The Spectrum of Scarring in Craniofacial Wound Repair

Abstract

Fibrosis is intimately linked to wound healing and is one of the largest causes of wound-related morbidity. While scar formation is the normal and inevitable outcome of adult mammalian cutaneous wound healing, scarring varies widely between different anatomical sites. The spectrum of craniofacial wound healing spans a particularly diverse range of outcomes. While most craniofacial wounds heal by scarring, which can be functionally and aesthetically devastating, healing of the oral mucosa represents a rare example of nearly scarless postnatal healing in humans. In this review, we describe the typical wound healing process in both skin and the oral cavity. We present clinical correlates and current therapies and discuss the current state of research into mechanisms of scarless healing, toward the ultimate goal of achieving scarless adult skin healing.

Keywords: craniofacial tissues; fibroblasts; fibrosis; oral mucosa; scarring; tissue regeneration; wound healing; wound repair.

FIGURE 1

Timeline of normal human cutaneous wound healing. Wound healing following hemostasis takes place in three overlapping stages: inflammation, proliferation, and maturation/remodeling. While differences exist in the soft tissue defect repair process between different species, developmental timepoints, and anatomical sites, the fundamental steps are conserved in the vast majority of examples of adult mammalian wound healing. During the inflammatory phase (which peaks at 24–48 h post-wounding and lasts for several days), immune cells such as neutrophils and macrophages debride the wound, eliminate contaminating microbes, and secrete an array of cytokines and growth factors to recruit other cells involved in healing to the wound site. The process of re-epithelialization begins within hours of injury and accomplishes wound closure over the course of days to weeks by reestablishing a functional epithelial cell barrier. The proliferative phase (which begins 4–5 days after wounding and may last for several weeks) involves the formation of granulation tissue (by fibroblasts, endothelial cells, etc.) as a temporary substrate to fill the soft tissue defect. Finally, during the maturation/remodeling phase (the longest stage, beginning at approximately week 3 post-wounding and lasting for as long as 1–2 years), the wound bed becomes less cellular via apoptosis, and the extracellular matrix is remodeled to gradually increase in strength.

FIGURE 2

The spectrum of human wound healing. Outcomes of human soft tissue defect repair represent a broad spectrum and vary based on wound context. Regenerative healing (top) (for example, in early gestation fetuses) is the “ideal” healing outcome and results in tissue that is indistinguishable from unwounded tissue. Typical adult cutaneous healing results in some fibrosis with formation of a normal scar (middle), which contains collagen oriented in a dense, parallel alignment and does not regrow any dermal appendages (e.g., hair follicles). In certain instances, a pathological scar (bottom), such as a hypertrophic scar or keloid, may be generated. Compared to normal scars, these hyperfibrotic scars have even denser and more collagen, are more grossly apparent with increased discoloration, and may be pruritic or painful.

FIGURE 3

Photographs of patients with cleft lip and palate repair resulting in maxillary growth restriction. Frontal photograph (A) and lateral photograph (B) of 16-year-old female with right cleft lip and palate. Note deficient midface projection associated with maxillary hypoplasia. (C) Intraoral photograph of same patient demonstrating significant malocclusion. Frontal photograph (D) and lateral photograph (E) of 18-year-old male with right cleft lip and palate. (F) Significant malocclusion can also be appreciated in this patient on intraoral examination. Written informed consent was obtained from the depicted individuals for the publication of these images.

FIGURE 4

Key differences between cutaneous and oral mucosal wound healing. Several distinctions exist between typical healing of cutaneous wounds involving the dermis (which results in fibrosis) and uncomplicated oral mucosal healing (which is minimally scarring). Notable differences, summarized above, exist both in the healing wound (with regard to participating cells and degree of angiogenesis) and in the fully healed wound (with regard to resulting matrix composition and gross appearance).