Overcoming foreign-body reaction through nanotopography: Biocompatibility and immunoisolation properties of a nanofibrous membrane

Abstract

Implantable immunoisolation membranes need to possess superior biocompatibility to prohibit the fibrotic deposition that would reduce the nutrient supply and impair the viability/function of the encapsulated cells. Here, electrospun membranes based on thermoplastic polyurethane (TPU) were fabricated to contain microfibers (PU-micro) or nanofibers (PU-nano). The two types of membranes were compared in terms of their interaction with macrophage cells and the host tissues. It was found that the fibrous membranes of different topographies possess distinct material properties: PU-nano caused minimal macrophage responses in vitro and in vivo and induced only mild foreign body reactions compared to PU-micro membranes. A flat macroencapsulation device was fabricated using PU-nano membranes and its immunoisolation function investigated in subcutaneous transplantation models. The nanofibrous device demonstrated the capability to effectively shield the allografts from the immune attack of the host. Nanotopography may confer biocompatibility to materials and nanofibrous materials warrant further study for development of “invisible” immunoisolation devices for cell transplantation.

Introduction

With rapid advancements in cell/stem cell technologies in recent years, there are great needs to develop biomaterial-based devices to aid cell transplantation in terms of maintaining cell viability and function in host. In particular, immunoisolation devices aim to provide solutions to protecting transplanted cells from the immune attack of the host. The concept typically involves a semipermeable material to carry out dual tasks: 1) prohibit the invasion of immune cells/cytokines into the device 2) allow exchange of nutrients across the artificial barrier so that the transplanted cells can function normally in the recipient's body [1]. The immunoisolation devices may find important applications in cell therapies, where the host's immune system imposes threats to transplanted cells, or vice versa, the transplants transmit potential risks (e.g. teratoma formation by embryonic stem cells) into the body [2]. Among different applications, designing devices to enable the transplantation of islet allo- or xeno-grafts to treat diabetes have been intensively investigated over the last four decades [3]. A few types of devices, e.g., alginate microcapsules and hollow fiber membranes encapsulating islets were shown to reverse hyperglycemic conditions in diabetic animal models [1], [4], [5].

Despite previous efforts, developing functional materials/devices facilitating cell transplantation and meeting all the requirements for clinical use remains a formidable challenge. One obstacle yet to be tackled is to search for semi-permeable materials having superior biocompatibility to combat tissue responses that are menaces to the encapsulated cells. It is thought that the long-term efficacy of an immunoisolation device would be affected by the foreign-body response (FBR), which is manifested in dense, fibrotic collagen capsules that could cut off the transportation of oxygen and nutrients into the device [1], [6]. Synthesizing new materials or alternating the chemistry of current materials has been pursued for immunoisolation devices [7], [8]. Another approach to modify or optimize the tissue interaction with materials is through designing appropriate topographical/structural characteristics of surfaces [9], [10]. Elucidating the fundamental relationship between the surface topographical structure and material biocompatibility properties therefore has important implications for developing high-performance devices.

In this work, we aim to investigating the fundamental properties inherent to nanofibrous electrospun materials for use as semipermeable immunoisolation membrane. Nanofibrous structure mimics the topographical features of natural extracellular matrices (ECM). In particular, electrospinning allows fabrication of fibrous matrices with controllable structural characteristics including fiber diameter, pore size and thickness via facile modulation of processing parameters [11]. Electrospun fibrous materials thereby have attracted intensive interests in recent years for different biomedical applications including filtration [12] and tissue scaffolds [13], [14]. Previous studies have shown that nanoscale fiber morphology may provide unique contact cues to modulate macrophage cells toward anti-inflammatory phenotypes in vitro [15], [16]. However, it is unknown whether nanofibrous membranes could also demonstrate advantages in mediating cell and tissue responses in vivo and find applications in immunoisolation devices.

Here, experiments were carried out to understand the fundamental properties of fibrous materials dictated by fiber sizes. Our study suggests that electrospun nanofibers induced only minimal FBRs with indiscernible activation of macrophage cells compared to microfibrous membranes. Nanofibrous materials can therefore serve as a new category of semipermeable materials for use in cell transplantation and immunoisolation.