Oral wound healing models and emerging regenerative therapies

Abstract

Following injury, the oral mucosa undergoes complex sequences of biological healing processes to restore homeostasis. While general similarities exist, there are marked differences in the genomics and kinetics of wound healing between the oral cavity and cutaneous epithelium. The lack of successful therapy for oral mucosal wounds has influenced clinicians to explore alternative treatments and potential autotherapies to enhance intraoral healing. The present in-depth review discusses current gold standards for oral mucosal wound healing and compares endogenous factors that dictate the quality of tissue remodeling. We conducted a review of the literature on in vivo oral wound healing models and emerging regenerative therapies published during the past twenty years. Studies were evaluated by injury models, therapy interventions, and outcome measures. The success of therapeutic approaches was assessed, and research outcomes were compared based on current hallmarks of oral wound healing. By leveraging therapeutic advancements, particularly within in cell-based biomaterials and immunoregulation, there is great potential for translational therapy in oral tissue regeneration.

Figure 1:

Graphical representation of the structural and functional differences in cutaneous epithelium versus oral mucosa. The cutaneous epithelium consists of three distinct layers: the epidermis, dermis, and hypodermis (1–1). The skin can utilize additional routes for enhanced transcutaneous permeability through intracellular, transcellular, and transappendageal pathways using pores and hair follicles. In contrast, the oral mucosa is composed of stratified squamous epithelium, followed by the basement membrane, lamina propria, and submucosa (1–2). Exclusive to the oral environment, saliva contains mucins, histatins, peptides, peroxidase, and growth factors that play a role in oral homeostasis. An injured oral mucosa is susceptible to infections caused by bacteremia, due to a complex oral microflora with an upward of millions of microorganisms.

Figure 2:

Timeline of oral wound healing and oral mucosal remodeling. Following injury, the hemostatic cascade is initiated to prevent excessive bleeding at the wound site (2–1). In the days following injury, inflammation peaks through neutrophil debridement and macrophage-mediated secretion of inflammatory cytokines (2–2). Within a week, the proliferation phase promotes fibroblast migration, increases vascular networks by angiogenesis, and enhances macrophage migration (2–3). Following fibroblast migration, the tissue surrounding the defect begins to re-epithelialize and mature by aligned fibrillar and dense collagen networks (2–4).

Figure 3:

Schematic of current models and therapeutics to promote oral wound healing. Injury models are primarily studied in the palatal, buccal, and gingival regions of the oral cavity. Current modalities for oral wound healing include a wide variety of delivery vehicles, such as polymeric scaffolds, biological matrices, or gel-like ointment. The delivery vehicles can also be coupled with drugs, cells, tissue, or growth factors to enhance therapeutic efficacy. Following treatment, studies evaluated the success of oral wound healing therapy using both qualitative and quantitative approaches, such as histology for tissue re-epithelialization, flow cytometry for immune cell infiltration, and microscopy images for wound closure.