Versatile Triblock Peptide Self-Assembly System to Mimic Collagen Structure and Function.

The construction of collagen mimetic peptides has been a hot topic in tissue engineering due to their attractive advantages, such as virus-free nature and low immunogenicity. However, all of the reported self-assembled peptides rely on the inclusion of risky elements of potential safety concerns or lack the capability of incorporating critical functional motifs. A versatile self-assembly design of pure synthetic peptides that can mimic the collagen structure and function remains an insurmountably challenging target. We have herein created a type of triblock peptide consisting of a central triple helical block and N-terminal/C-terminal blocks with oppositely charged amino acids. Favorable electrostatic interactions between the two terminal blocks have been demonstrated to trigger the triblock peptides to form collagen-like nanofibers with a distinct D-banding pattern. A length of 3 or above charged amino acid pairs as well as the maintenance of the triple helical conformation are required for the self-assembly of triblock peptides. Notably, integrin and discoidin domain receptor (DDR) binding sequences GFOGER and GVMGFO have been well demonstrated as vivid examples of convenient incorporation of functional motifs into the triblock peptides without interfering with their self-assembly. These triblock peptides provide a robust and versatile strategy to create next-generation peptide-based biomaterials that can recapitulate the structure and function of collagen, which have promising applications in the fields of tissue engineering and regenerative medicine.

Versatile Self-Assembly of Triblock Peptides into Stable Collagen Mimetic Heterotrimers.

The construction of peptides to mimic heterogeneous proteins such as type I collagen plays a pivotal role in deciphering their function and pathogenesis. However, progress in the field has been severely hampered by the lack of capability to create stable heterotrimers with desired functional sequences and without the effect of homotrimers. We have herein developed a set of triblock peptides that can assemble into collagen mimetic heterotrimers with desired amino acids and are free from the interference of homotrimers. The triblock peptides comprise a central collagen-like block and two oppositely charged N-/C-terminal blocks, which display inherent incompetency of homotrimer formation. The favorable electrostatic attraction between two paired triblock peptides with complementary terminal charged sequences promptly leads to stable heterotrimers with controlled chain composition. The independence of the collagen-like block from the two terminal blocks endows this system with the adaptability to incorporate desired amino acid sequences while maintaining the heterotrimer structure. The triblock peptides provide a versatile and robust tool to mimic the composition and function of heterotrimer collagen and may have great potential in the design of innovative peptides mimicking heterogeneous proteins.

A trehalose biosynthetic enzyme doubles as an osmotic stress sensor to regulate bacterial morphogenesis.

The dissacharide trehalose is an important intracellular osmoprotectant and the OtsA/B pathway is the principal pathway for trehalose biosynthesis in a wide range of bacterial species. Scaffolding proteins and other cytoskeletal elements play an essential role in morphogenetic processes in bacteria. Here we describe how OtsA, in addition to its role in trehalose biosynthesis, functions as an osmotic stress sensor to regulate cell morphology in Arthrobacter strain A3. In response to osmotic stress, this and other Arthrobacter species undergo a transition from bacillary to myceloid growth. An otsA null mutant exhibits constitutive myceloid growth. Osmotic stress leads to a depletion of trehalose-6-phosphate, the product of the OtsA enzyme, and experimental depletion of this metabolite also leads to constitutive myceloid growth independent of OtsA function. In vitro analyses indicate that OtsA can self-assemble into protein networks, promoted by trehalose-6-phosphate, a property that is not shared by the equivalent enzyme from E. coli, despite the latter's enzymatic activity when expressed in Arthrobacter. This, and the localization of the protein in non-stressed cells at the mid-cell and poles, indicates that OtsA from Arthrobacter likely functions as a cytoskeletal element regulating cell morphology. Recruiting a biosynthetic enzyme for this morphogenetic function represents an intriguing adaptation in bacteria that can survive in extreme environments.

