Self-Healing Injectable Polymer Hydrogel via Dynamic Thiol-Alkynone Double Addition Crosslinks

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.

Injectable PEG-induced silk nanofiber hydrogel for vancomycin delivery

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

Disulfide-Mediated Elongation of Amyloid Fibrils of α-Synuclein For Use in Producing Self-Healing Hydrogel and Dye-Absorbing Aerogel

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

The design of biocompatible, degradable, and injectable hydrogel has been attractive for achievement of safe and efficient tissue engineering. Herein, we designed a N-hydroxysuccinimide (NHS) ester-terminated ABA triblock copolymer composed of poly(ethylene glycol) (PEG) as hydrophilic A segments and poly(dl-lactide) (PLA) as B segment having hydrolysis property (NHS-PEG-b-PLA-b-PEG-NHS) to be a cross-linker of polymer segments having amine groups for facile construction of injectable and degradable hydrogel. The PLA domain, which is widely accepted hydrolyzable segments, is inherently hydrophobic and simple introduction of the NHS group on the ends of PLA would not have high reactivity in aqueous milieu to construct injectable hydrogel. Thus, in this design, hydrophilic PEG was introduced as A segments to increase the reactivity of NHS groups at the ends of linkers by increasing the mobility. To demonstrate the property as a cross-linker for constructing degradable and injectable hydrogel, carboxylmethyl chitosan (CH), which is a polymer segment having amine groups, and NHS-PEG-b-PLA-b-PEG-NHS solutions were mixed to form the hydrogel (CH/PEG-PLA-PEG) under physiological condition. The formation of CH/PEG-PLA-PEG hydrogel proceeded within minute-order period after mixing the solutions, suggesting NHS-PEG-b-PLA-b-PEG-NHS is applicable to the cross-linker for construction of injectable hydrogel system with time-dependent gelation property. Degradation of the obtained CH/PEG-PLA-PEG hydrogel was observed, whereas that of CH/PEG, which was prepared from NHS-PEG-NHS and CH, was not observed, appealing the degradation property of the CH/PEG-PLA-PEG hydrogel based on hydrolysis of the PLA domain. Furthermore, chondrocytes embedded in CH/PEG-PLA-PEG hydrogels promoted collagen synthesis compared to CH/PEG. These demonstrations indicate the designed NHS-PEG-b-PLA-b-PEG-NHS is a promising cross-linker to construct the injectable and degradable hydrogel and eventually promote hydrogel performance as a tissue regeneration scaffold.

Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality in those with hepatic encephalopathy (HE). Polyethylene glycol (PEG) 3350 electrolyte solution can ensure rapid gut catharsis, which may resolve HE more effectively than lactulose. In this open-label-randomized trial, we compared PEG+lactulose versus lactulose alone in ACLF with HE grade ≥2 for efficacy and outcome. Patients were randomized to receive PEG (2 L q12 h) followed by lactulose (30 mL q8 h) or standard medical treatment [SMT, lactulose (titrated 30 mL q8 h)]. Endpoints were HE grade improvement at 24 hours, 48 hours, and 7 days using hepatic encephalopathy scoring algorithm (HESA), ammonia reduction, HE resolution, and survival benefit. Of 60 patients, 29 were randomized to PEG+lactulose arm and 31 to SMT. In the PEG arm, early reduction in HESA score was noted in more persons [18 (62.1%) vs. 10 (32.2%); P=0.021] with a shorter median time to HE resolution [4.5 (3 to 9) d vs. 9 (8 to 11) d; P=0.023]. On multivariate analysis, age [hazard ratio (HR),1.06 (1.00 to 1.13); P=0.03], HESA score [HR, 6.01 (1.27 to 28.5); P=0.024], and model for end-stage liver disease [HR, 1.26 (1.01 to 1.53); P=0.022] were predictors of mortality at 28 days. Ammonia level or reduction did not correlate with HE grades. Adverse events included excessive diarrhea (20.6% vs. 9.6%) in the PEG and SMT arms, albeit without dyselectrolytemia or worsened renal function. In the PEG versus SMT arm, survival at 28 days were 93.1% versus 67.7% (P=0.010) and at 90 days was 68.9% versus 48.3% (P=0.940), respectively, with fewer persons relapsing with HE in the PEG arm. PEG resulted in early and sustained HE resolution with improved short-term survival making, it a suitable and safe drug in patients with acute HE in ACLF.

Articular cartilage degeneration and focal defects contribute to chronic pain and functional limitation, yet durable regeneration remains challenging because cartilage is avascular and has low cellularity. Injectable hydrogels adaptively fill defects, which can provide an extracellular matrix microenvironment and deliver therapeutic signals. This review surveys recent injectable hydrogel technologies for articular cartilage regeneration, emphasizing how network formation mechanisms govern retention and early function at the joint. Three representative strategies are discussed, including in situ gelling systems where precursor is injected and solidified on demand, shear thinning and self-healing hydrogels that flow under shear via reversible interactions and recover after injection, and injectable hydrogel microparticles where building blocks assemble into porous scaffolds. The results reveal that successful injectable hydrogels are a balance among operability, spatiotemporal control of network formation, early structural integrity, and tissue interaction.

