Silicone Cryogel Skeletons for Enhanced Survival and Mechanics of Hydrogel-Based Implantable Cell Therapies

The transplantation of cells engineered to secrete therapeutic proteins presents a promising method to address a range of chronic diseases including diabetes, cancer, and blood disorders. However, clinical translation faces several challenges regarding immune rejection, adequate nutrient supply to therapeutic cells, and the mechanical integrity of delivery constructs. Typically, non-degradable hydrogels are used to encase and protect therapeutic cells from immune rejection while still permitting the exchange of nutrients and therapeutics. However, a critical tradeoff exists wherein improving hydrogel mechanics (e.g., by increased crosslinking or molecular weight) often compromises biocompatibility and diffusion. Consequently, the design of macroscale, retrievable hydrogel devices often must balance the risks of mechanical failure and poor viability of encapsulated cells.<br/><br/>We address this challenge through a composite materials system centered around an oxygen-permeable silicone cryogel, which acts as an internal skeletal support for conventional hydrogel matrices coated by an anti-inflammatory polyelectrolyte for alleviating immunological responses towards foreign objects. We show that integration of the skeletal structure dramatically improves mechanical properties and effectively mitigates fracturing of implanted devices. Notably, our approach forgoes the use of commonly employed external housings, which can impede both the transport of nutrients to cells and the release of therapeutics to the host. By contrast, the skeleton leverages the superior oxygen diffusivity of silicone elastomers and a judiciously designed microstructure to improve the oxygenation of encapsulated cells. Fluorescence microscopy reveals that the skeleton acts as an internal scaffold that guides cellular proliferation and results in favorable changes in cell morphology. Pre-clinical studies demonstrate that these functionalities translate to significantly enhanced protein secretion from genetically engineered, xenogeneic cells in immunocompetent animals over 4 weeks, without the need for immunosuppression.<br/><br/>The resulting technology drives important improvements in the efficacy and practicality of implantable cell therapies. Namely, superior materials mechanics translates to easier device handling and reduces risk of mechanical failure, while the ability to sustain denser cell populations enables miniaturization of therapeutic implants. With the capability to modify encapsulated transgenic cells to secrete different biologics, the presented platform promises to support a broad spectrum of protein replacement therapies.