Culturing hypoxia-primed mesenchymal stem cells in xeno- and serum-free conditions facilitates the synthesis of an extracellular matrix-based biologic with augmented therapeutic potential for the treatment of diabetic wounds

Abstract Diabetic wound healing is severely impaired by poor angiogenesis, neuropathy, chronic inflammation, decreased cell proliferation and dysregulated extracellular matrix (ECM) synthesis. Here, we developed a human mesenchymal stem cell (MSC)-derived ECM-based biologic with augmented pro-angiogenic potential, free of any xeno- and serum-free components, aimed at treating diabetic wounds. Hypoxia-primed MSCs, cultured in chemically defined medium, synthesized a secretome enriched in pro-angiogenic factors. This secretome was aggregated and co-precipitated by a heparan sulfate mimetic, dextran sulfate (DxS), into the pericellular space. MSCs assembled the deposited secretome components into an insoluble ECM, which upon decellularization was processed into MIcroParticles of SOlidified Secretome (MIPSOS), an ECM-DxS composite biologic. This formulation of MIPSOS demonstrated augmented pro-angiogenic bioactivity in vitro and in vivo and accelerated revascularization, re-epithelization and wound closure by almost doubling wound closure rate, and outperforming GraftJacket®, a clinically utilized decellularized human dermis-derived biologic. MIPSOS-treated wounds showed enhanced cellular infiltration and granulation tissue formation, along with a reduced presence of macrophages, indicating progression toward inflammation resolution. MIPSOS thus provides a novel treatment alternative that overcomes major limitations of soluble factor-based, tissue-derived ECM-based, as well as cell-based therapies, offering significant improvements in diabetic wound management.