Morphology of Osteogenesis Imperfecta Collagen Mimetic Peptide Assemblies Correlates with the Identity of Glycine-Substituting Residue.

Osteogenesis imperfecta (OI) is a hereditary bone disorder with various phenotypes ranging from mild multiple fractures to perinatal lethal cases, and it mainly results from the substitution of Gly by a bulkier residue in type I collagen. Triple-helical peptide models of Gly mutations have been widely utilized to decipher the etiology of OI, although these studies are mainly limited to characterizing the peptide features, such as stability and conformation in the solution state. Herein, we have constructed a new series of triple-helical peptides DD(GPO)5 ZPO(GPO)4 DD (Z=Ala, Arg, Asp, Cys, Glu, Ser, and Val) mimicking the most common types of observed OI cases. The inclusion of special terminal aspartic acids enables these collagen mimetic peptides to self-assemble to form nanomaterials upon the trigger of lanthanide ions. We have for the first time systematically evaluated the effect of different OI mutations on the aggregated state of collagen mimetic peptides. We have revealed that the identity of the Gly-substituting residue plays a determinant role in the morphology and secondary structure of the collagen peptide assemblies, showing that bulkier residues tend to result in a disruptive secondary structure and defective morphology, which lead to more severe OI phenotypes. These findings of osteogenesis imperfecta collagen mimetic peptides in the aggregation state provide novel perspectives on the molecular mechanism of osteogenesis imperfecta, and may aid the development of new therapeutic strategies.

Luminescent Lanthanide-Collagen Peptide Framework for pH-Controlled Drug Delivery.

Collagen mimetic scaffolds play a pivotal role in regenerative medicine and tissue engineering due to their extraordinary structural and biological features. We have herein, for the first time, reported the construction of luminescent lanthanide-collagen peptide hybrid three-dimensional nanofibrous scaffolds, which well mimic the characteristic architectural structure of native collagen. Three collagen mimetic peptides, composed of repetitive central (GPO)7 sequences and altered terminal amino acids, have been shown to consistently self-assemble to form biocompatible nanofibers under the trigger of a variety of lanthanide ions, which also functionalize the assembled materials with easily tunable photoluminescence. Furthermore, the collagen peptide-lanthanide hybrid scaffolds possess programmable pH-responsive features. The lanthanide ion-mediated assembly of all three collagen peptides are conveniently and reversibly regulated by pH, while their pH-dependent patterns are finely tuned by the identity of terminal amino acids. Using camptothecin and cefoperazone sodium as two model drugs, the drug-loading and releasing efficiency of the collagen peptide-lanthanide scaffolds are nicely modulated by pH, demonstrating the efficacy of these nanofibrous scaffolds as pH-responsive drug carriers. These novel luminescent collagen peptide-lanthanide scaffolds provide a facile system for pH-controlled drug delivery, suggesting promising applications in the development of therapies for many diseases.

Unique Conformation in a Natural Interruption Sequence of Type XIX Collagen Revealed by Its High-Resolution Crystal Structure.

Naturally occurring interruptions in nonfibrillar collagen play key roles in molecular flexibility, collagen degradation, and ligand binding. The structural feature of the interruption sequences and the molecular basis for their functions have not been well studied. Here, we focused on a G5G type natural interruption sequence G-POALO-G from human type XIX collagen, a homotrimer collagen, as this sequence possesses distinct properties compared with those of a pathological similar Gly mutation sequence in collagen mimic peptides. We determined the crystal structures of the host-guest peptide (GPO)3-GPOALO-(GPO)4 to 1.03 Å resolution in two crystal forms. In these structures, the interruption zone brings localized disruptions to the triple helix and introduces a light 6-8° bend with the same directional preference to the whole molecule, which may correspond structurally to the first physiological kink site in type XIX collagen. Furthermore, at the G5G interruption site, the presence of Ala and Leu residues, both with free N-H groups, allows the formation of more direct and water-mediated interchain hydrogen bonds than in the related Gly → Ala structure. These could partly explain the difference in thermal stability between the different interruptions. In addition, our structures provide a detailed view of the dynamic property of such an interrupted zone with respect to hydrogen bonding topology, torsion angles, and helical parameters. Our results, for the first time, also identified the binding of zinc to the end of the triple helix. These findings will shed light on how the interruption sequence influences the conformation of the collagen molecule and provide a structural basis for further functional studies.

