Treatment for Peri-implantitis via Local Immunomodulation and Effect on the Microbiome

About This Grant

Each year roughly 500,000 implants are placed in the United States. Of these 500,000 implants approximately 5-10% fail due to a variety of complications, the most common one being peri-implantitis (PI). PI is considered an oral inflammatory condition where accumulation of bacteria on the implant surface leads to a dysbiotic oral microbiome, which triggers inflammation. This persistent inflammation causes an exacerbated host immune response leading to soft tissue damage and alveolar bone loss. Currently, there is no standard of care for the treatment of PI, and much of what we know about PI pathogenesis is in part due to its similarity to periodontitis (PD), an oral inflammatory condition that occurs around a natural tooth. While PD and PI do have some similarities, there remains a lot unknown regarding the pathogenesis of PI, specifically the role of the host immune response. Our group has focused on developing several novel microparticle (MPs) based drug delivery systems that provide local, sustained delivery of cytokines and chemokines. These local drug delivery systems are then able to modulate the host immune response to promote immune homeostasis. In this application, we will utilize two previously developed MPs drug delivery systems: CCL2-MPs to recruit and polarize macrophages towards an anti-inflammatory phenotype and CCL22-MPs to recruit regulatory T cells (Tregs). Promotion of these immunoregulatory cells within the oral cavity may then work to promote resolution of inflammation and immune homeostasis. Preliminary data in this grant demonstrates that there is an impaired healing process in PI and both CCL2 and CCL22-MPs promote immune homeostasis, halt disease progression, and alter the oral microbiome in a ligature-induced murine model of PI; however, the mechanisms in which they promote resolution of inflammation remains elusive. We hypothesize that the impaired healing response is a result of the dysregulated host immune response and dysbiotic oral microbiome and that local immunomodulation allows us to investigate the pathobiology of PI and develop novel therapeutic approaches. To test this hypothesis, we propose the following specific aims: 1) To determine the role of macrophages and neutrophils (innate response) in PI progression and repair; 2) To investigate the role of different T cell populations (adaptive response) in PI progression and resolution; 3) To evaluate the impact of selective antimicrobials on the host immune response. We anticipate that both CCL2 and CCL22-MPs will have a therapeutic benefit (per our preliminary data). Furthermore, as local immunomodulatory approaches halted disease progression and changes in the oral microbiome, we expect to see changes in the frequency and phenotype of different immune cell populations. In sum, our novel immunomodulatory treatments for PI will provide a therapeutic benefit and enable us to further understand the role of the host immune response and oral microbiome in PI progression and resolution.