Considerations for the use of porcine organ donation models in preclinical organ donor intervention research

Frazer I. Heinis , Shaheed Merani , Nicholas W. Markin , Kim F. Duncan , Michael J. Moulton , Lance Fristoe , William E. Thorell , Raechel A. Sherrick , Tami R. Wells , Matthew T. Andrews , Marian Urban

Animal Models and Experimental Medicine ›› 2024, Vol. 7 ›› Issue (3) : 283 -296.

PDF (4096KB)
Animal Models and Experimental Medicine ›› 2024, Vol. 7 ›› Issue (3) : 283 -296. DOI: 10.1002/ame2.12411
REVIEW

Considerations for the use of porcine organ donation models in preclinical organ donor intervention research

Author information +
History +
PDF (4096KB)

Abstract

Use of animal models in preclinical transplant research is essential to the optimization of human allografts for clinical transplantation. Animal models of organ donation and preservation help to advance and improve technical elements of solid organ recovery and facilitate research of ischemia–reperfusion injury, organ preservation strategies, and future donor-based interventions. Important considerations include cost, public opinion regarding the conduct of animal research, translational value, and relevance of the animal model for clinical practice. We present an overview of two porcine models of organ donation: donation following brain death (DBD) and donation following circulatory death (DCD). The cardiovascular anatomy and physiology of pigs closely resembles those of humans, making this species the most appropriate for pre-clinical research. Pigs are also considered a potential source of organs for human heart and kidney xenotransplantation. It is imperative to minimize animal loss during procedures that are surgically complex. We present our experience with these models and describe in detail the use cases, procedural approach, challenges, alternatives, and limitations of each model.

Keywords

animal model / brain death / circulatory death / organ transplantation

Cite this article

Download citation ▾
Frazer I. Heinis, Shaheed Merani, Nicholas W. Markin, Kim F. Duncan, Michael J. Moulton, Lance Fristoe, William E. Thorell, Raechel A. Sherrick, Tami R. Wells, Matthew T. Andrews, Marian Urban. Considerations for the use of porcine organ donation models in preclinical organ donor intervention research. Animal Models and Experimental Medicine, 2024, 7(3): 283-296 DOI:10.1002/ame2.12411

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Abouna GM. Organ shortage crisis: problems and possible solutions. Transplant Proc. 2008;40(1):34-38.

[2]

Dharmavaram N, Hess T, Jaeger H, et al. National Trends in heart donor usage rates: are we efficiently transplanting more hearts? J Am Heart Assoc. 2021;10(15):e019655.

[3]

Kwong AJ, Ebel NH, Kim WR, et al. OPTN/SRTR 2021 annual data report: liver. Am J Transplant. 2023;23(2 Suppl 1):S178-S263.

[4]

White CW, Messer SJ, Large SR, et al. Transplantation of hearts donated after circulatory death. Front Cardiovasc Med. 2018;5:8.

[5]

Scheuer SE, Jansz PC, Macdonald PS. Heart transplantation following donation after circulatory death: expanding the donor pool. J Heart Lung Transplant. 2021;40(9):882-889.

[6]

Laurence C, Nachum E, Henwood S, et al. Pediatric heart transplantation following donation after circulatory death, distant procurement, and ex-sit. perfusion. J Heart Lung Transplant. 2022;41(8):1104-1113.

[7]

Thuong M, Ruiz A, Evrard P, et al. New classification of donation after circulatory death donors definitions and terminology. Transpl Int. 2016;29(7):749-759.

[8]

Schroder JN, Patel CB, DeVore AD, et al. Transplantation outcomes with donor hearts after circulatory death. N Engl J Med. 2023;388(23):2121-2131.

[9]

Van Raemdonck D, Keshavjee S, Levvey B, et al. Donation after circulatory death in lung transplantation-five-year follow-up from ISHLT registry. J Heart Lung Transplant. 2019;38(12):1235-1245.

[10]

Schlegel A, van Reeven M, Croome K, et al. A multicentre outcome analysis to define global benchmarks for donation after circulatory death liver transplantation. J Hepatol. 2022;76(2):371-382.

[11]

Rijkse E, Ceuppens S, Qi H, IJzermans JNM, Hesselink DA, Minnee RC. Implementation of donation after circulatory death kidney transplantation can safely enlarge the donor pool: a systematic review and meta-analysis. Int J Surg. 2021;92:106021.

[12]

Mukherjee P, Roy S, Ghosh D, Nandi SK. Role of animal models in biomedical research: a review. Lab Anim Res. 2022;38(1):18.

[13]

Giraud S, Favreau F, Chatauret N, Thuillier R, Maiga S, Hauet T. Contribution of large pig for renal ischemia-reperfusion and transplantation studies: the preclinical model. J Biomed Biotechnol. 2011;2011:532127.

[14]

Lelovas PP, Kostomitsopoulos NG, Xanthos TT. A comparative anatomic and physiologic overview of the porcine heart. J Am Assoc Lab Anim Sci. 2014;53(5):432-438.

