AccScience Publishing / IJB / Online First / DOI: 10.36922/IJB026210206
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RESEARCH ARTICLE
Early Access

Engineering coordinated lymphatic–vascular responses with Haversian-mimetic IL-6-releasing scaffolds for bone regeneration

Ya’nan Wang1 Xinyi Lu2 Xiaoqin Qiu3 Yiming Li2 Yu Kong2 Jiaxiang Tian2 Jie Li2* Weiqing Kong2*
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1 Department of Nuclear Medicine, Xuzhou Central Hospital, Southeast University, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221009, China
2 Department of Spinal Surgery, Xuzhou Central Hospital, Southeast University, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221009, China
3 Cancer Prevention and Treatment Institute of Chengdu, Department of Oncology, Chengdu Fifth People’s Hospital, The Second Clinical Medical College,Affiliated Fifth People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China
Received: 22 May 2026 | Revised: 28 June 2026 | Accepted: 2 July 2026 | Published online: 2 July 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

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.

Keywords
Lymphatic–vascular coupling
Regenerative niche
Haversian-mimetic scaffold
IL-6–CXCL12 axis
Bone regeneration
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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing