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Our aim was to investigate axonal outgrowth from different tissue models on soft biomaterials based on hyaluronic acid (HA). We hypothesized that HA-based hydrogels differentially promote axonal outgrowth from different neural tissues. Spinal cord sliced cultures (SCSCs) and dorsal root ganglion cultures (DRGCs) were maintained on a collagen gel, a physically crosslinked HA-based hydrogel (Healon 5®) and a novel chemically crosslinked HA-based hydrogel, with or without the presence of neurotrophic factors (NF). Time-lapse microscopy was performed after two, five and eight days, where axonal outgrowth was assessed by automated image analysis. Neuroprotection was investigated by PCR. Outgrowth was observed in all groups; however, in the collagen group, it was scarce. At the middle timepoint, outgrowth from SCSCs was superior in both HA-based groups compared to collagen, regardless of the presence of NF. In DRGCs, the outgrowth in Healon 5® with NF was significantly higher compared to the rest of the groups. PCR revealed upregulation of NeuN gene expression in the HA-based groups compared to controls after excitotoxic injury. The differences in neurite outgrowth from the two different tissue models suggest that axons differentially respond to the two types of biomaterials.

3D bioprinting of stem cells shows promise for medical applications, but the development of an efficient bioink remains a challenge. Recently, the emergence of dynamically cross-linked hydrogels has advanced this field to obtain self-healing materials. However, more advanced bioinks are needed that display optimum gelling kinetics, viscoelasticity, shear-thinning property, structural fidelity, and hold the printed structures sufficiently long enough that allow maturation of the new tissue. Here, a novel extracellular matrix-based bioink for human mesenchymal stem cells (hMSCs) is presented. Hyaluronic acid (HA) is modified with cysteine and aldehyde functional groups, creating hydrogels with dual cross-linking of disulfide and thiazolidine products. The investigation demonstrates that this cross-linking significantly improves hydrogel stability and biological properties. The bioink exhibits fast gelation kinetics, shear-thinning, shape-maintaining properties, high cell survival after printing with >2-fold increase in stemness marker (OCT3/4 and NANOG), and supports cell proliferation and migration. Disulfide cross-linking contributes to self-healing and cell migration, while thiazolidine cross-linking reduces gelation time, enhances long-term stability, and supports cell proliferation. Overall, the HA-based bioink fulfills the requirements for successful 3D printing of stem cells, providing a promising solution for cell therapy and regenerative medicine.

Visualizing cells, tissues, and their components specifically without interference with cellular functions, such as biochemical reactions, and cellular viability remains important for biomedical researchers worldwide. For an improved understanding of disease progression, tissue formation during development, and tissue regeneration, labeling extracellular matrix (ECM) components secreted by cells persists is required. Bioorthogonal chemistry approaches offer solutions to visualizing and labeling ECM constituents without interfering with other chemical or biological events. Although biorthogonal chemistry has been studied extensively for several applications, this review summarizes the recent advancements in using biorthogonal chemistry specifically for metabolic labeling and visualization of ECM proteins and glycosaminoglycans that are secreted by cells and living tissues. Challenges, limitations, and future directions surrounding biorthogonal chemistry involved in the labeling of ECM components are discussed. Finally, potential solutions for improvements to biorthogonal chemical approaches are suggested. This would provide theoretical guidance for labeling and visualization of de novo proteins and polysaccharides present in ECM that are cell-secreted for example during tissue remodeling or in vitro differentiation of stem cells.

The immune system has a crucial role in skin wound healing and the application of specific cell-laden immunomodulating biomaterials emerged as a possible treatment option to drive skin tissue regeneration. Cell-laden tissue-engineered skin substitutes have the ability to activate immune pathways, even in the absence of other immune-stimulating signals. In particular, mesenchymal stem cells with their immunomodulatory properties can create a specific immune microenvironment to reduce inflammation, scarring, and support skin regeneration. This review presents an overview of current wound care techniques including skin tissue engineering and biomaterials as a novel and promising approach. We highlight the plasticity and different roles of immune cells, in particular macrophages during various stages of skin wound healing. These aspects are pivotal to promote the regeneration of nonhealing wounds such as ulcers in diabetic patients. We believe that a better understanding of the intrinsic immunomodulatory features of stem cells in implantable skin substitutes will lead to new translational opportunities. This, in turn, will improve skin tissue engineering and regenerative medicine applications.

Hyaluronic acid (HA), one of the main components of the extracellular matrix (ECM), is extensively used in the design of hydrogels and nanoparticles for different biomedical applications due to its critical role in vivo, degradability by endogenous enzymes, and absence of immunogenicity. HA-based hydrogels and nanoparticles have been developed by utilizing different crosslinking chemistries. The development of such crosslinking chemistries indicates that even subtle differences in the structure of reactive groups or the procedure of crosslinking may have a profound impact on the intended mechanical, physical and biological outcomes. There are widespread examples of modified HA polymers that can form either covalently or physically crosslinked biomaterials. More recently, studies have been focused on dynamic covalent crosslinked HA-based biomaterials since these types of crosslinking allow the preparation of dynamic structures with the ability to form in situ, be injectable, and have self-healing properties. In this review, HA-based hydrogels and nanomaterials that are crosslinked by dynamic-covalent coupling (DCC) chemistry have been critically assessed.

Recently, many studies have focused on carrageenan-based hydrogels for biomedical applications thanks to their intrinsic properties, including biodegradability, biocompatibility, resembling native glycosaminoglycans, antioxidants, antitumor, immunomodulatory, and anticoagulant properties. They can easily change to three-dimensional hydrogels using a simple ionic crosslinking process. However, there are some limitations, including the uncontrollable exchange of ions and the formation of a brittle hydrogel, which can be overcome via simple chemical modifications of polymer networks to form chemically crosslinked hydrogels with significant mechanical properties and a controlled degradation rate. Additionally, the incorporation of various types of nanoparticles and polymer networks into carrageenan hydrogels has resulted in the formation of hybrid platforms with significant mechanical, chemical and biological properties, making them suitable biomaterials for drug delivery (DD), tissue engineering (TE), and wound healing applications. Herein, we aim to overview the recent advances in various chemical modification approaches and hybrid carrageenan-based platforms for tissue engineering and drug delivery applications.