Exceeding the Limits of Static Cold Storage in Limb Transplantation Using Subnormothermic Machine Perfusion

Marion Goutard; Reinier J. De Vries; Pierre Tawa; Casie A. Pendexter; Ivy A. Rosales; Shannon N. Tessier; Laura C. Burlage; Laurent Lantieri; Mark A. Randolph; Alexandre G. Lellouch; Curtis L. Cetrulo; Korkut Uygun

doi:10.1055/a-1886-5697

Exceeding the Limits of Static Cold Storage in Limb Transplantation Using Subnormothermic Machine Perfusion

Marion Goutard, Reinier J. De Vries, Pierre Tawa, Casie A. Pendexter, Ivy A. Rosales, Shannon N. Tessier, Laura C. Burlage, Laurent Lantieri, Mark A. Randolph, Alexandre G. Lellouch, Curtis L. Cetrulo, Korkut Uygun

Advanced Technologies for Preservation of Biological Systems

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Background For 50 years, static cold storage (SCS) has been the gold standard for solid organ preservation in transplantation. Although logistically convenient, this preservation method presents important constraints in terms of duration and cold ischemia-induced lesions. We aimed to develop a machine perfusion (MP) protocol for recovery of vascularized composite allografts (VCA) after static cold preservation and determine its effects in a rat limb transplantation model. Methods Partial hindlimbs were procured from Lewis rats and subjected to SCS in Histidine-Tryptophan-Ketoglutarate solution for 0, 12, 18, 24, and 48 hours. They were then either transplanted (Txp), subjected to subnormothermic machine perfusion (SNMP) for 3 hours with a modified Steen solution, or to SNMP + Txp. Perfusion parameters were assessed for blood gas and electrolytes measurement, and flow rate and arterial pressures were monitored continuously. Histology was assessed at the end of perfusion. For select SCS durations, graft survival and clinical outcomes after transplantation were compared between groups at 21 days. Results Transplantation of limbs preserved for 0, 12, 18, and 24-hour SCS resulted in similar survival rates at postoperative day 21. Grafts cold-stored for 48 hours presented delayed graft failure (p = 0.0032). SNMP of limbs after 12-hour SCS recovered the vascular resistance, potassium, and lactate levels to values similar to limbs that were not subjected to SCS. However, 18-hour SCS grafts developed significant edema during SNMP recovery. Transplantation of grafts that had undergone a mixed preservation method (12-hour SCS + SNMP + Txp) resulted in better clinical outcomes based on skin clinical scores at day 21 post-transplantation when compared to the SCS + Txp group (p = 0.01613). Conclusion To date, VCA MP is still limited to animal models and no protocols are yet developed for graft recovery. Our study suggests that ex vivo SNMP could help increase the preservation duration and limit cold ischemia-induced injury in VCA transplantation.

Original language	English (US)
Pages (from-to)	350-360
Number of pages	11
Journal	Journal of Reconstructive Microsurgery
Volume	39
Issue number	5
DOIs	https://doi.org/10.1055/a-1886-5697
State	Published - Oct 14 2021

Bibliographical note

Funding Information:
Funding This work was supported by the Office of Assistant Secretary of Defense for Health Affairs, through the Reconstructive Transplant Research Program, Technology Development Award under Awards No. W81XWH-17-1-0680 and W81XWH-19-1-0440. This material is partially based upon work supported by the National Science Foundation under Grant No. EEC 1941543. Partial support from the US National Institutes of Health (R01EB028782) is gratefully acknowledged. Funding from the Shriners Children's is gratefully acknowledged, including the award 986579 to KU, and the support by Shriners Special Shared Facilities that enabled this work. Acknowledgments The authors thank the Shriners Boston Morphology and Imaging Core, Genomics and Proteomics Core, and the Translational Regenerative Medicine Special Shared Facility for access to equipment and expertise.

Publisher Copyright:
© 2022. Thieme. All rights reserved.

Keywords

cold storage
machine perfusion
preservation
reconstructive surgery
transplantation
VCA

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10.1055/a-1886-5697

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Goutard, M., De Vries, R. J., Tawa, P., Pendexter, C. A., Rosales, I. A., Tessier, S. N., Burlage, L. C., Lantieri, L., Randolph, M. A., Lellouch, A. G., Cetrulo, C. L., & Uygun, K. (2021). Exceeding the Limits of Static Cold Storage in Limb Transplantation Using Subnormothermic Machine Perfusion. Journal of Reconstructive Microsurgery, 39(5), 350-360. https://doi.org/10.1055/a-1886-5697