[15]

Wang W, He W, Ruan Y, Geng Q. First pig-to-human heart transplantation. Innovation (Camb). 2022;3(2):100223.

[16]

Locke JE, Kumar V, Anderson D, Porrett PM. Normal graft function after pig-to-human kidney Xenotransplant. JAMA Surg. 2023;158(10):1106-1108.

[17]

Michel SG, La Muraglia GM 2nd, Madariaga ML, et al. Preservation of donor hearts using hypothermic oxygenated perfusion. Ann Transplant. 2014;19:409-416.

[18]

Hatami S, Qi X, White CW, et al. The position of the heart during normothermic ex situ heart perfusion is an important factor in preservation and recovery of myocardial function. ASAIO J. 2021;67(11):1222-1231.

[19]

Bittner HB, Kendall SW, Campbell KA, Montine TJ, Van Trigt P. A valid experimental brain death organ donor model. J Heart Lung Transplant. 1995;14(2):308-317.

[20]

Sebening C, Hagl C, Szabo G, et al. Cardiocirculatory effects of acutely increased intracranial pressure and subsequent brain death. Eur J Cardiothorac Surg. 1995;9(7):360-372.

[21]

Bittner HB, Chen EP, Milano CA, et al. Myocardial beta-adrenergic receptor function and high-energy phosphates in brain death-related cardiac dysfunction. Circulation. 1995;92(9 Suppl):II472-II478.

[22]

Bittner HB, Kendall SW, Chen EP, Craig D, Van Trigt P. The effects of brain death on cardiopulmonary hemodynamics and pulmonary blood flow characteristics. Chest. 1995;108(5):1358-1363.

[23]

Chen EP, Bittner HB, Kendall SW, Van Trigt P. Hormonal and hemodynamic changes in a validated animal model of brain death. Crit Care Med. 1996;24(8):1352-1359.

[24]

Golling M, Mehrabi A, Blum K, et al. Effects of hemodynamic instability on brain death-induced prepreservation liver damage. Transplantation. 2003;75(8):1154-1159.

[25]

Purins K, Sedigh A, Molnar C, et al. Standardized experimental brain death model for studies of intracranial dynamics, organ preservation, and organ transplantation in the pig. Crit Care Med. 2011;39(3):512-517.

[26]

Belhaj A, Dewachter L, Hupkens E, et al. Tacrolimus prevents mechanical and humoral alterations in brain death-induced lung injury in pigs. Am J Respir Crit Care Med. 2022;206(5):584-595.

[27]

Belhaj A, Dewachter L, Rorive S, et al. Roles of inflammation and apoptosis in experimental brain death-induced right ventricular failure. J Heart Lung Transplant. 2016;35(12):1505-1518.

[28]

Iyer A, Gao L, Doyle A, et al. Increasing the tolerance of DCD hearts to warm ischemia by pharmacological postconditioning. Am J Transplant. 2014;14(8):1744-1752.

[29]

White CW, Lillico R, Sandha J, et al. Physiologic changes in the heart following cessation of mechanical ventilation in a porcine model of donation after circulatory death: implications for cardiac transplantation. Am J Transplant. 2016;16(3):783-793.

[30]

Soussi D, Rod X, Thuillier R, et al. Preclinical modeling of DCD class III donation: paving the way for the increased use of this challenging donor type. Biomed Res Int. 2019;2019:5924101.

[31]

Scheule AM, Jost D, Beierlein W, et al. Sodium-hydrogen inhibitor cariporide (HOE 642) improves in situ protection of hearts from non-heart-beating donors. J Heart Lung Transplant. 2003;22(12):1335-1342.

[32]

Osaki S, Ishino K, Kotani Y, et al. Resuscitation of non-beating donor hearts using continuous myocardial perfusion: the importance of controlled initial reperfusion. Ann Thorac Surg. 2006;81(6):2167-2171.

[33]

Kotani Y, Ishino K, Osaki S, et al. Efficacy of MCI-186, a free-radica. scavenger and antioxidant, for resuscitation of nonbeating donor hearts. J Thorac Cardiovasc Surg. 2007;133(6):1626-1632.

[34]

Allain G, Kerforne T, Thuret R, et al. Development of a preclinical model of donation after circulatory determination of death for translational application. Transplant Res. 2014;3:13.

[35]

White C, Avery E, Muller A, et al. Impact of reperfusion calcium and pH on the resuscitation of hearts donated after circulatory death. Ann Thorac Surg. 2017;103(1):122-130.

[36]

Guariento A, Doulamis IP, Duignan T, et al. Mitochondrial transplantation for myocardial protection in ex-situ-perfused hearts donated after circulatory death. J Heart Lung Transplant. 2020;39(11):1279-1288.

[37]

Saemann L, Hoorn F, Georgevici AI, et al. Cytokine Adsorber use during DCD heart perfusion counteracts coronary microvascular dysfunction. Antioxidants (Basel). 2022;11:2280.

