Background

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.

Methods

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 via nanochannels. Reprogramming/repair outcomes were evaluated in terms of vascularity and necrosis.

Results

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.

Conclusions

These results indicate that PolyHb and TNT technologies could potentially be synergistically deployed and used as early intervention measures to combat severe tissue ischemia.

中文翻译：

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用氧纳米载体对缺血组织进行早期干预有助于成功实施修复性细胞疗法

背景

组织缺血导致坏死和感染。虽然血管生成细胞疗法已成为一种有前途的抗缺血策略，但目前的细胞疗法方法面临着多重障碍。核重编程的最新进展可能会克服其中一些限制。然而，在严重缺血的情况下，坏死可能超过基于重编程的修复。因此，需要采取辅助措施来维持最低水平的组织活力/活动，以实现对恢复性干预的最佳反应。

方法

在这里，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) 驱动的修复的组合使用，以开发可能用作第一线护理的组织保存/修复策略。在缺血性损伤的小鼠模型中创建了随机模式的皮瓣。合成具有高和低氧亲和力的 PolyHbs，并在缺血性损伤的不同时间点注射到组织瓣中。根据灌注、氧合和由此产生的坏死来评估组织保存的程度。然后使用 TNT通过纳米通道将基于重编程的血管生成细胞疗法部署到皮瓣。根据血管分布和坏死评估重编程/修复结果。

结果

用 PolyHbs 处理的皮瓣随着干预时间的推移表现出逐渐减少的坏死，低氧亲和力 PolyHb 显示出最佳结果。与仅用 PolyHb 或 TNT 治疗的皮瓣相比，基于 TNT 的皮瓣干预与 PolyHb 相结合成功地减少了晚期坏死。

结论

这些结果表明，PolyHb 和 TNT 技术可能被协同部署并用作对抗严重组织缺血的早期干预措施。