NMR studies demonstrate a unique AAB composition and chain register for a heterotrimeric type IV collagen model peptide containing a natural interruption site.

All non-fibrillar collagens contain interruptions in the (Gly-X-Y)n repeating sequence, such as the more than 20 interruptions found in chains of basement membrane type IV collagen. Two selectively doubly labeled peptides are designed to model a site in type IV collagen with a GVG interruption in the α1(IV) and a corresponding GISLK sequence within the α2(IV) chain. CD and NMR studies on a 2:1 mixture of these two peptides support the formation of a single-component heterotrimer that maintains the one-residue staggering in the triple-helix, has a unique chain register, and contains hydrogen bonds at the interruption site. Formation of hydrogen bonds at interruption sites may provide a driving force for self-assembly and chain register in type IV and other non-fibrillar collagens. This study illustrates the potential role of interruptions in the structure, dynamics, and folding of natural collagen heterotrimers and forms a basis for understanding their biological role.

Ln3+ -Mediated Self-Assembly of a Collagen Peptide into Luminescent Banded Helical Nanoropes.

Design of biomimetic peptides to achieve the desired properties of natural collagen has much potential to build functional biomaterials. A collagen-peptide/Ln3+ system has been constructed and self-assembled to form helical nanoropes with a distinct periodic banding pattern characteristic of natural collagen. The fully reversible self-assembly is specifically mediated by lanthanide ions, but not by other commonly used divalent metal ions. Lanthanide ions not only provide an external biocompatible stimulus of the assembly, but also play as a functional unit to endow the assembled materials with easily tunable photoluminescence. To our knowledge, this is the first report of collagen-peptide-based materials with exquisite nanorope structure and excellent photoluminescent features. These novel luminescent nanomaterials may have great potential in cell imaging, medical diagnostics, and luminescent scaffolds for cell cultivation.

A Natural Interruption Displays Higher Global Stability and Local Conformational Flexibility than a Similar Gly Mutation Sequence in Collagen Mimic Peptides.

Natural interruptions in the repeating (Gly-X-Y)n amino acid sequence pattern are found normally in triple helix domains of all nonfibrillar collagens, while any Gly substitution in fibrillar collagens leads to pathological conditions. As revealed by our sequence analysis, two peptides, one modeling a natural G5G interruption (POALO) and the other one mimicking a pathological Gly-to-Ala substitution (LOAPO), are designed. Circular dichroism (CD), NMR, and computational simulation studies have discovered significant differences in stability, conformation, and folding between the two peptides. Compared with the Gly substitution sequence, the natural interruption maintains higher stability, higher triple helix content, and a higher folding rate while introducing more alterations in local triple helical conformation in terms of dihedral angles and hydrogen bonding. The conserved hydrophobic residues at the specific sites of interruptions may provide functional constraints for higher-order assembly as well as biomolecular interactions. These results suggest a molecular basis of different biological roles of natural interruptions and Gly substitutions and may guide the design of collagen mimic peptides containing functional natural interruptions.

Local amino acid sequence patterns dominate the heterogeneous phenotype for the collagen connective tissue disease Osteogenesis Imperfecta resulting from Gly mutations.

Osteogenesis Imperfecta (OI), a hereditary connective tissue disease in collagen that arises from a single Gly → X mutation in the collagen chain, varies widely in phenotype from perinatal lethal to mild. It is unclear why there is such a large variation in the severity of the disease considering the repeating (Gly-X-Y)n sequence and the uniform rod-like structure of collagen. We systematically evaluate the effect of local (Gly-X-Y)n sequence around the mutation site on OI phenotype using integrated bio-statistical approaches, including odds ratio analysis and decision tree modeling. We show that different Gly → X mutations have different local sequence patterns that are correlated with lethal and nonlethal phenotypes providing a mechanism for understanding the sensitivity of local context in defining lethal and non-lethal OI. A number of important trends about which factors are related to OI phenotypes are revealed by the bio-statistical analyses; most striking is the complementary relationship between the placement of Pro residues and small residues and their correlation to OI phenotype. When Pro is present or small flexible residues are absent nearby a mutation site, the OI case tends to be lethal; when Pro is present or small flexible residues are absent further away from the mutation site, the OI case tends to be nonlethal. The analysis also reveals the dominant role of local sequence around mutation sites in the Major Ligand Binding Regions that are primarily responsible for collagen binding to its receptors and shows that non-lethal mutations are highly predicted by local sequence considerations alone whereas lethal mutations are not as easily predicted and may be a result of more complex interactions. Understanding the sequence determinants of OI mutations will enhance genetic counseling and help establish which steps in the collagen hierarchy to target for drug therapy.

Immobilized trypsin on hydrophobic cellulose decorated nanoparticles shows good stability and reusability for protein digestion.

The preparation of biocatalysts based on immobilized trypsin is of great importance for both proteomic research and industrial applications. Here, we have developed a facile method to immobilize trypsin on hydrophobic cellulose-coated silica nanoparticles by surface adsorption. The immobilization conditions for the trypsin enzyme were optimized. The as-prepared biocatalyst was characterized by Fourier transform infrared spectroscopy, transmission electron microscopy, and elemental analysis. In comparison with free enzyme, the immobilized trypsin exhibited greater resistances against thermal inactivation and denaturants. In addition, the immobilized trypsin showed good durability for multiple recycling. The general applicability of the immobilized trypsin for proteomic studies was confirmed by enzymatic digestion of two widely used protein substrates: bovine serum albumin (BSA) and cytochrome c. The surface adsorption protocols for trypsin immobilization may provide a promising strategy for enzyme immobilization in general, with great potential for a range of applications in proteomic studies.

A robust and versatile host-guest peptide toolbox for developing highly stable and specific quantum dot-based peptide probes for imaging extracellular matrices and cells.

Multiplex fluorescence imaging plays a vital role in precision medicine for targeting complex diseases with diverse biomolecular signatures. Quantum dot (QD) probes with vibrant colors are promising candidates for multiplex imaging, but their stability and specificity are frequently compromised by the current tedious post-modification process. We have herein developed a robust and versatile host-guest peptide (HGP) toolbox for creating highly stable and specific QD-based peptide probes for imaging extracellular matrices and cells. The HGP system comprises a host peptide and a guest peptide with a shared sequence pattern of cysteine and negatively charged amino acids, allowing for QD stabilization and specificity towards targeted biomarkers. HGP has been demonstrated as a convenient one-step approach to construct hydrophilic QD-based peptide probes with superior stability under various conditions. Six multicolor HGP-modified QDs have been developed to specifically target extracellular matrix proteins such as collagen, laminin, and nidogen, as well as major cellular elements like the membrane, nucleus, and cytoplasm, providing an efficient tool for real-time monitoring of high-resolution interactions between cancer cells and the extracellular matrix. The HGP system represents a next-generation approach to developing QDs with unprecedented stability and specificity, holding great potential in multiplex imaging and precision medicine.

3D-Printed SERS Chips for Highly Specific Detection of Denatured Type I and IV Collagens in Blood for Early Hepatic Fibrosis Diagnosis.

