Controllable preparation of magnesium-hybridized PLA-PEG-PLA porous microspheres with anti-inflammatory function

Biodegradable polylactic acid-based microspheres have been widely used in biomedical applications such as drug delivery and tissue engineering, however, most of the microspheres typically possess simple surface structures, lacking bioactivity and the ability to promote cell adhesion. Our group previously synthesized poly (L-lactic acid) magnesium-doped microspheres (PMg) with immunomodulatory and osteogenic potential. However, several drawbacks of PMgs, such as high hydrophobicity, a narrow pore distribution and large average particle size, and limited sustainable Mg²⁺release, can affect cell adhesion and growth and thus restricting their biomedical applications. To address these limitations, in the current study, a poly (lactic acid)-poly (ethylene glycol)-poly (lactic acid) (PLEL) triblock copolymer was synthesized, and magnesium-incorporated PLEL porous microspheres (PEMg) were prepared through emulsion solvent evaporation combined with anin-situdoping method. Benefiting from hydrophilic PEG segments, PEMg displayed significantly improved surface wettability and structural stability. The optimized PEMg possessed nearly half of the average size of PMg. and an interconnected hierarchical larger pore structure (1-30 μm, average: 10 ± 1.4 μm), which effectively promoted cell adhesion and deep infiltration. Moreover, PEMg showed a sustained Mg²⁺release which is nearly 1.87-fold higher than PMg, capable of neutralizing acidic by-products and stabilizing the local microenvironment. The biocompatible PEMg could upregulate anti-inflammatory biomarkers (Arg-1, CD206) and inhibit pro-inflammatory factors (iNOS, TNF-α), achieving over 1.5 times anti-inflammatory capacity of PMg. In summary, the creatively developed PEMg microspheres integrate optimized structural features and enhanced biological performances. Compared with PMg, PEMg showed much better potential to satisfy the complex demands of tendon soft tissue repair and presents promising prospects for inflammatory microenvironment regulation and soft tissue regeneration.