Microspheric hierarchical controlled-release system and cell growth platform achieves sequential dual-exosomes delivery and promote bone regeneration

The repair of jaw bone defects faces dual challenges of functionality and aesthetics. The scarcity of jawbone-derived stem cells and imprecise regulation of these endogenous stem cells lead to uncertainties in osteogenic quality and speed. Constructing rational and effective biomimetic materials to regulate the dynamic balance of stem cell migration, proliferation, and differentiation represents a promising osteogenic strategy with broad prospects. Adult stem cells in different niches exhibit heterogeneity in phenotypic characteristics and lineage potential, and communication may exist between adjacent distinct stem cell populations. We hypothesize that exosomes with distinct functions secreted by osteogenic-predominant in situ stem cells may dominate the recruitment and phenotypic transition of adjacent stem cells, thereby enriching osteogenic sources, which represents a potential strategy for efficiently and stably promoting bone regeneration. This study uses bone regeneration in the maxillary posterior region (also known as the maxillary sinus area) as a research model, with PMSCs and LMSCs reported in our previous studies serving as the osteogenic-predominant in situ stem cell population and adjacent stem cell population, respectively. A "one-shell multi-core" microsphere dual sustained-release system was innovatively prepared using fibrinogen and GelMA via microemulsion combined with photocrosslinking method. This system enables sequential delivery of exosomes with distinct functions from PMSCs under conventional culture (C-exos) and osteogenesis-inductive culture (O-exos), mimicking inter-stem cell communication to promote recruitment, population expansion, and osteogenic efficiency of LMSCs. In vivo studies have shown that this system significantly enhances jawbone augmentation, achieves diversified osteogenic patterns, and provides an innovative solution for bone regeneration.