PDF(Pubmed)
Abstract：
Background: 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. Methods and Results: 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 Zn2+, 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 in situ with enhanced vascularization. In vivo 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. Conclusions: 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：
背景：糖尿病性骨缺损的综合管理仍然是一个巨大的临床挑战，由于其特征是炎症加重的恶劣的再生微环境。过量的活性氧（ROS），细菌感染,血管生成受损，和不平衡的骨骼稳态。因此，一个先进的多功能治疗平台，能够同时实现免疫调节，细菌消除，而组织再生是糖尿病病理环境下用于增强骨再生的迫切设计。方法和结果：本文，通过将聚多巴胺修饰的沸石咪唑酯框架-8负载的双网络水凝胶（软基质组件）引入3D打印的聚（ε-己内酯）（PCL）支架（硬基质组件）中，设计了一种光活化的软-硬组合支架系统（PGCZ）。因此，制备了基于双网络水凝胶和3D打印PCL的多功能PGCZ支架，并具有高度模拟细胞外基质的微观结构，合适的生物降解性和机械性能，和优异的光热性能，允许长期的结构稳定性和骨再生的机械支持。在周期性近红外（NIR）照射下，PGCZ的局部光热效应触发了Zn2+的按需释放，which,再加上反复的轻度高热，共同加速前成骨细胞的增殖和成骨分化，并有效抑制细菌生长和生物膜形成。此外,光活化PGCZ系统还具有出色的免疫调节和ROS清除能力，它调节巨噬细胞的M2极化并驱动功能性细胞因子分泌，从而导致原位促再生微环境，血管形成增强。体内实验进一步证明，PGCZ平台结合温和的光热治疗活性显着减弱局部炎症级联反应，启动内源性干细胞募集和新生血管形成，协调了成骨细胞/破骨细胞的平衡，最终加速糖尿病骨再生。结论：这项工作强调了光活化软硬组合系统的潜在应用，该系统可提供长期的生物物理（轻度光热刺激）和生化（按需离子输送）提示，以加速糖尿病性骨缺损的愈合。
