Zhao Jinhui, Luo Yiping, Zhang Lei, Chen Yunfeng, Chen Yixing, Wu Xinhui, Aierken Aihemaitijiang, Duolikun Dilixiati, Wang Tianlong, Zhou Zifei, Liu Zhiqing, Zheng Longpo
Department of Orthopedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
Shanghai Trauma Emergency Center, Shanghai, 200072, China.
Adv Sci (Weinh). 2025 Feb;12(8):e2409882. doi: 10.1002/advs.202409882. Epub 2024 Dec 31.
Mild hyperthermia therapy has garnered interest as an adjunctive treatment for bone repair. However, its optimal timing, duration, and underlying mechanisms remain unclear. In this study, how mild hyperthermia supports bone repair during the early stages is assesed. These findings reveal that mild hyperthermia accelerates bone regeneration by dynamically regulating inducible nitric oxide synthase/arginase 1 (iNOS/Arg1) balance. This process involves macrophage polarization to the M1 phenotype through iNOS activation, followed by a rapid transition to the M2 phenotype through Arg1 activation after 3 days of sustained mild hyperthermia. RNA-Seq reveals that a single day of mild hyperthermia induced immune alterations aligned with the early inflammatory phase of bone repair, characterized by osteoclast activation, cell recruitment, and neovascularization, thereby preparing for the transition to the repair phase. Experiments involving subcutaneous abscesses, subcutaneous embedding, and critical cranial bone defects further confirm that early mild hyperthermia treatment dynamically regulates macrophage phenotypes. This regulation enhances early antibacterial activity, promotes angiogenesis, and facilitates the transition from inflammation to repair, ultimately accelerating bone-defect repair. This study is the first to elucidate the dual temporal effects of early mild hyperthermia on immune regulation, offering insights into the optimal timing and duration of photothermal therapy following bone repair surgery.
轻度体温过高疗法作为一种辅助性骨修复治疗方法已引起关注。然而，其最佳时机、持续时间和潜在机制仍不清楚。在本研究中，评估了轻度体温过高在早期阶段如何支持骨修复。这些发现表明，轻度体温过高通过动态调节诱导型一氧化氮合酶/精氨酸酶1（iNOS/Arg1）平衡来加速骨再生。这一过程包括通过iNOS激活使巨噬细胞极化为M1表型，随后在持续轻度体温过高3天后通过Arg1激活迅速转变为M2表型。RNA测序显示，单日轻度体温过高诱导的免疫改变与骨修复的早期炎症阶段一致，其特征为破骨细胞激活、细胞募集和新血管形成，从而为向修复阶段的转变做好准备。涉及皮下脓肿、皮下植入和严重颅骨缺损的实验进一步证实，早期轻度体温过高治疗可动态调节巨噬细胞表型。这种调节增强了早期抗菌活性，促进了血管生成，并促进了从炎症到修复的转变，最终加速了骨缺损修复。本研究首次阐明了早期轻度体温过高对免疫调节的双重时间效应，为骨修复手术后光热疗法的最佳时机和持续时间提供了见解。
