Intraportal Islet Oxygenation

Abstract

Islet transplantation (IT) is a promising therapy for the treatment of diabetes. The large number of islets required to achieve insulin independence limit its cost-effectiveness and the number of patients who can be treated. It is believed that >50% of islets are lost in the immediate post-IT period. Poor oxygenation in the early post-IT period is recognized as a possible reason for islet loss and dysfunction but has not been extensively studied. Several key variables affect oxygenation in this setting, including (1) local oxygen partial pressure (pO 2 ), (2) islet oxygen consumption, (3) islet size (diameter, D), and (4) presence or absence of thrombosis on the islet surface. We discuss implications of oxygen-limiting conditions on intraportal islet viability and function. Of the 4 key variables, the islet size appears to be the most important determinant of the anoxic and nonfunctional islet volume fractions. Similarly, the effect of thrombus formation on the islet surface may be substantial. At the University of Minnesota, average size distribution data from clinical alloislet preparations (n = 10) indicate that >150-µm D islets account for only ~30% of the total islet number, but >85% of the total islet volume. This suggests that improved oxygen supply to the islets may have a profound impact on islet survivability and function since most of the β-cell volume is within large islets which are most susceptible to oxygen-limiting conditions. The assumption that the liver is a suitable islet transplant site from the standpoint of oxygenation should be reconsidered.

Oxygenation of the Intraportally Transplanted Pancreatic Islet

“…One of the possible causes for early islet loss may be inadequate oxygenation in the time preceding revascularization [10]. Of all causes of islet loss following intraportal IT, insufficient early islet oxygenation is overlooked in part due to the assumption that direct access to the blood stream should be enough to provide the necessary oxygen supply.…”

“…Many investigators believe that the liver may not be the optimal IT site and there are numerous reasons [10], including, but not limited to, (a) intraportal thrombus formation on the islet surface, complement-mediated islet cell lysis, and local inflammation [11], sometimes collectively referred to as the “instant blood-mediated inflammatory reaction,” which are believed to contribute to alloimmune rejection and early islet loss [12, 13]; (b) possible immediate exposure to islet cell-directed T memory cells and recurrence of autoimmune rejection [14]; (c) higher local concentrations of orally administered immunosuppressants [15], which can impair insulin secretion or islet revascularization [16, 17]; (d) slow reestablishment of surrounding extracellular matrix, which can adversely affect islet survival [18, 19]; (e) inability to easily track, image, or retrieve the graft [20, 21]; and (f) poor oxygenation due to the mixed portal circulation, significant oxygen gradients within the hepatic tissue [22], and slow and possibly incomplete revascularization [23–26], which is of particular importance since insulin-secreting β -cells are not designed to function under conditions of hypoxia [27]. …”

Effects of edaravone, a radical scavenger, on hepatocyte transplantation

“…The use of this agent, which inhibits the lipoxygenase pathway in the arachidonic acid cascade, has yielded positive results . Edaravone has been shown to exert protective effects against ischemia–reperfusion injuries in several animal organ transplantation models, including an islet transplantation model . In the present study, we examined the effects of edaravone administration during the early post‐transplantation period on the engraftment of intrasplenically transplanted hepatocytes.…”

Development and Validation of Noninvasive Magnetic Resonance Relaxometry for the In Vivo Assessment of Tissue-Engineered Graft Oxygenation

“…11 Noninvasive monitoring of the oxygen partial pressure (pO 2 ) within TEGs is critically important because of the deleterious effects of long-and short-term exposure of islet tissue to hypoxia or anoxia. 2,7,8,[11][12][13] Lack of oxygen is the most critical issue preventing widespread utilization of macroencapsulated islet transplantation, and delivery of exogenous oxygen has been shown to enhance TEG survival and function in vivo. 2,14,15 Noninvasive monitoring of pO 2 can improve TEG development and allow the evaluation of TEG viability 16 and local changes in pO 2 with the delivery of supplemental oxygen (DSO).…”