A Review of Collagen and Collagen-based Wound Dressings

David Brett, BS, BS, MS

Disclosures

Wounds. 2008;20(12) 

In This Article

Abstract and Collagen

Abstract

Collagen is a key component of a healing wound. In this review, a general description of the wound healing process is provided focusing on collagen's unique role. The mode of action (MoA) of collagen-based dressings is also addressed. Due to a number of potential stimuli (local tissue ischemia, bioburden, necrotic tissue, repeated trauma, etc.), wounds can stall in the inflammatory phase contributing to the chronicity of the wound. One key component of chronic wounds is an elevated level of matrix metalloproteinases (MMPs). At elevated levels, MMPs not only degrade nonviable collagen but also viable collagen. In addition, fibroblasts in a chronic wound may not secrete tissue inhibitors of MMPs (TIMPs) at an adequate level to control the activity of MMPs. These events prevent the formation of the scaffold needed for cell migration and ultimately prevent the formation of the extracellular matrix (ECM) and granulation tissue. Collagen based wound dressings are uniquely suited to address the issue of elevated levels of MMPs by acting as a 'sacrificial substrate' in the wound. It has also been demonstrated that collagen breakdown products are chemotactic for a variety of cell types required for the formation of granulation tissue. In addition, collagen based dressings have the ability to absorb wound exudates and maintain a moist wound environment.

Collagen

Proteins are natural polymers and make up almost 15% of the human body. The building blocks of all proteins are amino acids. Collagen is the major protein of the extracellular matrix (ECM) and is the most abundant protein found in mammals, comprising 25% of the total protein and 70% to 80% of skin (dry weight). Collagen acts as a structural scaffold in tissues. The central feature of all collagen molecules is their stiff, triple-stranded helical structure.[1] Types I, II, and III are the main types of collagen found in connective tissue and constitute 90% of all collagen in the body.

Function of Collagen in Wound Healing. Previously, collagens were thought to function only as a structural support; however, it is now evident that collagen and collagen-derived fragments control many cellular functions, including cell shape and differentiation,[2,3] migration,[4] and synthesis of a number of proteins.[5] Findings suggest that cell contact with precise extracellular matrix molecules influence cell behavior by regulating the quantity and quality of matrix deposition. Type I collagen is the most abundant structural component of the dermal matrix; migrating keratinocytes likely interact with this protein. Collagenase (via formation of gelatin) may aid in dissociating keratinocytes from collagen-rich matrix and thereby promote efficient migration over the dermal and provisional matrices. Cellular functions are regulated by the ECM. The information provided by ECM macromolecules is processed and transduced into the cells by specialized cell surface receptors.[5] Evidence demonstrates that the receptors play a major function in contraction of wounds,[6,7] migration of epithelial cells,[8] collagen deposition,[9] and induction of matrix-degrading collagenase. Although keratinocytes will adhere to denatured collagen (gelatin), collagenase production is not turned on in response to this substrate.[10] Keratinocytes have been known to recognize and migrate on Type I collagen substratum, resulting in enhanced collagenase production.[11] Collagen plays a key role in each phase of wound healing.

Hemostasis (Duration = Minutes). Platelets aggregate around exposed collagen. Platelets then secrete factors, which interact with and stimulate the intrinsic clotting cascade, which strengthens the platelet aggregate into a stable hemostatic "plug." Blood platelets also release αa-granules, which release a variety of growth factors (GFs) and cytokines, such as platelet derived GF (PDGF), insulin-like GF (IGF-1), epidermal GF (EGF), and transforming GF-beta (TGF-b),[12] which "call" a variety of inflammatory cells (neutrophils, eosinophils, and monocytes) to the wound site and initiate the inflammatory phase.

Inflammation (Duration = Days). Proteolytic enzymes are secreted by inflammatory cells that migrate to wound sites, notably neutrophils, eosinophils, and macrophages. The action of proteolytic enzymes on the macromolecular constituents of the ECM (such as collagen) gives rise to many peptides (protein fragments) during wound healing. These degradation products have a chemotactic effect in the recruitment of other cells, such as mononuclear cells, additional neutrophils, and macrophages. Activated macrophages secrete TNF-a, which among other things, induces macrophages to produce IL-1b. IL-1bβ is mitogenic for fibroblast and up-regulates matrix metalloproteinase (MMP) expression. TNF-α and IL-1bβ are key pro-inflammatory cytokines, which directly influence deposition of collagen in the wound by inducing synthesis of collagen via fibroblasts and down regulation of tissue inhibitors of matrix metalloproteinases (TIMPs).[12] Inflammatory cells also secrete growth factors including TGF-b, TGF-b, bHB-EGF, and bFGF.[12] These GFs continue to stimulate migration of fibroblasts, epithelial cells and vascular endothelial cells into the wound. As a result, the cellularity of the wound increases. This begins the proliferative phase.

