Therapeutic Biomaterial Approaches to Alleviate Chronic Limb Threatening Ischemia

Chronic limb threatening ischemia (CLTI) is a severe condition defined by the blockage of arteries in the lower extremities that leads to the degeneration of blood vessels and is characterized by the formation of non-healing ulcers and necrosis. The gold standard therapies such as bypass and endovascular surgery aim at the removal of the blockage. These therapies are not suitable for the so-called "no option patients" which present multiple artery occlusions with a likelihood of significant limb amputation. Therefore, CLTI represents a significant clinical challenge, and the efforts of developing new treatments have been focused on stimulating angiogenesis in the ischemic muscle. The delivery of pro-angiogenic nucleic acid, protein, and stem cell-based interventions have limited efficacy due to their short survival. Engineered biomaterials have emerged as a promising method to improve the effectiveness of these latter strategies. Several synthetic and natural biomaterials are tested in different formulations aiming to incorporate nucleic acid, proteins, stem cells, macrophages, or endothelial cells in supportive matrices. In this review, an overview of the biomaterials used alone and in combination with growth factors, nucleic acid, and cells in preclinical models is provided and their potential to induce revascularization and regeneration for CLTI applications is discussed.