Co-assembled Hydrogels Research Articles

Engineering Injectable Coassembled Hydrogel by Photothermal Driven Chitosan-Stabilized MoS2 Nanosheets for Infected Wound Healing.

The application of enzyme-like molybdenum disulfide (MoS2) in tissue repair was confronted with stable dispersion, solubilization, and biotoxicity. Here, the injectable self-healing hydrogel was successfully designed using a step-by-step coassembly of chitosan and MoS2. Polyphenolic chitosan as a "structural stabilizer" of MoS2 nanosheets reconstructed well-dispersed MoS2@CSH nanosheets, which improved the biocompatibility of traditional MoS2, and strengthened its photothermal conversion and enzyme-like activities, guaranteeing highly efficient radical scavenging and antimicrobial properties. Furthermore, the polyphenol chitosan was employed again as a "molecular cross-linking agent" to form the injectable NIR-responsive MoS2@CSH hydrogel by accelerating hydrogen-bond interaction among chitosan and the multicross-linking reaction among polyphenols. The rapid self-healing ability was conducive to wound closure and dynamic adaptability. An experimental study on infected wound healing demonstrated that MoS2@CSH hydrogel could substantially eradicate bacteria and accelerate the angiogenesis of infected wounds. The photothermal-driven coassembly of MoS2 and polycation provided an alternative strategy for infected wound healing.

Supramolecular Polymer Co-Assembled Multifunctional Chiral Hybrid Hydrogels with Adhesive, Self-Healing and Antibacterial Properties.

Amino acid-derived self-assembled nanofibers comprising supramolecular chiral hydrogels with unique physiochemical characteristics are highly demanded biomaterials for various biological applications. However, their narrow functionality often limits practical use, necessitating the development of biomaterials with multiple features within a single system. Herein, chiral co-assembled hybrid hydrogel systems termed LPH-EGCG and DPH-EGCG were constructed by co-assembling L/DPFEG gelators with epigallocatechin gallate (EGCG) followed by cross-linking with polyvinyl alcohol (PVA) and hyaluronic acid (HA). The developed hybrid hydrogels exhibit superior mechanical strength, self-healing capabilities, and adhesive properties, owing to synergistic non-covalent interactions. Integrating hydrophilic polymers enhances the system's capacity to demonstrate favorable swelling characteristics. Furthermore, the introduction of EGCG facilitated the hybrid gels to display notable antibacterial properties against both Gram-positive and Gram-negative bacterial strains, alongside showcasing strong antioxidant capabilities. In vitro investigation demonstrated enhanced cell adhesion and migration with the LPH-EGCG system in comparison to DPH-EGCG, thus emphasizing the promising prospects of these hybrid hydrogels in advanced tissue engineering applications.

Stepwise co-assembled biomimetic hydrogel with antibacterial, angiogenesis, and tissue regeneration acceleration for diabetic wound healing

Bacterial infections and inadequate tissue regeneration capacity are prevalent issues in diabetic wounds, impeding the healing process. To solve these problems, a biomimetic hydrogel combined with bacterial cellulose (BC), recombinant human collagen type III (RHC), and ε-poly-L-Lysine (EPL) is fabricated by stepwise co-assembly technology. Owing to the RHC and EPL modifications of BC, the biomimetic hydrogel exhibited antibacterial effects and promoted fibroblast proliferation and angiogenesis, which accelerated the healing of diabetic wounds. Biomimetic hydrogels exhibit good mechanical properties and excellent water absorption, that can protect wounds and provide a moist environment. In addition, in vitro studies have shown that the hydrogels exhibit excellent antibacterial activity and biocompatibility. In vivo studies on diabetic wound healing have shown that biomimetic hydrogels can promote angiogenesis, accelerate collagen deposition, and re-epithelialize wound sites to promote wound healing. This study provides a new and promising strategy for the treatment of diabetic wounds.

