Abstract Body (Do not enter title and authors here): Chronic limb-threatening ischemia (CLTI), a severe complication of lifestyle-related diseases such as diabetes and chronic kidney disease, remains a highly prevalent and challenging condition. Angiogenic therapy using autologous mononuclear cell or stem cell transplantation has been explored as a treatment option for CLTI patients at risk of amputation. However, its clinical efficacy has been limited, mainly due to poor cell retention at the transplantation site and impaired function of transplanted cells in CLTI patients. To address these limitations, we have developed an Injectable Cell Scaffold (ICS), a novel biomaterial designed to enhance angiogenic therapy. ICS consists of bioabsorbable polymer microspheres coated with hydroxyapatite nanocrystals and is formulated for intramuscular injection. When co-transplanted with cells, ICS enables prolonged local retention of transplanted cells and enhances their therapeutic angiogenic effects. Notably, ICS amplifies the effects of peripheral blood mononuclear cells (PBMNCs), which are easily collected but traditionally considered to have limited regenerative capacity. Building on this platform, we are conducting an exploratory, investigator-initiated clinical trial of ICS-001 at Hyogo Medical University Hospital and Oita Oka Hospital. In this trial, ICS-001 is combined with autologous stem cell CD34-rich PBMNCs mobilized by G-CSF and a CXCR4 inhibitor. This approach aims to develop a safe, cost-effective, and powerful new cell-based angiogenic therapy within the medical device framework. To date, five patients have been enrolled in the trial. No ICS-001-specific adverse events have been observed. Encouragingly, patients have shown clinical improvements in symptoms such as resting pain and ischemic ulcers. These preliminary findings suggest that ICS-001 has the potential to significantly improve the outcomes of cell-based therapies for CLTI. We report here the progress of this ongoing clinical study as a promising strategy to overcome the limitations of current angiogenic treatments for CLTI and provide an innovative therapeutic option using a combination of biomaterials and autologous cell transplantation.