[38]

Dalsgaard FF, Moeslund N, Zhang ZL, et al. Clamping of the aortic arch vessels during normothermic regional perfusion after circulatory death prevents the return of brain activity in a porcine model. Transplantation. 2022;106(9):1763-1769.

[39]

Khalil K, Ribeiro RVP, Alvarez JS, Badiwala MV, Der Sarkissian S, Noiseux N. Large-animal model of donation after circulatory death and normothermic regional perfusion for cardiac assessment. J Vis Exp. 2022;(183).

[40]

Moeslund N, Long Zhang Z, Bo Ilkjaer L, et al. High oxygenation during normothermic regional perfusion after circulatory death is beneficial on donor cardiac function in a porcine model. Transplantation. 2022;106(7):e326-e335.

[41]

Blondeel J, Gilbo N, Wylin T, Heedfeld V, Monbaliu D. Porcine normothermic isolated liver perfusion. J Vis Exp. 2023;(196):e65336.

[42]

Bittner HB, Kendall SW, Chen EP, Davis RD, Van Trigt P 3rd. Myocardial performance after graft preservation and subsequent cardiac transplantation from brain-dead donors. Ann Thorac Surg. 1995;60(1):47-54.

[43]

Kerforne T, Giraud S, Danion J, et al. Rapid or slow time to brain death? Impact on kidney graft injuries in an allotransplantation porcine model. Int J Mol Sci. 2019;20(15):671.

[44]

Abbasi Dezfouli S, Nikdad M, Ghamarnejad O, et al. Oral preconditioning of donors after brain death with Calcineurin inhibitors vs. inhibitors of mammalian target for rapamycin in pig kidney transplantation. Front Immunol. 2020;11:1222.

[45]

Martin J, Lutter G, Ihling C, et al. Myocardial viability twenty-four hours after orthotopic heart transplantation from non-heart-beating donors. J Thorac Cardiovasc Surg. 2003;125(6):1217-1228.

[46]

Ali AA, White P, Xiang B, et al. Hearts from DCD donors display acceptable biventricular function after heart transplantation in pigs. Am J Transplant. 2011;11(8):1621-1632.

[47]

Ribeiro RVP, Alvarez JS, Yu F, et al. Hearts donated after circulatory death and reconditioned using normothermic regional perfusion can Be successfully transplanted following an extended period of static storage. Circ Heart Fail. 2019;12(4):e005364.

[48]

Osaki S, Ishino K, Kotani Y, et al. Circulatory load during hypoxia impairs post-transplant myocardial functional recovery in donation after cardiac death. J Heart Lung Transplant. 2009;28(3):266-272.

[49]

White CW, Ali A, Hasanally D, et al. A cardioprotective preservation strategy employing ex vivo heart perfusion facilitates successful transplant of donor hearts after cardiocirculatory death. J Heart Lung Transplant. 2013;32(7):734-743.

[50]

Tillet S, Giraud S, Kerforne T, et al. Inhibition of coagulation proteases Xa and IIa decreases ischemia-reperfusion injuries in a preclinical renal transplantation model. Transl Res. 2016;178:95-106.e1.

[51]

Goerlich CE, Griffith B, Singh AK, et al. Blood cardioplegia induction, perfusion storage and graft dysfunction in cardiac xenotransplantation. Front Immunol. 2021;12:667093.

[52]

Ogurlu B, Pamplona CC, Van Tricht IM, et al. Prolonged controlled oxygenated rewarming improves immediate tubular function and energetic recovery of porcine kidneys during normothermic machine perfusion. Transplantation. 2023;107(3):639-647.

[53]

Zhang S, Shi J, Zhai W, Song Y, Chen S. Experimental study on the establishment and maintenance of brain death model with pigs. Front Med China. 2007;1(2):161-166.

[54]

Hautbergue TLF, Dang Van S, et al. Metabolomic profiling of cardiac allografts after controlled circulatory death. J Heart Lung Transplant. 2023;42(7):870-879.

[55]

Ram E, Lavee J, Freimark D, et al. Improved long-term outcomes after heart transplantation utilizing donors with a traumatic mode of brain death. J Cardiothorac Surg. 2019;14(1):138.

[56]

Langin M, Mayr T, Reichart B, et al. Consistent success in life-supporting porcine cardiac xenotransplantation. Nature. 2018;564(7736):430-433.

[57]

Langin M, Reichart B, Steen S, et al. Cold non-ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig-to-baboon xenotransplantation. Xenotransplantation. 2021;28(1):e12636.

[58]

Cooper DK, Novitzky D, Wicomb WN. The pathophysiological effects of brain death on potential donor organs, with particular reference to the heart. Ann R Coll Surg Engl. 1989;71(4):261-266.

[59]

Lundsgaard-Hansen P, Schilt W, Heitmann L, Oroz M, Buchler A, Lemeunier A. Influence of the agonal period on the postmortem metabolic state of the heart. A problem in cardiac preservation. Ann Surg. 1971;174(5):744-754.

RIGHTS & PERMISSIONS

2024 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.

AI Summary AI Mindmap
PDF (4096KB)

174

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/