Sun Yang, Zhou Qianrong, Du Yawei, Sun Jian, Bi Wei, Liu Wenjuan, Li Ruixue, Wu Xingwen, Yang Fei, Song Liang, Li Ni, Cui Wenguo, Yu Youcheng
Department of Stomatology, Zhongshan hospital, Fudan University, No. 180 Fenglin road, Shanghai, 200032, China.
Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China.
Small. 2022 Sep;18(36):e2201656. doi: 10.1002/smll.202201656. Epub 2022 Apr 14.
Bone defect regeneration depends on the population and lifespan of M2 macrophages, which are regulated by dual signals generated by the "physical" spatial configuration of biological tissues and "molecular" chemokines. Herein, inspired by the reprogramming of macrophages, immunoengineered porous microspheres are constructed to accelerate bone repair through the regulation of both "physical" and "molecular" signals. The porous structure of injectable poly (l-lactic acid) (PLLA) microspheres prepared by the microfluidic technique provides a "physical signal" for osteogenic differentiation. Additionally, interleukin (IL)-4-loaded liposomes (Ls) are modified on PLLA microspheres through amide bonds to produce IL-4/Ls/PLLA microspheres, providing a "molecular signal" in stimulating the differentiation of macrophages to M2 type. It is confirmed that IL-4/Ls/PLLA microspheres could induce M2-macrophages polarization and potentiate osteoblast proliferation and differentiation while coculturing with macrophages and osteoblasts in vitro. Besides, IL-4/Ls/PLLA microspheres are proved to promote bone defect regeneration by inducing the conversion of M1 macrophages to M2 through dual biosignal-functional regulation in both the calvaria defect and maxillary sinus defect models. Overall, the immuno-reprogrammed IL-4/Ls/PLLA microspheres achieve the precise immuno-reprogramming of macrophages by dual biosignal-functional regulation. This immune reengineering strategy paves a way for clinical bone defect treatment.
骨缺损再生取决于M2巨噬细胞的数量和寿命，而M2巨噬细胞受生物组织的“物理”空间构型和“分子”趋化因子产生的双重信号调控。在此，受巨噬细胞重编程的启发，构建了免疫工程化多孔微球，通过调控“物理”和“分子”信号来加速骨修复。通过微流控技术制备的可注射聚（L-乳酸）（PLLA）微球的多孔结构为成骨分化提供了“物理信号”。此外，通过酰胺键将负载白细胞介素（IL）-4的脂质体（Ls）修饰在PLLA微球上，制备出IL-4/Ls/PLLA微球，在刺激巨噬细胞向M2型分化方面提供“分子信号”。体外实验证实，IL-4/Ls/PLLA微球在与巨噬细胞和成骨细胞共培养时，可诱导M2巨噬细胞极化，并增强成骨细胞的增殖和分化。此外，在颅骨缺损和上颌窦缺损模型中，通过双重生物信号功能调控，IL-4/Ls/PLLA微球被证明可通过诱导M1巨噬细胞向M2巨噬细胞转化来促进骨缺损再生。总体而言，免疫重编程的IL-4/Ls/PLLA微球通过双重生物信号功能调控实现了巨噬细胞的精确免疫重编程。这种免疫工程策略为临床骨缺损治疗铺平了道路。
