Collagen in Wound Healing
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bioengineering Review Collagen in Wound Healing Shomita S. Mathew-Steiner, Sashwati Roy and Chandan K. Sen * Indiana Center for Regenerative Medicine and Engineering, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; [email protected] (S.S.M.-S.); [email protected] (S.R.) * Correspondence: [email protected]; Tel.: +1-317-278-2735 Abstract: Normal wound healing progresses through inflammatory, proliferative and remodeling phases in response to tissue injury. Collagen, a key component of the extracellular matrix, plays critical roles in the regulation of the phases of wound healing either in its native, fibrillar conformation or as soluble components in the wound milieu. Impairments in any of these phases stall the wound in a chronic, non-healing state that typically requires some form of intervention to guide the process back to completion. Key factors in the hostile environment of a chronic wound are persistent inflammation, increased destruction of ECM components caused by elevated metalloproteinases and other enzymes and improper activation of soluble mediators of the wound healing process. Collagen, being central in the regulation of several of these processes, has been utilized as an adjunct wound therapy to promote healing. In this work the significance of collagen in different biological processes relevant to wound healing are reviewed and a summary of the current literature on the use of collagen-based products in wound care is provided. Keywords: extracellular matrix; collagen; signaling; inflammation; wound healing; collagen dressings; engineered collagen Citation: Mathew-Steiner, S.S.; Roy, S.; Sen, C.K. Collagen in Wound 1. Introduction Healing. Bioengineering 2021, 8, 63. Sophisticated regulation by a number of key factors including the environment of the https://doi.org/10.3390/ wound which is rich in extracellular matrix (ECM) drives the process of wound healing [1,2]. bioengineering8050063 The complex macromolecules constituting the ECM include fibrous components (e.g., col- lagens and elastins) and glycoprotein components (e.g., fibronectin, proteoglycans and Academic Editor: Gunjan Agarwal laminins). Each of these molecules interact to drive the process of tissue function, growth and repair [3–5]. Wound repair is a complex process that is broadly categorized into the Received: 11 March 2021 following four phases which occur in a temporal sequence but are overlapping: hemostasis, Accepted: 1 May 2021 inflammation, proliferation (cellular infiltration, angiogenesis and re-epithelialization) and Published: 11 May 2021 maturation/remodeling (Figure1)[ 1]. Key steps of the wound healing process, such as hemostasis, inflammation and angiogenesis are responsive to the ECM, collagen and Publisher’s Note: MDPI stays neutral its compounds [1,6–13]. In response to injury, collagen induces platelet activation and with regard to jurisdictional claims in aggregation resulting in the deposition of a fibrin clot at the injury site. In the inflammatory published maps and institutional affil- stage of wound healing, immune cell activation drives the secretion of proinflammatory iations. cytokines which influence migration of fibroblasts, epithelial and endothelial cells. Fi- broblasts contribute to collagen deposition. Simultaneously, collagen degradation releases fragments that promote fibroblast proliferation and synthesis of growth factors that lead to angiogenesis and re-epithelialization. Finally, the remodeling of the ECM (balance of Copyright: © 2021 by the authors. new matrix synthesis and matrix metalloproteinase degradative activities) determines Licensee MDPI, Basel, Switzerland. the acquisition of tensile strength [14–16]. In this work we sought to briefly review the This article is an open access article significance of collagen in different biological processes relevant to wound healing. The distributed under the terms and current literature on the use of collagen-based products in wound care is summarized. conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Bioengineering 2021, 8, 63. https://doi.org/10.3390/bioengineering8050063 https://www.mdpi.com/journal/bioengineering BioengineeringBioengineering 20212021,, 88,, 63x FOR PEER REVIEW 22 of of 1516 Figure 1. Brief summary of wound healing phases. 