Diabetic wound healing in soft and hard oral tissues

Abstract

There is significant interest in understanding the cellular mechanisms responsible for expedited healing response in various oral tissues and how they are impacted by systemic diseases. Depending upon the types of oral tissue, wound healing may occur by predominantly re-eptihelialization, by re-epithelialization with substantial new connective tissue formation, or by a a combination of both plus new bone formation. As a result, the cells involved differ and are impacted by systemic diaseses in various ways. Diabetes mellitus is a prevalent metabolic disorder that impairs barrier function and healing responses throughout the human body. In the oral cavity, diabetes is a known risk factor for exacerbated periodontal disease and delayed wound healing, which includes both soft and hard tissue components. Here, we review the mechanisms of diabetic oral wound healing, particularly on impaired keratinocyte proliferation and migration, altered level of inflammation, and reduced formation of new connective tissue and bone. In particular, diabetes inhibits the expression of mitogenic growth factors whereas that of pro-inflammatory cytokines is elevated through epigenetic mechanisms. Moreover, hyperglycemia and oxidative stress induced by diabetes prevents the expansion of mesengenic cells that are involved in both soft and hard tissue oral wounds. A better understanding of how diabetes influences the healing processes is crucial for the prevention and treatment of diabetes-associated oral complications.

Figure 1.. Re-epithelialization in diabetic oral wounds.

Left, location of different types of oral mucosa Right graphical diagram of diabetic impact on epithelialization in oral wounds Diabetes causes hyperglycemia and production of advanced glycation end-produce (AGEs) and reactive oxygen species (ROS). This in tum increases recruitment of neutrophil recruitment and redues microbial diversity. oareover, salivary content for pro-healing factors (EGF end histatin) is reduced whereas those that cause destruction (MMP2 and MMP9) are enhanced Another mechanism is FOXO1-mediated overexpression of MMP9 by keratinocytes. The overall outcome is persistent inflammation and an environment that is conducive for keratinocyte apoptosis, coupled with reduced keratinocyte proliferation anti migration

Figure 2.. Connective tissue healing in diabetic oral wounds.

Gingiva is composed of a thick layer of lamina propria overlaying bone. Diabetes-mediated hyperglycemia and ROS are the major driving force for directly induced fibroblast apoptosis and inhibiting proliferation. Moreover, fibroblasts express enhanced levels of pro-inflammatory cytokines IL-6, IL-8 sad MMP-1 in diabetic gingival wounds. Diabetes also interferes with a phagocytic function of macrophages and ttuedir polarisation from pro-inflammatory (MI) to pro-resolving (M2) type. Diabetes-induced epigenetic changes prevent resolution of inflammation. The promoter region of TGFb1 in kerartinocytes are methylated by high glucose whereas that of ITNF in marcphages are acetylated, resulting in reduced anti-inflammatory TGFb1 expression and over-expression of pro-inflammatory TNF. The overall outcome is persistent inflammation, which reduces stromal healing outcome.

Figure 3.. Diabetic impact on various cases of intraoral bone healing.

In the oral cavity, bone healing takes place under different scenarios inch as. left right, periodontal bone regeneration, guided bone regeneration. healing after dental extraction, or pathological healing such as MRONJ. Diabetes significantly delays bone healing in each of these processes. In periodontal bone healing, diabetes enhances osteoclastogenesis while reducing the number of osteoblasts its and periodnotal fibroblasts This is accompanied by persistent inflammation and reduced growth factor expression. In guided bone regeneration, which, restores the hard tissue volume necessary for dental implant placement, diabetes has shown to inhtbit genes associated with cell division and osteogenesis. In exodontia, diabetes delays socket healing through elevation of pro-inflammatory cytokines such as TNF, which may indirectly suppress proper expansion of osteogenic stem cells. Diabetes is a significant co-morbidity for MRONJ. and although exact pathogenesis is unclear, experimental studies have shoun enhanced apoptosis, persistent inflammation and improper recruitment of leukocytes as a converging mechanism.