Injectable Nano-Scaffolds, Hydroxyapatite-Polymer Nanocomposite Microsphere, Enhance the Therapeutic Angiogenesis by Cell Transplantation

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Clinical trials demonstrate the effectiveness of cell-based therapeutic angiogenesis against patients with a variety of ischemic disease; however, the clinical success to date has been still limited. We have reported that nano-scaled sintered hydroxyapatite (HAp)-coating on artificial grafts reveals marked cell-adhesiveness, safety and high tissue-affinity. With this nanotechnology, the inorganic, biodegradable and injectable scaffold, HAp-coated poly L-lactic acid (PLLA) microsphere, has been generated : named nano-scaffold (NS). In this study, we examined its usefulness in cell-based therapeutic angiogenesis. Bone marrow-mononuclear cells (BMC) alone, with uncoated PLLAs (LA), or with HAp-coated microspheres (nano-scaffold : NS), were intramuscularly injected into mice ischemic hind-limbs generated by femoral artery occlusion. Kaplan-Meier analysis demonstrated that NS+BMC treatment markedly prevented limb necrosis after the operation (vs. BMC alone, and LA+BMC). Roles of NS to sustain BMC in ischemic tissues were demonstrated by the findings that immunohistochemistry revealed NS and BMC co-localized, and that NS+BMC group exhibited significantly elevated intramuscular levels of proangiogenic cytokines in ischemic tissues as compared with BMC alone. We demonstrated usefulness of injectable scaffold as an enhancer for cell-based therapeutic angiogenesis.