A nanofibrous macroencapsuiation device for cell-based therapy: evaluation of biocompatibility and the immunoisolation function

摘要

Introduction: Macroencapsuiation devices shield the transplanted cells from the immune attack while facilitating the exchange of nutrients, oxygen and therapeutic products. The successful immunoisolation relies on the biocompatible semi-permeable membranes with the mildest foreign body reaction (FBR). Although nanofibrous materials mimic the extracellular matrix in terms of morphology and porosity, whether nanofibers can be used for cell-encapsulation applications remains uninvestigated. Here, we fabricated a membrane-based device using electrospun fibers and studied its biocompatibility and the function of isolating transplanted cells in rat/mouse models. Materials and Methods: Fibrous polyurethane (PU) membranes were manufactured with different fiber diameters using an electrospinning setup. The planar macroencapsuiation device was fabricated by welding two layers of the electrospun membranes. The electrospun membrane or cell-laden devices were then implanted subcutaneously in SD rats or C57BL/6 mice. The host FBRs to membranes were analyzed by histological study. Noninvasive bioluminscence imaging (BLI) was performed to monitor the cells within the device. Results and Discussion: The impact of fiber size and porosity on the FBR to electrospun membranes was investigated. When implanted subcutaneously alone, the microfibrous membranes were surrounded and infiltrated with macrophages and foreign body giant cells; in contrast, macrophages were scarce and only present on the surface of the nanofibrous membrane following a 2-month implantation. Moreover, significantly more blood vessels and thinner fibrotic capsules were found surrounding the nanofibrous implants compared to the microfibers samples. These results indicate the nanofibrous membrane not only possesses superior biocompatibility, but also can act as cell barrier to prevent cell invasion. By loading breast cancer cell lines (4T1-luc) in PU nanofibrous macroencapsuiation devices and implanting the cells subcutaneously into allogenic mice (Fig. 1A), it is shown that the implanted cells survived and proliferated in vivo (Fig. 1B) up to 5 weeks. In another islet transplantation model in C57BL/6 mice, the encapsulated islets also survived and adapted to the encapsulation and implantation environment by reorganizing into four to five cell-thick flat layers within the device (Fig. 1C, D). The results indicate that although nanofibrous membranes prohibit cell invasion, they are able to support nutrients exchange and maintain the cell viability in vivo. Conclusions: Nanofibrous membranes are suitable materials to provide appropriate transport and biocompatibility properties for fabricating new immunoisolation devices. The encapsulated cells are useful for constructing artificial organs/models for cell therapy as well as fundamental immunology investigations.