Mapping and Modulating Endothelial Dysfunction in Peri-implantitis - ABSTRACT: Dental implants are among the most widely used and successful medical devices, with over 3 million Americans currently living with implants and more than 500,000 placed each year. However, nearly 20% of recipients develop peri-implantitis, a chronic inflammatory condition that leads to soft tissue destruction, rapid bone loss, and eventual implant failure. As implant use grows alongside an aging population, the clinical and economic burden of peri-implantitis is expected to rise sharply. Despite its prevalence, the disease remains poorly understood and lacks precision diagnostics or targeted therapies, representing a critical gap in oral health care and implant dentistry. Our preliminary work using spatial multiomics and AI-powered analysis has identified a distinct, disease-specific vasculopathy in peri-implantitis lesions—absent in periodontitis—including the emergence of CD38⁺ vascular endothelial cells (VECs), capillary rarefaction, and disruption of the NAD⁺ metabolic axis (CD38, NAMPT, PARP, SIRT1/5). These endothelial changes are embedded within spatially organized immune signaling hubs and may represent a druggable driver of chronic inflammation in implant- associated disease. This R21 project will test the hypothesis that peri-implantitis is a spatially restricted vascular disease sustained by NAD⁺-dependent endothelial dysfunction, and that this state is reversible through pharmacologic intervention. In Aim 1, we will construct a spatially resolved, multimodal atlas of peri-implantitis vasculopathy using Xenium spatial transcriptomics, CODEX proteomics, and AI tools (Astrograph, STARComm, Constellation) to define CD38⁺ endothelial subsets, their local immune neighborhoods, and to identify candidate therapeutic targets using our Spatial-Drug2Cell framework. In Aim 2, we will functionally assess CD38⁺ VECs isolated from peri-implantitis lesions and test whether pharmacologic interventions can reverse their pro- inflammatory state using nicotinamide and daratumumab. This will also set us up to test novel AI-predicted small molecules in a future R01. Experiments will leverage human tissue microarrays, flow cytometry, and in vitro endothelial culture systems. We will integrate spatial mapping with functional assays—including angiogenesis, cytokine profiling, and metabolic flux—to validate therapeutic potential. This work will establish a new mechanistic framework for precision vascular therapy in peri-implantitis and may offer broad relevance to other chronic diseases marked by endothelial injury and dysregulated NAD⁺ metabolism, including cardiovascular, metabolic, and autoimmune conditions.