Hepatic fibrosis, the insidious progression of chronic liver scarring leading to life-threatening cirrhosis and hepatocellular carcinoma, necessitates the urgent development of noninvasive and precise diagnostic methodologies. Denatured collagen emerges as a critical biomarker in the pathogenesis of hepatic fibrosis. Herein, we have for the first time developed 3D-printed collagen capture chips for highly specific surface-enhanced Raman scattering (SERS) detection of denatured type I and type IV collagen in blood, facilitating the early diagnosis of hepatic fibrosis. Employing a novel blend of denatured collagen-targeting peptide-modified silver nanoparticle probes (Ag@DCTP) and polyethylene glycol diacrylate (PEGDA), we engineered a robust ink for the 3D fabrication of these collagen capture chips. The chips are further equipped with specialized SERS peptide probes, Ag@ICTP@R1 (S-I) and Ag@IVCTP@R2 (S-IV), tailored for the targeted detection of type I and IV collagen, respectively. The SERS chip platform demonstrated exceptional specificity and sensitivity in capturing and detecting denatured type I and IV collagen, achieving detection limits of 3.5 ng/mL for type I and 3.2 ng/mL for type IV collagen within a 10-400 ng/mL range. When tested on serum samples from hepatic fibrosis mouse models across a spectrum of fibrosis stages (S0-S4), the chips consistently measured denatured type I collagen and detected a progressive increase in type IV collagen concentration, which correlated with the severity of fibrosis. This novel strategy establishes a benchmark for the multiplexed detection of collagen biomarkers, enhancing our capacity to assess the stages of hepatic fibrosis.

A highly biocompatible and bioactive transdermal nano collagen for enhanced healing of UV-damaged skin.

Skin damage caused by excessive UV radiation has gradually become one of the most prevalent skin diseases. Collagen has gradually found applications in the treatment of UV-damaged skin; however, their high molecular weight greatly limits their capacity to permeate the skin barrier and repair the damaged skin. Nano collagen has garnered growing attentions in the mimicking of collagen; while the investigation of its skin permeability and wound-healing capability remains vacancies. Herein, we have for the first time created a highly biocompatible and bioactive transdermal nano collagen demonstrating remarkable transdermal capacity and repair efficacy for UV-damaged skin. The transdermal nano collagen exhibited a stable triple-helix structure, effectively promoting the adhesion and proliferation of fibroblasts. Notably, the transdermal nano collagen displayed exceptional penetration capabilities, permeating fibroblast and healthy skin. Combo evaluations revealed that the transdermal nano collagen contributed to recovering the intensity and TEWL values of UV-damaged skin to normal level. Histological analysis further indicated that transdermal nano collagen significantly accelerated the repair of damaged skin by promoting the collagen regeneration and fibroblasts activation. This highly biocompatible and bioactive transdermal nano collagen provides a novel substituted strategy for the transdermal absorption of collagen, indicating great potential applications in cosmetics and dermatology.

Self-Assembling Triple-Helix Recombinant Collagen Hydrogel Enriched with Tyrosine.

The self-assembly of collagen within the human body creates a complex 3D fibrous network, providing structural integrity and mechanical strength to connective tissues. Recombinant collagen plays a pivotal role in the realm of biomimetic natural collagen. However, almost all of the reported recombinant collagens lack the capability of self-assembly, severely hindering their application in tissue engineering and regenerative medicine. Herein, we have for the first time constructed a series of self-assembling tyrosine-rich triple helix recombinant collagens, mimicking the structure and functionality of natural collagen. The recombinant collagen consists of a central triple-helical domain characterized by the (Gly-Xaa-Yaa)n sequence, along with N-terminal and C-terminal domains featuring the GYY sequence. The introduction of GYY has a negligible impact on the stability of the triple-helical structure of recombinant collagen while simultaneously promoting its self-assembly into fibers. In the presence of [Ru(bpy)3]Cl2 and APS as catalysts, tyrosine residues in the recombinant collagen undergo covalent cross-linking, resulting in a hydrogel with exceptional mechanical properties. The recombinant collagen hydrogel exhibits outstanding biocompatibility and bioactivity, significantly enhancing the proliferation, adhesion, migration, and differentiation of HFF-1 cells. This innovative self-assembled triple-helix recombinant collagen demonstrates significant potential in the fields of tissue engineering and medical materials.

