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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\u2010called \u201cno option patients\u201d 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\u2010angiogenic nucleic acid, protein, and stem cell\u2010based 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.<\/jats:p>","DOI":"10.1002\/advs.202003119","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T00:05:10Z","timestamp":1612829110000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Therapeutic Biomaterial Approaches to Alleviate Chronic Limb Threatening Ischemia"],"prefix":"10.1002","volume":"8","author":[{"given":"Grazia","family":"Marsico","sequence":"first","affiliation":[{"name":"C\u00daRAM SFI Research Centre for Medical Devices National University of Ireland  Galway Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Martin\u2010Salda\u00f1a","sequence":"additional","affiliation":[{"name":"C\u00daRAM SFI Research Centre for Medical Devices National University of Ireland  Galway Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6292-4933","authenticated-orcid":false,"given":"Abhay","family":"Pandit","sequence":"additional","affiliation":[{"name":"C\u00daRAM SFI Research Centre for Medical Devices National University of Ireland  Galway Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,8]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.115.002938"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejvs.2019.05.006"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.2147\/VHRM.S125065"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2019.04.002"},{"key":"e_1_2_7_5_1","first-page":"748","volume":"8","author":"Cundiff D. 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