Bioactive Hydrogels and Scaffolds for Oral Mucosal Regeneration After Oral Squamous Cell Carcinoma Therapy: A Comprehensive Review

Oral squamous cell carcinoma (OSCC) therapy frequently produces acute and chronic injury to the oral mucosa, including surgical lining defects and radiochemotherapy-associated oral mucositis (OM). Beyond pain and ulceration, these injuries compromise nutrition, speech, oral hygiene, and feasibility of dental/implant rehabilitation, and may disrupt oncologic treatment delivery. The oral cavity imposes stringent constraints on regenerative biomaterials-continuous salivary flow, high microbial load, and repeated mechanical shear-such that clinical success depends on reliable mucoadhesion/wet adhesion, barrier function, mechanical compliance, and safe, spatially confined bioactivity. This PRISMA-informed evidence-mapped structured narrative review provides an evidence map and structured qualitative synthesis of hydrogel and scaffold platforms relevant to post-OSCC care, spanning clinically used mucoadhesive barrier formulations through emerging wet-adhesive multifunctional patches, acellular matrices, and tissue-engineered oral mucosa (TEOM) constructs. Clinically, the strongest evidence base remains barrier-forming gels and liquids that reduce OM pain and improve oral function during active therapy, establishing performance benchmarks for intraoral retention and patient-reported benefit. Preclinical studies are rapidly expanding toward multifunctional designs that integrate antimicrobial, anti-inflammatory, pro-epithelialization, and pro-angiogenic cues. However, a pervasive limitation is the inconsistent use of OSCC-relevant models (e.g., irradiated/xerostomic tissue beds), standardized functional endpoints (e.g., oral intake, durability under mastication, and neurosensory outcomes), and explicit oncologic safety evaluation, which severely compromises translational validity. For reconstructive applications, dermal matrices and early TEOM reports suggest feasibility for selected defects, but controlled comparative trials and scalable manufacturing pathways remain limited. Translational priorities include oncologic-by-design bioactivity (time-limited, locally confined cues), clinically anchored outcome reporting, and quality-by-design manufacturing aligned with device/combination/advanced-therapy regulatory requirements.