Periodontitis is a highly prevalent chronic degenerative disease initiated by the bacteria present in biofilm on the surface of the teeth. The exposure to bacterial biofilm triggers host inflammatory response whose dysregulation is ultimately responsible for the destruction of hard and soft periodontal tissues resulting in tooth loss. Since chronically inflamed periodontal tissue exhibits extracellular matrix (ECM) degradation, the possible alternative and/or addition to standard periodontitis treatment is to restore ECM by supplementing its components, including heparan sulfate glycosaminoglycan (HS GAG). In experimental animal models of periodontitis, the use of synthetic derivatives of HS GAGs to supplement degraded ECM has shown effectiveness in reducing inflammation and promoting partial regeneration of both soft and hard periodontal tissues. However, the effects of HS GAG supplementation for treating periodontal disease in humans remains are still unknown. To address this uncertainty, a statistical model was developed to assess the effect of HS GAG supplementation on inflammatory infiltrate formation and alveolar bone resorption in humans with severe periodontitis. Gingival samples from patients with severe periodontitis were stained with markers for HS GAG and proteins functionally related to HS GAG (immunofluorescence). A statistical model in the form of a system of regression equations was constructed using quantified spatial gradients of IF staining and the ontology database for STRING reactomes, to predict the effects of changes in the expression of native HS GAG on the amount of inflammatory infiltrate (represented by the general inflammatory cell marker CD45) and alveolar bone resorption (represented by the expression ratio of receptor activator of nuclear ΚΒ-ligand (RANKL) and osteoprotegerin (OPG)). According to the model, increased expression of native HS GAG may stabilize the accumulation of inflammatory infiltrate in the gingiva and slow the resorption of alveolar bone, but not stimulate alveolar bone resorption Therefore, supplementation of native HS GAG may have limited benefits as a standalone treatment for severe periodontitis in humans.