Hypothermic oxygenated machine perfusion of the human pancreas for clinical islet isolation: a prospective feasibility study

Doppenberg, Jason B.; Leemkuil, Marjolein; Engelse, Marten A.; Krikke, Christina; Koning, Eelco J.P. de; Leuvenink, Henri G. D.

doi:10.1111/tri.13927

Cited by 12 publications

(8 citation statements)

References 52 publications

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“…In this study, we report our first experience of establishing HMPO 2 of the pancreas followed by a read‐out model of NR simulating the reperfusion period in transplantation. Similar to our work, Leemkuil et al in their recently published (2021) study [40] investigated the impact of HMPO 2 in human non‐transplanted DCD pancreases, compared with DBD SCS preserved pancreases, and used islet isolation to assess effect, evaluating the quality of the intervention in vitro and in vivo in an immunodeficient diabetic mouse model. They achieved successful islet isolation post‐HMPO 2 and observed no induction of oedema or apoptosis.…”

Section: Discussionmentioning

confidence: 60%

Development of ex situ normothermic reperfusion as an innovative method to assess pancreases after preservation

et al. 2021

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Summary Static cold storage (SCS) is the standard method for pancreas preservation prior to transplantation; however, it does not permit organ assessment. Normothermic reperfusion (NR) is utilized clinically for other organs to assess viability. Our aim was to develop NR using normothermic machine perfusion technique to simulate reperfusion at the time of transplantation, enabling evaluation of oxygenated hypothermic machine perfusion (HMPO2) as a newer strategy to optimize pancreas preservation. 13 porcine pancreases procured after circulatory death were divided into 3 groups: 4 pancreases preserved using SCS, and 2 groups preserved by HMPO2 (n = 4 and n = 5, differing by type of preservation solution). Duration of perfusion or cold storage was 6 hours before the 1‐hour assessment using NR. Outcome measures were perfusion characteristics, biochemistry and change in tissue water mass as oedema assessment. During NR, the HMPO2 groups demonstrated better perfusion characteristics, normal macroscopic appearances, decreased water mass and one HMPO2 group demonstrated a response to glucose stimulation. Conversely, the SCS group showed an increased water mass and developed early macroscopic appearances of oedema, interstitial haemorrhage and minimal portal outflow. This study suggests that ex situ assessment of pancreases by NR is promising, and that HMPO2 may be better than SCS.

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Section: Discussionmentioning

confidence: 60%

Development of ex situ normothermic reperfusion as an innovative method to assess pancreases after preservation

et al. 2021

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“…Once the oxygen has converted mitochondrial metabolisms and rebuilt energy in the entire gland, the perfusion pressure could potentially be reduced in cases, where longer perfusion is needed to bridge logistical challenges and to avoid relevant edema and necrosis. Such findings were further paralleled by a greater islet viability isolated from discarded human pancreas after HOPE as shown by Doppenberg et al in 2021 [74]. More studies are required to identify such timings and to explore the acceptable SCS-duration before and after HOPE-treatment.…”

Section: Discussionmentioning

confidence: 83%

“…This literature review and cases series of HOPE in pancreas confirms what is reported with other organs. HMP should be performed at limited systolic pressures of £ 25mmHg for at least 2hrs, but ideally not more than 6-12hrs [5,7,74]. Once the oxygen has converted mitochondrial metabolisms and rebuilt energy in the entire gland, the perfusion pressure could potentially be reduced in cases, where longer perfusion is needed to bridge logistical challenges and to avoid relevant edema and necrosis.…”

Section: Discussionmentioning

confidence: 99%

Machine Perfusion of the Pancreas: What Can We Learn from five Decades of Experimental Studies?

2023

J Surg

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Background: Pancreas transplantation is currently the best option for patients with severe complications of diabetes. This organ is however particularly vulnerable to Ischemia-Reperfusion-Injury (IRI) and the transplant procedure is associated with a high risk for recipient complications. It is therefore surprising, that testing and routine use of dynamic preservation strategies is lacking behind other solid organs.Methods: This study includes first, a literature review on the evolution of cold and warm pancreas machine perfusion strategies. Second, pressure-controlled hypothermic oxygenated perfusion (HOPE, pO 2 >60kPa) with fluoresceine is performed in porcine pancreases. Results:No single human pancreas transplant study with machine perfusion is available. A few older animal studies exist with prolonged Hypothermic Machine Perfusion (HMP), with however high perfusion pressures and a lack of active perfusate oxygenation. Tissue oedema and inflammation were the direct consequences. Only recently, such HMP-conditions were adapted, providing an actively oxygenated perfusate at lower perfusion pressures and shorter durations. Such HOPEtreatment was found superior to cold storage and normothermic perfusion in early experimental studies. In our series, HOPE achieved a complete pancreas perfusion, as confirmed by fluorescence despite lower perfusion pressures. Conclusion:HMP with active perfusate oxygenation may achieve similar protective effects in pancreases as seen with livers and kidneys. Lower perfusion pressures appear sufficient to distribute the required oxygen for mitochondrial reprogramming to reduce posttransplant IRI. Prospective clinical studies are planned to test the HOPE-technique in human pancreas transplantation.

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“…Moreover, to prevent the organ fragment from barotrauma caused by the hypothermic conditions and reduce the risk of edema, HMP and HMP O 2 preservation was performed at 25 mm Hg in line with others. 19 In addition, by the use of a split model, we had to take in account the heterogeneity of the endocrine component of the pancreas, particularly in the selection of outcomes. [36][37][38][39] Our study underscores a significant variability in outcomes regarding IEQ/g between head and tail isolation from both DCD and DBD organs.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the current literature, [19][20][21][22][23][24] a systolic hypothermic pressure of 25 mm Hg was applied, delivered via the splenic artery with venous return via the splenic vein.…”

Section: Study Design and Perfusion Protocolmentioning

confidence: 99%

Exploring Preservation Modalities in a Split Human Pancreas Model to Investigate the Effect on the Islet Isolation Outcomes

Buemi,

Mourad,

Bouzin

et al. 2024

Transplantation Direct

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Background. In islet transplantation, the use of dynamic hypothermic preservation techniques is a current challenge. This study compares the efficacy of 3 pancreas preservation methods: static cold storage, hypothermic machine perfusion (HMP), and oxygenated HMP. Methods. A standardized human pancreas split model was employed using discarded organs from both donation after brain death (n = 15) and donation after circulatory death (DCD) (n = 9) donors. The pancreas head was preserved using static cold storage (control group), whereas the tail was preserved using the 3 different methods (study group). Data on donor characteristics, pancreas histology, isolation outcomes, and functional tests of isolated islets were collected. Results. Insulin secretory function evaluated by calculating stimulation indices and total amount of secreted insulin during high glucose stimulation (area under the curve) through dynamic perifusion experiments was similar across all paired groups from both DCD and donation after brain death donors. In our hands, islet yield (IEQ/g) from the pancreas tails used as study groups was higher than that of the pancreas heads as expected although this difference did not always reach statistical significance because of great variability probably due to suboptimal quality of organs released for research purposes. Moreover, islets from DCD organs had greater purity than controls (P ≤ 0.01) in the HMP study group. Furthermore, our investigation revealed no significant differences in pancreas histology, oxidative stress markers, and apoptosis indicators. Conclusions. For the first time, a comparative analysis was conducted, using a split model, to assess the effects of various preservation methods on islets derived from pancreas donors. Nevertheless, no discernible variances were observed in terms of islet functionality, histological attributes, or isolation efficacy. Further investigations are needed to validate these findings for clinical application.

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Hypothermic oxygenated machine perfusion of the human pancreas for clinical islet isolation: a prospective feasibility study

Cited by 12 publications

References 52 publications

Development of ex situ normothermic reperfusion as an innovative method to assess pancreases after preservation

Development of ex situ normothermic reperfusion as an innovative method to assess pancreases after preservation

Machine Perfusion of the Pancreas: What Can We Learn from five Decades of Experimental Studies?

Exploring Preservation Modalities in a Split Human Pancreas Model to Investigate the Effect on the Islet Isolation Outcomes

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