Injectable Hydrogels for Articular Cartilage Regeneration: Design and Network Formation Strategies

Degradable conductive self-healing hydrogels based on dextran-graft-tetraaniline and N-carboxyethyl chitosan as injectable carriers for myoblast cell therapy and muscle regeneration

Introduction of dynamic thiol-alkynone double addition cross-links in a polymer network enable the formation of a self-healing injectable polymer hydrogel. A four-arm polyethylene glycol (PEG) tetra-thiol star polymer is cross-linked by a small molecule alkynone via the thiol-alkynone double adduct to generate a hydrogel network under ambient aqueous conditions (buffer pH = 7.4 or 8.2, room temperature). The mechanical properties of these hydrogels can be easily tuned by varying the concentration of polymer precursors. Through the dynamic thiol-alkynone double addition cross-link, these hydrogels are self-healing and shear thinning, as demonstrated by rheological measurements, macroscopic self-healing, and injection tests. These hydrogels can be injected through a 20G syringe needle and recover after extrusion. In addition, good cytocompatibility of these hydrogels is confirmed by cytotoxicity test. This work shows the application of the thiol-alkynone double addition dynamic covalent chemistry in the straightforward preparation of self-healing injectable hydrogels, which may find future biomedical applications such as tissue engineering and drug delivery.

Introduction of dynamic thiol-alkynone double addition crosslinks in a polymer network enable the formation of a self-healing injectable polymer hydrogel. A 4-arm polyethylene glycol (PEG) tetra-thiol star polymer is crosslinked by a small molecule alkynone via the thiol-alkynone double adduct, to generate a hydrogel network under ambient aqueous conditions (buffer pH=7.4 or 8.2, room temperature). The mechanical properties of these hydrogels can be easily tuned by varying the concentration of polymer precursors. Through the dynamic thiol-alkynone double addition crosslink, these hydrogels are self-healing and shear thinning, as demonstrated by rheological measurements, macroscopic self-healing and injection tests. These hydrogels can be injected through a 20G syringe needle and recover after extrusion. In addition, good cytocompatibility of these hydrogels is confirmed by cytotoxicity test. This work shows the application of a new type of dynamic covalent chemistry in the straightforward preparation of self-healing injectable hydrogels, which may find future biomedical applications such as tissue engineering and drug delivery.

Dynamic agent of an injectable and self-healing drug-loaded hydrogel for embolization therapy.

Articular cartilage plays an important role in human body. How to repair articular cartilage defects when they appear due to various factors has always been a major clinical challenge. Recently, studies have shown that slowing the degradation of cartilage extracellular matrix (ECM) and modulating the inflammatory response of the host thereby promoting cartilage tissue regeneration are important in the cartilage repair process. In this study, a drug-loaded injectable hydrogel was constructed for repairing articular cartilage. This hydrogel could not only maintain the phenotype of chondrocytes but also regulate the inflammatory response of the host. The injectable sodium alginate (SA)/bioglass (BG) hydrogel was mixed with the injectable thermal-responsive SA/agarose (AG)/quercetin (Que) hydrogel to obtain an injectable hydrogel containing both Que and BG (Que-BG hydrogel) for articular cartilage regeneration. The Que-BG hydrogel has a proper swelling ratio that can promote integration between the formed tissue and host tissue, and it allows Que to release slowly in situ to improve its bioavailability. The Que-BG hydrogel could upregulate SRY-box 9 (SOX9), aggrecan (ACAN), and collagen type II alpha 1 chain (COL2A1) of normal chondrocytes to maintain the normal chondrocyte phenotype. In addition, it could promote macrophage M2 polarization, reduce inflammation, and inhibit ECM degradation by downregulating the expression of inducible nitric oxide synthase (iNOS), matrix metalloproteinase-13 (MMP13), and matrix metalloproteinase-1 (MMP1) in degenerative chondrocytes. After injecting the Que-BG hydrogel into a rat cartilage defect model, the formed tissue was observed to be similar to the normal tissue and was highly integrated with the surrounding tissue. Therefore, the injectable Que-BG hydrogel improves Que bioavailability, maintains chondrocyte phenotype, inhibits ECM degradation, and reduces inflammatory response.

An injectable PEG hydrogel controlling neurotrophin-3 release by affinity peptides

Injectable hydrogels have received considerable interest in the biomedical field due to their potential applications in minimally invasive local drug delivery, more precise implantation, and site-specific drug delivery into poorly reachable tissue sites and into interface tissues, where wound healing takes a long time. Injectable hydrogels, such as in situ forming and/or shear-thinning hydrogels, can be generated using chemically and/or physically crosslinked hydrogels. Yet, for controlled and local drug delivery applications, the ideal injectable hydrogel should be able to provide controlled and sustained release of drug molecules to the target site when needed and should limit nonspecific drug molecule distribution in healthy tissues. Thus, such hydrogels should sense the environmental changes that arise in disease states and be able to release the optimal amount of drug over the necessary time period to the target region. To address this, researchers have designed stimuli-responsive injectable hydrogels. Stimuli-responsive hydrogels change their shape or volume when they sense environmental stimuli, e.g., pH, temperature, light, electrical signals, or enzymatic changes, and deliver an optimal concentration of drugs to the target site without affecting healthy tissues.

