Polymeric Approaches to Reduce Tissue Responses Against Devices Applied for Islet-Cell Encapsulation

Abstract

Immunoisolation of pancreatic islets is a technology in which islets are encapsulated in semipermeable but immunoprotective polymeric membranes. The technology allows for successful transplantation of insulin-producing cells in the absence of immunosuppression. Different approaches of immunoisolation are currently under development. These approaches involve intravascular devices that are connected to the bloodstream and extravascular devices that can be distinguished in micro- and macrocapsules and are usually implanted in the peritoneal cavity or under the skin. The technology has been subject of intense fundamental research in the past decade. It has co-evolved with novel replenishable cell sources for cure of diseases such as Type 1 Diabetes Mellitus that need to be protected for the host immune system. Although the devices have shown significant success in animal models and even in human safety studies most technologies still suffer from undesired tissue responses in the host. Here we review the past and current approaches to modulate and reduce tissue responses against extravascular cell-containing micro- and macrocapsules with a focus on rational choices for polymer (combinations). Choices for polymers but also choices for crosslinking agents that induce more stable and biocompatible capsules are discussed. Combining beneficial properties of molecules in diblock polymers or application of these molecules or other anti-biofouling molecules have been reviewed. Emerging are also the principles of polymer brushes that prevent protein and cell-adhesion. Recently also immunomodulating biomaterials that bind to specific immune receptors have entered the field. Several natural and synthetic polymers and even combinations of these polymers have demonstrated significant improvement in outcomes of encapsulated grafts. Adequate polymeric surface properties have been shown to be essential but how the surface should be composed to avoid host responses remains to be identified. Current insight is that optimal biocompatible devices can be created which raises optimism that immunoisolating devices can be created that allows for long term survival of encapsulated replenishable insulin-producing cell sources for treatment of Type 1 Diabetes Mellitus.

Keywords: biocompatibility; encapsulation; host response; islet; polymer; surface properties; transplantation.

Figure 1

Immunoisolating devices. (A) In macrocapsules, groups of islets are encapsulated in a selectively permeable membrane. Because of the unfavorable volume to surface ratio in macroencapsules insufficient supply of nutrients such as oxygen is a major issue. (B) Schematic illustration of Beta-O2 device. Beta-O2 is equipped with a refillable oxygen chamber that allows the diffusion of oxygen to the islet-containing chamber. (C) Schematic illustration of microcapsules with a better surface to volume ratio than macrocapsules which facilitates ingress of oxygen and glucose and egress of insulin.

Figure 2

Manufacturing islet-containing alginate-based microcapsules. Islets are suspended in an alginate solution solved in a balanced physiological salt solution in the absence of calcium. Alginate containing islet droplets are formed by an air- or electrostatic driven droplet generator. Droplets are collected in a CaCl₂ solution to form microcapsules. The basis of the gel formation is calcium crosslinking constitutive alginate molecules according to the egg-box model.

Figure 3

Microcapsule made from polymers might contain pathogen associated molecular patterns (PAMPs) that can be recognized by pattern-recognition receptors (PRRs) on macrophage and evoke subsequent a cascade of proinflammatory responses, ultimately leading to a pericapsular fibrotic overgrowth of capsules and necrosis of the islets.

Figure 4

(A) Principle of formation of polymer brushes. At low grafting density polymers will have a mushroom conformation at the surface of capsules. When the grafting density increases and space becomes limited, the polymers will stretch and form a polymer brush that does not allow for protein and cell adhesion. (B) Schematic illustration of antibiofouling polymer brush surface formatted from PEG-b-PLL. PEG has to be long to prevent penetration into the alginate network and to stimulate stretching of the molecules on the surface (Spasojevic et al., 2014b). The outer PEG layer blocks shed unbound cytotoxic PLL and simultaneously provides a protein resistant surface, which showed antibiofouling properties in vivo studies.

Figure 5

Schematics presentation of how immunomodulatory polymers block proinflammatory receptors and inhibit inflammatory signal pathways.