Review Periodontal Wound Healing and Tissue Regeneration: A Narrative Review pharmaceuticals Young-Dan Cho, Kyoung-Hwa Kim, Yong-Moo Lee, Young Ku and Yang-Jo Seol * Review Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University Periodontal Woundand Seoul Healing National University and Dental Tissue Hospital, Regeneration: Seoul 03080, Korea; [email protected] (Y.-D.C.); A Narrative [email protected] (K.-H.K.); [email protected] (Y.-M.L.); [email protected] (Y.K.) * Correspondence: [email protected]; Tel.: +82-2-2072-0308 Young-Dan Cho, Kyoung-Hwa Kim , Yong-Moo Lee, Young Ku and Yang-Jo Seol * Abstract: Periodontal disease is a major public health issue, and various periodontal therapies have beenDepartment performed of Periodontology, to regenerate School of periodontal Dentistry and Dental tissues Research. The Institute, periodontium Seoul National is Universitya complex and structure com- posedSeoul National of specialized University Dentaltissues Hospital, that support Seoul 03080, the Korea; teeth, [email protected] and most periodontal (Y.-D.C.); surgeries are invasive pro- [email protected] (K.-H.K.); [email protected] (Y.-M.L.); [email protected] (Y.K.) cedures,* Correspondence: including [email protected]; a resection Tel.: of +82-2-2072-0308 the gingiva or the alveolar bone. The periodontal wound healing process is slightly different from cutaneous wound healing and is similar to fetal healing, being almostAbstract: scar-free.Periodontal The disease aim of is athis major review public article health issue,is to andprovide various an periodontal overview therapiesof periodontal wound have been performed to regenerate periodontal tissues. The periodontium is a complex structure healing and discuss various surgical and pharmaceutical approaches to achieve stable wound heal- composed of specialized tissues that support the teeth, and most periodontal surgeries are invasive ingprocedures, and improve including the a resectiontreatment of the outc gingivaomes. or theIn addition, alveolar bone. detrimental The periodontal and woundlimiting healing factors that induce aprocess compromised is slightly prognosis different from are cutaneous discussed, wound along healing with and the is perspective similar to fetal and healing, future being direction for suc- Citation: Cho, Y.-D.; Kim, K.-H.; cessfulalmost scar-free.periodontal The aimtissue of thisregeneration. review article is to provide an overview of periodontal wound Lee, Y.-M.; Ku, Y.; Seol, Y.-J. Perio- healing and discuss various surgical and pharmaceutical approaches to achieve stable wound healing dontal Wound Healing and Tissue Keywords:and improve periodontium; the treatment outcomes. periodontal In addition, tissue detrimental regeneration; and limiting wound factors healing that induce a Regeneration: A Narrative Review. compromised prognosis are discussed, along with the perspective and future direction for successful Pharmaceuticals 2021, 14, x. periodontal tissue regeneration. https://doi.org/10.3390/xxxxx Keywords: periodontium; periodontal tissue regeneration; wound healing Citation: Cho, Y.-D.; Kim, K.-H.; Lee, Academic Editor: Yayoi Kawano, 1. Introduction Y.-M.; Ku, Y.; Seol, Y.-J. Periodontal Viorica Patrulea,Wound Healing Mitsutoshi and Tissue Sato, The periodontium acts as a supporting apparatus for the teeth and is a complex struc- Olivier JordanRegeneration: and Takehisa A Narrative Han- Review. ture1. Introduction consisting of soft and hard tissues [1]. The main functions of the periodontium are to awa Pharmaceuticals 2021, 14, 456. ensureThe that periodontium the teeth actsare asattached a supporting to the apparatus bones; to for protect the teeth the and nerves, is a complex blood vessels, and https://doi.org/10.3390/ph14050456 teethstructure from consisting injuries; of softand and to hardprovide tissues a [barrier1]. The main to the functions underlying of the periodontium structures from the oral Received: 15 April 2021 are to ensure that the teeth are attached to the bones; to protect the nerves, blood vessels, Academic Editors: Yayoi Kawano, microbiome. Soft tissue includes the gingiva, mucosa, and periodontal ligament (PDL), Accepted: 11 May 2021 and teeth from injuries; and to provide a barrier to the underlying structures from the oral Viorica Patrulea, Mitsutoshi Sato, andmicrobiome. hard tissue Soft tissueincludes includes the cementum the gingiva, mucosa,and the and alveolar periodontal bone ligament (Figure (PDL),1). Published:Olivier 12 May Jordan 2021 and Takehisa Hanawa and hard tissue includes the cementum and the alveolar bone (Figure1). Received: 15 April 2021 Publisher’s Note: MDPI stays neu- Accepted: 11 May 2021 tral with regard to jurisdictional Published: 12 May 2021 claims in published maps and institu- tional affiliations.Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article Copyright: © 2021 by the authors. distributedLicensee under MDPI, the terms Basel, and Switzerland. con- ditions ofThis the article Creative is an Commons open access At- article tributiondistributed (CC BY) license under (http://crea- the terms and conditions of the Creative Commons tivecommons.org/licenses/by/4.0/). Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ FigureFigure 1.1.The The structure structure of periodontium. of periodontium. 4.0/). Pharmaceuticals 2021, 14, 456. https://doi.org/10.3390/ph14050456 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 456 2 of 17 The gingiva is a covering tissue that protects the alveolar bone from external stimuli such as microbial attack or mechanical force and consists of epithelial and connective tissues. The general risk factor of periodontal disease is oral microbial infection, which can induce inflammation of the gingiva, and if not treated on time, it affects the periodontium in general [2,3]. Periodontal disease is the most common oral disease with a high prevalence of 20–50% of the world population [4]. Gingivitis and periodontitis are typical periodon- tal diseases [1]. Gingivitis is the mildest form of periodontal disease, which is limited to gingival inflammation and is reversible [5]. Conversely, periodontitis is irreversible, accompanied by alveolar bone defect, can induce tooth mobility when untreated, and finally, leads to tooth extraction [6]. Periodontal defect is caused by chronic pathological conditions, such as periodontitis, and exhibits the loss of gingiva, periodontal ligament, and alveolar bone. Various procedures to support the regeneration of the periodontal tissue as well as therapeutics to enhance the wound healing process have been studied. A specialized oral environment with saliva and oral microorganisms can affect the defect for- mation and wound healing process. The objective of this review is to provide an overview of periodontal wound healing and discuss the complications and factors influencing the healing process and therapeutics for improving periodontal wound healing. 2. Normal Wound Healing Wound healing is a dynamic process, which has been a challenge in the clinical setting after treatment. Much effort has been focused on wound management for developing healing techniques and new treatment approaches. Basically, the wound healing pro- cess consists of four distinct but overlapping phases [7]: 1. hemostasis and coagulation, 2. inflammation, 3. cell proliferation, and 4. wound remodeling and maturation (Figure2). This general principle of wound healing also applies to periodontal wound healing [8]. The wound healing procedure involves several types of cells, extracellular matrix, cytokines, and growth factors. Understanding wound healing with regard to various aspects of cells, molecules, physiology, and biochemistry is important to regenerate tissues that are functionally and structurally indistinguishable from the original tissue and not repaired tissue with fibrotic scars. If there is an injury that damages the vessel, hemorrhage is the first process to begin on the wound site. Under normal conditions, a molecular machinery for blood clot formation is immediately operated, protecting the injury site and serving the provisional matrix for cell migration. Blood clot formation continues to the initial in- flammatory stage, in which inflammatory cells, including polymorphonuclear neutrophils and monocytes, are activated. These cells clean the wounds of necrotic tissue and bacteria and secrete various enzymes for wound debridement. This inflammatory response shifts into the late phase where macrophages move into the wound area and secrete cytokines or growth factors for the cells involved in the wound healing process. Following the inflammatory stage, granulation tissue formation is initiated with collagen accumulation. Cytokines and growth factors by macrophages induce the migration and proliferation of fibroblasts and endothelial cells into the wound site. This cell-rich granulation tissue activates the phase of matrix formation and maturation. Fibroblasts replace the provisional extracellular matrix by producing a new collagen-rich matrix, and the endothelial cells are involved in angiogenesis for vascularization. Subsequently, wound epithelization is conducted by epithelial cells from the basal layer.