Topical Collagen-Based Biomaterials for Chronic Wounds: Rationale and Clinical Application

Abstract

Significance: The extracellular matrix (ECM) is known to be deficient in chronic wounds. Collagen is the major protein in the ECM. Many claims are made while extolling the virtues of collagen-based biomaterials in promoting cell growth and modulating matrix metalloproteinases. This review will explore the rationale for using topical collagen or ECM as an interface for healing. Recent Advances: Rapid improvements in electrospinning and nanotechnology have resulted in the creation of third-generation biomaterials that mimic the native ECM, stimulate cellular and genetic responses in the target tissue, and provide a platform for controlled release of bioactive molecules and live cells. Although the major focus is currently on development of artificial tissues and organ regeneration, better understanding of the mechanisms that stimulate wound healing can be applied to specific deficits in the chronic wound. Critical Issues: When choosing between the various advanced wound-care products and dressings, the clinician is challenged to select the most appropriate material at the right time. Understanding how the ECM components promote tissue regeneration and modulate the wound microenvironment will facilitate those choices. Laboratory discoveries of biomolecular and cellular strategies that promote skin regeneration rather than repair should be demonstrated to translate to deficits in the chronic wound. Future Directions: Cost-effective production of materials that utilize non-mammalian sources of collagen or ECM components combined with synthetic scaffolding will provide an optimal structure for cellular ingrowth and modulation of the chronic wound microenvironment to facilitate healing. These bioengineered materials will be customizable to provide time-released delivery of bioactive molecules or drugs based on the degradation rate of the scaffold or specific signals from the wound.

Lisa J. Gould, MD, PhD

Figure 1.

Comparison of collagen I and IV structures. (A) The fibrillar structure of type I collagen provides the extraordinary tensile strength that is characteristic of skin. Type I collagen fibrils assemble side by side in parallel bundles that are interconnected with inter- and intra-molecular cross-links. The complex post-translational modifications that result in collagen fibril assembly are not easily reproduced in synthetic collagens (reprinted with permission from Fang et al.). (B) In contrast to the amorphous lattice network of type I collagen, type IV collagen forms a complex branching network with the fibers linking head to head rather than in parallel. Triple helical segments are interrupted by long segments that cannot form a triple helix. The resulting two-dimensional network results in the formation of sheet-like structures (reprinted with permission from Kalluri). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 2.

ECM interactions and molecular organization. The ECM is composed of two distinct matrix entities. The protein composition of each leads to identifiable structural and functional differences; however, the two components interact to provide adhesive and structural support as well as influence cellular physiologic function. (A) The interstitial matrix, composed of fibrillar and nonfibrillar collagen, elastic fibers, and glycosaminoglycans, forms an amorphous structure that provides a repository for bioactive molecules. (B) With its high content of collagen IV, laminins, and heparin sulfate proteoglycans, the extracellular BM forms sheets that separate cells from the interstitial matrix (reprinted under CC BY license, Neve et al.). BM, basement membrane; ECM, extracellular matrix.

Figure 3.

BM interactions. Scanning electron micrograph showing the relationship between the BM (basal lamina), collagen fibrils, and migrating epithelial cells. Some of the epithelial cells (E) have been removed to expose the upper surface of the basal lamina (L). A network of collagen fibrils (C) interacts with the lower face of the lamina (Credit: Courtesy of the late Robert Trelstad). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 4.

Effect of processing on ECM structure. Scanning electron microscopy images of control small intestine samples (A), and tissues decellularized with 1.5 M NaCl (B), 3 M NaCl (C), 5 M NaCl (D), 0.1% SDS (E), 0.3% SDS (F), 0.6% SDS (G), 0.1% triton X-100 (H), 0.3% triton X-100 (I), 0.6% triton X-100 (J), 10 min SC (K), 20 min SC (L), 30 min SC (M), 10 min UV (N), 20 min UV (O), and 30 min UV (P). Scale bar represents 50 μm (reprinted under CC BY license, Oliveira et al.).

Figure 5.

Novel use of collagen mimetic peptides for sensing and delivery. CMP (red) can be engineered to bind to or displace weak or damaged collagen, increasing the stability of the triple helix. A probe that fluoresces, luminesces, or has a color reaction or a growth factor can be attached as a “pendant” to facilitate wound assessment or bioactive molecule delivery (reprinted with permission from Chattopadhyay and Raines). CMP, collagen mimetic peptides. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound