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

Abstract

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.

Design Considerations for Macroencapsulation Devices for Stem Cell Derived Islets for the Treatment of Type 1 Diabetes

“…A number of potential implant sites have been discussed in the literature for macroencapsulation devices for T1D: such as subcutaneous, [ 64 , 80 , 81 ] intramuscular, [ 68 ] peritoneal, [ 15 , 82 ] and omentum. [ 83 ] The ability for minimally invasive delivery makes the subcutaneous sites an attractive option for device implantation, but success has been limited due to the low vascular density of this space.…”

“…pO 2 measurements of pre‐vascularized devices were 4.4–12.2% (equivalent to 32.66–90.55 mm Hg, n = 14), with most readings exceeding 5% (37.1 mm Hg), which is comparable to the mean pO 2 measured within vascularized islets in the native pancreas. [ 15 , 114 ]…”

“…A macroencapsulation device incorporates islets into a selectively permeable membrane which evades the immune response, whilst enabling delivery of insulin from the transplanted cells. [ 13 , 14 , 15 ] These macroencapsulation systems have to meet a number of stringent and challenging functional requirements in order to achieve the ultimate goal of reversing T1D. Critically, they need to maintain viability of the transplanted cells, and this is further complicated by the fact that stem cell derived insulin producing cells have been shown to exhibit major changes and phenotypic maturation when transplanted in vivo.…”

Human pluripotent stem cell-derived insulin-producing cells: A regenerative medicine perspective

“…As vascularization of implanted devices typically takes on the order of 2 to 3 weeks, several approaches are being taken to prevent or address the resulting hypoxia during the peri-transplant period (Schweicher et al, 2014). These include attempts to accelerate vascularization with growth factors such as VEGF (Trivedi et al, 2000); the incorporation of oxygen carriers, oxygen-generating biomaterials, or access ports to deliver oxygen, such as the bAir device developed by Beta-O 2 (Pedraza et al, 2012;Schweicher et al, 2014;Barkai et al, 2013;Neufeld et al, 2013); and the prevascularization of the macrocapsule before addition of cells, such as Defymed's MailPan (Magisson et al, 2020;Pileggi et al, 2006). A thin-film cell macroencapsulation device fabricated from polycaprolactone has demonstrated favorable vascularization, limited fibrosis, and immunoprotection, leading to improved viability of encapsulated hPSC-derived islet-like cells (Chang et al, 2017;Nyitray et al, 2015).…”

Developing a morphomics framework to optimize implant site-specific design parameters for islet macroencapsulation devices

“…Such a site must be clinically accessible via a low-risk procedure, enable longterm monitoring of islet function, enable retrievability in the event of a complication and provide a suitable environment for the safeguarding of efficacious islet function. A number of potential implant sites have been discussed, such as the subcutaneous [24][25][26] and submuscular spaces [27], the peritoneum [28,29] and the omentum [30]. Currently, there has not been consensus on the optimal anatomical location.…”