Biophysical Approaches for Oral Wound Healing: Emphasis on Photobiomodulation

Abstract

Significance: Oral wounds can lead to significant pain and discomfort as well as affect overall general health due to poor diet and inadequate nutrition. Besides many biological and pharmaceutical methods being investigated, there is growing interest in exploring various biophysical devices that utilize electric, magnetic, ultrasound, pressure, and light energy. Recent Advances: Significant insight into mechanisms of these biophysical devices could provide a clear rationale for their clinical use. Preclinical studies are essential precursors in determining physiological mechanisms and elucidation of causal pathways. This will lead to development of safe and effective therapeutic protocols for clinical wound management. Critical Issues: Identification of precise events initiated by biophysical devices, specifically photobiomodulation-the major focus of this review, offers promising avenues in improving oral wound management. The primary phase responses initiated by the interventions that distinctly contribute to the therapeutic response must be clearly delineated from secondary phase responses. The latter events are a consequence of the wound healing process and must not be confused with causal mechanisms. Future Direction: Clinical adoption of these biophysical devices needs robust and efficacious protocols that can be developed by well-designed preclinical and clinical studies. Elucidation of the precise molecular mechanisms of these biophysical approaches could determine optimization of their applications for predictive oral wound care.

Figures

Praveen Arany, DDS, PhD

Figure 1.

Different stages of wound healing. (A) Hemostasis: wound closure starts with the first phase of clotting involving formation of immediate platelet plug, followed by initiation of the coagulation cascade. Oral wounds have a rich vascular supply and the salivary proteins which aid in forming a temporary hemostatic plug. (B) Inflammation: the second phase involves migration of acute (neutrophils) and eventually chronic inflammatory (monocytes–macrophages and lymphocytes) cells into the wound area. Moist oral mucosa possesses both innate (neutrophils and macrophages) and adaptive (immunoglobulins) immunities, which quickly resolve inflammation. This is well supported by chemical and enzymatic actions of salivary constituents. (C) Proliferation: the third phase consists of migration and proliferation of keratinocytes, endothelial cells, and fibroblasts that complete closure of wound. Proliferation and activation of fibroblasts to myofibroblasts hastens wound closure. (D) Maturation: the final fourth phase involves remodeling and reorganization that can be partial (scarring) or complete (regeneration).

Figure 2.

Strategy of dissecting mechanistic events following interventions. Wound healing progression over time has discrete biological responses that include immediate events (primary—direct and indirect) and subsequent (secondary phase) events. The former represent a causal relationship with the biophysical interventions, while the latter are effector pathways that are a sequela of the wound healing process.

Figure 3.

Biophysical energies in current wound management. (A) Microcurrent: outline showing application of microcurrent energy using electrodes positioned on opposite sides of a wound in mice. (B) Pulsed electromagnetic fields (PEMFs): outline of induction of PEMFs on wounds in mice to promote healing. (C) Ultrasound: outline showing MIST™ therapy that uses low-frequency ultrasound delivered along with saline mist to the wound bed in mice.

Figure 4.

Mechanisms of photobiomodulation (PBM). Interaction of light and biological tissues leads to generation of transient and extremely reactive chemical intermediates, reactive oxygen species (ROS), in both extracellular and intracellular compartments. These ROS can react rapidly with various components inducing potent cellular responses. Among the best characterized pathways, intracellular photoabsorption by cytochrome C oxidase disrupts mitochondrial function, resulting in increased ATP synthesis and nitric oxide (NO) release. A recently elucidated extracellular pathway noted generation of ROS-mediated activation of transforming growth factor-β1 (TGF-β1) following PBM therapy. Both intracellular and extracellular pathways induce specific signal transduction pathways that recruit transcription factors leading to a concerted gene expression contributing to therapeutic PBM effects on wound healing.