Engineering coordinated lymphatic–vascular responses with Haversian-mimetic IL-6-releasing scaffolds for bone regeneration
Bone regeneration requires coordinated vascularization and microenvironmental remodeling; however, most bone biomaterials have primarily emphasized angiogenesis and have less explicitly addressed lymphatic-associated responses. Here, inspired by developmental bone formation and emerging evidence implicating the IL-6-CXCL12 axis in regenerative processes, we developed a biomimetic platform designed to promote bone repair accompanied by coordinated blood vascular and lymphatic-associated responses. A 3D-printed Haversian-mimetic scaffold with architecturally defined microchannels was fabricated to support guided tissue infiltration and vascular organization. To provide instructive biochemical signaling, a GelMA-based coating enabled sustained, low-dose delivery of interleukin-6 (IL-6). Developmental immunofluorescence analysis revealed pronounced spatial association between CXCL12 and osteocalcin-positive osteogenic regions, providing a biological rationale for engaging this axis as a regeneration-associated cue. In vitro studies demonstrated enhanced osteogenic differentiation and concomitant upregulation of angiogenic and lymphatic-associated markers. Transcriptomic profiling further indicated activation of gene programs associated with extracellular matrix remodeling, vascular-related signaling, and tissue regeneration. In a critical-sized defect model, the IL-6-functionalized Haversian-mimetic scaffold promoted new bone deposition and was accompanied by increased CD31-positive vascular structures, LYVE1-positive lymphatic-associated structures, and CXCL12 expression. Collectively, this work demonstrates a strategy that integrates architectural mimicry with cytokine signaling to enhance bone regeneration while explicitly evaluating lymphatic-associated responses as a design parameter for next-generation bone biomaterials.
