**6.2. Persufflation**

the fact that all recipients remained free of severe hypoglycemia, only three patients achieved insulin independence for 14, 79, and 215 days. HbA1c levels and requirement of exogenous insulin were significantly improved in all patients [116]. In the more traditional DCD setting the Edmonton group have recently reported their findings comparing islet isolations from 15 DCD and 418 DBD donors performed between September 2008 and September 2014. Compared to DBD, pancreata from DCD were procured locally and donors required less vasopressive support (P < 0.001 and P = 0.023, respectively), but the other variables were similar between groups. The metabolic function was similar between DBD and DCD, as well as the mean decrease in insulin requirement at 1-month post-transplantation (DBD: 64.82%; DCD: 60.17% reduction, P = 0.517). These results support the broader use of DCD pancreata for islet isolation. However, a much larger DCD islet experience will be required to truly

There has been considerable interest regarding the utility and advantages of dynamic preservation methods in comparison to CS alone for organs such as the liver, kidneys, heart, and lungs. The pancreas has not remained immune to attempts adapting such techniques during the post-procurement phase, although their current clinical success remains limited. Non-

• Reduce graft discard by allowing more accurate graft assessment after retrieval in compari-

• Improve organ quality by reducing ischemia-reperfusion-related damage, including by the targeted delivery of pharmacotherapies aimed against ischemia-reperfusion injury, and

Machine (*ex vivo*) perfusion (MP) entails cannulation and mechanical perfusion of the pancreas via its inflow vessels; perfusion fluid is re-circulated through the circuit for the duration of perfusion. Broadly, MP can be hypothermic, subnormothermic or normothermic, pulsatile or non-pulsatile, and continuous or for a limited proportion of the preservation/transport phase (e.g. pre-implantation). Current pancreatic MP work is lacking in the sphere of clinical transplantation, and is limited to pre-clinical animal and discarded human pancreas studies; only the latter will be the focus of this section, with experimental animal work summarized

There are certain pancreas-specific issues that need to be considered with respect to MP that do not apply to other organs such as the kidney. Most importantly, the pancreas is a low-flow organ, and even relatively low pressures in a MP setup can result in significant graft edema and weight gain [121]. Furthermore, higher perfusion pressures can contribute to vascular thrombosis secondary to endothelial damage [120]. However, especially if MP is undertaken

determine non-inferiority of both short and long-term outcomes [117].

172 Organ Donation and Transplantation - Current Status and Future Challenges

**6. Future perspectives**

**6.1. Machine perfusion**

in detail elsewhere [118–120].

static methods of preservation can potentially:

son to current methods, which are largely subjective; and

also gene therapies and stem cells, into the pancreas.

Persufflation is a technique in which the pancreas is directly perfused with a humidified gas such as oxygen via the SMA and/or splenic arteries. Non-utilized human DBD pancreata have been perfused by this method, and subsequent graft assessment showed an increase in pancreatic ATP levels [130]. Porcine data from the same group showed significantly improved pancreatic histology after 24 hours of persufflation in comparison to utilization of the TLM [131]. Islet isolation after 24 hours of persufflation, including in human pancreata, is likely increased, compared to other methods such as the TLM [132]. This was confirmed in a later study, whereby islets of sufficient quantity and quality for transplantation were isolated from all five human pancreata that underwent persufflation using 40% humidified oxygen perfused at 10–25 mmHg [133]. Similar to MP however, pancreas persufflation has not yet been followed by clinical islet and/or whole organ pancreas transplantation although some research is now underway by a limited number of groups.

#### **6.3. Normothermic regional perfusion**

Normothermic Regional Perfusion (NRP) of the abdomen was initially utilized in Spain in the uncontrolled DCD setting, and has since been utilized in the controlled DCD setting in other European countries and Asia [134–138]. The donor's systemic arterial and venous systems are rapidly cannulated, and an *ex vivo* pump/oxygenator system is used to maintain an effective artificial circulation of the abdominal viscera. Cerebral and thoracic perfusion is avoided by clamping the supra-celiac aorta. This system reduces the organ's warm ischemic insult, and proposed benefits include facilitation of a more effective subsequent *in situ* cold flush, ATP replenishment, and reduced oxidative stress [139]. Current experience for NRP exists mainly in the sphere of kidney and liver transplantation. However, utilization of this technique for DCD pancreas preservation and transplantation is appealing, especially because DCD pancreata can have sustained, long-term graft function (as discussed above). Within the UK, five pancreata have been procured after initial NRP, resulting in two SPK transplants and one islet cell transplantation [136]. In Spain, one NRP pancreas has been transplanted in the context of a controlled DCD donor [140]. Future studies are required to more effectively classify evidence for this strategy, and define its comparative role or efficacy with respect to MP. In the DCD setting, NRP may prove to be a more feasible strategy than MP owing to the aforementioned difficulties of maintaining a pancreas on an *ex vivo* machine circuit, although no direct comparisons exist between the two methods.

number of suitable whole pancreata, as well as their quality, which will simultaneously lead to

Pancreas Retrieval for Whole Organ and Islet Cell Transplantation

http://dx.doi.org/10.5772/intechopen.75151

175

The authors wish to thank Callista Rainey for assistance with the figures in this chapter. The authors also wish to acknowledge support from the Royal Australasian College of Surgeons

improved islet cell numbers and function in the cell therapy sphere of Diabetes care.

**Acknowledgements**

**Conflicts of interest**

**Abbreviations**

(Sir Roy McCaughey Surgical Research Fellowship).

The authors declare no conflicts of interest.

BMI body mass index

CIT cold ischemic time

PFC perfluorochemical T1D type 1 diabetes

TLM two-layer method

T1D type 1 diabetes

**Author details**

Sydney, Australia

DBD donation after brain death

UW solution University of Wisconsin

DCD donation after circulatory death

SPK simultaneous pancreas and kidney

Wayne J. Hawthorne1,2,3\*, Ahmer Hameed1,2,3 and Henry Pleass1,3 \*Address all correspondence to: wayne.hawthorne@sydney.edu.au 1 Department of Surgery, Westmead Hospital, Sydney, Australia

3 Sydney Medical School, University of Sydney, Sydney, Australia

2 Centre for Transplant and Renal Research, Westmead Institute for Medical Research,

CS Celsior

#### **7. Conclusions**

This chapter outlines the numerous advances that have occurred over the past few decades in pancreas retrieval techniques for both whole organ and cellular transplantation. It clearly demonstrates the improved outcomes in both whole pancreas and islet cell transplantation from significant improvements to organ donor selection and management, and organ perfusion and retrieval surgery. We have seen insulin independence rates for more than 10 years post-transplant in both settings with minimal complications. Whole organ transplantation is obviously now a well-accepted clinical therapy for many patients worldwide. However, islet transplantation still has limited application to the broader population of patients with T1D due to its reliance on the availability of cadaveric donors and selection, isolation results and transplant engraftment, the side effects of immunosuppression and issues associated with the requirement for lifelong immunosuppression. The future holds many interesting potential new therapies that may or may not yield appropriate and safe methods for treatment of type 1 diabetes. From what has been outlined in this chapter we can see that outcomes for patients have improved significantly. If, unfortunately, patients cannot be treated prior to the advent of their type 1 diabetes then they can still be treated by transplantation. Moving forward, researchers and clinicians have numerous fronts and multiple strategies arising at different stages of development in which to be able to offer patients treatments tailored to them and their disease. In the foreseeable future, transplantation and in particular the focus on organ retrieval and organ preservation will play a significant role in further improving outcomes, particularly with newer technologies such as machine perfusion and normothermic regional perfusion. Such technologies are hoped to increase both the number of suitable whole pancreata, as well as their quality, which will simultaneously lead to improved islet cell numbers and function in the cell therapy sphere of Diabetes care.
