Nitric oxide-releasing hyaluronic acid therapeutics for treating periodontal disease

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SUMMARY Microbial plaque biofilms that form at and below the gum line are the perpetrators of periodontal diseases, which are a class of diseases associated with non-resolving inflammation that results in soft and hard tissue destruction. Periodontitis is characterized by an unending cycle of chronic inflammation which leads to tissue destruction and prevents wound healing but cannot control the biofilms microbial dysbiosis. Under conditions of systemic inflammation, these host factors are amplified leading to more severe and refractory periodontal disease conditions. As such, periodontal diseases are affected by and can be risk factors for a number of systemic health issues such as diabetes. Current treatment of periodontitis involves mechanical removal of supra- and sub-gingival bacterial plaque and calculus and is often accompanied by the use of locally administered adjunctive therapies aimed at restoring microbial homeostasis. Current adjunctive therapies do not address the need to break the unending cycle of chronic inflammation and restore tissue homeostasis. Thus, there is a profound need to develop an adjunctive therapeutic that: a) possesses broad-spectrum activity against biofilms with minimal toxicity to mammalian cells; b) provides anti-inflammatory activity; and, c) promotes tissue healing. Due to its antibacterial and immunomodulatory functions, nitric oxide (NO) is an attractive adjunctive agent in the treatment of periodontal diseases. In the proposed research program, we will synthesize, characterize and evaluate nitric oxide-releasing hyaluronic acid (HA) as a multi-action NO-release system. Upon release, the NO will serve as a broad-spectrum antibacterial and pro-wound healing agent. The macromolecule that remains (HA) will then further serve to mitigate immunmodulation and wound healing. We will evaluate the efficacy and associated mechanisms of this multi-action therapeutic (e.g., NO: antibacterial, HA and NO: immunomodulatory, and NO and HA: pro-wound healing). We propose this approach will reduce the frequency of and/or augment clinical interventions and promote improved resolution of disease. We aim to: 1) synthesize nitric oxide-releasing hyaluronic acid nanomaterials and formulations, showing the influence of NO- releasing HA on antibacterial and antibiofilm action, mammalian cell cytotoxicity, and inflammation in various oral delivery formulations; 2) delineate the mechanisms modulating microbial dysbiosis, immune dysfunction and tissue-stasis; and, 3) test in vivo therapeutic efficacy in preventing and/or halting periodontal disease progression.