Citation: Mony,M.P.; Harmon, K.A.; Hess, R.; Dorafshar, A.H.; Shafikhani, S.H. An Updated Review of Hypertrophic Scarring. Cells 2023, 12, 678. https://doi.org/10.3390/ cells12050678 Academic Editor: Mohamad Goldust Received: 20 December 2022 Revised: 1 February 2023 Accepted: 8 February 2023 Published: 21 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cells Review An Updated Review of Hypertrophic Scarring Manjula P. Mony 1,† , Kelly A. Harmon 1,† , Ryan Hess 1 , Amir H. Dorafshar 1 and Sasha H. Shafikhani 2,3, * 1 Department of Surgery, Division of Plastic & Reconstructive Surgery, Rush University Medical Center, Chicago, IL 60612, USA 2 Department of Medicine, Division of Hematology and Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA 3 Cancer Center, Rush University Medical Center, Chicago, IL 60612, USA * Correspondence: sasha_shafikhani@rush.edu † These authors contributed equally to this work. Abstract: Hypertrophic scarring (HTS) is an aberrant form of wound healing that is associated with excessive deposition of extracellular matrix and connective tissue at the site of injury. In this review article, we provide an overview of normal (acute) wound healing phases (hemostasis, inflammation, proliferation, and remodeling). We next discuss the dysregulated and/or impaired mechanisms in wound healing phases that are associated with HTS development. We next discuss the animal models of HTS and their limitations, and review the current and emerging treatments of HTS. Keywords: normal (acute) wound healing; hypertrophic scar; keloids; animal models; treatments 1. Introduction Wound healing is a complex physiologic process in which the body attempts to replace destroyed and damaged tissue with newly generated tissue and restore the skin’s barrier functions. It is an overlapping and sequential process of hemostasis, inflammation, prolifer- ation, and remodeling that involves communication between many different cell types [1]. When this process does not occur in a sequential and finite manner, aberrant wound healing with hypertrophic scarring (HTS) or keloids may occur. These fibroproliferative disorders can be appreciated as elevated scars above the skin level with abundant deposition of extracellular matrix (ECM) components, especially collagen [2]. Although HTS and keloids are often used interchangeably, they are not the same. In HTS, excess scarring is limited to the original site of injury, whereas in keloids, scarring can extend beyond the original wound and is often regarded as a form of benign skin tumor [3,4]. Scarring is a major clinical problem, affecting some 100 million patients in the devel- oped world alone [5]. The reported prevalence of hypertrophic scarring ranges from 32 to 72% [6,7]. Hypertrophic scars are particularly prevalent among adult burn patients, with those with darker skin, younger age, female sex, burns greater than 20% of total body sur- face area (TBSA), and burns on the neck and upper limbs experiencing the highest risk [6,8]. Following burn injury, nearly 75% of patients develop neuropathic pain [9]. Factors such as scar height, pigmentation, vascularity, and hyperplasia have been associated with increased levels of pain [9]. In one study, nearly 60% of patients who underwent bilateral reduction mammoplasty or median sternotomy incision developed HTS postoperatively, with an increased risk in those who were young [10]. Keloids have been reported in all ethnic groups, but they are significantly more common in individuals of African, Asian, and to a lesser degree, Hispanic descent, with the incidence ranging from 0.09% amongst the European white population, to 16% in the black population in Africa [11–13]. Severe HTS may result in scar contractures which can be significantly disfiguring and disabling and may lead to loss of mobility and affect patients’ ability to carry out routine daily activities [14, 15]. In patients with severe burns, HTS is associated with decreased quality of life and delayed reintegration into society, in part due to the effect on self-esteem and the Cells 2023, 12, 678. https://doi.org/10.3390/cells12050678 https://www.mdpi.com/journal/cells