Efficient chiral hydrogel template based on supramolecular self-assembly driven by chiral carbon dots for circularly polarized luminescence

Since the chiral emission of excited states is observed on carbon dots (CDs), exploration towards the design and synthesis of chiral CDs nanomaterials with circularly polarized luminescence (CPL) properties has been at a brisk pace. In this regard, the “host and guest” co-assembly strategy based on the combination of CDs and chiral templates has been of unique interest recently for its convenient operation, multicolor tunable CPL, and wide application of prepared CDs-composited materials in optoelectronic devices and information encryption. However, the existing chiral templates that match perfectly with chiral CDs exhibiting optical activity both in ground and excited states are rather scarce. In this work, we synthesize the chiral CDs that could induce the spontaneous supramolecular self-assembly of N-(9-fluorenylmethox-ycarbonyl) (Fmoc)-protected glutamic acid to form chiral hydrogels with helical nanostructure. The co-assembled hydrogels show powerful chiral template function, which not only enable chiral CDs with a luminescence dissymmetry factor (glum) up to 10-2, but also have universal chiral transfer to inserted dye molecules, realizing full-color CPL and Förster resonance energy transfer (FRET) CPL as well as the distinction between left and right circularly polarized light. This CPL-active template based on chiral CDs enriches the design scenario of chiral functionalized nanomaterials.

Extracellular Matrix Mimicking Wound Microenvironment Responsive Amyloid-Heparin@TAAgNP Co-Assembled Hydrogel: An Effective Conductive Antibacterial Wound Healing Material.

Bioengineered composite hydrogel platforms made of a supramolecular coassembly have recently garnered significant attention as promising biomaterial-based healthcare therapeutics. The mechanical durability of amyloids, in conjunction with the structured charged framework rendered by biologically abundant key ECM component glycosaminoglycan, enables us to design minimalistic customized biomaterial suited for stimuli responsive therapy. In this study, by harnessing the heparin sulfate-binding aptitude of amyloid fibrils, we have constructed a pH-responsive extracellular matrix (ECM) mimicking hydrogel matrix. This effective biocompatible platform comprising heparin sulfate-amyloid coassembled hydrogel embedded with polyphenol functionalized silver nanoparticles not only provide a native skin ECM-like conductive environment but also provide wound-microenvironment responsive on-demand superior antibacterial efficacy for effective diabetic wound healing. Interestingly, both the cytocompatibility and antibacterial properties of this bioinspired matrix can be fine-tuned by controlling the mutual ratio of heparin sulfate-amyloid and incubated silver nanoparticle components, respectively. The designed biomaterial platform exhibits notable effectiveness in the treatment of chronic hyperglycemic wounds infected with multidrug-resistant bacteria, because of the integration of pH-responsive release characteristics of the incubated functionalized AgNP and the antibacterial amyloid fibrils. In addition to this, the aforementioned assemblage shows exceptional hemocompatibility with significant antibiofilm and antioxidant characteristics. Histological evidence of the incised skin tissue sections indicates that the fabricated composite hydrogel is also effective in controlling pro-inflammatory cytokines such as IL6 and TNFα expressions at the wound vicinity with significant upregulation of angiogenesis markers like CD31 and α-SMA.

PH-Responsive Co-Assembled Peptide Hydrogel to Inhibit Drug-Resistant Bacterial Infection and Promote Wound Healing.

Drug-resistant bacterial infection and biofilm formation are the key inhibitors of wound healing, and new strategies are urgently needed to address these issues. In this study, we designed a pH-responsive co-assembled peptide hydrogel to inhibit Methicillin-resistant Staphylococcus aureus (MRSA) infection and promote wound healing. We synthesized a cationic short peptide (Nap-FFKKK) and a co-assembled hydrogel with curcumin at pH ∼ 7.8. The loaded curcumin was continuously released in a weak acid environment (pH ∼ 5.5). The lysine-rich cationic peptide inhibited biofilm formation in MRSA via electrostatic interaction with the negatively charged bacterial cell surface and, thus, provided a reinforcing antibacterial effect with curcumin. In vitro antibacterial experiments showed that the co-assembled system considerably reduced the minimum inhibitory concentration of curcumin against MRSA by 10-fold and promoted wound healing in a mouse model of MRSA-infected wounds. This study provides a simple and promising strategy to treat drug-resistant bacterial infections in wounds.

