Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (8): 3706-3716.doi: 10.4103/NRR.NRR-D-25-00067

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Interferon regulatory factor 4–releasing 3D-printed scaffolds enhance spinal cord repair by modulating macrophage polarization

Jianhao Wang1, 2, #, Jiawei Du1, #, Tuo Fang1, Di Zhang1, Yigang Lv1, Zhongju Shi1, *, Hengxing Zhou3, *, Shiqing Feng1, 3, 4, 5, *   

  1. 1Department of Orthopedics, Tianjin Medical University General Hospital, International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin, China; 
    2Department of Spine Surgery, Peking University People’s Hospital, Beijing, China; 
    3Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China; 
    4Department of Orthopedics, the Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China; 
    5Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
  • Online:2026-08-18 Published:2026-04-27
  • Contact: Zhongju Shi, PhD, fantasyszj@126.com; Hengxing Zhou, PhD, zhouhengxing@sdu.edu.cn; Shiqing Feng, PhD, sqfeng@tmu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81930070 (to SF), 82002309 (to ZS); the Tianjin Key Medical Discipline (Specialty) Construct Project, No. TJYXZDXK-027A (to SF); and a grant from Tianjin Institute of Orthopedic Innovation and Transformation (to SF).

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Abstract: Three-dimensional (3D)-printed hydrogel scaffolds are widely used in spinal cord injury repair, with gelatin methacrylate being particularly favored owing to its excellent biocompatibility. However, traditional scaffolds have a small contact area with tissues and lack the ability to regulate the inflammatory microenvironment. Therefore, there is a need to develop smart scaffolds with drug delivery and immune regulation functions. In this study, a 3D-printed gelatin methacrylate scaffold was developed to deliver interferon regulatory factor 4 in a targeted and sustained manner. The scaffold showed good mechanical properties, biocompatibility, and sustained interferon regulatory factor 4 release. The sustained-release interferon regulatory factor 4 competitively bound to myeloid differentiation factor 88 to inhibit the pro-inflammatory effects of interferon regulatory factor 5, and activated the signal transducer and activator of transcription 6 pathway to promote M2 macrophage polarization, thereby facilitating neural regeneration and recovery of spinal cord function. This indicates that the constructed interferon regulatory factor 4-loaded 3D-printed methyl acrylate-modified gelatin scaffold can regulate macrophage polarization through the interferon regulatory factor 4/5 axis, improve the inflammatory microenvironment after spinal cord injury, and thus provide a new target for promoting neural regeneration.

Key words: 3D-printed scaffold, inflammatory microenvironment, interferon regulatory factor 4, JAK1/STAT6 signaling pathway, macrophage polarization, microglia, nerve regeneration, spinal cord injury