The Bigger Picture: Why Oral Mucosa Heals Better Than Skin
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biomolecules Review The Bigger Picture: Why Oral Mucosa Heals Better Than Skin Maaike Waasdorp 1,* , Bastiaan P. Krom 2 , Floris J. Bikker 3 , Paul P. M. van Zuijlen 4,5,6, Frank B. Niessen 5 and Susan Gibbs 1,7 1 Department of Molecular Cell Biology and Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands; [email protected] 2 Department of Preventive Dentistry, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands; [email protected] 3 Department of Oral Biochemistry, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands; [email protected] 4 Burn Centre, and Department of Plastic, Reconstructive and Hand Surgery, Red Cross Hospital, Vondellaan 13, 1942 LE Beverwijk, The Netherlands; [email protected] 5 Department of Plastic, Reconstructive and Hand Surgery, Amsterdam Movement Sciences, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1007 MB Amsterdam, The Netherlands; [email protected] 6 Department of Pediatric Surgery, Amsterdam University Medical Centers, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands 7 Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands * Correspondence: [email protected] Abstract: Wound healing is an essential process to restore tissue integrity after trauma. Large Citation: Waasdorp, M.; Krom, B.P.; skin wounds such as burns often heal with hypertrophic scarring and contractures, resulting in Bikker, F.J.; van Zuijlen, P.P.M.; disfigurements and reduced joint mobility. Such adverse healing outcomes are less common in Niessen, F.B.; Gibbs, S. The Bigger the oral mucosa, which generally heals faster compared to skin. Several studies have identified Picture: Why Oral Mucosa Heals differences between oral and skin wound healing. Most of these studies however focus only on Better Than Skin. Biomolecules 2021, 11, 1165. https://doi.org/ a single stage of wound healing or a single cell type. The aim of this review is to provide an 10.3390/biom11081165 extensive overview of wound healing in skin versus oral mucosa during all stages of wound healing and including all cell types and molecules involved in the process and also taking into account Academic Editors: Ryan Moseley, environmental specific factors such as exposure to saliva and the microbiome. Next to intrinsic Robert Steadman and Adam C. properties of resident cells and differential expression of cytokines and growth factors, multiple Midgley external factors have been identified that contribute to oral wound healing. It can be concluded that faster wound closure, the presence of saliva, a more rapid immune response, and increased Received: 11 June 2021 extracellular matrix remodeling all contribute to the superior wound healing and reduced scar Accepted: 2 August 2021 formation in oral mucosa, compared to skin. Published: 6 August 2021 Keywords: wound healing; skin; oral; saliva; microbiome; scar; cytokines; growth factors Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Wound healing is a tightly regulated process aiming to restore tissues upon damage. Irrespective of the type of wounded tissue, the process of wound healing follows four partially overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Copyright: © 2021 by the authors. Each stage specifically involves unique cell types and (signaling) molecules. Dysregulation Licensee MDPI, Basel, Switzerland. at any phase, for example wound infection, may result in delayed wound healing, hyper- This article is an open access article distributed under the terms and trophic scar formation, and contractures [1]. Hypertrophic scars are red, raised, painful, conditions of the Creative Commons and itchy. Contractures are very stiff and often cause reduced joint mobility, thus requiring Attribution (CC BY) license (https:// multiple corrective surgeries. Up to 90% of (deep) burn wounds and 30% of surgical creativecommons.org/licenses/by/ wounds heal with hypertrophic scarring [2,3]. Hypertrophic scar formation is associated 4.0/). with increased angiogenesis and a suppressed and delayed inflammatory response [4,5]. Biomolecules 2021, 11, 1165. https://doi.org/10.3390/biom11081165 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x FOR PEER REVIEW 2 of 23 Biomolecules 2021, 11, 1165 2 of 22 surgical wounds heal with hypertrophic scarring [2,3]. Hypertrophic scar formation is as- sociated with increased angiogenesis and a suppressed and delayed inflammatory re- In general, wounds in the oral mucosa heal relatively fast and with little scarring, despite sponse [4,5]. In general, wounds in the oral mucosa heal relatively fast and with little scar- being continuously exposed to motion, tension, mechanical abrasion, and a great variety ring, despite being continuously exposed to motion, tension, mechanical abrasion, and a of microbes. In recent literature, it has been suggested that certain microbes may have a great variety of microbes. In recent literature, it has been suggested that certain microbes positivemay have effect a positive on wound effect healing, on wound for healing, example for by example training by or training alerting or the alerting immune the systemim- andmune thereby system influencing and thereby the influencing wound-healing the woun cascaded-healing [6–9 ].cascade Similar [6–9]. to skin, Similar complications to skin, duringcomplications oral wound during healing oral wound and healing underlying and underlying (autoimmune) (autoimmune) diseases diseases such as such cicatricial as pemphigoid,cicatricial pemphigoid, pemphigus pemphigus vulgaris, or vulgaris, diabetes or cause diabetes delayed cause wound delayed healing wound and healing scarring inand the scarring oral mucosa in the [10 oral,11 ].mucosa External [10,11]. factors External such as factors alcohol such and as cigarette alcohol smoke and cigarette have been shownsmoke tohave impair been oral shown wound to impair healing oral as wound well [12 healing]. Figure as1 wellillustrates [12]. Figure clinical 1 illustrates examples of humanclinical skinexamples and oral of human wounds skin and and healing oral wounds outcome. and healing outcome. FigureFigure 1.1. ComparisonComparison of of human human skin skin and and or oralal mucosal mucosal wounds wounds and and scars. scars. (a) Clinical (a) Clinical example example of a of aburn burn wound wound in inskin skin (upper (upper pictur picture)e) and andan oral an oralwound wound from fromschisis schisis corrective corrective surgery surgery (lower pic- (lower picture);ture); (b) ( clinicalb) clinical example example of a skin of a scar skin after scar burn after injury burn ( injuryupper picture (upper) pictureand an oral) and scar an after oral schisis scar after schisiscorrective corrective surgery surgery (lower (picturelower). picture ). ByBy understandingunderstanding the mechanisms mechanisms behind behind oral oral wound wound healing healing leading leading to acceptable to acceptable scarscar formation, formation, it it may may be be possible possible toto getget insightsinsights intointo howhow toto achieveachieve reducedreduced scarringscarring ofof the skinthe skin or even or even complete complete tissue tissue regeneration regeneration after after wound wound healing. healing. Several Several studies studies examinedexam- theined differences the differences between between skin and skin oral and wound oral wound healing healing that maythat explainmay explain the superior the superior healing outcomehealing outcome in oral mucosa. in oral mucosa. Most of Most these of studies these studies however however focus onlyfocus ononly a singleon a single stage of woundstage of healing wound orhealing a single or cella single type cell and type do notand takedo not into take account into account the presence the presence of saliva of or thesaliva site-specific or the site-specific microbiome. microbiome. The aim The of this aim review of this isreview therefore is therefore to compare to compare oral and oral skin woundand skin healing wound during healing the during entire the healing entire healing process, process, including including all cells all cells participating participating in the healingin the healing process process as well as as well the effectas theof effect environmental of environmental factors factors suchas such the as presence the presence of saliva andof saliva the oral and microbiome. the oral microbiome. 2. The Intrinsic Differences between Skin and Oral Mucosa When comparing the general tissue architecture, healthy skin and oral mucosa share many features, as well as have intrinsic histological differences, as illustrated in Figure2. Both tissues comprise stratified epithelia, containing keratinocytes, melanocytes, Merkel cells, and Langerhans cells, which provide protection against body fluid loss, exposure to toxins, and microbial invasion [13,14]. Although skin and oral mucosa are generally alike Biomolecules 2021, 11, 1165 3 of 22 in morphology and functions, there are differences already in homeostatic conditions