Molecular co-assembled strategy tuning protein conformation for cartilage regeneration.

The assembly of oligopeptide and polypeptide molecules can reconstruct various ordered advanced structures through intermolecular interactions to achieve protein-like biofunction. Here, we develop a "molecular velcro"-inspired peptide and gelatin co-assembly strategy, in which amphiphilic supramolecular tripeptides are attached to the molecular chain of gelatin methacryloyl via intra-/intermolecular interactions. We perform molecular docking and dynamics simulations to demonstrate the feasibility of this strategy and reveal the advanced structural transition of the co-assembled hydrogel, which brings more ordered β-sheet content and 10-fold or more compressive strength improvement. We conduct transcriptome analysis to reveal the role of co-assembled hydrogel in promoting cell proliferation and chondrogenic differentiation. Subcutaneous implantation evaluation confirms considerably reduced inflammatory responses and immunogenicity in comparison with type I collagen. We demonstrate that bone mesenchymal stem cells-laden co-assembled hydrogel can be stably fixed in rabbit knee joint defects by photocuring, which significantly facilitates hyaline cartilage regeneration after three months. This co-assembly strategy provides an approach for developing cartilage regenerative biomaterials.

Mimicking the extracellular world: from natural to fully synthetic matrices utilizing supramolecular biomaterials.

The extracellular matrix (ECM) has evolved around complex covalent and non-covalent interactions to create impressive function-from cellular signaling to constant remodeling. A major challenge in the biomedical field is the de novo design and control of synthetic ECMs for applications ranging from tissue engineering to neuromodulation to bioelectronics. As we move towards recreating the ECM's complexity in hydrogels, the field has taken several approaches to recapitulate the main important features of the native ECM (i.e. mechanical, bioactive and dynamic properties). In this review, we first describe the wide variety of hydrogel systems that are currently used, ranging from fully natural to completely synthetic to hybrid versions, highlighting the advantages and limitations of each class. Then, we shift towards supramolecular hydrogels that show great potential for their use as ECM mimics due to their biomimetic hierarchical structure, inherent (controllable) dynamic properties and their modular design, allowing for precise control over their mechanical and biochemical properties. In order to make the next step in the complexity of synthetic ECM-mimetic hydrogels, we must leverage the supramolecular self-assembly seen in the native ECM; we therefore propose to use supramolecular monomers to create larger, hierarchical, co-assembled hydrogels with complex and synergistic mechanical, bioactive and dynamic features.

A natural food-grade supramolecular self-assembly system for creation of hierarchically structured hydrogels.

We develop a novel hierarchically structured hydrogel by the supramolecular self-assembly of all-natural food-grade building blocks, glycyrrhizic acid (GA) and carrageenan (CG). The co-assembled GA-CG hydrogel system displays an unusual structural transition with the appearance from opacity to translucence and then to opacity, as a function of the concentration of metal ions. The unique GA-CG supramolecular hydrogel system can serve as solid, edible, and responsive active cargo delivery platforms for food and biomedical applications.

A broad-spectrum antibacterial hydrogel based on the synergistic action of Fmoc-phenylalanine and Fmoc-lysine in a co-assembled state.

Multicomponent biomolecular self-assembly is fundamental for accomplishing complex functionalities of biosystems. Self-assembling peptides, amino acids, and their conjugates serve as a versatile platform for developing biomaterials. However, the co-assembly of multiple building blocks showing synergistic interplay between individual components and producing biomaterials with emergent functional attributes is much less explored. In this study, we have formulated minimalistic co-assembled hydrogels composed of Fmoc-phenylalanine and Fmoc-lysine. The co-assembled systems display broad-spectrum antimicrobial potency, a feature absent in individual building blocks. A comprehensive biophysical analysis demonstrates the physicochemical features of the hydrogels eliciting the antibacterial response. MD simulation further reveals a unique fibrillar architecture with Fmoc-phenylalanine forming the fibril core surrounded by positively charged Fmoc-lysine surface residues, thereby enhancing the interaction with negatively charged bacterial membranes, causing membrane disruption and cell death. Thus, this study provides molecular-level insight into the emergent properties of a multicomponent system, affording an excellent paradigm for developing novel biomaterials.

