Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA.
Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA.
J Control Release. 2021 Mar 10;331:376-389. doi: 10.1016/j.jconrel.2021.01.034. Epub 2021 Jan 27.
Stem cell transplantation has been extensively explored to promote ischemic limb vascularization and skeletal muscle regeneration. Yet the therapeutic efficacy is low due to limited cell survival under low oxygen environment of the ischemic limbs. Therefore, continuously oxygenating the transplanted cells has potential to increase their survival. During tissue regeneration, the number of blood vessels are gradually increased, leading to the elevation of tissue oxygen content. Accordingly, less exogenous oxygen is needed for the transplanted cells. Excessive oxygen may induce reactive oxygen species (ROS) formation, causing cell apoptosis. Thus, it is attractive to develop oxygen-release biomaterials that are responsive to the environmental oxygen level. Herein, we developed oxygen-release microspheres whose oxygen release was controlled by oxygen-responsive shell. The shell hydrophilicity and degradation rate decreased as the environmental oxygen level increased, leading to slower oxygen release. The microspheres were capable of directly releasing molecular oxygen, which are safer than those oxygen-release biomaterials that release hydrogen peroxide and rely on its decomposition to form oxygen. The released oxygen significantly enhanced mesenchymal stem cell (MSC) survival without inducing ROS production under hypoxic condition. Co-delivery of MSCs and microspheres to the mouse ischemic limbs ameliorated MSC survival, proliferation and paracrine effects under ischemic conditions. It also significantly accelerated angiogenesis, blood flow restoration, and skeletal muscle regeneration without provoking tissue inflammation. The above results demonstrate that the developed microspheres have potential to augment cell survival in ischemic tissues, and promote ischemic tissue regeneration in a safer and more efficient manner.
干细胞移植已被广泛探索用于促进缺血肢体的血管生成和骨骼肌再生。然而，由于缺血肢体低氧环境下细胞存活率有限，其治疗效果较低。因此，持续为移植细胞供氧有可能增加其存活率。在组织再生过程中，血管数量逐渐增加，导致组织氧含量升高。因此，移植细胞所需的外源性氧气减少。过多的氧气可能会诱导活性氧（ROS）的形成，导致细胞凋亡。因此，开发对环境氧水平有响应的释氧生物材料具有吸引力。在此，我们开发了一种释氧微球，其释氧由氧响应外壳控制。随着环境氧水平的升高，外壳的亲水性和降解率降低，导致氧释放减慢。微球能够直接释放分子氧，与那些释放过氧化氢并依赖其分解产生氧气的释氧生物材料相比，更安全。在缺氧条件下，释放的氧气显著提高了间充质干细胞（MSC）的存活率，而不会诱导 ROS 的产生。将 MSC 和微球共同递送至小鼠缺血肢体，在缺血条件下改善了 MSC 的存活、增殖和旁分泌作用。它还显著加速了血管生成、血流恢复和骨骼肌再生，而不会引起组织炎症。上述结果表明，所开发的微球有可能增加缺血组织中的细胞存活率，并以更安全、更有效的方式促进缺血组织的再生。
