Hyaluronic Acid-Based Gels and Biomaterial Systems for Oral Wound Healing: Design and Clinical Translation
Summary: Published March 22, 2026 in Gels (MDPI, Special Issue: Designing Gels for Wound Healing and Drug Delivery Systems), this narrative review from Grigore T. Popa University of Medicine and Pharmacy (Iași, Romania), led by Vlad Constantin and Ionut Luchian (corresponding author), with co-authors from multiple clinical and basic science departments, provides a comprehensive synthesis of hyaluronic acid (HA) biology, material design principles, and clinical performance evidence specifically within the oral wound healing context. While focused on oral and periodontal wounds, the biological and biomaterial principles covered are directly relevant to wound care clinicians managing non-healing wounds, skin grafts, and biomaterial-based dressing systems, as HA is one of the most widely investigated biomaterials across all wound healing applications. HA is a non-sulfated glycosaminoglycan and fundamental ECM component that plays critical roles in tissue hydration, cellular signalling, angiogenesis, inflammation modulation, and matrix remodelling throughout the four wound healing phases. Its biological behaviour is strongly molecular weight-dependent: high-molecular-weight HA (>1,000 kDa) exerts anti-inflammatory, anti-edematous, and protective/barrier effects, contributing to tissue homeostasis; low-molecular-weight HA fragments (<20 kDa) act as endogenous danger signals (DAMPs) activating innate immunity via TLR-4, and also promote cell migration, angiogenesis, and tissue remodelling. In oral wounds — complicated by salivary dilution, mechanical stress, microbial exposure, and enzymatic degradation — formulation design is critical. The review systematically covers: topical HA gels (0.1–0.8% concentration range; shear-thinning rheology essential for retention; salivary ionic composition affects gel viscosity and structural integrity); cross-linked HA hydrogels (BDDE, DVS, carbodiimide, and enzymatic cross-linking strategies; enhanced mechanical stability vs. reduced receptor accessibility trade-off; optimal degree of modification balances CD44/RHAMM receptor interaction with degradation resistance); and HA-based membranes and 3D scaffolds (fabricated by freeze-drying, electrospinning, or composite blending with collagen or chitosan; provide guided tissue regeneration, structural support, and bioactive modulation in periodontal and surgical contexts). Clinical evidence covers applications in post-extraction socket healing, periodontal flap surgery, peri-implant soft tissue management, and oral mucosal ulceration — with consistent findings of reduced postoperative pain, accelerated re-epithelialisation, and decreased edema in short-term follow-up. The review is candid about limitations: substantial heterogeneity in formulation parameters across clinical studies makes direct comparison impossible; most trials have small sample sizes and short follow-up; and few studies systematically correlate physicochemical properties with clinical outcomes. The authors call for well-designed multicenter RCTs with standardised HA formulations and harmonised outcome measures.
Key Highlights:
- Molecular weight-dependent biology: high-MW HA (>1,000 kDa) is anti-inflammatory and barrier-protective; low-MW HA fragments (<20 kDa) activate TLR-4 innate immune signalling, promote angiogenesis, and stimulate cell migration — size-dependent effects must inform formulation design for targeted wound healing applications
- Receptor signalling: HA exerts key wound healing effects via CD44 and RHAMM (Receptor for Hyaluronan-Mediated Motility) receptor interactions — regulating cytoskeletal organisation, cell migration, proliferation, and fibroblast-mediated ECM deposition; cross-linking density can mask receptor-interacting domains, reducing biological activity if over-engineered
- Formulation design imperatives for oral wounds: HA gels must exhibit shear-thinning (pseudoplastic) rheology; storage modulus (G′) must exceed loss modulus (G″) for structural retention against salivary washout; ionic composition of saliva (Na, Ca, phosphate) affects intermolecular charge screening and viscosity — requiring formulation-specific rheological optimisation
- Cross-linking strategy comparison: BDDE and DVS cross-linking provide superior mechanical stability but risk cytotoxicity at high concentrations and reduced CD44 accessibility; carbodiimide and enzymatic cross-linking offer improved biocompatibility with moderate stability; physical/self-assembly systems are safest but most susceptible to salivary dilution
- Clinical evidence summary: HA gels consistently reduce postoperative pain, edema, and inflammatory markers, and accelerate re-epithelialisation in periodontal surgery, extraction sockets, peri-implant procedures, and mucosal ulceration — with best evidence in short-term applications; long-term data and standardised RCT evidence remain limited
- Transferability to general wound care: the biological principles and formulation design challenges described — MW-dependent effects, cross-linking optimisation, receptor-mediated signalling, hydrogel rheology — are directly applicable to HA-based dressings used in non-oral chronic wounds including venous ulcers, DFUs, and post-surgical wounds
Keywords: hyaluronic acid wound healing, HA gel wound dressing design, hyaluronan biomaterial tissue repair, cross-linked hydrogel wound healing, CD44 wound healing ECM, extracellular matrix wound repair
Vlad Constantin, Ionut Luchian, Dragos Ioan Virvescu, Mihaela Scurtu, Nicoleta Tofan, Dan Nicolae Bosinceanu, Elena Raluca Baciu, Carina Balcos, Monica Mihaela Scutariu, Dana Gabriela Budala