Ntekoumes Dimitris, Song Jiyeon, Liu Haohao, Amelung Connor, Guan Ya, Gerecht Sharon
Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
Adv Healthc Mater. 2025 Jan;14(2):e2403860. doi: 10.1002/adhm.202403860. Epub 2024 Dec 2.
Hypoxia elicits a multitude of tissue responses depending on the severity and duration of the exposure. While chronic hypoxia is shown to impact development, regeneration, and cancer, the understanding of the threats of acute (i.e., short-term) hypoxia is limited mainly due to its transient nature. Here, a novel gelatin-dextran (Gel-Dex) hydrogel is established that decouples hydrogel formation and oxygen consumption and thus facilitates 3D sprouting from endothelial spheroids and, subsequently, induces hypoxia "on-demand." The Gel-Dex platform rapidly achieves acute moderate hypoxic conditions without compromising its mechanical properties. Acute exposure to hypoxia leads to increased endothelial cell migration and proliferation, promoting the total length and number of vascular sprouts. This work finds that the enhanced angiogenic response is mediated by reactive oxygen species, independently of hypoxia-inducible factors. Reactive oxygen species-dependent matrix metalloproteinases activity mediated angiogenic sprouting is observed following acute hypoxia. Overall, the Gel-Dex hydrogel offers a novel platform to study how "on-demand" acute moderate hypoxia impacts angiogenesis, with broad applicability to the development of novel sensing technologies.
缺氧会引发多种组织反应，这取决于暴露的严重程度和持续时间。虽然慢性缺氧已被证明会影响发育、再生和癌症，但对急性（即短期）缺氧威胁的理解主要因其短暂性而受到限制。在此，一种新型的明胶 - 葡聚糖（Gel - Dex）水凝胶被开发出来，它将水凝胶形成与氧气消耗解耦，从而促进内皮球体的三维发芽，并随后“按需”诱导缺氧。Gel - Dex平台能迅速实现急性中度缺氧条件，同时不损害其机械性能。急性缺氧暴露会导致内皮细胞迁移和增殖增加，促进血管芽的总长度和数量。这项研究发现，增强的血管生成反应是由活性氧介导的，与缺氧诱导因子无关。急性缺氧后观察到活性氧依赖性基质金属蛋白酶活性介导血管生成发芽。总体而言，Gel - Dex水凝胶提供了一个新平台，用于研究“按需”急性中度缺氧如何影响血管生成，在新型传感技术开发中具有广泛的适用性。
