Attenuation of protease activity in chronic wound fluid with bisphosphonate-functionalised hydrogels

Abstract

Chronic ulcers are an important and costly medical issue, imposing considerable pain, reduced mobility and decreased quality of life. The common pathology in these chronic wounds is excessive proteolytic activity, resulting in degradation of key factors critical to the ulcer's ability to heal. Matrix metalloproteinases (MMPs), a large family of zinc-dependent endopeptidases, have been shown to have increased activity in chronic wound fluid (CWF), with many authors suggesting that they need to be inhibited for the ulcer to heal. The studies we report here show that the excessive MMP activity in CWF can be inhibited with the bisphosphonate alendronate, in the form of a sodium salt, a functionalised analogue, and tethered to a poly(2-hydroxy methacrylate) (PHEMA) hydrogel. Furthermore, these functionalised alendronate hydrogels appear to be biologically inert as assessed in a three-dimensional ex vivo human skin equivalent model. Together, these results highlight the potential use of a tethered MMP inhibitor to inhibit protease activity in wound fluid. This approach may improve wound healing as it still allows MMPs to remain active in the upper cellular layers of the ulcer bed where they perform vital roles in wound healing; thus may offer an attractive new device-orientated wound therapy.

Non-cytotoxic, in situ gelable hydrogels composed of N-carboxyethyl chitosan and oxidized dextran

“…The capacity of an implantable to maintain a moist environment has been implicated as an important factor in accelerating the wound repair process. Hydrogels, with their high water contents and retention capacity, appear to be optimal media to enhance wound healing [39], and thus, much interest has been focused on developing hydrogel-based wound dressings from biomaterials [39–42]. In situ forming hydrogels are capable of fully conforming to wound beds and are thus advantageous over performed scaffolds.…”

Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering

“…Mass transfer of calcium into bisphosphonated hydrogel can also have an effect outside of the hydrogel. Thus, N-methacryl Ale was co-polymerized with 2-hydroxyethyl methacrylate and the obtained hydrogel demonstrated MMP inhibitory action [68]. Here, Ca 2+ -binding capacity of the bisphosphonated hydrogel was proposed to withdraw Ca 2+ ions from chronic wound fluid and subsequently reduce Ca 2+ -dependent catalytic activity of MMPs upon topical treatment in the wound bed.…”

Positively and negatively charged ionic modifications to cellulose assessed as cotton-based protease-lowering and hemostatic wound agents

“…In a healthy person healing occurs in 21 days from coagulation, and the remodeling phase consisting of scar transformation based on collagen synthesis continues for months following injury Cellulose (2009) 16:911-921 913 selectively bind the enzyme to the wound dressing in the presence of other wound proteins that promote wound healing. Mechanism-based dressings include and are composed of collagen and oxidized regenerated cellulose (Cullen et al 2002), nanocrystalline silver-coated high density polyethylene (Wright et al 2002), deferroxamine-linked cellulose (Meyer-Ingold et al 2000), electrophilic and ionically derivatized cotton (Edwards et al 2001), peptide (Edwards et al 1999) or carbohydrate conjugates (Edwards et al 2002), and bisphosphonate MMP inhibitors (Rayment et al 2008) and sulfonated ion exchange derivatives of hydrogel polymers (Vachon and Yager 2006). We discuss here the relative activities of two negatively charged cellulose fibers for their abilities to sequester proteases.…”