Multi-Factor Microparticle Formulation for Local Induction of Regulatory Lymphocytes and Treatment of Periodontal Disease

According to the American Dental Association, periodontal disease is a critical oral health care issue affecting over 65 million adults in the United States alone. Characterized by an overburden of invasive bacteria, gum inflammation and plaque buildup, periodontitis can result in severe loss of gingival tissue attachment and bone resorption. Current treatment focuses on the removal of the oral bacterial load through procedures such as scaling and root planing often accompanied by antibiotic treatments. However, literature suggests periodontal disease is not merely a consequence of the overburden of invasive bacteria but a result of immune imbalance caused by the inflammatory response to the invasive bacteria. Therefore, we’ve sought to reverse the underlying immune imbalance through the local presence of regulatory lymphocytes (Tregs) that are known to restore immunological homeostasis. Previously, we showed that local recruitment of endogenous regulatory lymphocytes aids in reversing the progression of periodontitis. The local, controlled release of the chemokine CCL22, induced Tregs recruitment which re-established periodontal homeostasis. However, this approach relies on the availability of functional, natural, regulatory T cells, and it is becoming more apparent that many inflammatory diseases may result from dysfunctional or deficient Tregs. Therefore, we hypothesize that the local induction of regulatory lymphocytes may provide a more robust mechanism to change the ratio of regulatory T cells in the periodontium, and reverse disease conditions. To this end, we have fabricated controlled release microparticles containing Treg-inducing factors; TGF-β (growth factor essential for Treg differentiation) , Rapamycin (mTorr inhibitor) and IL-2 (cytokine that promotes the differentiation of immature T cells into regulatory T cells) which have been shown to locally induce regulatory lymphocytes. Using a mouse model for periodontal disease, we have shown that the use of these controlled release microparticles significantly reduced disease outcomes. Hence, our multi-factor microparticle formulation to restore immunological balance through the induction of Tregs may be able to serve as a platform delivery system to treat other inflammatory diseases.