Min Ge,Yaqi Sheng,Shuyue Qi,Lei Cao,Yan Zhang,Jun Yang
Incorporating poly(lactic-co-glycolic) acid (PLGA) microparticles into human mesenchymal stem cells (hMSC) aggregates has shown promising application prospects. However, the acidic degradation products and burst release of PLGA microparticles still need to be ameliorated. In this study, the PLGA/chitosan–heparin (P/C–h) composite microparticles were successfully fabricated by integrating the double emulsion and microfluidic technology through the precise manipulation of the emulsion composition and flow rate of the two-phase in a flow-focusing chip. The P/C–h microparticles were highly monodispersed with a diameter of 23.45 ± 0.25 μm and shell–core structure of the PLGA encapsulated C–h complex, which were suitable for the fabrication of hMSC aggregates. When the mass ratio of PLGA to the C–h complex was optimized to 2 : 1, the pH of the leach liquor of P/C–h microparticles remained neutral. Compared with those of PLGA microparticles, the cytotoxicity and the initial burst release (loaded FGF-2 and VEGF) were both significantly reduced in P/C–h microparticles. Furthermore, the survival, stemness, as well as secretion and migration abilities of cells in hMSC aggregates incorporating P/C–h microparticles were also enhanced. In summary, the P/C–h composite microparticles prepared by the droplet microfluidic technique support the optimal biological and functional profile of the hMSC aggregates, which may facilitate the clinical applications of MSC-based therapy.
Inflammatory bowel disease (IBD) is an incurable condition driven by chronic inflammatory dysregulation. Human mesenchymal stem cells (hMSCs) offer therapeutic promise, but limited persistence and functional heterogeneity constrain their clinical efficacy. Here, we present a bio-inspired priming platform built on poly(lactic- co -glycolic acid)/chitosan-heparin microparticles, engineered to display E/N-cadherin motifs and to enable controlled interleukin-1β release through PLGA biodegradation. These functionalized microparticles (hE/N-cad@P/C-h-IL-1β) assemble with hMSCs into hybrid aggregates that enhance cell survival under stress and improve adaptability to microenvironment cues. The priming process upregulates endogenous cadherin expression and modulates AKT/STAT signaling, conferring stimulus- and dose-responsive immune activity. In vitro , hybrid aggregates polarize macrophages toward an anti-inflammatory phenotype, expand regulatory T cells, and suppress pathogenic lymphocyte activation. In a dextran sulfate sodium (DSS) colitis model, intraperitoneal delivery of hybrid aggregates restores intestinal immune homeostasis, accelerates epithelial repair, and reduces disease severity to near baseline within fourteen days. By integrating cell-adhesive and cytokine signals within a modular platform, this strategy overcomes critical translational barriers in hMSC therapy and provides a blueprint for precisely targeted treatment of IBD and related inflammatory disorders.
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