Hydroxyapatite‐Coated Small Intestinal Submucosa Membranes Enhanced Periodontal Tissue Regeneration through Immunomodulation and Osteogenesis via BMP‐2/Smad Signaling Pathway

Abstract Periodontitis, a chronic infection causing periodontal tissue loss, may be effectively addressed with in situ tissue engineering. Small intestinal submucosa (SIS) offers exceptional biocompatibility and biodegradability but lacks sufficient osteoconductive and osteoinductive properties. This study develops and characterizes SIS coated with hydroxyapatite (SIS‐HA) and gelatin methacrylate hydroxyapatite (SIS‐Gel‐HA) using biomineralization and chemical crosslinking. The impact on periodontal tissue regeneration is assessed by evaluating macrophage immune response and osteogenic differentiation potential of periodontal ligament stem cells (PDLSCs) in vitro and rat periodontal defects in vivo. The jejunum segment, with the highest collagen type I content, is optimal for SIS preparation. SIS retains collagen fiber structure and bioactive factors. Calcium content is 2.21% in SIS‐HA and 2.45% in SIS‐Gel‐HA, with no significant differences in hydrophilicity, physicochemical properties, protein composition, or biocompatibility among SIS, SIS‐HA, SIS‐Gel, and SIS‐Gel‐HA. SIS is found to upregulate M2 marker expression, both SIS‐HA and SIS‐Gel‐HA enhance the osteogenic differentiation of PDLSCs through the BMP‐2/Smad signaling pathway, and SIS‐HA demonstrates superior in vitro osteogenic activity. In vivo, SIS‐HA and SIS‐Gel‐HA yield denser, more mature bones with the highest BMP‐2 and Smad expression. SIS‐HA and SIS‐Gel‐HA demonstrate enhanced immunity–osteogenesis coupling, representing a promising periodontal tissue regeneration approach.