Applications of particulate oxygen-generating substances (POGS) in the bioartificial pancreas

Abstract

Type-1 Diabetes (T1D) is a devastating autoimmune disorder which results in the destruction of beta cells within the pancreas. A promising treatment strategy for T1D is the replacement of the lost beta cell mass through implantation of immune-isolated microencapsulated islets referred to as the bioartificial pancreas. The goal of this approach is to restore blood glucose regulation and prevent the long-term comorbidities of T1D without the need for immunosuppressants. A major requirement in the quest to achieve this goal is to address the oxygen needs of islet cells. Islets are highly metabolically active and require a significant amount of oxygen for normal function. During the process of isolation, microencapsulation, and processing prior to transplantation, the islets’ oxygen supply is disrupted, and a large amount of islet cells are therefore lost due to extended hypoxia, thus creating a major barrier to clinical success with this treatment. In this work, we have investigated the oxygen generating compounds, sodium percarbonate (SPO) and calcium peroxide (CPO) as potential supplemental oxygen sources for islets during isolation and encapsulation before and immediately after transplantation. First, SPO particles were used as an oxygen source for islets during isolation. Secondly, silicone films containing SPO were used to provide supplemental oxygen to islets for up to 4 days in culture. Finally, CPO was used as an oxygen source for encapsulated cells by co-encapsulating CPO particles with islets in permselective alginate microspheres. These studies provide an important proof of concept for the utilization of these oxygen generating materials to prevent beta cell death caused by hypoxia.

Extracellular hemoglobin combined with an O2‐generating material overcomes O2 limitation in the bioartificial pancreas

“…In keeping with the literature describing the impact of ischemia or hypoxia on human pancreatic islets (Brandhorst et al, 2016;Cantley et al, 2012;Giuliani et al, 2005;Hals, Rokstad, Strand, Oberholzer & Grill, 2013;Lai et al, 2009;Moritz et al, 2002), our results suggest that the innovative oxygen supply strategy developed in the present study may also meet the challenges of hypoxia during allotransplantation of macroencapsulated human pancreatic islets. material only in situations where hypoxia is a concern was also proposed by McQuilling, Sittadjody, Pendergraft, Farney, and Opara (2017). Similarly, in our study, the benefit of silicone-CaO 2 in preventing hypoxia-induced islet damage was observed, whereas its addition in normoxic conditions may decrease ATP content and glucose-dependent insulin secretion, and seemed to increase islet oxidative stress, as shown by increased HO-1 mRNA expression.…”

“…Pedraza et al () highlighted that the effect of the PDMS‐CaO 2 disk on the murine MIN6 cell line was only effective when O 2 concentration was limiting (high cell concentration and/or low O 2 tension), whereas a deleterious effect occurred in case of local excess in O 2 . The importance to use this O 2‐ generating material only in situations where hypoxia is a concern was also proposed by McQuilling, Sittadjody, Pendergraft, Farney, and Opara (). Similarly, in our study, the benefit of silicone‐CaO 2 in preventing hypoxia‐induced islet damage was observed, whereas its addition in normoxic conditions may decrease ATP content and glucose‐dependent insulin secretion, and seemed to increase islet oxidative stress, as shown by increased HO‐1 mRNA expression.…”

“…However, according to Pedraza et al (), the use of this device in 3D‐construct leads to O 2 gradients and inhomogeneous distribution throughout the BAP. Moreover, such O 2 ‐generating device could produce deleterious reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ; Camci‐Unal, Alemdar, Annabi & Khademhosseini, ; Forget et al, ; McQuilling et al, ). O 2 ‐carriers, such as hemoglobin, can store and release O 2 according to the pericellular environment pO 2 (Avila et al, ; Khattak, Chin, Bhatia & Roberts, ; Le Pape et al, ).…”

“…Pedraza, Coronel, Fraker, Ricordi, and Stabler (2012) designed a polydimethylsiloxane-CaO 2 device (10 mm diameter, 1 mm height) able to release O 2 for 3 weeks. This device was shown to prevent the apparition of necrotic cores of adult porcine islets cultured in normoxia (McQuilling, Sittadjody, Pendergraft, Farney, & Opara, 2017) and the hypoxia damage of murine MIN6 beta cells (Pedraza et al, 2012;Forget et al, 2017), rat pancreatic islets (Pedraza et al, 2012) and NPIs (Lee et al, 2017) for few days. However, according to Pedraza et al (2012), the use of this device in 3D-construct leads to O 2 gradients and inhomogeneous distribution throughout the BAP.…”

“…However, according to Pedraza et al (2012), the use of this device in 3D-construct leads to O 2 gradients and inhomogeneous distribution throughout the BAP. Moreover, such O 2 -generating device could produce deleterious reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ; Camci-Unal, Alemdar, Annabi & Khademhosseini, 2013;Forget et al, 2017;McQuilling et al, 2017).…”