Engineered Chitosan Nanoparticle Platform Enables Controlled Ibuprofen Delivery and Coordinated Neuroimmune Regulation in a Human Microphysiological Model

Controlled delivery of anti-inflammatory agents using bioactive nanomaterials offers a strategy to achieve localized and temporally regulated modulation of inflammatory and neurogenic signaling. Here, we engineered an adsorption-based chitosan nanoparticle platform for controlled Ibuprofen delivery to coordinate inflammatory and neurogenic responses during the acute postoperative phase. The formulation was designed to generate an initial burst release followed by sustained drug delivery while leveraging the intrinsic immunomodulatory properties of chitosan. Therapeutic performance was evaluated using a previously established human three-dimensional tri-culture microfluidic platform (3TMP) that recreates the periodontal ligament neuroimmune microenvironment under lipopolysaccharide (LPS)-induced inflammatory conditions. The engineered platform exhibited a two-phase release profile characterized by an initial burst followed by a plateau that translated into coordinated suppression of interconnected inflammatory and neuronal pathways, including the reduction of pro-inflammatory cytokines, prostaglandin E2 (PGE2), calcitonin gene-related peptide (CGRP), and the nociceptive ion channels TRPV1 and TRPA1. In comparison, free Ibuprofen only partially reduced TNF-α, IL-6, and IL-8 and failed to suppress IL-1β, PGE2, TRPV1, or TRPA1. These findings demonstrate how controlled-release biomaterial design governs therapeutic performance by coordinating interconnected neuroimmune pathways. Furthermore, this work establishes human microphysiological systems as robust platforms for evaluating structure-function relationships in bioactive nanotherapeutic systems for periodontal inflammation.