Conductive, injectable, and self-healing collagen-hyaluronic acid hydrogels loaded with bacterial cellulose and gold nanoparticles for heart tissue engineering

Synthesis and characterization of injectable self-healing hydrogels based on oxidized alginate-hybrid-hydroxyapatite nanoparticles and carboxymethyl chitosan

We report here an injectable, self-healing coordinative hydrogel with antibacterial and angiogenic properties for diabetic wound regeneration. The hydrogel was prepared by coordinative cross-linking of multi-arm thiolated polyethylene glycol (SH-PEG) with silver nitrate (AgNO3). Due to the dynamic nature of Ag-S coordination bond and bacteria-killing activity of Ag+, the resultant coordinative hydrogel featured self-healing, injectable and antibacterial properties. In this study, we synchronously loaded an angiogenic drug, desferrioxamine (DFO), in the coordinative hydrogel during cross-linking. We finally obtained a multifunctional hydrogel that is manageable, resistant to mechanical irritation, antibacterial and angiogenic in vitro. Our in vivo studies further demonstrated that the injectable self-healing hydrogel could efficiently repair diabetic skin wounds with low bacteria-infection and enhance angiogenic activity. In short, besides diabetic skin wound repair, such dynamic multifunctional hydrogel scaffolds would show great promise in the regeneration of different types of exposed wounds, in particular, in situations with disturbed physiological functions, high risk of bacterial infections, and external mechanical irritation.

Easily injectable gelatin-nonanal hydrogel for endoscopic resectioning of gastrointestinal polyps

Biodegradable self-healing hydrogels are highly desirable materials for therapeutic systems, reusable devices, and intelligent cell/drug carriers. Many research efforts focus on additional functionalities of self-healing hydrogels through physical or chemical strategies/designs. Herein, N-[3-(4-hydroxyphenyl)propanamido] chitosan and a difunctional Pluronic-F127 crosslinker (DF-PF) were synthesized and reacted to form the phenolic-chitosan self-healing hydrogel (CPF) with a high water content (96.5 wt%). Coherent small-angle X-ray scattering (SAXS) analyses of the hydrogel revealed a fast-forming primary fractal network followed by the gradual formation of a secondary micellar structure (∼12 nm). Such core–shell micellar architectures reinforced the hierarchical structure and endowed the hydrogel with thermoresponsiveness, verified by rheology and SAXS. Owing to the bioinspired phenolic chemistry, the CPF hydrogel was adhesive (binding strength 4–7 kPa) to artificial skin. Together with the rapid (<30 s) gelation kinetics, the hydrogel can be delivered by a dual-syringe as a fast adhesive. Moreover, the fast-gelled nature of the CPF hydrogel allowed spatially homogeneous embedding of mesenchymal stem cells that further developed into multicellular spheroids in 14 days. This new self-healing hydrogel shows multifunctionalities, benefiting from micellar architectures and phenolic modification. The corresponding hierarchical structure investigation provides an insight into the multiscale designs of a next-generation self-healing hydrogel for biomedical applications.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by chronic inflammation and immune dysregulation, significantly impacting multiple organ systems, including the joints. While SLE is known to contribute to musculoskeletal complications, its role in hip arthritis development and the underlying mechanisms remain poorly understood. This study aims to investigate the relationship between SLE and hip arthritis progression using MRL/lpr mice, which exhibit early-onset SLE, compared with MRL/MpJ control mice at 14 weeks of age. Through comprehensive histological, immunohistochemical and molecular analyses, we evaluated articular cartilage (AC) degeneration, extracellular matrix (ECM) metabolism, inflammatory responses, and chondrocyte pyroptosis. Our results demonstrated that MRL/lpr mice developed an accelerated hip arthritis-like phenotype, manifesting as enhanced AC degeneration, impaired chondrocyte proliferation, heightened apoptosis and promoted inflammatory cytokine production. Notably, SLE markedly stimulated chondrocyte pyroptosis by increasing pyroptosis-related proteins, including NLRP3, ASC, CASPASE-1 and GSDMD, via activating the NF-κB pathway. These findings establish a novel mechanistic link between SLE and hip arthritis progression, demonstrating that SLE promotes chondrocyte pyroptosis to exacerbate AC degeneration via NF-κB activation, highlighting chondrocyte pyroptosis as a key driver of SLE-associated hip arthritis and a potential therapeutic target for mitigating SLE-induced joint manifestations.

Chronic synovial inflammation play important roles to establish residual pain in monoiodoacetic acid induced arthritis rat model

Ehun ingeniaritzak kaltetuta dauden ehunen ordezko funtzionalak sintetizatzeko helburua dauka. Horretarako, zelulaz, molekula bioaktiboz eta euskarri porotsuz osatutako matrizeak beharrezkoak dira, hazkuntza eta zelulen diferentziazio prozesuak gerta daitezen. Matrize horiek solidotzeko gai den aitzindari baten injekzioz eratu daitezke kaltetuta dauden ehunetan. Hori dela eta, hidrogel injektagarriak ikerkuntza arlo biomedikoan izugarri hedatu dira azken urteotan. Biomaterial horien injektagarriak izateko gaitasuna sare polimerikoen in situ gurutzaketan oinarritzen da. Gurutzaketa horiek, alde batetik, interakzio fisiko itzulgarrien bidez gerta daitezke. Hala, hidrogel termosentikorrak, pH-sentikorrak edo ionikoak eratzen dira. Bestalde, erreakzio kimikoetan ere oinarritu daitezke, zeinetan hidrogel fotopolimerizagarriak edo entzimek katalizatutako gurutzaketa bidezko hidrogelak lor daitezkeen. Lan honen helburua da hidrogel injektagarriak sintetizatzeko erabiltzen diren estrategien eta ehun ingeniaritzan ikertutako sistemen aplikazioen berrikuspen bat egitea.