NDI based C2-symmetric Chiral Supramolecular Hydrogels Towards Enhanced Conductivity.

To comprehend the significance of improved conductive properties in C2-symmetric hydrogels, it is vital to investigate how non-gelating achiral functional group isomers influence the conductivity of such supramolecular hydrogels, whereas understanding the major driving forces behind this regulatory process is first and foremost. Herein, we report a hydrogel system containing tryptophan-conjugated NDI as the backbone (L/D-NTrp), enabling effective supramolecular assembly with the bipyridyl functional group isomers. This co-assembly behavior results in materials with exceptional mechanical properties and high conductivities, surpassing most previously reported C2-symmetrical hydrogels, as well as the ability to form controlled morphologies. Notably, the co-hydrogels displayed an eight-fold increase in mechanical strength, making them more robust and resistant to deformation compared to the original gel. Additionally, all hydrogels exhibited favorable electrical conductivity, with the co-assembled hydrogels showcasing notable performance, making them a promising candidate for use in electronic devices and sensors. This report lays the foundation for further investigation into the properties and potential applications of L/D-NTrp compound in the range of fields, including drug delivery, tissue engineering, and electronics.

Dipeptide-polysaccharides hydrogels through co-assembly.

Self-assembling dipeptide hydrogels are attracting attention in food, materials, and biomedicine. However, there are still limitations such as weak hydrogel properties. Herein, we introduced two types of polysaccharides (Arabic gum and citrus pectin) into an alkyl-chain modified dipeptide (C13-tryptophan-tyrosine (C13-WY)) to generate co-assembled C13-WY-arabic gum and C13-WY-pectin hydrogels. The co-assembled hydrogels exhibited enhanced mechanical properties and stability. The G' value of C13-WY-arabic gum and C13-WY-pectin hydrogels was 3 and 10 times larger than that of C13-WY hydrogel, respectively. The addition of Arabic gum and citrus pectin led to the co-assembly and molecular rearrangement. Moreover, co-assembled hydrogels showed more β-sheet structure and hydrogen bonds. Importantly, the self-/co-assembled hydrogels showed low cytotoxicity. We utilized these hydrogels for the encapsulation of docetaxel and they showed a high embedding rate and slow-release. Our findings provide a novel strategy for the development of stable supramolecular peptide hydrogels with good biocompatibility through simple co-assembly.

Co-assembled Supramolecular Hydrogel of Salvianolic Acid B and a Phosphopeptide for Enhanced Wound Healing.

Supramolecular natural product gels (NPGs) have emerged as promising biomaterials for scalable and adjustable drug delivery systems. These gels possess biocompatibility, biodegradability, and the ability to mimic the extracellular matrix. Salvianolic acid B (SAB), derived from Salvia miltiorrhiza, a Chinese medicinal plant, exhibits various beneficial properties such as antioxidant, antifibrotic, and angiogenic effects. In our research, we serendipitously discovered that the co-assembly of SAB and a soluble phosphopeptide results in the formation of a robust and adhesive hydrogel termed 1&SAB hydrogel. This hydrogel effectively prolongs the retention time of the therapeutic agents on the skin's wound surface, thereby promoting wound healing. The hydrogel demonstrates antioxidant effects, enhances cell migration, accelerates angiogenesis, and inhibits scar hyperplasia. This innovative gel material offers a simple and efficient approach to managing skin wounds and holds promise for application in complex wound-healing treatments.

