain assumptions, only two basic types of structures are possible for collagen, and detailed work on the coordinates and Fourier transforms of one of these models (collagen II), and a comparison between these predictions and the observed X-ray diffraction data.
750 citations
TL;DR: A new class of ionic self-complementary oligopeptides that consist of regular repeats of alternating ionic hydrophilic and hydrophobic amino acids and associate to form stable beta-sheet structures in water are described.
694 citations
TL;DR: It has been found that it is possible to build up a two-bonded structure (two hydrogen bonds for three residues) while retaining all contacts within permissible values, and the actual parameters of the minor helix of the collagen structure have been re-determined.
Abstract: AN arrangement of three non-coaxial helical chains linked to one another by hydrogen bonds approximately perpendicular to the length of the chains was suggested as the basis of the structure of collagen two years ago1 This structure explained the occurrence of a fraction of more than one-third of glycine residues and could readily accommodate proline and hydroxyproline residues, besides explaining the infra-red dichroism The exact nature of the helices (namely, three residues per turn) was later found not to be quite correct for collagen, the X-ray pattern of stretched collagen2 indicating the occurrence of 3
residues per turn3 The presence of such a non-integral number of residues per turn required that the three chains must all be further coiled around The coiled-coil structure4 retained the essential features of the earlier one as regards the location of amino-acid residues and the orientation of the NH- and CO-bonds However, it is interesting to note that the simpler non-coiled-coil structure has been found to be the basis of the arrangement of polypeptide chains in polyproline5 and in polyglycine II 6 Thus, it appears that the triple chain structure, with minor modifications, is a configuration which might be found also in other proteins and polypeptides There is, in fact, good evidence to show that elastin belongs to this type7
656 citations
TL;DR: This reassembly process is important for fabrication of new scaffolds for 3D cell culture, tissue repair, and regenerative medicine, and a plausible sliding diffusion model is proposed to interpret the reassembly involving complementary nanofiber cohesive ends.
Abstract: Nanofiber structures of some peptides and proteins as biological materials have been studied extensively, but their molecular mechanism of self-assembly and reassembly still remains unclear We report here the reassembly of an ionic self-complementary peptide RADARADARADARADA (RADA16-I) that forms a well defined nanofiber scaffold The 16-residue peptide forms stable beta-sheet structure and undergoes molecular self-assembly into nanofibers and eventually a scaffold hydrogel consisting of >995% water In this study, the nanofiber scaffold was sonicated into smaller fragments Circular dichroism, atomic force microscopy, and rheology were used to follow the kinetics of the reassembly These sonicated fragments not only quickly reassemble into nanofibers that were indistinguishable from the original material, but their reassembly also correlated with the rheological analyses showing an increase of scaffold rigidity as a function of nanofiber length The disassembly and reassembly processes were repeated four times and, each time, the reassembly reached the original length We proposed a plausible sliding diffusion model to interpret the reassembly involving complementary nanofiber cohesive ends This reassembly process is important for fabrication of new scaffolds for 3D cell culture, tissue repair, and regenerative medicine
624 citations