Elastatropin® in Wound Healing
Wound healing is a complex process that involves many different cell types and matrix proteins. Most wounds heal rapidly and efficiently but the result is far from perfect. Scar tissue is less flexible than normal skin and can be cosmetically disfiguring, and wound contraction can lead to disablement4. Scars lack elastin and consist of a poorly reconstituted collagen matrix in dense bundles5, so scare tissue is not as strong as unscarred tissue. Two major goals of tissue repair are more rapid healing and more complete reconstruction of the damage.
Wound healing has several phases including formation of a clot and "scab", recruitment of inflammatory cells, reepitheliazation, and matrix formation and remodeling. Reepithelialization of the wound site begins after several hours6 and is performed by the basal keratinocytes which crawl over the extracellular matrix of fibrin and fibronectin and secrete components of the Extracellular Matrix. Some time later, epidermal cells begin to reproduce. Cells of the new epidermis undergo the standard differentiation program of cells in the outer layers of unwounded epidermis. A new stratified epidermis is reestablished from the margins of the wound inward. New Extacellular Matrix formation begins simultaneously with reepithelialization. The matrix is continuously altered over time with the accumulation of collagen that provides the scar with tensile strength. Elastin fibers, which are responsible for the elasticity of tissue, are only detected in human scars years after the injury7.
Many methods have been proposed and tested to promote wound healing and limit scarring; however, better methods and compositions are still needed. These older methods include cyanoacrylate tissue adhesives, a combination of epidermal transplantation and a collagen/elastin dermal substitute, application of collagen and glycosaminoglycans to the site of injury, and biocompatible adhesives with collagen.
We are evaluating elastin compositions and methods for the promotion of wound healing. These compositions comprise virgin monomers of tropoelastin and the cross-linking enzyme, lysyl oxidase (catalyst). The method of application is mixing these two components of the composition together (much like mixing together "tube A" and "tube B" of Epoxy adhesive) and applying them to a wound before substantial cross-linking has occurred. The tropoelastin monomers and lysyl oxidase only come in contact with each other immediately before application to the wound or during application to the wound, and cause the elastin to "gel" in the wound.
The lysyl oxidase catalyzes the oxidative deamination of the lysine residues of the tropoelastin monomers at the site of the wound. Then in a non-enzymatic step, cross-links form between the tropoelastin monomers as well as between tropoelastin monomers and other proteins of the extracellular matrix such as collagen. The cross-linked elastin at the site of injury helps to hold the injured tissue together and thereby promotes healing. The elastin is also chemotactic for fibroblasts, endothelial cells, and inflammatory cells, thereby promoting healing in another manner. Elastin at the site of injury also helps to lessen scarring since scar tissue is devoid of elastin, and elastin is an important component of uninjured skin. The cross-linked elastin also generally provides a favorable environment for the cells that participate in the healing process. The elastin solution can also be used to carry other cells and healing-promoting matrix proteins into the site of the wound.
We make the tropoelastin monomers and lysyl oxidase recombinantly and purify them to homogeneity using standard techniques. The purified tropoelastin and lysyl oxidase may then be suspended an aqueous solution (e.g., water or saline) or in a lyophilized formand kept separate from each other until right before use.
The mixed monomer and catalyst can be applied at the time of the injury or more than once over the course of wound healing. The tropoelastin and lysyl oxidase may also be used in conjunction with sutures, staples, or adhesive strips in closing the wound. This approach may also be used in promoting the healing of wounds involving structures with elastic fibers such as arteries, lung tissue, or skin. In particular, the composition may be used in surgeries involving arteries, lungs, or the skin by closing and sealing the surgical incision.