Mode of Action
Chronic wounds are characterized by an over abundance of matrix metalloproteinases (MMPs). At high levels, MMPs not only degrade non-viable collagen, but also degrade viable collagen, preventing the formation of granulation tissue and wound closure.1 When either BIOSTEP or BIOSTEP Ag is placed in a wound, MMPs attack and break down the collagen-based dressing since it serves as a ‘sacrificial substrate' for the MMPs.2 The resulting degradation products call in other cells, such as fibroblasts and endothelial cells, necessary for the formation of granulation tissue3-10 Unique to BIOSTEP and BIOSTEP Ag is the addition of ethylenediaminetetracetic acid (EDTA), which permanently deactivates a portion of the MMPs, preventing them from degrading viable collagen in the wound bed. MMPs contain zinc ions, necessary for their activity. EDTA binds with zinc ions to deactivate MMPs. Other collagen dressings available on the market attempt to reduce MMP activity through modes of acton separate from those of BIOSTEP and BIOSTEP Ag. For example, some contain oxidized regenerated cellulose (ORC) which creates a pH of ~ 2.5, well below physiological pH, to hydrolyze and deactivate MMPs. However, this low pH can damage growth factors as well as various cell types. While some other collagen dressings contain only collagen as a ‘sacrificial substrate'. In this type of system, once the MMPs have broken down the dressing, the MMPs are released back into the wound, fully functional and able to degrade viable collagen again. Also unique to BIOSTEP and BIOSTEP Ag is the types of collagen used. Both are the only collagen dressings on the market to date which contain both type I collagen and denatured collagen. This recipe attracts a greater variety of MMPs than do other dressings, thus protecting the “good” collagen in the wound from a wider variety of MMPs. For example, type I (native) collagen attracts MMP-1, and denatured collagen (gelatin) attracts MMP-2 and MMP-9.11,12 Denatured collagen also attracts stromelysins and matrilysin.13 MMP-1, MMP-2, and MMP-9 (among others) are each found in excess in chronic wounds and contribute to a wound's chronicity. When a migrating cell (i.e., keratinocyte) comes in contact with type 1 collagen the cell secrets MMPs in order to denature the type 1 collagen to gelatin.14 A critical reason for this is that once type 1 collagen is converted into gelatin many actives sites (i.e. RGD sequences) are made accessible to the cells. RGD (Arg-Gly-Asp) sequences are attachment sites and chemotactic for a variety of cells responsible for creating granulation tissue. The gelatin component of BIOSTEP and BIOSTEP Ag provides enhanced signaling to the cells responsible for creating granulation tissue. Other collagen dressings do not contain gelatin; as a result, cells in the wound must first release MMP-1 into a wound that already has an overabundance of MMPs to change the type 1 collagen into gelatin to achieve this benefit. Finally, unique to BIOSTEP and BIOSTEP Ag is a longer wear time than that of other collagen dressings. BIOSTEP and BIOSTEP Ag are FDA approved for 6 days of use; whereas, other collagen dressings are only approved for 3 days of wear. Due to the carboxymethylcellulose (CMC) and alginate components of BIOSTEP and BIOSTEP AG, they are more absorbent than other collagen dressings.15
- Schultz G, Mast B. Molecular Analysis of the Environment of Healing and Chronic Wounds: Cytokines, Proteases and Growth Factors. Wounds 1998;10:1F-9F.
- Bailey A. Perspective article: the fate of collagen implants in tissue defects. Wound Repair Regen 2000;8:5-12.
- Montesano R, Orci L, Vasselli F. In vitro rapid organization of endothelial cells into capillary-like networks is promoted by collagen matrices. J Cell Biol 1983;97:1648-52.
- Madri JA, Marx M. matrix composition, organization and soluble factors: Modulation of microvascualr cell differentiation in vitro Kidney Int 1992;41:560-5.
- Albini A, Dadelmann-Grill BC. Collagenolytic cleavage products of collagen type I as chemoatractants for human dermal fibroblasts, Eur. J Cell Biol 1985;36:104-7.
- Doillon CJ, Silver FH. Collagen-Based Wound Dressing: Effects of Hyaluronic Acid and Fibronectin on Wound Healing. Biomaterials 1986; 7:3-7.
- Doillon CJ, Silver FH, Olson RM, Kamath CY, Berg RA. Fibroblast and Epidermal Cell-Type I Collagen Interactions: Cell Culture and Human Studies. Scanning Microscopy 1988; 2(2):985-992.
- Burton JL, Etherington DJ, Peachey RDG. Collagen Sponge for Leg Ulcers. British Journal of Dermatology 1978; 5:726.
- Doillon CJ, Whyne CF, Berg RA, Olson RM, Silver FH. Fibroblast-Collagen Sponge Interactions and Spatial Deposition of Newly Synthesized Collagen Fibers in Vitro and in Vivo. Scanning Electron Microscopy 1984; 3:1313-1320.
- Palmieri B. Heterologous Collagen in Wound Healing: A Clinical Study. International Journal of Tissue Reaction 1992; 14:21-25.
- Jeffrey J. Metalloproteinases and Tissue Turnover. WOUNDS, A Compendium of Clinical Research and Practice. Vol 7, Supplement A, September/October 1995, p13A-22A.
- Parks WC. The Production, Role, and Regulation of Matrix Metalloproteinsases in the Healing Epidermis. WOUNDS, A Compendium of Clinical Research and Practice. Vol 7, Supplement A, September/October 1995, p23A-A33).
- Clark RAF, ed: In The Molecular and Cellular Biology of Wound Repair, 2nd Edition. NY, Plenum Press, 1996, pp. 443.
- Pilcher, BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG, Parks WC. The Activity of Collagenase-1 Is Required for Keratinocyte Migration on a Type I Collagen Matrix. The Journal of Cell Biology, Volume 137, Number 6, June 16, 1997 1445-1457.
- Data on file: Determination of Degradation Profile of Collagen Dressings (WRP_TW042_641).