Model-Guided Design and Optimization of CPA Perfusion Protocols for Whole Organ Cryopreservation

Zonghu Han, Joseph Sushil Rao, Srivasupradha Ramesh, Jan Hergesell, Bat-Erdene Namsrai, Michael L Etheridge, Erik B Finger, John C. Bischof

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Vitrification could enable long-term organ preservation, but only after loading high-concentration, potentially toxic cryoprotective agents (CPAs) by perfusion. In this paper, we combine a two-compartment Krogh cylinder model with a toxicity cost function to theoretically optimize the loading of CPA (VMP) in rat kidneys as a model system. First, based on kidney perfusion experiments, we systematically derived the parameters for a CPA transport loading model, including the following: V b = 86.0% (r a = 3.86 μm), L p = 1.5 × 10–14 m3/(N·s), ω = 7.0 × 10–13 mol/(N·s), σ = 0.10. Next, we measured the toxicity cost function model parameters as α = 3.12 and β = 9.39 × 10–6. Combining these models, we developed an improved kidney-loading protocol predicted to achieve vitrification while minimizing toxicity. The optimized protocol resulted in shorter exposure (25 min or 18.5% less) than the gold standard kidney-loading protocol for VMP, which had been developed based on decades of empirical practice. After testing both protocols on rat kidneys, we found comparable physical and biological outcomes. While we did not dramatically reduce toxicity, we did reduce the time. As our approach is now validated, it can be used on other organs lacking defined toxicity data to reduce CPA exposure time and provide a rapid path toward developing CPA perfusion protocols for other organs and CPAs.

Original languageEnglish (US)
Pages (from-to)2216-2228
Number of pages13
JournalAnnals of Biomedical Engineering
Volume51
Issue number10
DOIs
StatePublished - Oct 2023

Bibliographical note

Funding Information:
This work was supported by NIH R01DK117425, NIH R01DK132211, NIH R01HL135046, NSF EEC 1941543, and a generous gift from the Biostasis Research Institute.

Publisher Copyright:
© 2023, The Author(s).

Keywords

  • Cryoprotectant
  • Organ perfusion optimization
  • Organ vitrification
  • Toxicity
  • Transport

PubMed: MeSH publication types

  • Journal Article

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