仿生软硬结合体系具有温和的光热治疗活性,通过免疫激活和血管生成的协同作用促进糖尿病骨缺损愈合。

Bioinspired soft-hard combined system with mild photothermal therapeutic activity promotes diabetic bone defect healing via synergetic effects of immune activation and angiogenesis.

机构信息

Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, 168 Donghu Street, Wuchang District, Wuhan 430071 Hubei, China.

Department of Anesthesiology, Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.

出版信息

Theranostics. 2024 Jul 1;14(10):4014-4057. doi: 10.7150/thno.97335. eCollection 2024.

Abstract

The comprehensive management of diabetic bone defects remains a substantial clinical challenge due to the hostile regenerative microenvironment characterized by aggravated inflammation, excessive reactive oxygen species (ROS), bacterial infection, impaired angiogenesis, and unbalanced bone homeostasis. Thus, an advanced multifunctional therapeutic platform capable of simultaneously achieving immune regulation, bacterial elimination, and tissue regeneration is urgently designed for augmented bone regeneration under diabetic pathological milieu. Herein, a photoactivated soft-hard combined scaffold system (PGCZ) was engineered by introducing polydopamine-modified zeolitic imidazolate framework-8-loaded double-network hydrogel (soft matrix component) into 3D-printed poly(ε-caprolactone) (PCL) scaffold (hard matrix component). The versatile PGCZ scaffold based on double-network hydrogel and 3D-printed PCL was thus prepared and features highly extracellular matrix-mimicking microstructure, suitable biodegradability and mechanical properties, and excellent photothermal performance, allowing long-term structural stability and mechanical support for bone regeneration. Under periodic near-infrared (NIR) irradiation, the localized photothermal effect of PGCZ triggers the on-demand release of Zn, which, together with repeated mild hyperthermia, collectively accelerates the proliferation and osteogenic differentiation of preosteoblasts and potently inhibits bacterial growth and biofilm formation. Additionally, the photoactivated PGCZ system also presents outstanding immunomodulatory and ROS scavenging capacities, which regulate M2 polarization of macrophages and drive functional cytokine secretion, thus leading to a pro-regenerative microenvironment with enhanced vascularization. experiments further demonstrated that the PGCZ platform in conjunction with mild photothermal therapeutic activity remarkably attenuated the local inflammatory cascade, initiated endogenous stem cell recruitment and neovascularization, and orchestrated the osteoblast/osteoclast balance, ultimately accelerating diabetic bone regeneration. This work highlights the potential application of a photoactivated soft-hard combined system that provides long-term biophysical (mild photothermal stimulation) and biochemical (on-demand ion delivery) cues for accelerated healing of diabetic bone defects.

摘要

由于以加重炎症、过量活性氧 (ROS)、细菌感染、血管生成受损和骨稳态失衡为特征的恶劣再生微环境,糖尿病骨缺损的综合管理仍然是一个重大的临床挑战。因此,迫切需要设计一种先进的多功能治疗平台,使其能够在糖尿病病理环境下同时实现免疫调节、细菌消除和组织再生,从而增强骨再生。在此,通过将载有聚多巴胺修饰沸石咪唑酯骨架-8 的双网络水凝胶(软基质成分)引入 3D 打印聚(ε-己内酯)(PCL)支架(硬基质成分),构建了一种光激活软硬结合支架系统(PGCZ)。基于双网络水凝胶和 3D 打印 PCL 的多功能 PGCZ 支架由此制备而成,具有高度模仿细胞外基质的微观结构、合适的生物降解性和机械性能以及出色的光热性能,可实现长期的结构稳定性和对骨再生的机械支撑。在周期性近红外 (NIR) 辐射下,PGCZ 的局部光热效应引发 Zn 的按需释放,再加上反复的温和热疗,共同加速了前成骨细胞的增殖和成骨分化,并有效抑制了细菌的生长和生物膜的形成。此外,光激活的 PGCZ 系统还具有出色的免疫调节和 ROS 清除能力,可调节巨噬细胞的 M2 极化并驱动功能性细胞因子的分泌,从而形成具有增强血管化功能的促再生微环境。实验进一步表明,PGCZ 平台与温和的光热治疗活性相结合,可显著减弱局部炎症级联反应,启动内源性干细胞募集和新血管生成,并协调成骨细胞/破骨细胞平衡,最终加速糖尿病骨再生。这项工作强调了光激活软硬结合系统的潜在应用,该系统为加速糖尿病骨缺损的愈合提供了长期的生物物理(温和光热刺激)和生化(按需离子输送)线索。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90e9/11234279/36b5266f4e68/thnov14p4014g001.jpg

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