Biomimetic tri-layered artificial skin comprising silica gel-collagen membrane-collagen porous scaffold for enhanced full-thickness wound healing.

Full-thickness wounds are severe cutaneous damages with destroyed self-healing function, which need efficient clinical interventions. Inspired by the hierarchical structure of natural skin, we have for the first time developed a biomimetic tri-layered artificial skin (TLAS) comprising silica gel-collagen membrane-collagen porous scaffold for enhanced full-thickness wound healing. The TLAS with the thickness of 3-7 mm displays a hierarchical nanostructure consisting of the top homogeneous silica gel film, the middle compact collagen membrane, and the bottom porous collagen scaffold, exquisitely mimicking the epidermis, basement membrane and dermis of natural skin, respectively. The 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide/N-Hydroxysuccinimide-dehydrothermal (EDC/NHS-DHT) dual-crosslinked collagen composite bilayer, with a crosslinking degree of 79.5 %, displays remarkable biocompatibility, bioactivity, and biosafety with no risk of hemolysis and pyrogen reactions. Notably, the extra collagen membrane layer provides a robust barrier to block the penetration of silica gel into the collagen porous scaffold, leading to the TLAS with enhanced biocompatibility and bioactivity. The full-thickness wound rat model studies have indicated the TLAS significantly facilitates the regeneration of full-thickness defects by accelerating re-epithelization, collagen deposition and migration of skin appendages. The highly biocompatible and bioactive tri-layered artificial skin provides an improved treatment for full-thickness wounds, which has great potential in tissue engineering.

A highly bioactive THPC-crosslinked recombinant collagen hydrogel implant for aging skin rejuvenation.

Skin aging, a complex physiological progression marked by collagen degradation, poses substantial challenges in dermatology. Recombinant collagen emerges as a potential option for skin revitalization, yet its application is constrained by difficulties in forming hydrogels. We have for the first time developed a highly bioactive Tetrakis(hydroxymethyl) phosphonium chloride (THPC)-crosslinked recombinant collagen hydrogel implant for aging skin rejuvenation. THPC demonstrated superior crosslinking efficiency compared to traditional agents such as EDC/NHS and BDDE, achieving complete recombinant collagen crosslinking at minimal concentrations and effectively inducing hydrogel formation. THPC's four reactive hydroxymethyl groups facilitate robust crosslinking with triple helical recombinant collagen, producing hydrogels with enhanced mechanical strength, excellent injectability, increased stability, and greater durability. Moreover, the hydrogel exhibited remarkable biocompatibility and bioactivity, significantly promoting the proliferation, adhesion, and migration of human foreskin fibroblast-1. In photoaged mice skin models, the THPC-crosslinked collagen hydrogel implant notably improved dermal density, skin elasticity, and reduced transepidermal water loss, creating a conducive environment for fibroblast activity and healthy collagen regeneration. Additionally, it elevated superoxide dismutase (SOD) activity and displayed substantial anti-calcification properties. The THPC-crosslinked recombinant collagen hydrogel implant presents an innovative methodology in combating skin aging, offering significant promise in dermatology and tissue engineering.

A robust acid-resistant chelating polymer for enhanced stabilization of lead ions in fly ash.

Fly ash derived from municipal solid waste incinerators (MSWIs) harbors significant quantities of heavy metals with high leaching toxicity, resulting in detrimental environmental effects. Pb2+ in fly ash is the ion most likely to exceed permissible levels. However, chemical stabilization methods demonstrate poor efficacy in stabilizing Pb2+ under acidic conditions. Herein, we have developed a robust acid-resistant chelating polymer (25DTF) for enhanced stabilization of Pb2+ in fly ash. 25DTF was synthesized through the reaction of formaldehyde with 2,5-dithiourea. 25DTF exhibited remarkable chelation efficiency, nearing 100%, for Pb2+ in fly ash. 25DTF demonstrated exceptional chelation efficiency, surpassing 99.9%, when interacting with Pb2+ in fly ash at pH ≤ 7. Even under acidic conditions, 25DTF effectively prevented the secondary dissolution of Pb2+. Additionally, it indicated outstanding Pb2+ chelation efficiency across diverse regions of China. The 25DTF chelating agent shows considerable potential in alleviating metal ion contamination in soil, wastewater, and urban environmental management, thereby fostering advancements in environmental stewardship.

A highly biocompatible CE-crosslinked collagen implant with exceptional anti-calcification and collagen regeneration capabilities for aging skin rejuvenation.

Skin aging, a complex and inevitable biological process, results in wrinkles, dermal laxity, and skin cancer, profoundly influencing appearance and overall health. Collagen serves as the fundamental element of the dermal matrix; nevertheless, collagen is susceptible to enzymatic degradation within the body. Crosslinking is employed to enhance the physicochemical properties of collagen. However, conventional crosslinking agents may harbor potential issues such as cytotoxicity and calcification risks, constraining their application in the biomedical field. Therefore, we have for the first time developed a highly biocompatible CE-crosslinked collagen implant with exceptional anti-calcification and collagen regeneration capabilities for aging skin rejuvenation. A novel collagen crosslinking agent (CE) was synthesized through a reaction involving chitosan quaternary ammonium salt with 1,4-butanediol diglycidyl ether. Compared to collagen crosslinked with glutaraldehyde (GA), the CE-crosslinked collagen implant exhibited notable stability and durability. The implant demonstrated excellent injectability and viscosity, resisting displacement after implantation. Additionally, the CE-crosslinked collagen implant displayed superior biocompatibility, effectively promoting the proliferation and adhesion of HFF-1 cells compared with the GA-crosslinked collagen. The CE-crosslinked collagen represented a safer and more biologically active implant material. In vivo experiments further substantiated that the implant significantly facilitated collagen regeneration without inducing calcification. The innovative collagen implant has made substantial strides in enhancing aesthetics and reducing wrinkles, presenting the potential for revolutionary progress in the fields of skin rejuvenation and collagen regeneration.

Ferrous/Ferric Ions Crosslinked Type II Collagen Multifunctional Hydrogel for Advanced Osteoarthritis Treatment.

Osteoarthritis (OA) is a highly prevalent and intricate degenerative joint disease affecting an estimated 500 million individuals worldwide. Collagen-based hydrogels have sparked immense interest in cartilage tissue engineering, but substantial challenges persist in developing biocompatible and robust crosslinking strategies, as well as improving their effectiveness against the multifaceted nature of OA. Herein, a novel discovery wherein the simple incorporation of ferrous/ferric ions enables efficient dynamic crosslinking of type II collagen, leading to the development of injectable, self-healing hydrogels with 3D interconnected porous nanostructures, is unveiled. The ferrous/ferric ions crosslinked type II collagen hydrogels demonstrate exceptional physical properties, such as significantly enhanced mechanical strength, minimal swelling ratios, and remarkable resistance to degradation, while also exhibiting extraordinary biocompatibility and bioactivity, effectively promoting cell proliferation, adhesion, and chondrogenic differentiation. Additionally, the hydrogels reveal potent anti-inflammatory effects by upregulating anti-inflammatory cytokines while downregulating pro-inflammatory cytokines. In a rat model of cartilage defects, these hydrogels exhibit impressive efficacy, substantially accelerating cartilage tissue regeneration through enhanced collagen deposition and increased proteoglycan secretion. The innovative discovery of the multifunctional role of ferrous/ferric ions in endowing type II collagen hydrogels with a myriad of beneficial properties presents exciting prospects for developing advanced biomaterials with potential applications in OA.