Diaz-Starokozheva Ludmila, Das Devleena, Gu Xiangming, Moore Jordan T, Lemmerman Luke R, Valerio Ian, Powell Heather M, Higuita-Castro Natalia, Go Michael R, Palmer Andre F, Gallego-Perez Daniel
Department of Biomedical Engineering, The Ohio State University, Columbus, OH USA.
Department of Surgery, The Ohio State University, Columbus, OH USA.
Cell Mol Bioeng. 2020 May 29;13(5):435-446. doi: 10.1007/s12195-020-00621-4. eCollection 2020 Oct.
Tissue ischemia contributes to necrosis and infection. While angiogenic cell therapies have emerged as a promising strategy against ischemia, current approaches to cell therapies face multiple hurdles. Recent advances in nuclear reprogramming could potentially overcome some of these limitations. However, under severely ischemic conditions necrosis could outpace reprogramming-based repair. As such, adjunctive measures are required to maintain a minimum level of tissue viability/activity for optimal response to restorative interventions.
Here we explored the combined use of polymerized hemoglobin (PolyHb)-based oxygen nanocarriers with Tissue Nano-Transfection (TNT)-driven restoration to develop tissue preservation/repair strategies that could potentially be used as a first line of care. Random-pattern cutaneous flaps were created in a mouse model of ischemic injury. PolyHbs with high and low oxygen affinity were synthesized and injected into the tissue flap at various timepoints of ischemic injury. The degree of tissue preservation was evaluated in terms of perfusion, oxygenation, and resulting necrosis. TNT was then used to deploy reprogramming-based vasculogenic cell therapies to the flaps nanochannels. Reprogramming/repair outcomes were evaluated in terms of vascularity and necrosis.
Flaps treated with PolyHbs exhibited a gradual decrease in necrosis as a function of time-to-intervention, with low oxygen affinity PolyHb showing the best outcomes. TNT-based intervention of the flap in combination with PolyHb successfully curtailed advanced necrosis compared to flaps treated with only PolyHb or TNT alone.
These results indicate that PolyHb and TNT technologies could potentially be synergistically deployed and used as early intervention measures to combat severe tissue ischemia.
组织缺血会导致坏死和感染。虽然血管生成细胞疗法已成为对抗缺血的一种有前景的策略，但目前的细胞疗法面临多重障碍。核重编程的最新进展可能会克服其中一些局限性。然而，在严重缺血条件下，坏死速度可能超过基于重编程的修复速度。因此，需要采取辅助措施来维持组织活力/活性的最低水平，以实现对恢复性干预的最佳反应。
在此，我们探索了基于聚合血红蛋白（PolyHb）的氧纳米载体与组织纳米转染（TNT）驱动的修复联合使用，以开发可能用作一线治疗的组织保存/修复策略。在缺血性损伤小鼠模型中创建随机模式皮瓣。合成了具有高氧亲和力和低氧亲和力的PolyHb，并在缺血性损伤的不同时间点注入组织皮瓣。从灌注、氧合和由此产生的坏死方面评估组织保存程度。然后使用TNT将基于重编程的血管生成细胞疗法部署到皮瓣纳米通道中。从血管生成和坏死方面评估重编程/修复结果。
用PolyHb处理的皮瓣坏死程度随干预时间逐渐降低，低氧亲和力的PolyHb显示出最佳结果。与仅用PolyHb或仅用TNT处理的皮瓣相比，基于TNT的皮瓣干预与PolyHb联合使用成功减少了晚期坏死。
这些结果表明，PolyHb和TNT技术可能会协同部署，并用作对抗严重组织缺血的早期干预措施。
