Ultrasound-Triggered Biomimetic Ultrashort Peptide Nanofiber Hydrogels Promote Bone Regeneration by Modulating Macrophage and the Osteogenic Immune Microenvironment

Abstract

The immune microenvironment plays a vital role in bone defect repair. To create an immune microenvironment that promotes osteogenesis, researchers are exploring ways to enhance the differentiation of M2-type macrophages. Functional peptides have been discovered that can effectively improve this process, but they are limited by low efficiency and rapid degradation in vivo. To overcome these issues, an ultrashort peptide with both M2 regulatory and self-assembly modules was designed as a building block to construct an ultrasound-responsive nanofiber hydrogel. These nanofibers can be released from the hydrogel in a time-dependent manner upon ultrasound stimulation, activating mitochondrial glycolytic metabolism and the tricarboxylic acid cycle, inhibiting reactive oxygen species production and enhancing M2 macrophage polarization. The hydrogel exhibits advanced therapeutic potential for bone regeneration by triggering M2 macrophages to secrete BMP-2 and IGF-I, accelerating the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts. Thus, modularly designed biomimetic ultrashort peptide nanofiber-based hydrogels provide a novel strategy to rebuild osteogenic immune microenvironments for bone repair.

Note:
Funding declaration: This work was financially supported by National Key R&D Program of China (2022YFA1103200; Yao Sun); National Natural Science Foundation of China (81822012, 82061130222, 81771043; Yao Sun); National Natural Science Foundation of China (21925505; Jianzhong Du); National Natural Science Foundation of China (22075212; Zhen Fan); Shanghai Academic Leader of Science and Technology Innovation Action Plan (20XD1424000; Yao Sun); Innovation Program of Shanghai Municipal Education Commission (2023ZKZD28; Jianzhong Du); the Shanghai Experimental Animal Research Project of Science and Technology Innovation Action Plan (8191101676, 201409006400; Yao Sun); and Shanghai International Scientific Collaboration Fund (21520710100; Jianzhong Du).

Conflict of Interests: The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: This experiment was approved by the Medical Ethics Committee of the School of Stomatology of Tongji University (2019-DW-040)

Keywords: oligopeptide, nanofiber hydrogel, immune microenvironment, bone tissue regeneration