SC Site Components and Their Properties

Accessing the SC site is typically achieved using a needle to penetrate the epidermis and dermis; as it does so, the needle has the potential to come in contact with a number of anatomical elements present within the skin that include vessels and nerves (Fig. 1). Cells of the epidermis originate from a single layer of basal cells, called the basal layer, which lie immediately superficial to an acellular basement membrane. Beneath the epidermis lies the dermis, a complex arrangement of proteins secreted by resident fibroblasts and referred to as the extracellular matrix (ECM). The ECM is composed of an interlocking mesh of fibrous proteins and glycosaminoglycans (GAGs). GAGs are carbohydrate polymers attached to ECM proteins to form proteoglycans (PGs) [hyaluronic acid (HA) is a notable exception, discussed below]. Having a net negative charge, PGs attract water molecules to maintain a level of hydration in the ECM. The negative charge density of PGs also helps to trap and store growth factors within the ECM.

ECM proteins serve many functions; including providing support and anchorage for cells and regulating intercellular communication through their ability to sequester a wide range of cellular growth factors to stabilize them within the ECM (11). Heparan sulfate (HS), a linear polysaccharide that occurs as a PG, is one example of an ECM protein that can bind growth factors (12). ECM multidomain proteins perlecan, agrin, and collagen XVIII are the main proteins to which HS is attached. The non-PG matrix component HA, or "hyaluronan," is a polysaccharide consisting of alternative residues of D-glucuronic acid and N-acetylglucosamine. Unlike other GAGs, HA is not found as a PG. HA in the SC site confers an ability to resist compression by providing a counteracting turgor (swelling) force through its ability to absorb water. Thus, HA is found in load-bearing joints, is a chief component of the interstitial space, and can regulate cell behavior during embryonic development, healing processes, inflammation, and tumor development through its specific interaction with the transmembrane receptor CD44 (13).

Collagens, fibronectins, elastins, and laminins are also present in the SC space, being organized into a complex matrix within the ECM. Collagen accounts for the majority of these proteins and is exocytosed in a precursor form known as procollagen and processed by proteinases to facilitate extracellular assembly. There are at least 10 different isoforms of collagen, the selective distribution of these various isoforms being organized around tissue and cellular functions (14). Fibronectins are proteins that facilitate cellular contacts with collagen fibers within the ECM by binding both collagen and cell surface protein complexes known as integrins. These fibronectin-mediated interactions are critical for cell movement (migration) through the ECM. Fibronectins are secreted by cells in an unfolded, inactive form, and their binding to integrins induces dimeric associations into dimers so that they can function properly.

Elastins, in contrast to collagens, give elasticity to tissues, allowing them to stretch when needed and then return to their original state. While collagens account for up to 75% by weight of the dermis, elastins account for less than 5%. Elastins are highly insoluble; tropoelastins are secreted as a complex with other proteins to stabilize them prior to their contact with a fiber of mature elastin. Tropoelastins are deaminated within the ECM to allow their incorporation into the elastin strand. Unlike collagen-containing fibers, laminins form networks of weblike structures that resist tensile forces and assist in cell adhesion. Laminins bind other ECM components such as collagens, nidogens, and entactins (15). Cell surface integrins associate not only with fibronectin but also with laminin. Thus, there is a wide range of protein elements that make up the ECM of the SC site environment that have the potential to interact with each other as well as cell surface components. Delivery of a protein or peptide therapeutic into this environment provides the opportunity for these bioactive agents to interact with or modulate the function of these ECM materials.

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