Fluorescent hydrogels with emission enhancement and CPL-activity depending on gelation states

Different gelation states of a peptide amphiphile lead to distinct emission and chiroptical properties of co-assembled fluorescent hydrogels.

Long and Covalently Conjugated Branched DNA Structures for in Situ Gelation in Vivo

Long and Covalently Conjugated Branched DNA Structures for in Situ Gelation in Vivo

Supramolecular Coassembled Peptide Hydrogels for Efficient Anticancer Therapy by RNS-Based PDT and Immune Microenvironment Regulation.

Photodynamic therapy (PDT) has attracted much attention in cancer treatment due to its tumor selectivity and noninvasive nature. Recent studies have demonstrated that PDT mediated reactive oxygen species (ROS) generation in tumor microenvironment (TME) synergistically improves the efficacy of immune checkpoint blockade (ICB) therapy. However, the instability and short half-life of theROS generated by PDT limit its clinical applications. Herein, a coassembled peptide hydrogel comprising two short peptides that contained the same assembly unit, Ce6-KKFKFEFEF (KEF-Ce6) and RRRRRRRR-KFKFEFEF (KEF-R8) is developed. When exposed to 635nm laser irradiation, KEF-Ce6 released ROS, while KEF-R8 plays as nitric oxide (NO) donor. Subsequently, ROS reacts with NO to produce reactive nitrogen species (RNS). Both in vitro and in vivo experiments provethat converting ROS into more cytotoxic RNS caused intense cell death. Importantly, it is observed that tumor-associated macrophages (TAMs) are polarized to proinflammatory types (M1-type) by the RNS-based PDT. The increase of M1 macrophages relieves the immunosuppressive situation in TME. Thus, when combined with αPD-L1 treatment, the survival time of tumor-bearing mice is prolonged. Overall, a simple yet efficient coassembled hydrogel that can cascade release ROS/NO/RNS and strengthen antitumor T cell responses to boost cancer immunotherapy by reprogramming TAMs is provided.

Co-assembled C13-dipeptide hydrogels by Gallic Acid (CA) and epigallocatechin gallate (EGCG) with antibacterial activity

The self-assembled peptide-based hydrogels have been widely utilized in foods. However, the self-assembled hydrogels still have some shortages such as low mechanical properties and hydrogel stabilities. Herein, we designed two co-assembled C13-WS hydrogels conjugated by Gallic Acid (CA) and Epigallocatechin Gallate (EGCG). The introduction of CA and EGCG into C13-WS hydrogels can significantly improve the mechanical properties and hydrogel stabilities. The storage modulus (G’) values of co-assembled C13-WS/CA and C13-WS/EGCG were 13.33 KPa and 16 KPa, respectively. From transmission electron microscope (TEM) results, CA and EGCG contributed to the rearrangement of C13-WS molecules during co-assembly. Moreover, the self-/co-assembled C13-WS hydrogels showed antimicrobial activity against E. coli, P. aeruginosa, and S. epidermidis. The introduction of CA and EGCG significantly enhanced the antibacterial activity of C13-WS hydrogels. Our findings provide a novel strategy for the development of stable supramolecular antibacterial short peptide hydrogels through co-assembly.

An injectable co-assembled hydrogel blocks reactive oxygen species and inflammation cycle resisting myocardial ischemia-reperfusion injury

