Curry Corinne W, Sturgeon Sarah M, O'Grady Brian J, Yates Alexis K, Kjar Andrew, Paige Hayden A, Mowery Lucas S, Katdare Ketaki A, Patel Riya V, Mlouk Kate, Stiefbold Madison R, Vafaie-Partin Sidney, Kawabata Atsuyuki, McKee Rachel M, Moore-Lotridge Stephanie, Hawkes Adrienne, Kusunose Jiro, Gibson-Corley Katherine N, Schmeckpeper Jeffrey, Schoenecker Jonathan G, Caskey Charles F, Lippmann Ethan S
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
Interdisciplinary Materials Science Program, Vanderbilt University, Nashville, TN, USA.
bioRxiv. 2023 May 25:2023.05.24.542150. doi: 10.1101/2023.05.24.542150.
Critical limb ischemia (CLI) occurs when blood flow is restricted through the arteries, resulting in ulcers, necrosis, and chronic wounds in the downstream extremities. The development of collateral arterioles (i.e. arteriogenesis), either by remodeling of pre-existing vascular networks or growth of new vessels, can prevent or reverse ischemic damage, but it remains challenging to stimulate collateral arteriole development in a therapeutic context. Here, we show that a gelatin-based hydrogel, devoid of growth factors or encapsulated cells, promotes arteriogenesis and attenuates tissue damage in a murine CLI model. The gelatin hydrogel is functionalized with a peptide derived from the extracellular epitope of Type 1 cadherins. Mechanistically, these "GelCad" hydrogels promote arteriogenesis by recruiting smooth muscle cells to vessel structures in both and assays. In a murine femoral artery ligation model of CLI, delivery of crosslinking GelCad hydrogels was sufficient to restore limb perfusion and maintain tissue health for 14 days, whereas mice treated with gelatin hydrogels had extensive necrosis and autoamputated within 7 days. A small cohort of mice receiving the GelCad hydrogels were aged out to 5 months and exhibited no decline in tissue quality, indicating durability of the collateral arteriole networks. Overall, given the simplicity and off-the-shelf format of the GelCad hydrogel platform, we suggest it could have utility for CLI treatment and potentially other indications that would benefit from arteriole development.
严重肢体缺血（CLI）是指动脉血流受限，导致下游肢体出现溃疡、坏死和慢性伤口。通过重塑现有血管网络或新生血管生长形成侧支小动脉（即动脉生成），可以预防或逆转缺血性损伤，但在治疗环境中刺激侧支小动脉发育仍然具有挑战性。在此，我们表明一种不含生长因子或包封细胞的明胶基水凝胶，在小鼠CLI模型中可促进动脉生成并减轻组织损伤。该明胶水凝胶用源自1型钙黏蛋白细胞外表位的肽进行功能化修饰。从机制上讲，这些“GelCad”水凝胶在体外和体内试验中，通过将平滑肌细胞募集到血管结构来促进动脉生成。在CLI的小鼠股动脉结扎模型中，递送交联的GelCad水凝胶足以恢复肢体灌注并维持组织健康14天，而用明胶水凝胶治疗的小鼠在7天内出现广泛坏死并自行截肢。一小群接受GelCad水凝胶治疗的小鼠存活至5个月，组织质量未下降，表明侧支小动脉网络具有持久性。总体而言，鉴于GelCad水凝胶平台的简单性和现成可用的形式，我们认为它可能对CLI治疗以及可能受益于小动脉发育的其他适应症有用。
