Inducible nitric oxide releasing poly-(ethylene glycol)-fibrinogen adhesive hydrogels for tissue regeneration
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Inducible nitric oxide releasing poly-(ethylene glycol)-fibrinogen adhesive hydrogels for tissue regeneration Margaret Brunette, Hal Holmes, Michael G. Lancina, Weilue He, Bruce P. Lee, Megan C. Frost, Rupak M. Rajachar
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Department of Biomedical Engineering, Michigan Technological University, Houghton, MI 49931, U. S. A. ABSTRACT Nitric oxide (NO) release can promote healthy tissue regeneration. A PEG-fibrinogen adhesive hydrogel that would allow for inducible NO release was created with mechanical properties that could be tailored to specific applications and tissue types. PEG (4-arm)-fibrinogen hydrogels of varying ratios were derivatized with S-nitroso-N-acetyl-D, L-penicillamine (SNAP)-thiolactone to create an active NO donor material. Controlled release from gels was established using light as the activating source, although temperature, pH, and external mechanical loading are also means to induce active NO release. Gels with varying ratios of fibrinogen to PEG were made, derivatized, and tested. Gels below a ratio of 1.5:1 (fibrinogen:PEG) did not gel, while at ratio of 1.5:1 gelation occurs and NO release can be induced. Interestingly, the release from 1.5:1 gels was significantly lower compared to 2:1 and 3:1 gel formulations. Rheometric data show that lower ratio gels are more elastic than viscous. Derivatized gels exhibited linear elastic moduli, behaving more like other more synthetic hydrogels. Swelling data indicates that as the ratio of fibrinogen to PEG increases the swelling ratio decreases, likely due to the hydrophobic nature of the NO donor. Cells remain viable on both derivatized and non-derivatized gels. INTRODUCTION In tendinopathy, overload of tendon tissue is central to the pathologic process. Overload may result in incremental weakening and failure of tendon tissue [1]. Repetitive micro-trauma (loss of structure in underlying collagen matrix) can eventually reach a threshold that results in altered mechanical properties, ultimately producing abnormal loading, as well as localized fiber degeneration and pain in injured tissues [2]. Nitric oxide (NO) is a necessary factor in various wound-injury healing conditions including tendinopathy [3]. The beneficial effects of NO are bound to its controlled availability. Inhibition of NO production during tendon repair results in a significant reduction in stable
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reparative tissue volume. Although recent work has shown the efficacy of NO therapy (i.e. injected and topical NO-donor group delivery) on soft tissue healing and regeneration [3], inducible NO release systems remain limited. The overall goal of this work is to develop a novel inducible NO releasing adhesive-hydrogel. We hypothesize that these adhesive-hydrogels could be used as injectable delivery systems to bind to injured tissue and deliver controlled NO as a regenerative support to accelerate wound healing. The adhesive-hydrogel is composed of a base adhesive poly(ethylene glycol) (PEG)-fibrinogen with the fibrinogen unit derivatized into an inducible NO donor. For this work we cho
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