Proliferation (Duration = Weeks). Cleavage products resulting from collagen degradation stimulate fibroblast proliferation. Fibroblasts secrete a variety of GFs (IGF-1, bFGF, TGF-b, PDGF, and KGF),[12] which guide the formation of the ECM. The collagen cleavage products also stimulate vascular endothelial cell proliferation. These cells secrete a variety of GFs (VEGF, βFGF, PDGF),[12] which promote angiogenesis. With a vascularized ECM, granulation is achieved. Collagen cleavage products also stimulate keratinocyte migration and proliferation. Keratinocytes secrete a variety of GFs and cytokines, such as TGF-b, TGF-b, and IL-1.[12] As keratinocytes migrate from the edge of the wound across the newly formed granulation tissue, re-epithelization is achieved.

Remodeling (Duration = 1 Year +). A balance is reached between the synthesis of new components of the scar matrix and their degradation by MMPs, such as collagenase, gelatinase, and stromelysin. Fibroblasts are the major cell type that synthesizes collagen, elastin, and proteoglycans. They are also the major source of MMPs and TIMPs. In addition, they secrete lysyl oxidase, which cross-links components of the ECM. Angiogenesis ceases and the density of capillaries in the wound site decreases as the scar matures. The result is the creation of a stronger scar, though the skin only regains almost 75% of its original tensile strength. The phases of acute wound healing are further described in Figures 1-5.

The epidermis is the upper layer of the skin and provides the first barrier of protection from the invasion of foreign substances into the body. The principal cell of the epidermis us called keratinocyte. The dermis (the layer just below the epidermis) assumes the important functions of the thermoregulation and supports the vascular network to supply the avascular epidermis with nutrients. The dermis contains mistly fibroblasts, which are responsible for secreting collagen, elastin, and ground substance that give support and elasticity to the skin. Immune cells are also present and defend against foreign invaders that pass through the epidermis. The hypodermis, also called the hypoderm, subcutaneous tissue, or superficial fascia, is the lowest layer of the skin. Types of cells found in the hypodermis are fibroblasts, adipose (fat) cells, and macrophages. Upon injury, a series of biochemical events are initiated. These activities are generally grouped into 4 overlapping phases (hemostasis, inflammation, proliferation, and remodeling).

This shows the wound bed and key cells involved in wound healing. the macrophage (green-colored cells) is just one of the inflammatory cells involved. Initially, macrophages act to remove the cell debris and bacteria. However, macrophages also secrete cytokines and growth factors, which guide the wound through the inflammatory phase into the proliferative phase. Endothalial cells (tan-colored cells) create new blood vessels. Fibroblasts are depicted here as the purple colored cells. Collagen is also a key component of the extracellular matrix (ECM). Fribroblasts secrete matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), and glycosaminoglyacans (GAGs). Glycosaminoglyacans bind with water to create a gel medium, which aids in cell movement.

Macrophages have secreted pro-inflammatory cytokines (eg, TNF-α and IL-1β), which have signaled the fibroblasts to secrete MMPs (the orange colored cells), TIMPs (purpe-colored cells), and GAGs. The MMPs are degrading the nonviable collagen in order to prepare the wound bed for granulation. The degradation products are chemotactic agents, which stimuate migration of fribroblasts, epithelial cells, and vascular endothelial cells in the wound. TIMPs inhibit MMPs to a certain extent to assure the level of activity of the MMPs remains at the optimal level for wound healing.

Fribroblasts have secreted new fibrous proteins, such as collagen and GAGs. The fibrous proteins act as a scaffold upon which cells can migrate. Glycosaminoglycans and the fibrous proteins make up the ECM. In addition, endothelial cells are creating new capillaries. Thus the cells in the wound bed have created ciable granulation tissue. Keratinocytes (epidermal cells) will also start migrating from the wound edge.

A layer of keratinocytes has moved across the viable granulation tissue initiating re-epithelialization. Re-epithelialization will continue until the epidermis is full. The next phase of healing is the remodeling phase; wherein, fibroblasts will remodel and cross-link the collagen fibers to make a stronger scar.

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