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  • Review Article
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Mechanisms and strategies for organ recovery

Nature Reviews Bioengineering volume 3, pages 596–611 (2025)Cite this article

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Abstract

Oxygen is essential for the viability of mammalian cells. Disruptions in circulation lead to a cessation of oxygen delivery, which causes decreased ATP production, intracellular acidosis and oedema. If blood flow is reintroduced, this initiates secondary cellular damage usually facilitating cell death. Nonetheless, such outcomes are not inevitable; cells from various organs have been recovered in vitro after extended periods without blood supply, with emerging technologies aimed at scaling up these findings. Perfusion systems, inspired by heart–lung machines, provide mechanical support by restoring circulation, regulating temperature, exchanging gases and modifying circulating perfusate with various pharmacological compounds. Together, perfusion systems and perfusates have mitigated cellular demise and recovered injured tissues, potentially revolutionizing resuscitation medicine and organ transplantation. This Review summarizes the biological mechanisms of cellular injury, perfusate modifications and mechanistic approaches for reinstating circulation, and offers perspectives on the future of organ and whole-body recovery.

Key points

  • Circulatory cessation causes detrimental metabolic changes in mammalian cells due to limited ATP and oxygen reserves, whereas restoring blood flow leads to even more pronounced secondary damage, termed ischaemia–reperfusion injury.

  • In vitro cultures first demonstrated that cell death is not inevitable as previously thought even hours after circulatory cessation, with viable cells successfully recovered from multiple organs.

  • Perfusion systems, inspired by heart–lung machines, use perfusates with blood or synthetic agents to restore circulation, support metabolism and recover compromised tissues.

  • Multimodal perfusion approaches substantially improve organs or whole-body recovery following prolonged circulatory cessation.

  • Perfusion systems with new perfusates are slowly being translated into clinical settings with approaches towards whole-body or isolated-organ recovery in resuscitation and transplant medicine.

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Fig. 1: The cascade of molecular and cellular responses initiated by reduced blood flow or ischaemia and its reintroduction.
Fig. 2: Different cell-death pathways implicated in pathophysiology of ischaemia–reperfusion injury and their pharmacological targets.
Fig. 3: Pathophysiology of post-cardiac arrest syndrome.
Fig. 4: Approaches to modify the perfusate to promote cellular recovery.
Fig. 5: Perfusion system components and mechanistic approaches to organ recovery.
Fig. 6: Emerging strategies and technologies for organ recovery and reconditioning.

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Authors and Affiliations

  1. Department of Surgery, NYU Grossman School of Medicine, New York City, NY, USA

    David Andrijevic, Adam D. Griesemer & Robert A. Montgomery

  2. Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA

    Ana Spajic, Irbaz Hameed & Nenad Sestan

  3. Division of Cardiac Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT, USA

    Irbaz Hameed

  4. Department of Neurology, Yale Center for Brain and Mind Health, Yale School of Medicine, New Haven, CT, USA

    Kevin N. Sheth

  5. Critical Care and Resuscitation Research, Division of Pulmonary and Critical Care Medicine, Department of Medicine, NYU Grossman School of Medicine, New York City, NY, USA

    Sam Parnia

  6. NYU Langone Transplant Institute, NYU Langone Health, New York City, NY, USA

    Adam D. Griesemer & Robert A. Montgomery

  7. Yale Child Study Center, Yale School of Medicine, New Haven, CT, USA

    Nenad Sestan

  8. Department of Psychiatry, Yale Schoole of Medicine, CT, New Haven, USA

    Nenad Sestan

  9. Wu Tsai Institute, Yale University, New Haven, CT, USA

    Nenad Sestan

  10. Department of Comparative Medicine, Yale University, New Haven, CT, USA

    Nenad Sestan

  11. Department of Genetics, Yale University, New Haven, CT, USA

    Nenad Sestan

  12. Kavli Institute for Neuroscience, Yale University, New Haven, CT, USA

    Nenad Sestan

  13. Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA

    Nenad Sestan

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All authors contributed to the conceptualization of the article, data search and discussion of content. The initial draft of the manuscript was authored by D.A., with contributions from all co-authors. D.A. and A.S. were responsible for the generation of all figures. Subsequently, all authors reviewed and edited the manuscript prior to its submission.

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N.S. is a co-founder of Bexorg, in which he holds equity and serves on the board. R.A.M. has received research funds from Lung Biotechnology, a wholly owned subsidiary of United Therapeutics Corporation, PBC; serves on the advisory board of eGenesis; and has been a strategic advisor for Recombinetics. The remaining authors declare no competing interests.

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Andrijevic, D., Spajic, A., Hameed, I. et al. Mechanisms and strategies for organ recovery. Nat Rev Bioeng 3, 596–611 (2025). https://doi.org/10.1038/s44222-025-00293-7

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