The overproduction of reactive oxygen species (ROS) and burst of inflammation following cardiac ischemia–reperfusion (I/R) are the leading causes of cardiomyocyte injury. Monotherapeutic strategies designed to enhance anti-inflammatory or anti-ROS activity explicitly for treating I/R injury have demonstrated limited success because of the complex mechanisms of ROS production and induction of inflammation. Intense oxidative stress leads to sustained injury, necrosis, and apoptosis of cardiomyocytes. The damaged and necrotic cells can release danger-associated molecular patterns (DAMPs) that can cause the aggregation of immune cells by activating Toll-like receptor 4 (TLR4). These immune cells also promote ROS production by expressing NADPH oxidase. Finally, ROS production and inflammation form a vicious cycle, and ROS and TLR4 are critical nodes of this cycle. In the present study, we designed and prepared an injectable hydrogel system of EGCG@Rh-gel by co-assembling epigallocatechin-3-gallate (EGCG) and the rhein-peptide hydrogel (Rh-gel). The co-assembled hydrogel efficiently blocked the ROS–inflammation cycle by ROS scavenging and TLR4 inhibition. Benefited by the abundant noncovalent interactions of π–π stacking and hydrogen bonding between EGCG and Rh-gel, the co-assembled hydrogel had good mechanical strength and injectable property. Following the injection EGCG@Rh-gel into the damaged region of the mice's heart after I/R, the hydrogel enabled to achieve long-term sustained release and treatment, improve cardiac function, and significantly reduce the formation of scarring. Further studies demonstrated that these beneficial outcomes arise from the reduction of ROS production, inhibition of inflammation, and induction of anti-apoptosis in cardiomyocytes. Therefore, EGCG@Rh-gel is a promising drug delivery system to block the ROS-inflammation cycle for resisting myocardial I/R injury. Statement of Significance1. Monotherapeutic strategies designed to enhance anti-inflammatory or anti-ROS effects for treating I/R injury have demonstrated limited success because of the complex mechanisms of ROS and inflammation.2. ROS production and inflammation form a vicious cycle, and ROS and TLR4 are critical nodes of this cycle.3. Here, we designed an injectable hydrogel system of EGCG@Rh-gel by co-assembling epigallocatechin-3-gallate (EGCG) and a rhein-peptide hydrogel (Rh-gel). EGCG@Rh-gel efficiently blocked the ROS–inflammation cycle by ROS scavenging and TLR4 inhibition.4. EGCG@Rh-gel achieved long-term sustained release and treatment, improved cardiac function, and significantly reduced the formation of scarring after I/R.5. The beneficial outcomes arise from reducing ROS production, inhibiting inflammation, and inducing anti-apoptosis in cardiomyocytes.

Bicomponent Coassembled Hydrogel as a Template for Selective Enzymatic Generation of DOPA

In living organisms, tyrosinase selectively produces l-DOPA from l-tyrosine. Here, a bicomponent hydrogel is used as a template for tyrosinase-catalyzed selective generation of l-DOPA from tyrosine. An amphiphilic molecule 1,5-diaminonaphthalene (DAN) coassembles with 1,3,5-benzenetricarboxylic acid (BTC) to form a self-supporting hydrogel. After alteration of complementary acids, DAN does not coassemble to form a hydrogel. The coassembly mechanism is investigated using spectroscopic techniques. The transmission electron microscopy and scanning electron microscopy images reveal the morphology details. The l-DOPA is kept from being oxidized when the hydrogel is used as a template. The enzymatically synthesized l-DOPA can also be separated from the mixture by easy tuning of the bicomponent coassembly.

Chiral helical supramolecular hydrogels with adjustable pitch and diameter towards high-performance chiroptical detecting

Helical architectures with adjustable helical parameters and chiroptical functions are expected to play a fundamental role in biomedicine and nanoscience fields but is still in its early stage of study. Herein, chiral phenylalanine-derived hydrogelators (DG1 and LG1) can self-assemble into left-handed or right-handed helical nanofibrous hydrogels. Achiral carbon dots with different charges are co-assembled with DG1 or LG1 through electrostatic interactions and hydrogen bonds, helical supramolecular hydrogels with controllable helical pitch and diameter are readily obtained. Typically, the co-assembled hydrogels show both circular dichroism (CD) and circularly polarized luminescence (CPL) signals in the absorption regions. The nanofibers with the largest helical pitch and smallest diameter show the highest luminescence dissymmetry g-factors (glum) up to -3.80 × 10−3, which are able to efficiently differentiate between left and right circularly polarized light. This work not only paves a universal method to obtain chiral helical nanostructures with adjustable pitch and diameter, but also shines light on these advanced helical nanostructures for potential applications in chiroptical detectors.