2. Types of Collagens inin thethe SkinSkin andand WoundWound Collagens are the most abundant protein foundfound throughout the body.body. InIn thethe healinghealing wound, these these collagens collagens are are synthesized synthesized by by cell cellss such such as fibroblasts as fibroblasts and andmodified modified into com- into complexplex morphologies morphologies [17–21]. [17– The21]. type, The type,amount amount and organization and organization of collagen of collagen changes changes in the inhealing the healing wound wound and determines and determines the tensile the streng tensileth strength of the healed of the skin. healed Collagen skin. Collagen III is the IIIfirst is to the be first synthesized to be synthesized in the early in stages the early of wound stages ofhealing wound and healing is replaced and is by replaced collagen by I, collagen I, the dominant skin collagen. The initial random deposition of collagen during the dominant skin collagen. The initial random deposition of collagen during the granu- the granulation tissue formation is further enhanced by lysyl oxidase enzyme-induced lation tissue formation is further enhanced by lysyl oxidase enzyme-induced covalent covalent cross-linking. This process matures the collagen into complex structures that are cross-linking. This process matures the collagen into complex structures that are reori- reoriented for tensile strength restoration. Collagen remodeling continues for months after ented for tensile strength restoration. Collagen remodeling continues for months after wound closure and the tensile strength of the repaired tissue increases to about 80–85% of wound closure and the tensile strength of the repaired tissue increases to about 80–85% of normal tissue if all processes proceed without any perturbations [16]. normal tissue if all processes proceed without any perturbations [16]. In the skin, the fibrillar collagens types I, III and V are the most common, followed by In the skin, the fibrillar collagens types I, III and V are the most common, followed fibril-associated collagens type XII, XIV, XVI, and VI. The non-fibrillar collagens type IV, by fibril-associated collagens type XII, XIV, XVI, and VI. The non-fibrillar collagens type XVIII are found in the basement membrane of the skin [14,18,19,22,23]. IV, XVIII are found in the basement membrane of the skin [14,18,19,22,23]. 3. Processing of Collagen in the Skin and Wound 3.1.3. Processing Biosynthesis of andCollagen Cross-Linking in the Skin and Wound 3.1. BiosynthesisIn the healing and wound, Cross-Linking cells such as fibroblasts (resident, and myeloid cell converted fibroblasts)In the healing [24] are thewound, main cells source such of as newly fibroblasts synthesized (resident, collagen. and Themyeloid biosynthesis cell converted activi- tiesfibroblasts) of fibril-forming [24] are the collagens main source are the of most newly extensively synthesized studied collagen. among The allbiosynthesis the collagens ac- andtivities involve of fibril-forming multiple complex collagens steps are the requiring most extensively the temporal studied and spatialamong coordinationall the collagens of severaland involve biochemical multiple events complex [21,25 steps]. Following requiring transcription, the temporal the and nascent/pre-pro-collagen spatial coordination of isseveral post-translationally biochemical events modified [21,25]. in theFollowing endoplasmic transcription, reticulum the into nascent/pre-pro-collagen pro-collagen with the removalis post-translationally of the signal modified peptide on in thethe N-terminus.endoplasmic Hydroxylationreticulum into pro-collagen and glycosylation with the of aminoremoval acid of residuesthe signal results peptide in theon formationthe N-terminus. of the triple-helicalHydroxylation structure and glycosylation characteristic of ofamino collagens. acid residues Supported results by chaperonein the formation proteins, of the the triple-helical pro-collagen structure triple-helical characteristic structure of is stabilizedcollagens. forSupported further processing by chaperone and maturationproteins, th ine thepro-collagen Golgi apparatus triple-helical and assembled structure into is secretorystabilized vesiclesfor further that processing are extruded and into maturation the extracellular in the Golgi space apparatus where the and pro-collagen assembled is enzymaticallyinto secretory vesicles modified that into are tropocollagen. extruded into Thethe finalextracellular collagen space fibril where assembly the occurspro-colla- by covalentgen is enzymatically cross-linking. modified The mechanical into tropocolla propertiesgen. The (elasticity final collagen and reversible fibril assembly deformation) occurs ofby fibrillarcovalent collagens cross-linking. are dependent The mechanical on this cross-linkingproperties (elasticity process. and Some reversible of these defor- cross- linksmation) include: of fibrillar (1) disulfide collagens bonds; are dependent (2) reducible on andthis maturecross-linking cross-links process. produced Some of via these the Bioengineering 2021, 8, 63 3 of 15 lysyl oxidase pathway; (3) transglutaminase cross-links; and (4) advanced glycation end (AGE) product-mediated cross-links,