Safety and function of a new pre-vascularized bioartificial pancreas in an allogeneic rat model.

Cell encapsulation could overcome limitations of free islets transplantation but is currently limited by inefficient cells immune protection and hypoxia. As a response to these challenges, we tested in vitro and in vivo the safety and efficacy of a new macroencapsulation device named MailPan®. Membranes of MailPan® device were tested in vitro in static conditions. Its bio-integration and level of oxygenation was assessed after implantation in non-diabetic rats. Immune protection properties were also assessed in rat with injection in the device of allogeneic islets with incompatible Major Histocompatibility Complex. Finally, function was assessed in diabetic rats with a Beta cell line injected in MailPan®. In vitro, membranes of the device showed high permeability to glucose, insulin, and rejected IgG. In rat, the device displayed good bio-integration, efficient vascularization, and satisfactory oxygenation (>5%), while positron emission tomography (PET)-scan and angiography also highlighted rapid exchanges between blood circulation and the MailPan®. The device showed its immune protection properties by preventing formation, by the rat recipient, of antibodies against encapsulated allogenic islets. Injection of a rat beta cell line into the device normalized fasting glycemia of diabetic rat with retrieval of viable cell clusters after 2 months. These data suggest that MailPan® constitutes a promising encapsulation device for widespread use of cell therapy for type 1 diabetes.

A fully implantable device for diffuse insulin delivery at extraperitoneal site for physiological treatment of type 1 diabetes.

Intraperitoneal insulin delivery has higher benefits than subcutaneous insulin administration but has limitations, including obstruction of the catheter used in delivery devices. To overcome these limitations this study assessed safety and efficacy of an alternative approach involving a new delivery device, named ExOlin®, allowing diffuse release of insulin in the extraperitoneal site. The aim of this study is to validate both safety and efficacy of insulin delivery in extraperitoneal using ExOlin® device. Safety of the ExOlin® device implantation in the extraperitoneal site was investigated over a 3-month period in Wistar rat and landrace swine models before comparing efficacy pharmacokinetics and hepatic first-pass metabolism of insulin after focal delivery using a catheter or diffuse release via ExOlin® device in extraperitoneal. Implantation in rat and swine models demonstrated good integration of the device, validating the safety of the extraperitoneal site. In diabetic rats, direct insulin administration at the extraperitoneal showed an efficacy comparable to intraperitoneal and statistically significantly higher than subcutaneous route as shown by 23% lower AUC calculated from glycaemia profile. Diffuse extraperitoneal delivery of insulin via ExOlin® device in diabetic rats exhibited better efficacy than the subcutaneous route with up to six-fold lower peripheral insulin and higher hepatic first-pass than with intraperitoneal injection. Similar results were confirmed in the swine model after injecting insulin lispro via the device at the extraperitoneal site. In conclusion, diffuse administration of insulin at the extraperitoneal site via ExOlin® device is a new promising approach to physiologically treating type 1 diabetes. It can therefore be considered as a promising alternative to intraperitoneal route.

Comparison of Perfluorodecalin and HEMOXCell as Oxygen Carriers for Islet Oxygenation in an In Vitro Model of Encapsulation.

Transplantation of encapsulated islets in a bioartificial pancreas is a promising alternative to free islet cell therapy to avoid immunosuppressive regimens. However, hypoxia, which can induce a rapid loss of islets, is a major limiting factor. The efficiency of oxygen delivery in an in vitro model of bioartificial pancreas involving hypoxia and confined conditions has never been investigated. Oxygen carriers such as perfluorocarbons and hemoglobin might improve oxygenation. To verify this hypothesis, this study aimed to identify the best candidate of perfluorodecalin (PFD) or HEMOXCell® to reduce cellular hypoxia in a bioartificial pancreas in an in vitro model of encapsulation ex vivo. The survival, hypoxia, and inflammation markers and function of rat islets seeded at 600 islet equivalents (IEQ)/cm2 and under 2% pO2 were assessed in the presence of 50 µg/mL of HEMOXCell or 10% PFD with or without adenosine. Both PFD and HEMOXCell increased the cell viability and decreased markers of hypoxia (hypoxia-inducible factor mRNA and protein). In these culture conditions, adenosine had deleterious effects, including an increase in cyclooxygenase-2 and interleukin-6, in correlation with unregulated proinsulin release. Despite the effectiveness of PFD in decreasing hypoxia, no restoration of function was observed and only HEMOXCell had the capacity to restore insulin secretion to a normal level. Thus, it appeared that the decrease in cell hypoxia as well as the intrinsic superoxide dismutase activity of HEMOXCell were both mandatory to maintain islet function under hypoxia and confinement. In the context of islet encapsulation in a bioartificial pancreas, HEMOXCell is the candidate of choice for application in vivo.