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

Tissue engineering intends to create functionalized tissues/organs for regenerating the injured parts of the body using cells and scaffolds. A scaffold as a supporting substrate affects the cells' fate and behavior, including growth, proliferation, migration, and differentiation. Hydrogel as a biomimetic scaffold plays an important role in cellular behaviors and tissue repair, providing a microenvironment close to the extracellular matrix with adjustable mechanical and chemical features that can provide sufficient nutrients and oxygen. To enhance the hydrogel performance and compatibility with native niche, the cell-laden hydrogel is an attractive choice to mimic the function of the targeted tissue. Injectable hydrogels, due to the injectability, are ideal options for in vivo minimally invasive treatment. Cell-laden injectable hydrogels can be utilized for tissue regeneration in a noninvasive way. This article reviews the recent advances and future opportunities of cell-laden injectable hydrogels and their functions in tissue engineering. It is expected that this strategy allows medical scientists to develop a minimally invasive method for tissue regeneration in clinical settings. Impact statement Cell-laden hydrogels have been vastly utilized in biomedical application, especially tissue engineering. It is expected that this upcoming review article will be a motivation for the community. Although this strategy is still in its early stages, this concept is so alluring that it has attracted all scientists in the community and specialists at academic health centers. Certainly, this approach requires more development, and a bunch of crucial challenges have yet to be solved. In this review, we discuss this various aspects of this approach, the questions that must be answered, the expectations associated with it, and rational restrictions to develop injectable cell-laden hydrogels.

Utilizing the abnormal physiological conditions of disease tissues can result in a site-specific functionality with high control and efficiency of stimuli-responsive hydrogels. Here, a physiologically relevant pH-responsive and self-healing hydrogel is reported based on coordination between Ni2+ and four-arm poly(ethylene glycol)-b-polyhistidine (4PEG-PHis) that is synthesized by a novel and facile PHis preparation method using amino-terminalized four-arm PEG as the macroinitiator. Reversible PHisNi coordination bonds endow the hydrogel with multistimuli-triggered sol-gel transition (physiologically relevant pH, EDTA) and self-healing properties. It is also demonstrated that 4PEG-PHis could be used as an injectable hydrogel in phosphate buffer (pH 7.4), and excellent stability in neutral buffer via multivalent coordination is shown, thus indicating its potential applications in controlled drug release systems.

For treating bone defects in periarticular fractures, there is a lack of biomaterial with injectable characteristics, tough structure, and osteogenic capacity for providing a whole-structure support and osteogenesis in the defect area. An injectable hydrogel is an ideal implant, however is weak as load-bearing scaffolds. Herein, a new strategy, i.e., an in situ formation of "active" composite double network (DN), is raised for the preparation of an injectable strong hydrogel particularly against compression. As a demonstration, 4-carboxyphenylboronic acid grafted poly(vinyl alcohol) (PVA) is crosslinked using calcium ions to provide a tough frame while bioactive glass (BG) microspheres are associated by poly(ethylene glycol) to obtain an interpenetrated inorganic network for reinforcement. The injected PVA/BG DN hydrogel gains compressive strength, modulus, and fracture energy of 34 MPa, 0.8 MPa, and 40 kJ m-2 , respectively. Then, the properties can be "autostrengthened" to 57 MPa, 2 MPa, and 65 kJ m-2 by mineralization in 14 days. In vivo experiments prove that the injected DN hydrogel is more efficient to treat femoral supracondylar bone defects than the implanted bulk DN gel. The work suggests a facile way to obtain a strong hydrogel with injectability, cytocompatibility, and tailorable functionality.

Recently, injectable hydrogels have been considered smart materials and have been widely researched for their use as scaffolds. They resemble the extracellular matrix of native tissue and have the capability for homogeneous mixing with therapeutic agents. It can be implanted into living bodies with minimal invasiveness and usability for irregularly shaped sites. Such unique features make the injectable hydrogels as promising materials in tissue engineering, drug delivery system, and gene/protein delivery. This review article provides a comprehensive overview of the different mechanisms employed in the preparation of injectable hydrogel, as well as a detailed exploration of its applications in the biomedical field. Furthermore, the article highlights the critical importance of developing injectable hydrogels as market‐viable products, highlighting their potential impact in the field of regenerative medicine.

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

Self-healing injectable hydrogels can be formulated as three-dimensional carriers for the treatment of neurological diseases with desirable advantages, such as avoiding the potential risks of cell loss during injection, protecting cells from the shearing force of injection. However, the demands for biocompatible self-healing injectable hydrogels to meet above requirements and to promote the differentiation of neural stem cells (NSCs) into neurons remain a challenge. Herein, we developed a biocompatible self-healing polysaccharide-based hydrogel system as a novel injectable carrier for the delivery of NSCs. N-carboxyethyl chitosan (CEC) and oxidized sodium alginate (OSA) are the main backbones of the hydrogel networks, denoted as CEC-l-OSA hydrogel (“l” means “linked-by”). Owing to the dynamic imine cross-links formed by a Schiff reaction between amino groups on CEC and aldehyde groups on OSA, the hydrogel possesses the ability to self-heal into a integrity after being injected from needles under physiological conditions. The CEC-l-OSA hydrogel in which the stiffness mimicking nature brain tissues (100~1000 Pa) can be finely tuned to support the proliferation and neuronal differentiation of NSCs. The multi-functional, injectable, and self-healing CEC-l-OSA hydrogels hold great promises for NSC transplantation and further treatment of neurological diseases.