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Early Intervention in Ischemic Tissue with Oxygen Nanocarriers Enables Successful Implementation of Restorative Cell Therapies

  • 2020 CMBE Young Innovators Issue
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Abstract

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.

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Acknowledgments

Funding was partly provided by NINDS/NIH (R21NS099869), NIBIB/NIH (DP2EB028110) NHLBI/NIH (R01HL126945), NIBIB/NIH (R01EB021926), and NHLBI/NIH (R01HL138116). Some of the illustrations were created with BioRender.com.

Conflict of interest

Ludmila Diaz-Starokozheva, Devleena Das, Xiangming Gu, Jordan Moore, Luke R. Lemmerman, Ian Valerio, Heather M. Powell, Natalia Higuita-Castro, Michael R. Go, Andre F. Palmer, and Daniel Gallego-Perez declare that they have no conflicts of interest.

Ethical Approval

All animal studies were performed in accordance with protocols approved by the Laboratory Animal Care and Use Committee of The Ohio State University. No human studies were carried out by the authors of this article.

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Diaz-Starokozheva, L., Das, D., Gu, X. et al. Early Intervention in Ischemic Tissue with Oxygen Nanocarriers Enables Successful Implementation of Restorative Cell Therapies. Cel. Mol. Bioeng. 13, 435–446 (2020). https://doi.org/10.1007/s12195-020-00621-4

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