Immunomodulatory Potential and Biocompatibility of Chitosan–Hydroxyapatite Biocomposites for Tissue Engineering

Chitosan–hydroxyapatite (CS-HAp) biocomposites, combining the biocompatibility and bioactivity of chitosan with the osteoconductive properties of hydroxyapatite, are emerging as promising candidates for tissue engineering applications. These materials consistently exhibit excellent cytocompatibility, with cell viability rates greater than 95% in MTT and Neutral Red Uptake assays, and minimal cytotoxicity, as demonstrated by low levels of cell death in DAPI and Trypan blue staining. More importantly, CS-HAp biocomposites modulate the immune environment by enhancing the expression of anti-inflammatory cytokines (IL-10 and IL-4) and the pro-inflammatory cytokine TGF-β, while avoiding significant increases in TNF-α, IL-6, or NF-κB expression in fibroblast cells exposed to HAC and HACF scaffolds. In an in vivo dermatitis model, these biocomposites reduced mast cell counts and plasma histamine levels and significantly decreased pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), JAK1/3, VEGF, and AnxA1 levels. Structurally, HACF scaffolds demonstrated larger average pore sizes (95 µm) compared to HAC scaffolds (74 µm), with porosities of 77.37 ± 2.4% and 65.26 ± 3.1%, respectively. These materials exhibited high swelling ability, equilibrium water content, and controlled degradation over a week in culture media. In addition to their immunomodulatory effects, CS-HAp composites promote essential cellular activities, such as attachment, proliferation, and differentiation, thereby supporting tissue integration and healing. Despite these promising findings, significant gaps remain in understanding the underlying mechanisms of immune modulation by CS-HAp biocomposites, and formulation-dependent variability raises concerns about reproducibility and clinical application. Therefore, a comprehensive review is essential to consolidate existing data, identify key knowledge gaps, and standardize the design of CS/HAp composites for broader clinical use, particularly in immunomodulatory and regenerative medicine contexts.