Robust, nanofiber-enabled hydrogel devices for islet encapsulation and delivery

摘要

Islet encapsulation holds enormous clinical potential for the treatment of type 1 diabetes. In islet encapsulation, a biomaterial or device with semipermeable membranes protects the islet cells from Immune rejection, without the use of immunosuppression, while simultaneously allowing facile mass transfer toRobust, nanofiber-enabled hydrogel devices for islet encapsulation and delivery maintain the cell survival and function. Polymer based islet encapsulation devices have been developed for decades with some of them already commercialized, such as TheraCyte™. Although mechanically durable and easy to use, these current encapsulation devices, mostly made from phase inverted membranes or expanded Teflon, often suffer from insufficient biocompatibility and fibrosis. As an alternative, biocompatible hydrogels have been widely employed for islet encapsulation and delivery. However, the mechanical robustness of commonly used hydrogels such as alginate is inadequate, which causes concerns about the long-term stability and safety especially when stem cell-derived beta-like cells are used. Here, we report our first attempt to address these challenges by designing robust, hydrogel-based, nanofiber-enabled, encapsulation devices (NEEDs) for islet encapsulation and delivery. In this design, we take advantage of the well-known capillary action that holds wetting liquid in porous media. By impregnating the highly porous electrospun nanofiber membranes of pre-made tubular or planar devices with hydrogel precursor solutions and subsequent crosslinking, we obtained various nanofiber-enabled hydrogel devices. This approach is broadly applicable and does not alter the water content or the intrinsic chemistry of the hydrogels. The devices retained the properties of both the hydrogel (e.g. the biocompatibility) and the nanofibers (e.g. the mechanical robustness). We fabricated the NEEDs from a range of hydrogels including PEG and alginate, and with different compartmentalizations (Figure 1a,b). Mechanical testing confirmed their superior robustness (Figure 1c). Using both model cells and rat islets, we demonstrated the facile mass transfer and flexible cell loading in single or multiple compartments with a control over the cell-dispersing matrix (Figure 1 d). Lastly, we evaluated the biocompatibility, functionality and retrievability of the NEEDs by encapsulating and delivering rat islets into a chemically-induced diabetic mouse model. The diabetes was corrected for the duration of the experiment (8 weeks) right before the implants were retrieved (Figure 1 e). The retrieved devices showed minimal fibrosis according to histological studies and as expected, live and functional islets were observed within the devices (Figure 1f). Taken together, these data suggest that the NEED design can potentially overcome some of the challenges in the islet encapsulation field and may therefore contribute to the development of beta cell replacement therapies for insulin-dependent diabetes.