Modulating oxygen release via manipulated microspheres embedded in thermoresponsive hydrogels for enhanced stem cell survival under hypoxia

Ensuring a stable oxygen supply for transplanted cells remains a major challenge in the clinical translation of tissue engineering and regenerative medicine. Hypoxic environments caused by insufficient vascularization are a key factor leading to cell death and graft failure. To address this issue, we developed an injectable, oxygen-generating thermoresponsive hydrogel system based on poly(organophosphazene) (PPZ). By modulating the gelatin and calcium peroxide (CaO₂) content, we fabricated calcium peroxide-loaded (CPO) microspheres with distinct oxygen release profiles and incorporated them into the PPZ hydrogel, forming a hydrogel based oxygen delivery platform, termed OxyCellgel. This platform, composed solely of PPZ and CPO microspheres, allows for precise control over oxygen release rates and amounts, enabling adaptation to both mild and severe hypoxic environments. The interaction between the microspheres and hydrogel matrix facilitated uniform and sustained oxygen release. Subsequently, human mesenchymal stem cells (hMSCs) were co-delivered with this OxyCellgel system to evaluate cell viability and function under hypoxic conditions. The system significantly enhanced the survival and proliferation of hMSCs and promoted angiogenesis through their paracrine effects under hypoxia. Notably, hMSCs co-encapsulated with OxyCellgel showed markedly improved viability under hypoxic conditions compared to controls. This study presents a hydrogel-based oxygen delivery platform with controllable release kinetics as a promising strategy to improve the efficacy of stem cell-based therapies under diverse hypoxic conditions.