Goutard, M, De Vries, RJ, Tawa, P, Pendexter, CA, Rosales, IA, Tessier, SN, Burlage, LC, Lantieri, L, Randolph, MA, Lellouch, AG, Cetrulo, CL & Uygun, K 2021, 'Exceeding the Limits of Static Cold Storage in Limb Transplantation Using Subnormothermic Machine Perfusion', Journal of Reconstructive Microsurgery, vol. 39, no. 5, pp. 350-360. https://doi.org/10.1055/a-1886-5697

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title = "Exceeding the Limits of Static Cold Storage in Limb Transplantation Using Subnormothermic Machine Perfusion",

abstract = "Background For 50 years, static cold storage (SCS) has been the gold standard for solid organ preservation in transplantation. Although logistically convenient, this preservation method presents important constraints in terms of duration and cold ischemia-induced lesions. We aimed to develop a machine perfusion (MP) protocol for recovery of vascularized composite allografts (VCA) after static cold preservation and determine its effects in a rat limb transplantation model. Methods Partial hindlimbs were procured from Lewis rats and subjected to SCS in Histidine-Tryptophan-Ketoglutarate solution for 0, 12, 18, 24, and 48 hours. They were then either transplanted (Txp), subjected to subnormothermic machine perfusion (SNMP) for 3 hours with a modified Steen solution, or to SNMP + Txp. Perfusion parameters were assessed for blood gas and electrolytes measurement, and flow rate and arterial pressures were monitored continuously. Histology was assessed at the end of perfusion. For select SCS durations, graft survival and clinical outcomes after transplantation were compared between groups at 21 days. Results Transplantation of limbs preserved for 0, 12, 18, and 24-hour SCS resulted in similar survival rates at postoperative day 21. Grafts cold-stored for 48 hours presented delayed graft failure (p = 0.0032). SNMP of limbs after 12-hour SCS recovered the vascular resistance, potassium, and lactate levels to values similar to limbs that were not subjected to SCS. However, 18-hour SCS grafts developed significant edema during SNMP recovery. Transplantation of grafts that had undergone a mixed preservation method (12-hour SCS + SNMP + Txp) resulted in better clinical outcomes based on skin clinical scores at day 21 post-transplantation when compared to the SCS + Txp group (p = 0.01613). Conclusion To date, VCA MP is still limited to animal models and no protocols are yet developed for graft recovery. Our study suggests that ex vivo SNMP could help increase the preservation duration and limit cold ischemia-induced injury in VCA transplantation.",

keywords = "cold storage, machine perfusion, preservation, reconstructive surgery, transplantation, VCA",

author = "Marion Goutard and {De Vries}, {Reinier J.} and Pierre Tawa and Pendexter, {Casie A.} and Rosales, {Ivy A.} and Tessier, {Shannon N.} and Burlage, {Laura C.} and Laurent Lantieri and Randolph, {Mark A.} and Lellouch, {Alexandre G.} and Cetrulo, {Curtis L.} and Korkut Uygun",

note = "Funding Information: Funding This work was supported by the Office of Assistant Secretary of Defense for Health Affairs, through the Reconstructive Transplant Research Program, Technology Development Award under Awards No. W81XWH-17-1-0680 and W81XWH-19-1-0440. This material is partially based upon work supported by the National Science Foundation under Grant No. EEC 1941543. Partial support from the US National Institutes of Health (R01EB028782) is gratefully acknowledged. Funding from the Shriners Children's is gratefully acknowledged, including the award 986579 to KU, and the support by Shriners Special Shared Facilities that enabled this work. Acknowledgments The authors thank the Shriners Boston Morphology and Imaging Core, Genomics and Proteomics Core, and the Translational Regenerative Medicine Special Shared Facility for access to equipment and expertise. Publisher Copyright: {\textcopyright} 2022. Thieme. All rights reserved.",

year = "2021",

month = oct,

day = "14",

doi = "10.1055/a-1886-5697",

language = "English (US)",

volume = "39",

pages = "350--360",

journal = "Journal of Reconstructive Microsurgery",

issn = "0743-684X",

publisher = "Thieme Medical Publishers",

number = "5",

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TY - JOUR

T1 - Exceeding the Limits of Static Cold Storage in Limb Transplantation Using Subnormothermic Machine Perfusion

AU - Goutard, Marion

AU - De Vries, Reinier J.

AU - Tawa, Pierre

AU - Pendexter, Casie A.

AU - Rosales, Ivy A.

AU - Tessier, Shannon N.

AU - Burlage, Laura C.

AU - Lantieri, Laurent

AU - Randolph, Mark A.

AU - Lellouch, Alexandre G.

AU - Cetrulo, Curtis L.

AU - Uygun, Korkut

N1 - Funding Information: Funding This work was supported by the Office of Assistant Secretary of Defense for Health Affairs, through the Reconstructive Transplant Research Program, Technology Development Award under Awards No. W81XWH-17-1-0680 and W81XWH-19-1-0440. This material is partially based upon work supported by the National Science Foundation under Grant No. EEC 1941543. Partial support from the US National Institutes of Health (R01EB028782) is gratefully acknowledged. Funding from the Shriners Children's is gratefully acknowledged, including the award 986579 to KU, and the support by Shriners Special Shared Facilities that enabled this work. Acknowledgments The authors thank the Shriners Boston Morphology and Imaging Core, Genomics and Proteomics Core, and the Translational Regenerative Medicine Special Shared Facility for access to equipment and expertise. Publisher Copyright: © 2022. Thieme. All rights reserved.

PY - 2021/10/14

Y1 - 2021/10/14

N2 - Background For 50 years, static cold storage (SCS) has been the gold standard for solid organ preservation in transplantation. Although logistically convenient, this preservation method presents important constraints in terms of duration and cold ischemia-induced lesions. We aimed to develop a machine perfusion (MP) protocol for recovery of vascularized composite allografts (VCA) after static cold preservation and determine its effects in a rat limb transplantation model. Methods Partial hindlimbs were procured from Lewis rats and subjected to SCS in Histidine-Tryptophan-Ketoglutarate solution for 0, 12, 18, 24, and 48 hours. They were then either transplanted (Txp), subjected to subnormothermic machine perfusion (SNMP) for 3 hours with a modified Steen solution, or to SNMP + Txp. Perfusion parameters were assessed for blood gas and electrolytes measurement, and flow rate and arterial pressures were monitored continuously. Histology was assessed at the end of perfusion. For select SCS durations, graft survival and clinical outcomes after transplantation were compared between groups at 21 days. Results Transplantation of limbs preserved for 0, 12, 18, and 24-hour SCS resulted in similar survival rates at postoperative day 21. Grafts cold-stored for 48 hours presented delayed graft failure (p = 0.0032). SNMP of limbs after 12-hour SCS recovered the vascular resistance, potassium, and lactate levels to values similar to limbs that were not subjected to SCS. However, 18-hour SCS grafts developed significant edema during SNMP recovery. Transplantation of grafts that had undergone a mixed preservation method (12-hour SCS + SNMP + Txp) resulted in better clinical outcomes based on skin clinical scores at day 21 post-transplantation when compared to the SCS + Txp group (p = 0.01613). Conclusion To date, VCA MP is still limited to animal models and no protocols are yet developed for graft recovery. Our study suggests that ex vivo SNMP could help increase the preservation duration and limit cold ischemia-induced injury in VCA transplantation.

AB - Background For 50 years, static cold storage (SCS) has been the gold standard for solid organ preservation in transplantation. Although logistically convenient, this preservation method presents important constraints in terms of duration and cold ischemia-induced lesions. We aimed to develop a machine perfusion (MP) protocol for recovery of vascularized composite allografts (VCA) after static cold preservation and determine its effects in a rat limb transplantation model. Methods Partial hindlimbs were procured from Lewis rats and subjected to SCS in Histidine-Tryptophan-Ketoglutarate solution for 0, 12, 18, 24, and 48 hours. They were then either transplanted (Txp), subjected to subnormothermic machine perfusion (SNMP) for 3 hours with a modified Steen solution, or to SNMP + Txp. Perfusion parameters were assessed for blood gas and electrolytes measurement, and flow rate and arterial pressures were monitored continuously. Histology was assessed at the end of perfusion. For select SCS durations, graft survival and clinical outcomes after transplantation were compared between groups at 21 days. Results Transplantation of limbs preserved for 0, 12, 18, and 24-hour SCS resulted in similar survival rates at postoperative day 21. Grafts cold-stored for 48 hours presented delayed graft failure (p = 0.0032). SNMP of limbs after 12-hour SCS recovered the vascular resistance, potassium, and lactate levels to values similar to limbs that were not subjected to SCS. However, 18-hour SCS grafts developed significant edema during SNMP recovery. Transplantation of grafts that had undergone a mixed preservation method (12-hour SCS + SNMP + Txp) resulted in better clinical outcomes based on skin clinical scores at day 21 post-transplantation when compared to the SCS + Txp group (p = 0.01613). Conclusion To date, VCA MP is still limited to animal models and no protocols are yet developed for graft recovery. Our study suggests that ex vivo SNMP could help increase the preservation duration and limit cold ischemia-induced injury in VCA transplantation.

KW - cold storage

KW - machine perfusion

KW - preservation

KW - reconstructive surgery

KW - transplantation

KW - VCA

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EP - 360

JO - Journal of Reconstructive Microsurgery

JF - Journal of Reconstructive Microsurgery

IS - 5

ER -

Exceeding the Limits of Static Cold Storage in Limb Transplantation Using Subnormothermic Machine Perfusion

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