Natural polymer-based injectable hydrogels for cutaneous repair: polymer network design, bioactive delivery, and skin barrier restoration

Abstract

Natural polymer-based injectable hydrogels are emerging as skin-adaptive biomaterials for cutaneous repair because their hydrated networks can conform to irregular wound defects, maintain a moist microenvironment, and locally retain therapeutic agents. This review examines the relationships among natural polymer selection, network construction, bioactive delivery, and functional skin barrier restoration. Representative polymers, including γ-polyglutamic acid, alginate, chitosan, hyaluronic acid, gelatin, cellulose derivatives, dextran, silk fibroin, pullulan, agarose, and chitin, are discussed in terms of their sources, ionic characteristics, degradation behavior, and suitability for injectable hydrogel formation. Dynamic covalent bonding, Michael addition, photo-crosslinking, supramolecular assembly, metal coordination, enzyme-mediated crosslinking, and thermosensitive gelation enable networks with tunable injectability, self-healing, wet adhesion, controlled release, and biodegradation. Bioactive cargos, including polyphenols, growth factors, exosomes, antimicrobial agents, and metal-based components, further allow regulation of oxidative stress, inflammation, infection, angiogenesis, and extracellular-matrix remodeling. Particular emphasis is placed on distinguishing wound closure from functional barrier recovery through epidermal differentiation proteins, tight-junction components, transepidermal water loss, electrical resistance, and permeability assays. Current clinical evidence remains limited and is concentrated in flowable wound matrices, topical hydrogels, and injectable hyaluronic acid systems used for scar-related or adjacent aesthetic indications. Among the representative marketed products examined, no formulation combines natural-polymer injectability, in situ network formation, active-cargo delivery, and a direct indication for open-wound repair. By integrating material design, biological validation, clinical evidence, and regulatory considerations, this review highlights key requirements and remaining gaps in the development of reproducible and clinically translatable injectable hydrogels for cutaneous repair.